TY  - JOUR
A1  - Barlinn, J.
A1  - Winzer, S.
A1  - Worthmann, H.
A1  - Urbanek, C.
A1  - Häusler, K. G.
A1  - Günther, A.
A1  - Erdur, H.
A1  - Görtler, M.
A1  - Busetto, L.
A1  - Wojciechowski, C.
A1  - Schmitt, J.
A1  - Shah, Y.
A1  - Büchele, B.
A1  - Sokolowski, P.
A1  - Kraya, T.
A1  - Merkelbach, S.
A1  - Rosengarten, B.
A1  - Stangenberg-Gliss, K.
A1  - Weber, J.
A1  - Schlachetzki, F.
A1  - Abu-Mugheisib, M.
A1  - Petersen, M.
A1  - Schwartz, A.
A1  - Palm, F.
A1  - Jowaed, A.
A1  - Volbers, B.
A1  - Zickler, P.
A1  - Remi, J.
A1  - Bardutzky, J.
A1  - Bösel, J.
A1  - Audebert, H. J.
A1  - Hubert, G. J.
A1  - Gumbinger, C.
T1  - Telemedizin in der Schlaganfallversorgung – versorgungsrelevant für Deutschland
T1  - Telemedicine in stroke—pertinent to stroke care in Germany
JF  - Der Nervenarzt
N2  - Hintergrund und Ziel
Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, ländlichen Regionen zu gewährleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur.

Methoden
Die Kommission „Telemedizinische Schlaganfallversorgung“ der Deutschen Schlaganfall-Gesellschaft führte eine Umfragestudie in allen Schlaganfall-Netzwerken durch.

Ergebnisse
In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1–3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4–17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung für 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319–2758) durchgeführt. Die Thrombolyserate betrug 14,1 % (95 %-Konfidenzintervall 13,6–14,7 %), eine Verlegung zur Thrombektomie wurde bei 7,9 % (95 %-Konfidenzintervall 7,5–8,4 %) der ischämischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Vergütungssystem für die Zentrumsleistungen in nur drei Bundesländern.

Diskussion
Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer flächendeckenden Schlaganfallversorgung bei. Eine netzwerkübergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualitätssicherungsdaten haben das Potenzial diese Versorgungsstruktur zukünftig weiter zu stärken.
N2  - Background and objective
Telemedical stroke networks improve stroke care and provide access to time-dependent acute stroke treatment in predominantly rural regions. The aim is a presentation of data on its utility and regional distribution.

Methods
The working group on telemedical stroke care of the German Stroke Society performed a survey study among all telestroke networks.

Results
Currently, 22 telemedical stroke networks including 43 centers (per network: median 1.5, interquartile range, IQR, 1–3) as well as 225 cooperating hospitals (per network: median 9, IQR 4–17) operate in Germany and contribute to acute stroke care delivery to 48 million people. In 2018, 38,211 teleconsultations (per network: median 1340, IQR 319–2758) were performed. The thrombolysis rate was 14.1% (95% confidence interval 13.6–14.7%) and transfer for thrombectomy was initiated in 7.9% (95% confidence interval 7.5–8.4%) of ischemic stroke patients. Financial reimbursement differs regionally with compensation for telemedical stroke care in only three federal states.

Conclusion
Telemedical stroke care is utilized in about 1 out of 10 stroke patients in Germany. Telemedical stroke networks achieve similar rates of thrombolysis and transfer for thrombectomy compared with neurological stroke units and contribute to stroke care in rural regions. Standardization of network structures, financial assurance and uniform quality measurements may further strengthen the importance of telestroke networks in the future.
KW  - Schlaganfall
KW  - Stroke-Unit
KW  - Telemedizin
KW  - Schlaganfall-Netzwerk
KW  - Umfragestudie
KW  - stroke
KW  - stroke unit
KW  - telemedicine
KW  - stroke networks
KW  - survey
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307752
SN  - 0028-2804
SN  - 1433-0407
VL  - 92
IS  - 6
ER  - 
TY  - JOUR
A1  - Schraut, K. G.
A1  - Jakob, S. B.
A1  - Weidner, M. T.
A1  - Schmitt, A. G.
A1  - Scholz, C. J.
A1  - Strekalova, T.
A1  - El Hajj, N.
A1  - Eijssen, L. M. T.
A1  - Domschke, K.
A1  - Reif, A.
A1  - Haaf, T.
A1  - Ortega, G.
A1  - Steinbusch, H. W. M.
A1  - Lesch, K. P.
A1  - Van den Hove, D. L.
T1  - Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice
JF  - Translational Psychiatry
N2  - The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.
KW  - mice
KW  - DNA
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119199
VL  - 4
ER  - 
TY  - JOUR
A1  - Bisti, F.
A1  - Rogalev, V. A.
A1  - Karolak, M.
A1  - Paul, S.
A1  - Gupta, A.
A1  - Schmitt, T.
A1  - Güntherodt, G.
A1  - Eyert, V.
A1  - Sangiovanni, G.
A1  - Profeta, G.
A1  - Strocov, V. N.
T1  - Weakly-correlated nature of ferromagnetism in nonsymmorphic CrO\(_2\) revealed by bulk-sensitive soft-X-ray ARPES
JF  - Physical Review X
N2  - Chromium dioxide CrO\(_2\) belongs to a class of materials called ferromagnetic half-metals, whose peculiar aspect is that they act as a metal in one spin orientation and as a semiconductor or insulator in the opposite one. Despite numerous experimental and theoretical studies motivated by technologically important applications of this material in spintronics, its fundamental properties such as momentumresolved electron dispersions and the Fermi surface have so far remained experimentally inaccessible because of metastability of its surface, which instantly reduces to amorphous Cr\(_2\)O\(_3\). In this work, we demonstrate that direct access to the native electronic structure of CrO\(_2\) can be achieved with soft-x-ray angle-resolved photoemission spectroscopy whose large probing depth penetrates through the Cr\(_2\)O\(_3\) layer. For the first time, the electronic dispersions and Fermi surface of CrO\(_2\) are measured, which are fundamental prerequisites to solve the long debate on the nature of electronic correlations in this material. Since density functional theory augmented by a relatively weak local Coulomb repulsion gives an exhaustive description of our spectroscopic data, we rule out strong-coupling theories of CrO\(_2\). Crucial for the correct interpretation of our experimental data in terms of the valence-band dispersions is the understanding of a nontrivial spectral response of CrO\(_2\) caused by interference effects in the photoemission process originating from the nonsymmorphic space group of the rutile crystal structure of CrO\(_2\).
KW  - physics
KW  - electronic structure
KW  - half-metals
KW  - angle-resolved photoemission spectroscopy
KW  - band structure methods
KW  - DFT+U
KW  - condensed matter physics
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172251
VL  - 7
IS  - 4
ER  - 
TY  - JOUR
A1  - Neufang, S.
A1  - Akhrif, A.
A1  - Herrmann, C.G.
A1  - Drepper, C.
A1  - Homola, G.A.
A1  - Nowak, J.
A1  - Waider, J.
A1  - Schmitt, A.G.
A1  - Lesch, K.-P.
A1  - Romanos, M.
T1  - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans
JF  - Translational Psychiatry
N2  - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies.
KW  - Clinical Genetics
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418
IS  - 6
ER  - 
TY  - JOUR
A1  - Dammert, Marcel A.
A1  - Brägelmann, Johannes
A1  - Olsen, Rachelle R.
A1  - Böhm, Stefanie
A1  - Monhasery, Niloufar
A1  - Whitney, Christopher P.
A1  - Chalishazar, Milind D.
A1  - Tumbrink, Hannah L.
A1  - Guthrie, Matthew R.
A1  - Klein, Sebastian
A1  - Ireland, Abbie S.
A1  - Ryan, Jeremy
A1  - Schmitt, Anna
A1  - Marx, Annika
A1  - Ozretić, Luka
A1  - Castiglione, Roberta
A1  - Lorenz, Carina
A1  - Jachimowicz, Ron D.
A1  - Wolf, Elmar
A1  - Thomas, Roman K.
A1  - Poirier, John T.
A1  - Büttner, Reinhard
A1  - Sen, Triparna
A1  - Byers, Lauren A.
A1  - Reinhardt, H. Christian
A1  - Letai, Anthony
A1  - Oliver, Trudy G.
A1  - Sos, Martin L.
T1  - MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
JF  - Nature Communications
N2  - MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
KW  - genetic engineering
KW  - oncogenes
KW  - small-cell lung cancer
KW  - targeted therapies
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223569
VL  - 10
ER  - 
TY  - JOUR
A1  - Schmitt, T.
A1  - Egu, D.T.
A1  - Walter, E.
A1  - Sigmund, A.M.
A1  - Eichkorn, R.
A1  - Yazdi, A.
A1  - Schmidt, E.
A1  - Sárdy, M.
A1  - Eming, R.
A1  - Goebeler, M.
A1  - Waschke, J.
T1  - Ca\(^{2+}\) signalling is critical for autoantibody‐induced blistering of human epidermis in pemphigus
JF  - British Journal of Dermatology
N2  - Background
Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) by anti‐Dsg3 IgG inducing erosions in the mucosa; and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3.
Objectives
To characterize the Ca\(^{2+}\) flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles.
Methods
Immunoprecipitation, Ca\(^{2+}\) flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used.
Results
PV IgG and PF IgG, but neither Dsg3‐specific monoclonal antibody (AK23) nor mPV IgG, caused Ca\(^{2+}\) influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (PLC) – was activated by PV IgG and PF IgG but not AK23 or mPV IgG. PLC releases inositol 1,4,5‐trisphosphate (IP3) causing IP3 receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ release‐activated channels (CRAC)‐mediated Ca\(^{2+}\) influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca\(^{2+}\) influx; ameliorated alterations of Dsg1 and Dsg3 localization, and reorganization of keratin and actin filaments; and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV IgG‐induced blister formation and redistribution of Dsg1 and Dsg3 in human skin ex vivo.
Conclusions
Ca2+‐mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca\(^{2+}\) signalling may be a promising approach to treat epidermal manifestations of pemphigus.
KW  - pemphigus
KW  - epidermis
KW  - Ca\(^{2+}\) signalling
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262810
VL  - 185
IS  - 3
SP  - 595
EP  - 604
ER  - 
TY  - JOUR
A1  - Bonn, M.
A1  - Schmitt, A.
A1  - Lesch, K.-P.
A1  - Van Bockstaele, E. J.
A1  - Asan, E.
T1  - Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei
JF  - Brain Structure and Function
N2  - Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30–40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.
KW  - NPY
KW  - serotonergic system
KW  - amygdala
KW  - anxiety
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132591
VL  - 218
IS  - 2
ER  - 
TY  - JOUR
A1  - Weiss, B.
A1  - Haas, S.
A1  - Lessner, G.
A1  - Mikkat, S.
A1  - Kreutzer, M.
A1  - Glocker, M. O.
A1  - Wree, A.
A1  - Schmitt, O.
T1  - The Proteome of the Differentiating Mesencephalic Progenitor Cell Line CSM14.1 In Vitro
JF  - BioMed Research International
N2  - The treatment of Parkinson's disease by transplantation of dopaminergic (DA) neurons from human embryonic mesencephalic tissue is a promising approach. However, the origin of these cells causes major problems: availability and standardization of the graft. Therefore, the generation of unlimited numbers of DA neurons from various types of stem or progenitor cells has been brought into focus. A source for DA neurons might be conditionally immortalized progenitor cells. The temperature-sensitive immortalized cell line CSM14.1 derived from the mesencephalon of an embryonic rat has been used successfully for transplantation experiments. This cell line was analyzed by unbiased stereology of cell type specific marker proteins and 2D-gel electrophoresis followed by mass spectrometry to characterize the differentially expressed proteome. Undifferentiated CSM14.1 cells only expressed the stem cell marker nestin, whereas differentiated cells expressed GFAP or NeuN and tyrosine hydroxylase. An increase of the latter cells during differentiation could be shown. By using proteomics an explanation on the protein level was found for the observed changes in cell morphology during differentiation, when CSM14.1 cells possessed the morphology of multipolar neurons. The results obtained in this study confirm the suitability of CSM14.1 cells as an in vitro model for the study of neuronal and dopaminergic differentiation in rats.
KW  - spinal-cord-injury
KW  - Parkinsons disease
KW  - annecin-V
KW  - ERM proteins
KW  - neuronal differentiation
KW  - phospholipase A(2)
KW  - gesolin function
KW  - binding proteins
KW  - actin filament
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117992
SN  - 2314-6141
IS  - 351821
ER  - 
TY  - JOUR
A1  - Waider, Jonas
A1  - Popp, Sandy
A1  - Mlinar, Boris
A1  - Montalbano, Alberto
A1  - Bonfiglio, Francesco
A1  - Aboagye, Benjamin
A1  - Thuy, Elisabeth
A1  - Kern, Raphael
A1  - Thiel, Christopher
A1  - Araragi, Naozumi
A1  - Svirin, Evgeniy
A1  - Schmitt-Böhrer, Angelika G.
A1  - Corradetti, Renato
A1  - Lowry, Christopher A.
A1  - Lesch, Klaus-Peter
T1  - Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity
JF  - Frontiers in Neuroscience
N2  - Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.
KW  - tryptophan hydroxylase 2
KW  - knockout
KW  - fear learning
KW  - extinction
KW  - long-term potentiation
KW  - hippocampus
KW  - immediate-early gene
KW  - serotonin deficiency
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196077
SN  - 1662-453X
VL  - 13
IS  - 245
ER  - 
TY  - JOUR
A1  - Kuzkina, Anastasia
A1  - Bargar, Connor
A1  - Schmitt, Daniela
A1  - Rößle, Jonas
A1  - Wang, Wen
A1  - Schubert, Anna-Lena
A1  - Tatsuoka, Curtis
A1  - Gunzler, Steven A.
A1  - Zou, Wen-Quan
A1  - Volkmann, Jens
A1  - Sommer, Claudia
A1  - Doppler, Kathrin
A1  - Chen, Shu G.
T1  - Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study
JF  - NPJ Parkinson's Disease
N2  - Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.
KW  - diagnostic markers
KW  - Parkinson's disease
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260451
VL  - 7
IS  - 1
ER  - 
TY  - JOUR
A1  - Czysch, Christian
A1  - Medina‐Montano, Carolina
A1  - Zhong, Zifu
A1  - Fuchs, Alexander
A1  - Stickdorn, Judith
A1  - Winterwerber, Pia
A1  - Schmitt, Sascha
A1  - Deswarte, Kim
A1  - Raabe, Marco
A1  - Scherger, Maximilian
A1  - Combes, Francis
A1  - De Vrieze, Jana
A1  - Kasmi, Sabah
A1  - Sandners, Niek N.
A1  - Lienenklaus, Stefan
A1  - Koynov, Kaloian
A1  - Räder, Hans‐Joachim
A1  - Lambrecht, Bart N.
A1  - David, Sunil A.
A1  - Bros, Matthias
A1  - Schild, Hansjörg
A1  - Grabbe, Stephan
A1  - De Geest, Bruno G.
A1  - Nuhn, Lutz
T1  - Transient Lymph Node Immune Activation by Hydrolysable Polycarbonate Nanogels
JF  - Advanced Functional Materials
N2  - The development of controlled biodegradable materials is of fundamental importance in immunodrug delivery to spatiotemporally controlled immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation of lymph nodes. An imidazoquinoline‐type TLR7/8 agonist is covalently conjugated via reactive ester chemistry to these nanocarriers. The nanogels not only provide access to complete disintegration by the hydrolysable polymer backbone, but also demonstrate a gradual disintegration within several days at physiological conditions (PBS, pH 6.4–7.4, 37 °C). These intrinsic properties limit the lifetime of the carriers but their payload can still be successfully leveraged for immunological studies in vitro on primary immune cells as well as in vivo. For the latter, a spatiotemporal control of immune cell activation in the draining lymph node is found after subcutaneous injection. Overall, these features render polycarbonate nanogels a promising delivery system for transient activation of the immune system in lymph nodes and may consequently become very attractive for further development toward vaccination or cancer immunotherapy. Due to the intrinsic biodegradability combined with the high chemical control during the manufacturing process, these polycarbonate‐based nanogels may also be of great importance for clinical translation.
KW  - biodegradable
KW  - immunodrug delivery
KW  - lymph nodes
KW  - nanogels
KW  - polycarbonates
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287255
VL  - 32
IS  - 35
ER  - 
TY  - JOUR
A1  - Weidner, Magdalena T.
A1  - Lardenoije, Roy
A1  - Eijssen, Lars
A1  - Mogavero, Floriana
A1  - De Groodt, Lilian P. M. T.
A1  - Popp, Sandy
A1  - Palme, Rupert
A1  - Förstner, Konrad U.
A1  - Strekalova, Tatyana
A1  - Steinbusch, Harry W. M.
A1  - Schmitt-Böhrer, Angelika G.
A1  - Glennon, Jeffrey C.
A1  - Waider, Jonas
A1  - van den Hove, Daniel L. A.
A1  - Lesch, Klaus-Peter
T1  - Identification of cholecystokinin by genome-wide profiling as potential mediator of serotonin-dependent behavioral effects of maternal separation in the amygdala
JF  - Frontiers in Neuroscience
N2  - Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.
KW  - serotonin
KW  - maternal separation
KW  - mouse
KW  - emotional behavior
KW  - DNA methylation
KW  - RNA expression
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201340
VL  - 13
ER  - 
TY  - JOUR
A1  - Moris, Victoria C.
A1  - Christmann, Katharina
A1  - Wirtgen, Aline
A1  - Belokobylskij, Sergey A.
A1  - Berg, Alexander
A1  - Liebig, Wolf-Harald
A1  - Soon, Villu
A1  - Baur, Hannes
A1  - Schmitt, Thomas
A1  - Niehuis, Oliver
T1  - Cuticular hydrocarbons on old museum specimens of the spiny mason wasp, Odynerus spinipes (Hymenoptera: Vespidae: Eumeninae), shed light on the distribution and on regional frequencies of distinct chemotypes
JF  - Chemoecology
N2  - The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.
KW  - cuticular hydrocarbons
KW  - chemotypes
KW  - dry-mounted samples
KW  - collections
KW  - distribution
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306999
SN  - 0937-7409
SN  - 1423-0445
VL  - 31
IS  - 5
ER  - 
TY  - JOUR
A1  - Waider, J
A1  - Popp, S
A1  - Lange, MD
A1  - Kern, R
A1  - Kolter, JF
A1  - Kobler, J
A1  - Donner, NC
A1  - Lowe, KR
A1  - Malzbender, JH
A1  - Brazell, CJ
A1  - Arnold, MR
A1  - Aboagye, B
A1  - Schmitt-Böhrer, A
A1  - Lowry, CA
A1  - Pape, HC
A1  - Lesch, KP
T1  - Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice
JF  - Translational Psychiatry
N2  - Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2\(^{-/-}\)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph\(^{+/-}\)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.
KW  - anxiety
KW  - stress
KW  - serotonin
KW  - genetics
KW  - mice
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170239
VL  - 7
IS  - e1246
ER  -