TY - JOUR A1 - Marquardt, André A1 - Landwehr, Laura-Sophie A1 - Ronchi, Cristina L. A1 - di Dalmazi, Guido A1 - Riester, Anna A1 - Kollmannsberger, Philip A1 - Altieri, Barbara A1 - Fassnacht, Martin A1 - Sbiera, Silviu T1 - Identifying New Potential Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning JF - Cancers N2 - Simple Summary Using a visual-based clustering method on the TCGA RNA sequencing data of a large adrenocortical carcinoma (ACC) cohort, we were able to classify these tumors in two distinct clusters largely overlapping with previously identified ones. As previously shown, the identified clusters also correlated with patient survival. Applying the visual clustering method to a second dataset also including benign adrenocortical samples additionally revealed that one of the ACC clusters is more closely located to the benign samples, providing a possible explanation for the better survival of this ACC cluster. Furthermore, the subsequent use of machine learning identified new possible biomarker genes with prognostic potential for this rare disease, that are significantly differentially expressed in the different survival clusters and should be further evaluated. Abstract Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC. KW - adrenocortical carcinoma KW - in silico analysis KW - machine learning KW - bioinformatic clustering KW - biomarker prediction Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246245 SN - 2072-6694 VL - 13 IS - 18 ER - TY - JOUR A1 - Brych, Mareike A1 - Murali, Supriya A1 - Händel, Barbara T1 - The Role of Blinks, Microsaccades and their Retinal Consequences in Bistable Motion Perception JF - Frontiers in Psychology N2 - Eye-related movements such as blinks and microsaccades are modulated during bistable perceptual tasks. However, if they play an active role during internal perceptual switches is not known. We conducted two experiments involving an ambiguous plaid stimulus, wherein participants were asked to continuously report their percept, which could consist of either unidirectional coherent or bidirectional component movement. Our main results show that blinks and microsaccades did not facilitate perceptual switches. On the contrary, a reduction in eye movements preceded the perceptual switch. Blanks, on the other hand, thought to mimic the retinal consequences of a blink, consistently led to a switch. Through the timing of the blank-introduced perceptual change, we were able to estimate the delay between the internal switch and the response. This delay further allowed us to evaluate that the reduction in blink probability co-occurred with the internal perceptual switch. Additionally, our results indicate that distinct internal processes underlie the switch to coherent vs. component percept. Blanks exclusively facilitated a switch to the coherent percept, and only the switch to coherent percept was followed by an increase in blink rate. In a second study, we largely replicated the findings and included a microsaccade analysis. Microsaccades only showed a weak relation with perceptual switches, but their direction was correlated with the perceived motion direction. Nevertheless, our data suggests an interaction between microsaccades and blinks by showing that microsaccades were differently modulated around blinks compared with blanks. This study shows that a reduction in eye movements precedes internal perceptual switches indicating that the rate of blinks can set the stage for a reinterpretation of sensory input. While a perceptual switch based on changed sensory input usually leads to an increase in blink rate, such an increase was only present after the perceptual switch to coherent motion but absent after the switch to component percept. This provides evidence of different underlying mechanism or internal consequence of the two perceptual switches and suggests that blinks can uncover differences in internal percept-related processes that are not evident from the percept itself. KW - eye movements KW - spontaneous eye blink KW - microsaccade rate KW - microsaccade direction KW - bistable perception KW - ambiguous plaid 4 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235217 SN - 1664-1078 VL - 12 ER - TY - JOUR A1 - Wagner-Drouet, Eva A1 - Teschner, Daniel A1 - Wolschke, Christine A1 - Schäfer-Eckart, Kerstin A1 - Gärtner, Johannes A1 - Mielke, Stephan A1 - Schreder, Martin A1 - Kobbe, Guido A1 - Hilgendorf, Inken A1 - Klein, Stefan A1 - Verbeek, Mareike A1 - Ditschkowski, Markus A1 - Koch, Martina A1 - Lindemann, Monika A1 - Schmidt, Traudel A1 - Rascle, Anne A1 - Barabas, Sascha A1 - Deml, Ludwig A1 - Wagner, Ralf A1 - Wolff, Daniel T1 - Comparison of cytomegalovirus-specific immune cell response to proteins versus peptides using an IFN-γ ELISpot assay after hematopoietic stem cell transplantation JF - Diagnostics N2 - Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8\(^+\) counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients. KW - CMV KW - CMV-specific cellular immunity KW - hematopoietic stem cell transplantation KW - recall antigen KW - peptide KW - immune monitoring KW - IFN-γ ELISpot KW - T cells KW - antigen processing and presentation KW - immunosuppression Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228843 SN - 2075-4418 VL - 11 IS - 2 ER - TY - JOUR A1 - Huang, Mingming A1 - Wu, Zhu A1 - Krebs, Johannes A1 - Friedrich, Alexandra A1 - Luo, Xiaoling A1 - Westcott, Stephen A. A1 - Radius, Udo A1 - Marder, Todd B. T1 - Ni-Catalyzed Borylation of Aryl Sulfoxides JF - Chemistry—A European Journal N2 - A nickel/N-heterocyclic carbene (NHC) catalytic system has been developed for the borylation of aryl sulfoxides with B\(_{2}\)(neop)\(_{2}\) (neop=neopentyl glycolato). A wide range of aryl sulfoxides with different electronic and steric properties were converted into the corresponding arylboronic esters in good yields. The regioselective borylation of unsymmetric diaryl sulfoxides was also feasible leading to borylation of the sterically less encumbered aryl substituent. Competition experiments demonstrated that an electron-deficient aryl moiety reacts preferentially. The origin of the selectivity in the Ni-catalyzed borylation of electronically biased unsymmetrical diaryl sulfoxide lies in the oxidative addition step of the catalytic cycle, as oxidative addition of methoxyphenyl 4-(trifluoromethyl)phenyl sulfoxide to the Ni(0) complex occurs selectively to give the structurally characterized complex trans-[Ni(ICy)\(_{2}\)(4-CF\(_{3}\)-C\(_{6}\)H\(_{4}\)){(SO)-4-MeO-C\(_{6}\)H\(_{4}\)}] 4. For complex 5, the isomer trans-[Ni(ICy)\(_{2}\)(C\(_{6}\)H\(_{5}\))(OSC\(_{6}\)H\(_{5}\))] 5-I was structurally characterized in which the phenyl sulfinyl ligand is bound via the oxygen atom to nickel. In solution, the complex trans-[Ni(ICy)\(_{2}\)(C\(_{6}\)H\(_{5}\))(OSC\(_{6}\)H\(_{5}\))] 5-I is in equilibrium with the S-bonded isomer trans-[Ni(ICy)\(_{2}\)(C\(_{6}\)H\(_{5}\))(SOC\(_{6}\)H\(_{5}\))] 5, as shown by NMR spectroscopy. DFT calculations reveal that these isomers are separated by a mere 0.3 kJ/mol (M06/def2-TZVP-level of theory) and connected via a transition state trans-[Ni(ICy)\(_{2}\)(C\(_{6}\)H\(_{5}\))(η\(^{2}\)-{SO}-C\(_{6}\)H\(_{5}\))], which lies only 10.8 kcal/mol above 5. KW - Boron KW - cross-coupling KW - N-heterocyclic carbenes KW - nickel KW - borylation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256778 VL - 27 IS - 31 ER - TY - JOUR A1 - Gehrmann, Robin A1 - Hertlein, Tobias A1 - Hopke, Elisa A1 - Ohlsen, Knut A1 - Lalk, Michael A1 - Hilgeroth, Andreas T1 - Novel small-molecule hybrid-antibacterial agents against S. aureus and MRSA strains JF - Molecules N2 - Ongoing resistance developments against antibiotics that also affect last-resort antibiotics require novel antibacterial compounds. Strategies to discover such novel structures have been dimerization or hybridization of known antibacterial agents. We found novel antibacterial agents by dimerization of indols and hybridization with carbazoles. They were obtained in a simple one-pot reaction as bisindole tetrahydrocarbazoles. Further oxidation led to bisindole carbazoles with varied substitutions of both the indole and the carbazole scaffold. Both the tetrahydrocarbazoles and the carbazoles have been evaluated in various S. aureus strains, including MRSA strains. Those 5-cyano substituted derivatives showed best activities as determined by MIC values. The tetrahydrocarbazoles partly exceed the activity of the carbazole compounds and thus the activity of the used standard antibiotics. Thus, promising lead compounds could be identified for further studies. KW - antibacterial activity KW - synthesis KW - substituent KW - structure–activity KW - inhibition Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252371 SN - 1420-3049 VL - 27 IS - 1 ER - TY - JOUR A1 - Bunzmann, Nikolai A1 - Krugmann, Benjamin A1 - Weissenseel, Sebastian A1 - Kudriashova, Liudmila A1 - Ivaniuk, Khrystyna A1 - Stakhira, Pavlo A1 - Cherpak, Vladyslav A1 - Chapran, Marian A1 - Grybauskaite‐Kaminskiene, Gintare A1 - Grazulevicius, Juozas Vidas A1 - Dyakonov, Vladimir A1 - Sperlich, Andreas T1 - Spin‐ and Voltage‐Dependent Emission from Intra‐ and Intermolecular TADF OLEDs JF - Advanced Electronic Materials N2 - Organic light emitting diodes (OLEDs) based on thermally activated delayed fluorescence (TADF) utilize molecular systems with a small energy splitting between singlet and triplet states. This can either be realized in intramolecular charge transfer states of molecules with near‐orthogonal donor and acceptor moieties or in intermolecular exciplex states formed between a suitable combination of individual donor and acceptor materials. Here, 4,4′‐(9H,9′H‐[3,3′‐bicarbazole]‐9,9′‐diyl)bis(3‐(trifluoromethyl) benzonitrile) (pCNBCzoCF\(_{3}\)) is investigated, which shows intramolecular TADF but can also form exciplex states in combination with 4,4′,4′′‐tris[phenyl(m‐tolyl)amino]triphenylamine (m‐MTDATA). Orange emitting exciplex‐based OLEDs additionally generate a sky‐blue emission from the intramolecular emitter with an intensity that can be voltage‐controlled. Electroluminescence detected magnetic resonance (ELDMR) is applied to study the thermally activated spin‐dependent triplet to singlet up‐conversion in operating devices. Thereby, intermediate excited states involved in OLED operation can be investigated and the corresponding activation energy for both, intra‐ and intermolecular based TADF can be derived. Furthermore, a lower estimate is given for the extent of the triplet wavefunction to be ≥ 1.2 nm. Photoluminescence detected magnetic resonance (PLDMR) reveals the population of molecular triplets in optically excited thin films. Overall, the findings allow to draw a comprehensive picture of the spin‐dependent emission from intra‐ and intermolecular TADF OLEDs. KW - color tuning KW - exciplexes KW - organic light emitting diodes KW - spin KW - triplets Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224434 VL - 7 IS - 3 ER - TY - JOUR A1 - Brych, Mareike A1 - Händel, Barbara F. A1 - Riechelmann, Eva A1 - Pieczykolan, Aleksandra A1 - Huestegge, Lynn T1 - Effects of vocal demands on pupil dilation JF - Psychophysiology N2 - Pupil dilation is known to be affected by a variety of factors, including physical (e.g., light) and cognitive sources of influence (e.g., mental load due to working memory demands, stimulus/response competition etc.). In the present experiment, we tested the extent to which vocal demands (speaking) can affect pupil dilation. Based on corresponding preliminary evidence found in a reanalysis of an existing data set from our lab, we setup a new experiment that systematically investigated vocal response‐related effects compared to mere jaw/lip movement and button press responses. Conditions changed on a trial‐by‐trial basis while participants were instructed to keep fixating a central cross on a screen throughout. In line with our prediction (and previous observation), speaking caused the pupils to dilate strongest, followed by nonvocal movements and finally a baseline condition without any vocal or muscular demands. An additional analysis of blink rates showed no difference in blink frequency between vocal and baseline conditions, but different blink dynamics. Finally, simultaneously recorded electromyographic activity showed that muscle activity may contribute to some (but not all) aspects of the observed effects on pupil size. The results are discussed in the context of other recent research indicating effects of perceived (instead of executed) vocal action on pupil dynamics. KW - blink rate KW - eye movements KW - movement interaction KW - pupil dilation KW - vocal responses Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224425 VL - 58 IS - 2 ER - TY - JOUR A1 - Mechau, Jannik A1 - Frank, Andreas A1 - Bakirci, Ezgi A1 - Gumbel, Simon A1 - Jungst, Tomasz A1 - Giesa, Reiner A1 - Groll, Jürgen A1 - Dalton, Paul D. A1 - Schmidt, Hans‐Werner T1 - Hydrophilic (AB)\(_{n}\) Segmented Copolymers for Melt Extrusion‐Based Additive Manufacturing JF - Macromolecular Chemistry and Physics N2 - Several manufacturing technologies beneficially involve processing from the melt, including extrusion‐based printing, electrospinning, and electrohydrodynamic jetting. In this study, (AB)\(_{n}\) segmented copolymers are tailored for melt‐processing to form physically crosslinked hydrogels after swelling. The copolymers are composed of hydrophilic poly(ethylene glycol)‐based segments and hydrophobic bisurea segments, which form physical crosslinks via hydrogen bonds. The degree of polymerization was adjusted to match the melt viscosity to the different melt‐processing techniques. Using extrusion‐based printing, a width of approximately 260 µm is printed into 3D constructs, with excellent interlayer bonding at fiber junctions, due to hydrogen bonding between the layers. For melt electrospinning, much thinner fibers in the range of about 1–15 µm are obtained and produced in a typical nonwoven morphology. With melt electrowriting, fibers are deposited in a controlled way to well‐defined 3D constructs. In this case, multiple fiber layers fuse together enabling constructs with line width in the range of 70 to 160 µm. If exposed to water the printed constructs swell and form physically crosslinked hydrogels that slowly disintegrate, which is a feature for soluble inks within biofabrication strategies. In this context, cytotoxicity tests confirm the viability of cells and thus demonstrating biocompatibility of this class of copolymers. KW - 3D printing KW - (AB)\(_{n}\) segmented copolymers KW - biocompatibility KW - melt electrowriting Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224513 VL - 222 IS - 1 ER - TY - JOUR A1 - Kelm, Matthias A1 - Anger, Friedrich A1 - Eichlinger, Robin A1 - Brand, Markus A1 - Kim, Mia A1 - Reibetanz, Joachim A1 - Krajinovic, Katica A1 - Germer, Christoph-Thomas A1 - Schlegel, Nicolas A1 - Flemming, Sven T1 - Early Ileocecal Resection Is an Effective Therapy in Isolated Crohn’s Disease JF - Journal of Clinical Medicine N2 - Despite the increasing incidence and prevalence of Crohn’s Disease (CD), no curative options exist and treatment remains complex. While therapy has mainly focused on medical approaches in the past, growing evidence reveals that in cases of limited inflammation, surgery can suffice as an alternative primary treatment. We retrospectively assessed the disease course and outcomes of 103 patients with terminal Ileitis who underwent primary surgery (n = 29) or received primary medical treatment followed by surgery (n = 74). Primary endpoint was the need for immunosuppressive medication after surgical treatment (ileocecal resection, ICR) during a two-years follow-up. Rates for laparoscopic ICR were enhanced in case of early surgery, but no differences were seen for postoperative complications. In case of immunosuppressive medication, patients with ICR at an early state of disease needed significantly less anti-inflammatory medication during the two-year postoperative follow-up compared to patients who were primarily treated medically. Furthermore, in a subgroup analysis for patients with localized ileocecal disease manifestation, early surgery consistently resulted in a decreased amount of medical therapy postoperatively. In conclusion primary ICR is safe and effective in patients with limited CD, and the need for immunosuppressive medication during the postoperative follow-up is low compared to patients receiving surgery at a later stage of disease. KW - Crohn’s Disease KW - surgical therapy KW - ileocecal resection Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228822 SN - 2077-0383 VL - 10 IS - 4 ER - TY - JOUR A1 - Petruseva, Irina A1 - Naumenko, Natalia A1 - Kuper, Jochen A1 - Anarbaev, Rashid A1 - Kappenberger, Jeannette A1 - Kisker, Caroline A1 - Lavrik, Olga T1 - The Interaction Efficiency of XPD-p44 With Bulky DNA Damages Depends on the Structure of the Damage JF - Frontiers in Cell and Developmental Biology N2 - The successful elimination of bulky DNA damages via the nucleotide excision repair (NER) system is largely determined by the damage recognition step. This step consists of primary recognition and verification of the damage. The TFIIH helicase XPD plays a key role in the verification step during NER. To date, the mechanism of damage verification is not sufficiently understood and requires further detailed research. This study is a systematic investigation of the interaction of ctXPD (Chaetomium thermophilum) as well as ctXPD-ctp44 with model DNAs, which contain structurally different bulky lesions with previously estimated NER repair efficiencies. We have used ATPase and DNA binding studies to assess the interaction of ctXPD with damaged DNA. The result of the analysis of ctXPD-ctp44 binding to DNA containing fluorescent and photoactivatable lesions demonstrates the relationship between the affinity of XPD for DNAs containing bulky damages and the ability of the NER system to eliminate the damage. Photo-cross-linking of ctXPD with DNA probes containing repairable and unrepairable photoactivatable damages reveals differences in the DNA interaction efficiency in the presence and absence of ctp44. In general, the results obtained indicate the ability of ctXPD-ctp44 to interact with a damage and suggest a significant role for ctp44 subunit in the verification process. KW - nucleotide excision repair KW - XPD helicase KW - DNA damage KW - protein-DNA interaction KW - bulky damages recognition KW - photo-cross-linking Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231806 SN - 2296-634X VL - 9 ER - TY - JOUR A1 - Rupp, Mira T. A1 - Auvray, Thomas A1 - Hanan, Garry S. A1 - Kurth, Dirk G. T1 - Electrochemical and photophysical study of homoleptic and heteroleptic methylated Ru(II) Bis-terpyridine complexes JF - European Journal of Inorganic Chemistry N2 - In this study, we investigate the impact of N-methylation on the electronic and photophysical properties of both homoleptic and heteroleptic Ru(II) bis-terpyridine complexes based on the recently reported ligand 4’-(4-bromophenyl)-4,4’’’: 4’’,4’’’’-dipyr-idinyl-2,2’ : 6’,2’’-terpyridine (Bipytpy), with pyridine substituents in the 4- and 4’’-position. The first reduction of the methylated complexes takes place at the pyridinium site and is observed as multi-electron process. Following N-methylation, the complexes exhibit higher luminescence quantum yields and longer excited-state lifetimes. Interestingly, the photophysical properties of the heteroleptic and homoleptic complexes are rather similar. TD-DFT calculations support the experimental results. Furthermore, the complexes are tested as photosensitizers for photocatalytic hydrogen production, as the parent complex 1[Ru(Bipytpy)(Tolyltpy)](PF \(_6\))\(_2\) (Tolyltpy: 4’-tolyl-2,2’: 6’,2’’-terpyri-dine) was recently shown to be active and highly stable underphotocatalytic conditions. However, the methylated complexes reported herein are inactive as photosensitizers under the chosen conditions, presumably due to loss of the methyl groups, converting them to the non-methylated parent complexes. KW - Ruthenium KW - Luminescence KW - Electrochemistry KW - Ligand effects KW - Photocatalysis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248769 VL - 2021 IS - 28 SP - 2822 EP - 2829 ER - TY - JOUR A1 - Leverkus, Alexandro B. A1 - Thorn, Simon A1 - Gustafsson, Lena A1 - Noss, Reed A1 - Müller, Jörg A1 - Pausas, Juli G. A1 - Lindenmayer, David B. T1 - Environmental policies to cope with novel disturbance regimes–steps to address a world scientists’ warning to humanity JF - Environmental Research Letters N2 - No abstract available. KW - global change KW - novel disturbance KW - regime shift KW - forest management KW - risk management Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254180 SN - 1748-9326 VL - 16 IS - 2 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Rajendran, Vinothkumar A1 - Giraldo-Velasquez, Mario A1 - Megalofonou, Fevronia-Foivi A1 - Gurski, Fynn A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG\(_{35-55}\)-induced EAE JF - International Journal of Molecular Sciences N2 - Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1\(^{ind−/−}\) was achieved by tamoxifen application, EAE was induced using the MOG\(_{35-55}\) peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1\(^{ind−/−}\) mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1\(^{ind−/−}\)mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1\(^{ind−/−}\) mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1\(^{ind−/−}\) mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS. KW - FGFR1 KW - oligodendrocytes KW - demyelination KW - inflammation KW - cerebellum KW - EAE KW - MS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284296 SN - 1422-0067 VL - 22 IS - 17 ER - TY - JOUR A1 - Majumder, Snigdha A1 - Jugovic, Isabelle A1 - Saul, Domenica A1 - Bell, Luisa A1 - Hundhausen, Nadine A1 - Seal, Rishav A1 - Beilhack, Andreas A1 - Rosenwald, Andreas A1 - Mougiakakos, Dimitrios A1 - Berberich-Siebelt, Friederike T1 - Rapid and Efficient Gene Editing for Direct Transplantation of Naive Murine Cas9\(^+\) T Cells JF - Frontiers in Immunology N2 - Gene editing of primary T cells is a difficult task. However, it is important for research and especially for clinical T-cell transfers. CRISPR/Cas9 is the most powerful gene-editing technique. It has to be applied to cells by either retroviral transduction or electroporation of ribonucleoprotein complexes. Only the latter is possible with resting T cells. Here, we make use of Cas9 transgenic mice and demonstrate nucleofection of pre-stimulated and, importantly, of naive CD3\(^+\) T cells with guideRNA only. This proved to be rapid and efficient with no need of further selection. In the mixture of Cas9\(^+\)CD3\(^+\) T cells, CD4\(^+\) and CD8\(^+\) conventional as well as regulatory T cells were targeted concurrently. IL-7 supported survival and naivety in vitro, but T cells were also transplantable immediately after nucleofection and elicited their function like unprocessed T cells. Accordingly, metabolic reprogramming reached normal levels within days. In a major mismatch model of GvHD, not only ablation of NFATc1 and/or NFATc2, but also of the NFAT-target gene IRF4 in naïve primary murine Cas9\(^+\)CD3\(^+\) T cells by gRNA-only nucleofection ameliorated GvHD. However, pre-activated murine T cells could not achieve long-term protection from GvHD upon single NFATc1 or NFATc2 knockout. This emphasizes the necessity of gene-editing and transferring unstimulated human T cells during allogenic hematopoietic stem cell transplantation. KW - CRISPR/Cas9 KW - gRNA-only KW - GvHD KW - metabolism KW - NFAT KW - naive T-cell gene editing KW - T-cell transfer KW - IRF4 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242896 SN - 1664-3224 VL - 12 ER - TY - JOUR A1 - Colizzi, Francesca Sara A1 - Beer, Katharina A1 - Cuti, Paolo A1 - Deppisch, Peter A1 - Martínez Torres, David A1 - Yoshii, Taishi A1 - Helfrich-Förster, Charlotte T1 - Antibodies Against the Clock Proteins Period and Cryptochrome Reveal the Neuronal Organization of the Circadian Clock in the Pea Aphid JF - Frontiers in Physiology N2 - Circadian clocks prepare the organism to cyclic environmental changes in light, temperature, or food availability. Here, we characterized the master clock in the brain of a strongly photoperiodic insect, the aphid Acyrthosiphon pisum, immunohistochemically with antibodies against A. pisum Period (PER), Drosophila melanogaster Cryptochrome (CRY1), and crab Pigment-Dispersing Hormone (PDH). The latter antibody detects all so far known PDHs and PDFs (Pigment-Dispersing Factors), which play a dominant role in the circadian system of many arthropods. We found that, under long days, PER and CRY are expressed in a rhythmic manner in three regions of the brain: the dorsal and lateral protocerebrum and the lamina. No staining was detected with anti-PDH, suggesting that aphids lack PDF. All the CRY1-positive cells co-expressed PER and showed daily PER/CRY1 oscillations of high amplitude, while the PER oscillations of the CRY1-negative PER neurons were of considerable lower amplitude. The CRY1 oscillations were highly synchronous in all neurons, suggesting that aphid CRY1, similarly to Drosophila CRY1, is light sensitive and its oscillations are synchronized by light-dark cycles. Nevertheless, in contrast to Drosophila CRY1, aphid CRY1 was not degraded by light, but steadily increased during the day and decreased during the night. PER was always located in the nuclei of the clock neurons, while CRY was predominantly cytoplasmic and revealed the projections of the PER/CRY1-positive neurons. We traced the PER/CRY1-positive neurons through the aphid protocerebrum discovering striking similarities with the circadian clock of D. melanogaster: The CRY1 fibers innervate the dorsal and lateral protocerebrum and putatively connect the different PER-positive neurons with each other. They also run toward the pars intercerebralis, which controls hormone release via the neurohemal organ, the corpora cardiaca. In contrast to Drosophila, the CRY1-positive fibers additionally travel directly toward the corpora cardiaca and the close-by endocrine gland, corpora allata. This suggests a direct link between the circadian clock and the photoperiodic control of hormone release that can be studied in the future. KW - aphids KW - circadian clock KW - cryptochrome KW - period KW - hemiptera KW - insects KW - photoperiodism Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242909 SN - 1664-042X VL - 12 ER - TY - JOUR A1 - Sommer, Claudia A1 - Carroll, Antonia S. A1 - Koike, Haruki A1 - Katsuno, Masahisa A1 - Ort, Nora A1 - Sobue, Gen A1 - Vucic, Steve A1 - Spies, Judith M. A1 - Doppler, Kathrin A1 - Kiernan, Matthew C. T1 - Nerve biopsy in acquired neuropathies JF - Journal of the Peripheral Nervous System N2 - A diagnosis of neuropathy can typically be determined through clinical assessment and focused investigation. With technological advances, including significant progress in genomics, the role of nerve biopsy has receded over recent years. However, making a specific and, in some cases, tissue-based diagnosis is essential across a wide array of potentially treatable acquired peripheral neuropathies. When laboratory investigations do not suggest a definitive diagnosis, nerve biopsy remains the final step to ascertain the etiology of the disease. The present review highlights the utility of nerve biopsy in confirming a diagnosis, while further illustrating the importance of a tissue-based diagnosis in relation to treatment strategies, particularly when linked to long-term immunosuppressive therapies, KW - inflammatory neuropathy KW - nerve biopsy KW - nerve tumor KW - neuroleukemiosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259555 VL - 26 IS - S2 ER - TY - JOUR A1 - Geisinger, Adriana A1 - Rodríguez-Casuriaga, Rosana A1 - Benavente, Ricardo T1 - Transcriptomics of Meiosis in the Male Mouse JF - Frontiers in Cell and Developmental Biology N2 - Molecular studies of meiosis in mammals have been long relegated due to some intrinsic obstacles, namely the impossibility to reproduce the process in vitro, and the difficulty to obtain highly pure isolated cells of the different meiotic stages. In the recent years, some technical advances, from the improvement of flow cytometry sorting protocols to single-cell RNAseq, are enabling to profile the transcriptome and its fluctuations along the meiotic process. In this mini-review we will outline the diverse methodological approaches that have been employed, and some of the main findings that have started to arise from these studies. As for practical reasons most studies have been carried out in males, and mostly using mouse as a model, our focus will be on murine male meiosis, although also including specific comments about humans. Particularly, we will center on the controversy about gene expression during early meiotic prophase; the widespread existing gap between transcription and translation in meiotic cells; the expression patterns and potential roles of meiotic long non-coding RNAs; and the visualization of meiotic sex chromosome inactivation from the RNAseq perspective. KW - meiosis KW - transcriptomics KW - RNAseq KW - meiotic prophase KW - spermatogenesis KW - lncRNAs KW - MSCI KW - spermatogenic cell sorting Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231032 SN - 2296-634X VL - 9 ER - TY - JOUR A1 - Hartmann, Oliver A1 - Reissland, Michaela A1 - Maier, Carina R. A1 - Fischer, Thomas A1 - Prieto-Garcia, Cristian A1 - Baluapuri, Apoorva A1 - Schwarz, Jessica A1 - Schmitz, Werner A1 - Garrido-Rodriguez, Martin A1 - Pahor, Nikolett A1 - Davies, Clare C. A1 - Bassermann, Florian A1 - Orian, Amir A1 - Wolf, Elmar A1 - Schulze, Almut A1 - Calzado, Marco A. A1 - Rosenfeldt, Mathias T. A1 - Diefenbacher, Markus E. T1 - Implementation of CRISPR/Cas9 Genome Editing to Generate Murine Lung Cancer Models That Depict the Mutational Landscape of Human Disease JF - Frontiers in Cell and Developmental Biology N2 - Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research. KW - non-small cell lung cancer KW - CRISPR-Cas9 KW - mouse model KW - lung cancer KW - MYC KW - JUN Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230949 SN - 2296-634X VL - 9 ER - TY - JOUR A1 - Yu, Yidong A1 - Wolf, Ann-Katrin A1 - Thusek, Sina A1 - Heinekamp, Thorsten A1 - Bromley, Michael A1 - Krappmann, Sven A1 - Terpitz, Ulrich A1 - Voigt, Kerstin A1 - Brakhage, Axel A. A1 - Beilhack, Andreas T1 - Direct Visualization of Fungal Burden in Filamentous Fungus-Infected Silkworms JF - Journal of Fungi N2 - Invasive fungal infections (IFIs) are difficult to diagnose and to treat and, despite several available antifungal drugs, cause high mortality rates. In the past decades, the incidence of IFIs has continuously increased. More recently, SARS-CoV-2-associated lethal IFIs have been reported worldwide in critically ill patients. Combating IFIs requires a more profound understanding of fungal pathogenicity to facilitate the development of novel antifungal strategies. Animal models are indispensable for studying fungal infections and to develop new antifungals. However, using mammalian animal models faces various hurdles including ethical issues and high costs, which makes large-scale infection experiments extremely challenging. To overcome these limitations, we optimized an invertebrate model and introduced a simple calcofluor white (CW) staining protocol to macroscopically and microscopically monitor disease progression in silkworms (Bombyx mori) infected with the human pathogenic filamentous fungi Aspergillus fumigatus and Lichtheimia corymbifera. This advanced silkworm A. fumigatus infection model could validate knockout mutants with either attenuated, strongly attenuated or unchanged virulence. Finally, CW staining allowed us to efficiently visualize antifungal treatment outcomes in infected silkworms. Conclusively, we here present a powerful animal model combined with a straightforward staining protocol to expedite large-scale in vivo research of fungal pathogenicity and to investigate novel antifungal candidates. KW - fungal infection model KW - calcofluor white staining KW - Aspergillus KW - Lichtheimia KW - silkworm Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228855 SN - 2309-608X VL - 7 IS - 2 ER - TY - JOUR A1 - Rang, Maximilian A1 - Fantuzzi, Felipe A1 - Arrowsmith, Merle A1 - Krummenacher, Ivo A1 - Beck, Eva A1 - Witte, Robert A1 - Matler, Alexander A1 - Rempel, Anna A1 - Bischof, Tobias A1 - Radacki, Krzysztof A1 - Engels, Bernd A1 - Braunschweig, Holger T1 - Reduktion und Umlagerung eines Bor(I)‐Carbonylkomplexes JF - Angewandte Chemie N2 - Bei der Einelektronenreduktion eines durch eine cyclisches (Alkyl)(amino)carben (CAAC) stabilisierten Arylborylen-Carbonylkomplexes erfolgt die Bildung eines dimeren Borylketyl-Radikalanions, bedingt durch eine intramolekulare Arylmigration zum CO Kohlenstoffatom. Computergestützte Analyse liefert Hinweise auf eine radikalanionische [(CAAC)B(CO)Ar]\(^{.-}\) Zwischenstufe. Weiterführende Reduktion des entstandenen Komplexes liefert ein hoch nukleophiles (Boranyliden)methanolat. KW - Biradikale KW - Bor-Carbonylkomplexe KW - Dichtefunktionalrechnungen KW - Reduktionen KW - Umlagerungen Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224409 VL - 133 IS - 6 SP - 3000 EP - 3005 ER - TY - JOUR A1 - Kim, Jin Hong A1 - Liess, Andreas A1 - Stolte, Matthias A1 - Krause, Ana-Maria A1 - Stepanenko, Vladimir A1 - Zhong, Chuwei A1 - Bialas, David A1 - Spano, Frank A1 - Würthner, Frank T1 - An Efficient Narrowband Near-Infrared at 1040 nm Organic Photodetector Realized by Intermolecular Charge Transfer Mediated Coupling Based on a Squaraine Dye JF - Advanced Materials N2 - A highly sensitive short-wave infrared (SWIR, λ > 1000 nm) organic photodiode (OPD) is described based on a well-organized nanocrystalline bulk-heterojunction (BHJ) active layer composed of a dicyanovinyl-functionalized squaraine dye (SQ-H) donor material in combination with PC\(_{61}\)BM. Through thermal annealing, dipolar SQ-H chromophores self-assemble in a nanoscale structure with intermolecular charge transfer mediated coupling, resulting in a redshifted and narrow absorption band at 1040 nm as well as enhanced charge carrier mobility. The optimized OPD exhibits an external quantum efficiency (EQE) of 12.3% and a full-width at half-maximum of only 85 nm (815 cm\(^{-1}\)) at 1050 nm under 0 V, which is the first efficient SWIR OPD based on J-type aggregates. Photoplethysmography application for heart-rate monitoring is successfully demonstrated on flexible substrates without applying reverse bias, indicating the potential of OPDs based on short-range coupled dye aggregates for low-power operating wearable applications. KW - squaraine dyes KW - crystal engineering KW - J-aggregates KW - near-infrared sensitivity KW - organic photodiodes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256374 VL - 33 IS - 26 ER - TY - JOUR A1 - Vollmuth, Christoph A1 - Muljukov, Olga A1 - Abu-Mugheisib, Mazen A1 - Angermeier, Anselm A1 - Barlinn, Jessica A1 - Busetto, Loraine A1 - Grau, Armin J. A1 - Günther, Albrecht A1 - Gumbinger, Christoph A1 - Hubert, Nikolai A1 - Hüttemann, Katrin A1 - Klingner, Carsten A1 - Naumann, Markus A1 - Palm, Frederick A1 - Remi, Jan A1 - Rücker, Viktoria A1 - Schessl, Joachim A1 - Schlachetzki, Felix A1 - Schuppner, Ramona A1 - Schwab, Stefan A1 - Schwartz, Andreas A1 - Trommer, Adrian A1 - Urbanek, Christian A1 - Volbers, Bastian A1 - Weber, Joachim A1 - Wojciechowski, Claudia A1 - Worthmann, Hans A1 - Zickler, Philipp A1 - Heuschmann, Peter U. A1 - Haeusler, Karl Georg A1 - Hubert, Gordian Jan T1 - Impact of the coronavirus disease 2019 pandemic on stroke teleconsultations in Germany in the first half of 2020 JF - European Journal of Neurology N2 - Background and purpose The effects of the coronavirus disease 2019 (COVID-19) pandemic on telemedical care have not been described on a national level. Thus, we investigated the medical stroke treatment situation before, during, and after the first lockdown in Germany. Methods In this nationwide, multicenter study, data from 14 telemedical networks including 31 network centers and 155 spoke hospitals covering large parts of Germany were analyzed regarding patients' characteristics, stroke type/severity, and acute stroke treatment. A survey focusing on potential shortcomings of in-hospital and (telemedical) stroke care during the pandemic was conducted. Results Between January 2018 and June 2020, 67,033 telemedical consultations and 38,895 telemedical stroke consultations were conducted. A significant decline of telemedical (p < 0.001) and telemedical stroke consultations (p < 0.001) during the lockdown in March/April 2020 and a reciprocal increase after relaxation of COVID-19 measures in May/June 2020 were observed. Compared to 2018–2019, neither stroke patients' age (p = 0.38), gender (p = 0.44), nor severity of ischemic stroke (p = 0.32) differed in March/April 2020. Whereas the proportion of ischemic stroke patients for whom endovascular treatment (14.3% vs. 14.6%; p = 0.85) was recommended remained stable, there was a nonsignificant trend toward a lower proportion of recommendation of intravenous thrombolysis during the lockdown (19.0% vs. 22.1%; p = 0.052). Despite the majority of participating network centers treating patients with COVID-19, there were no relevant shortcomings reported regarding in-hospital stroke treatment or telemedical stroke care. Conclusions Telemedical stroke care in Germany was able to provide full service despite the COVID-19 pandemic, but telemedical consultations declined abruptly during the lockdown period and normalized after relaxation of COVID-19 measures in Germany. KW - COVID-19 KW - SARS-CoV- 2 KW - stroke KW - telemedicine KW - survey Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259396 VL - 28 IS - 10 ER - TY - JOUR A1 - Mieszczanek, Pawel A1 - Robinson, Thomas M. A1 - Dalton, Paul D. A1 - Hutmacher, Dietmar W. T1 - Convergence of Machine Vision and Melt Electrowriting JF - Advanced Materials N2 - Melt electrowriting (MEW) is a high-resolution additive manufacturing technology that balances multiple parametric variables to arrive at a stable fabrication process. The better understanding of this balance is underscored here using high-resolution camera vision of jet stability profiles in different electrical fields. Complementing this visual information are fiber-diameter measurements obtained at precise points, allowing the correlation to electrified jet properties. Two process signatures—the jet angle and for the first time, the Taylor cone area—are monitored and analyzed with a machine vision system, while SEM imaging for diameter measurement correlates real-time information. This information, in turn, allows the detection and correction of fiber pulsing for accurate jet placement on the collector, and the in-process assessment of the fiber diameter. Improved process control is used to successfully fabricate collapsible MEW tubes; structures that require exceptional accuracy and printing stability. Using a precise winding angle of 60° and 300 layers, the resulting 12 mm-thick tubular structures have elastic snap-through instabilities associated with mechanical metamaterials. This study provides a detailed analysis of the fiber pulsing occurrence in MEW and highlights the importance of real-time monitoring of the Taylor cone volume to better understand, control, and predict printing instabilities. KW - polycaprolactone KW - 3D printing KW - digitization KW - electrohydrodynamic KW - melt electrospinning writing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256365 VL - 33 IS - 29 ER - TY - JOUR A1 - Peseschkian, Tara A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Büchner, Boriana A1 - Weiland, Ulrike A1 - Schönfelder, Erik A1 - Heinrich, Felix A1 - Osmanovic, Alma A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - A nation-wide, multi-center study on the quality of life of ALS patients in Germany JF - Brain Sciences N2 - Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care. KW - Amyotrophic Lateral Sclerosis (ALS) KW - Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) KW - ALS treatment KW - “bulbar-onset” ALS (bALS) KW - “limb-onset” ALS (lALS) KW - EuroQol Five Dimension Five Level Scale (EQ-5D-5L) KW - health-related quality of life (HRQoL) KW - quality of life (QoL) KW - symptom-specific treatment KW - assistive devices Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234147 SN - 2076-3425 VL - 11 IS - 3 ER - TY - JOUR A1 - Detomas, Mario A1 - Altieri, Barbara A1 - Schlötelburg, Wiebke A1 - Appenzeller, Silke A1 - Schlaffer, Sven A1 - Coras, Roland A1 - Schirbel, Andreas A1 - Wild, Vanessa A1 - Kroiss, Matthias A1 - Sbiera, Silviu A1 - Fassnacht, Martin A1 - Deutschbein, Timo T1 - Case Report: Consecutive Adrenal Cushing’s Syndrome and Cushing’s Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations JF - Frontiers in Endocrinology N2 - The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background. KW - Cushing’s syndrome KW - Cushing’s disease KW - hypercortisolism KW - glucocorticoid excess KW - USP8 KW - CTNNB1 KW - NR3C1 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244596 SN - 1664-2392 VL - 12 ER - TY - JOUR A1 - Liu, Zhiqiang A1 - Kole, Goutam Kumar A1 - Budiman, Yudha P. A1 - Tian, Ya-Ming A1 - Friedrich, Alexandra A1 - Luo, Xiaoling A1 - Westcott, Stephen A. A1 - Radius, Udo A1 - Marder, Todd B. T1 - Transition metal catalyst-free, base-promoted 1,2-additions of polyfluorophenylboronates to aldehydes and ketones JF - Angewandte Chemie International Edition N2 - A novel protocol for the transition metal-free 1,2-addition of polyfluoroaryl boronate esters to aldehydes and ketones is reported, which provides secondary alcohols, tertiary alcohols, and ketones. Control experiments and DFT calculations indicate that both the ortho-F substituents on the polyfluorophenyl boronates and the counterion K\(^+\) in the carbonate base are critical. The distinguishing features of this procedure include the employment of commercially available starting materials and the broad scope of the reaction with a wide variety of carbonyl compounds giving moderate to excellent yields. Intriguing structural features involving O−H⋅⋅⋅O and O−H⋅⋅⋅N hydrogen bonding, as well as arene-perfluoroarene interactions, in this series of racemic polyfluoroaryl carbinols have also been addressed. KW - inorganic chemistry KW - transition metal-free KW - alcohol KW - 1,2-additionreaction KW - boronateesters KW - fluoroarene Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256487 VL - 60 IS - 30 ER - TY - JOUR A1 - Shen, Chia-An A1 - Bialas, David A1 - Hecht, Markus A1 - Stepanenko, Vladimir A1 - Sugiyasu, Kazunori A1 - Würthner, Frank T1 - Polymorphism in squaraine dye aggregates by self-assembly pathway differentiation: panchromatic tubular dye nanorods versus J-aggregate nanosheets JF - Angewandte Chemie International Edition N2 - A bis(squaraine) dye equipped with alkyl and oligoethyleneglycol chains was synthesized by connecting two dicyanomethylene substituted squaraine dyes with a phenylene spacer unit. The aggregation behavior of this bis(squaraine) was investigated in non-polar toluene/tetrachloroethane (98:2) solvent mixture, which revealed competing cooperative self-assembly pathways into two supramolecular polymorphs with entirely different packing structures and UV/Vis/NIR absorption properties. The self-assembly pathway can be controlled by the cooling rate from a heated solution of the monomers. For both polymorphs, quasi-equilibrium conditions between monomers and the respective aggregates can be established to derive thermodynamic parameters and insights into the self-assembly mechanisms. AFM measurements revealed a nanosheet structure with a height of 2 nm for the thermodynamically more stable polymorph and a tubular nanorod structure with a helical pitch of 13 nm and a diameter of 5 nm for the kinetically favored polymorph. Together with wide angle X-ray scattering measurements, packing models were derived: the thermodynamic polymorph consists of brick-work type nanosheets that exhibit red-shifted absorption bands as typical for J-aggregates, while the nanorod polymorph consists of eight supramolecular polymer strands of the bis(squaraine) intertwined to form a chimney-type tubular structure. The absorption of this aggregate covers a large spectral range from 550 to 875 nm, which cannot be rationalized by the conventional exciton theory. By applying the Essential States Model and considering intermolecular charge transfer, the aggregate spectrum was adequately reproduced, revealing that the broad absorption spectrum is due to pronounced donor-acceptor overlap within the bis(squaraine) nanorods. The latter is also responsible for the pronounced bathochromic shift observed for the nanosheet structure as a result of the slip-stacked arranged squaraine chromophores. KW - organic chemistry KW - supramolecular polymers KW - nanorods and nanosheets KW - polymorphism KW - squaraine dyes KW - cooperative self-assembly Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256443 IS - 21 ET - 60 ER - TY - JOUR A1 - Hagspiel, Stephan A1 - Fantuzzi, Felipe A1 - Dewhurst, Rian D. A1 - Gärtner, Annalena A1 - Lindl, Felix A1 - Lamprecht, Anna A1 - Braunschweig, Holger T1 - Adducts of the parent boraphosphaketene H\(_2\)BPCO and their decarbonylative insertion chemistry JF - Angewandte Chemie International Edition N2 - The first examples of Lewis base adducts of the parent boraphosphaketene (H\(_2\)B-PCO) and their cyclodimers are prepared. One of these adducts is shown to undergo mild decarbonylation and phosphinidene insertion into a B−C bond of a borole, forming very rare examples of 1,2-phosphaborinines, B/P isosteres of benzene. The strong donor properties of these 1,2-phosphaborinines are confirmed by the synthesis of their π complexes with the Group 6 metals. KW - inorganic chemistry KW - phosphorus KW - boron KW - decarbonylation KW - heterocycles KW - ketenes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256470 VL - 60 IS - 24 ER - TY - JOUR A1 - Kremer, Naomi I. A1 - Pauwels, Rik W. J. A1 - Pozzi, Nicolò G. A1 - Lange, Florian A1 - Roothans, Jonas A1 - Volkmann, Jens A1 - Reich, Martin M. T1 - Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions JF - Journal of Clinical Medicine N2 - Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus is one of the main advanced neurosurgical treatments for drug-resistant tremor. However, not every patient may be eligible for this procedure. Nowadays, various other functional neurosurgical procedures are available. In particular cases, radiofrequency thalamotomy, focused ultrasound and radiosurgery are proven alternatives to DBS. Besides, other DBS targets, such as the posterior subthalamic area (PSA) or the dentato-rubro-thalamic tract (DRT), may be appraised as well. In this review, the clinical characteristics and pathophysiology of tremor syndromes, as well as long-term outcomes of DBS in different targets, will be summarized. The effectiveness and safety of lesioning procedures will be discussed, and an evidence-based clinical treatment approach for patients with drug-resistant tremor will be presented. Lastly, the future directions in the treatment of severe tremor syndromes will be elaborated. KW - deep brain stimulation KW - tremor KW - essential tremor KW - Parkinson’s disease KW - outcomes KW - clinical approach KW - target considerations KW - future directions Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244982 SN - 2077-0383 VL - 10 IS - 16 ER - TY - JOUR A1 - Zhou, Yang A1 - Ding, Meiqi A1 - Duan, Xiaodong A1 - Konrad, Kai R. A1 - Nagel, Georg A1 - Gao, Shiqiang T1 - Extending the Anion Channelrhodopsin-Based Toolbox for Plant Optogenetics JF - Membranes N2 - Optogenetics was developed in the field of neuroscience and is most commonly using light-sensitive rhodopsins to control the neural activities. Lately, we have expanded this technique into plant science by co-expression of a chloroplast-targeted β-carotene dioxygenase and an improved anion channelrhodopsin GtACR1 from the green alga Guillardia theta. The growth of Nicotiana tabacum pollen tube can then be manipulated by localized green light illumination. To extend the application of analogous optogenetic tools in the pollen tube system, we engineered another two ACRs, GtACR2, and ZipACR, which have different action spectra, light sensitivity and kinetic features, and characterized them in Xenopus laevis oocytes, Nicotiana benthamiana leaves and N. tabacum pollen tubes. We found that the similar molecular engineering method used to improve GtACR1 also enhanced GtACR2 and ZipACR performance in Xenopus laevis oocytes. The ZipACR1 performed in N. benthamiana mesophyll cells and N. tabacum pollen tubes with faster kinetics and reduced light sensitivity, allowing for optogenetic control of anion fluxes with better temporal resolution. The reduced light sensitivity would potentially facilitate future application in plants, grown under low ambient white light, combined with an optogenetic manipulation triggered by stronger green light. KW - optogenetics KW - rhodopsin KW - light-sensitive anion channel KW - surface potential recording KW - pollen tube Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236617 SN - 2077-0375 VL - 11 IS - 4 ER - TY - JOUR A1 - Hensgen, Ronja A1 - England, Laura A1 - Homberg, Uwe A1 - Pfeiffer, Keram T1 - Neuroarchitecture of the central complex in the brain of the honeybee: Neuronal cell types JF - Journal of Comparative Neurology N2 - The central complex (CX) in the insect brain is a higher order integration center that controls a number of behaviors, most prominently goal directed locomotion. The CX comprises the protocerebral bridge (PB), the upper division of the central body (CBU), the lower division of the central body (CBL), and the paired noduli (NO). Although spatial orientation has been extensively studied in honeybees at the behavioral level, most electrophysiological and anatomical analyses have been carried out in other insect species, leaving the morphology and physiology of neurons that constitute the CX in the honeybee mostly enigmatic. The goal of this study was to morphologically identify neuronal cell types of the CX in the honeybee Apis mellifera. By performing iontophoretic dye injections into the CX, we traced 16 subtypes of neuron that connect a subdivision of the CX with other regions in the bee's central brain, and eight subtypes that mainly interconnect different subdivisions of the CX. They establish extensive connections between the CX and the lateral complex, the superior protocerebrum and the posterior protocerebrum. Characterized neuron classes and subtypes are morphologically similar to those described in other insects, suggesting considerable conservation in the neural network relevant for orientation. KW - RRID: AB_2337244 KW - RRID: AB_2315425 KW - central complex KW - insect brain KW - neuroanatomy KW - sky compass KW - Apis mellifera Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215566 VL - 529 ER - TY - JOUR A1 - Kunz, Tobias C. A1 - Rühling, Marcel A1 - Moldovan, Adriana A1 - Paprotka, Kerstin A1 - Kozjak-Pavlovic, Vera A1 - Rudel, Thomas A1 - Fraunholz, Martin T1 - The Expandables: Cracking the Staphylococcal Cell Wall for Expansion Microscopy JF - Frontiers in Cellular and Infection Microbiology N2 - Expansion Microscopy (ExM) is a novel tool improving the resolution of fluorescence microscopy by linking the sample into a hydrogel that gets physically expanded in water. Previously, we have used ExM to visualize the intracellular Gram-negative pathogens Chlamydia trachomatis, Simkania negevensis, and Neisseria gonorrhoeae. Gram-positive bacteria have a rigid and thick cell wall that impedes classic expansion strategies. Here we developed an approach, which included a series of enzymatic treatments resulting in isotropic 4× expansion of the Gram-positive pathogen Staphylococcus aureus. We further demonstrate the suitability of the technique for imaging of planktonic bacteria as well as endocytosed, intracellular bacteria at a spatial resolution of approximately 60 nm with conventional confocal laser scanning microscopy. KW - high-resolution imaging KW - endosomes KW - autophagosomes KW - host-pathogen interaction KW - expansion microscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232292 SN - 2235-2988 VL - 11 ER - TY - JOUR A1 - Augustin, Anne Marie A1 - Welsch, Stefan A1 - Bley, Thorsten Alexander A1 - Lopau, Kai A1 - Kickuth, Ralph T1 - Color-coded summation images in the evaluation of renal artery stenosis before and after percutaneous transluminal angioplasty JF - BMC Medical Imaging N2 - Background: Endovascular therapy is the gold standard in patients with hemodynamic relevant renal artery stenosis (RAS) resistant to medical therapy. The severity grading of the stenosis as well as the result assessment after endovascular approach is predominantly based on visible estimations of the anatomic appearance. We aim to investigate the application of color-coded DSA parameters to gain hemodynamic information during endovascular renal artery interventions and for the assessment of the procedures technical success. Methods: We retrospectively evaluated 32 patients who underwent endovascular renal artery revascularization and applied color-coded summation imaging on selected monochromatic DSA images. The differences in time to peak (dTTP) of contrast enhancement in predefined anatomical measuring points were analyzed. Furthermore, differences in systolic blood pressure values (SBP) and serum creatinine were obtained. The value of underlying diabetes mellitus as a predictor for clinical outcome was assessed. Correlation analysis between the patients gender as well as the presence of diabetes mellitus and dTTP was performed. Results: Endovascular revascularization resulted in statistically significant improvement in 4/7 regions of interest. Highly significant improvement of perfusion in terms of shortened TTP values could be found at the segmental artery level and in the intrastenotical segment (p<0.001), significant improvement prestenotical and in the apical renal parenchyma (p<0.05). In the other anatomic regions, differences revealed not to be significant. Differences between SBP and serum creatinine levels before and after the procedure were significant (p=0.004 and 0.0004). Patients ' gender as well as the presence of diabetes mellitus did not reveal to be predictors for the clinical success of the procedure. Furthermore, diabetes and gender did not show relevant correlation with dTTP in the parenchymal measuring points. Conclusions: The supplementary use of color-coding DSA and the data gained from parametric images may provide helpful information in the evaluation of the procedures ' technical success. The segmental artery might be a particularly suitable vascular territory for analyzing differences in blood flow characteristics. Further studies with larger cohorts are needed to further confirm the diagnostic value of this technique. KW - digital subtraction angiography KW - color-coded KW - endovascular KW - renal artery KW - PTA Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259086 VL - 21 IS - 1 ER - TY - JOUR A1 - Pinzner, Florian A1 - Keller, Thorsten A1 - Mut, Jürgen A1 - Bechold, Julian A1 - Seibel, Jürgen A1 - Groll, Jürgen T1 - Polyoxazolines with a vicinally double-bioactivated terminus for biomacromolecular affinity assessment JF - Sensors N2 - Interactions between proteins and carbohydrates with larger biomacromolecules, e.g., lectins, are usually examined using self-assembled monolayers on target gold surfaces as a simplified model measuring setup. However, most of those measuring setups are either limited to a single substrate or do not allow for control over ligand distance and spacing. Here, we develop a synthetic strategy, consisting of a cascade of a thioesterification, native chemical ligation (NCL) and thiol-ene reaction, in order to create three-component polymer conjugates with a defined double bioactivation at the chain end. The target architecture is the vicinal attachment of two biomolecule residues to the α telechelic end point of a polymer and a thioether group at the ω chain end for fixating the conjugate to a gold sensor chip surface. As proof-of-principle studies for affinity measurements, we demonstrate the interaction between covalently bound mannose and ConA in surface acoustic wave (SAW) and surface plasmon resonance (SPR) experiments. KW - polyoxazolines KW - functionalization KW - lectin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239530 SN - 1424-8220 VL - 21 IS - 9 ER - TY - JOUR A1 - Klein, Igor A1 - Oppelt, Natascha A1 - Kuenzer, Claudia T1 - Application of remote sensing data for locust research and management — a review JF - Insects N2 - Recently, locust outbreaks around the world have destroyed agricultural and natural vegetation and caused massive damage endangering food security. Unusual heavy rainfalls in habitats of the desert locust (Schistocerca gregaria) and lack of monitoring due to political conflicts or inaccessibility of those habitats lead to massive desert locust outbreaks and swarms migrating over the Arabian Peninsula, East Africa, India and Pakistan. At the same time, swarms of the Moroccan locust (Dociostaurus maroccanus) in some Central Asian countries and swarms of the Italian locust (Calliptamus italicus) in Russia and China destroyed crops despite developed and ongoing monitoring and control measurements. These recent events underline that the risk and damage caused by locust pests is as present as ever and affects 100 million of human lives despite technical progress in locust monitoring, prediction and control approaches. Remote sensing has become one of the most important data sources in locust management. Since the 1980s, remote sensing data and applications have accompanied many locust management activities and contributed to an improved and more effective control of locust outbreaks and plagues. Recently, open-access remote sensing data archives as well as progress in cloud computing provide unprecedented opportunity for remote sensing-based locust management and research. Additionally, unmanned aerial vehicle (UAV) systems bring up new prospects for a more effective and faster locust control. Nevertheless, the full capacity of available remote sensing applications and possibilities have not been exploited yet. This review paper provides a comprehensive and quantitative overview of international research articles focusing on remote sensing application for locust management and research. We reviewed 110 articles published over the last four decades, and categorized them into different aspects and main research topics to summarize achievements and gaps for further research and application development. The results reveal a strong focus on three species — the desert locust, the migratory locust (Locusta migratoria), and the Australian plague locust (Chortoicetes terminifera) — and corresponding regions of interest. There is still a lack of international studies for other pest species such as the Italian locust, the Moroccan locust, the Central American locust (Schistocerca piceifrons), the South American locust (Schistocerca cancellata), the brown locust (Locustana pardalina) and the red locust (Nomadacris septemfasciata). In terms of applied sensors, most studies utilized Advanced Very-High-Resolution Radiometer (AVHRR), Satellite Pour l’Observation de la Terre VEGETATION (SPOT-VGT), Moderate-Resolution Imaging Spectroradiometer (MODIS) as well as Landsat data focusing mainly on vegetation monitoring or land cover mapping. Application of geomorphological metrics as well as radar-based soil moisture data is comparably rare despite previous acknowledgement of their importance for locust outbreaks. Despite great advance and usage of available remote sensing resources, we identify several gaps and potential for future research to further improve the understanding and capacities of the use of remote sensing in supporting locust outbreak- research and management. KW - locust monitoring KW - locust outbreak KW - remote sensing KW - locust habitat KW - locust pest Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234090 SN - 2075-4450 VL - 12 IS - 3 ER - TY - JOUR A1 - Schwaab, Bernhard A1 - Bjarnason-Wehrens, Birna A1 - Meng, Karin A1 - Albus, Christian A1 - Salzwedel, Annett A1 - Schmid, Jean-Paul A1 - Benzer, Werner A1 - Metz, Matthes A1 - Jensen, Katrin A1 - Rauch, Bernhard A1 - Bönner, Gerd A1 - Brzoska, Patrick A1 - Buhr-Schinner, Heike A1 - Charrier, Albrecht A1 - Cordes, Carsten A1 - Dörr, Gesine A1 - Eichler, Sarah A1 - Exner, Anne-Kathrin A1 - Fromm, Bernd A1 - Gielen, Stephan A1 - Glatz, Johannes A1 - Gohlke, Helmut A1 - Grilli, Maurizio A1 - Gysan, Detlef A1 - Härtel, Ursula A1 - Hahmann, Harry A1 - Herrmann-Lingen, Christoph A1 - Karger, Gabriele A1 - Karoff, Marthin A1 - Kiwus, Ulrich A1 - Knoglinger, Ernst A1 - Krusch, Christian-Wolfgang A1 - Langheim, Eike A1 - Mann, Johannes A1 - Max, Regina A1 - Metzendorf, Maria-Inti A1 - Nebel, Roland A1 - Niebauer, Josef A1 - Predel, Hans-Georg A1 - Preßler, Axel A1 - Razum, Oliver A1 - Reiss, Nils A1 - Saure, Daniel A1 - von Schacky, Clemens A1 - Schütt, Morten A1 - Schultz, Konrad A1 - Skoda, Eva-Maria A1 - Steube, Diethard A1 - Streibelt, Marco A1 - Stüttgen, Martin A1 - Stüttgen, Michaela A1 - Teufel, Martin A1 - Tschanz, Hansueli A1 - Völler, Heinz A1 - Vogel, Heiner A1 - Westphal, Ronja T1 - Cardiac rehabilitation in German speaking countries of Europe — evidence-based guidelines from Germany, Austria and Switzerland LLKardReha-DACH — part 2 JF - Journal of Clinical Medicine N2 - Background: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients' groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. Methods: Generation of evidence and search of literature have been described in part 1. Results: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for “distress management” and “lifestyle changes”. PE is able to increase patients’ knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients’ groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. Conclusions: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively. KW - cardiac rehabilitation KW - scientific guidelines KW - secondary prevention KW - physical activity KW - exercise training KW - psychological interventions KW - education KW - gender KW - frailty KW - migration KW - old patients KW - young patients KW - tele-medicine KW - home-based-rehabilitation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242645 SN - 2077-0383 VL - 10 IS - 14 ER - TY - JOUR A1 - Kirsch, Wladimir A1 - Kunde, Wilfried A1 - Herbort, Oliver T1 - Impact of proprioception on the perceived size and distance of external objects in a virtual action task JF - Psychonomic Bulletin & Review N2 - Previous research has revealed changes in the perception of objects due to changes of object-oriented actions. In present study, we varied the arm and finger postures in the context of a virtual reaching and grasping task and tested whether this manipulation can simultaneously affect the perceived size and distance of external objects. Participants manually controlled visual cursors, aiming at reaching and enclosing a distant target object, and judged the size and distance of this object. We observed that a visual-proprioceptive discrepancy introduced during the reaching part of the action simultaneously affected the judgments of target distance and of target size (Experiment 1). A related variation applied to the grasping part of the action affected the judgments of size, but not of distance of the target (Experiment 2). These results indicate that perceptual effects observed in the context of actions can directly arise through sensory integration of multimodal redundant signals and indirectly through perceptual constancy mechanisms. KW - visual perception KW - motor control KW - object-oriented actions Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-273235 SN - 1531-5320 VL - 28 IS - 4 ER - TY - JOUR A1 - Kern, Florian A1 - Kullmann, Peter A1 - Ganal, Elisabeth A1 - Korwisi, Kristof A1 - Stingl, René A1 - Niebling, Florian A1 - Latoschik, Marc Erich T1 - Off-The-Shelf Stylus: Using XR Devices for Handwriting and Sketching on Physically Aligned Virtual Surfaces JF - Frontiers in Virtual Reality N2 - This article introduces the Off-The-Shelf Stylus (OTSS), a framework for 2D interaction (in 3D) as well as for handwriting and sketching with digital pen, ink, and paper on physically aligned virtual surfaces in Virtual, Augmented, and Mixed Reality (VR, AR, MR: XR for short). OTSS supports self-made XR styluses based on consumer-grade six-degrees-of-freedom XR controllers and commercially available styluses. The framework provides separate modules for three basic but vital features: 1) The stylus module provides stylus construction and calibration features. 2) The surface module provides surface calibration and visual feedback features for virtual-physical 2D surface alignment using our so-called 3ViSuAl procedure, and surface interaction features. 3) The evaluation suite provides a comprehensive test bed combining technical measurements for precision, accuracy, and latency with extensive usability evaluations including handwriting and sketching tasks based on established visuomotor, graphomotor, and handwriting research. The framework’s development is accompanied by an extensive open source reference implementation targeting the Unity game engine using an Oculus Rift S headset and Oculus Touch controllers. The development compares three low-cost and low-tech options to equip controllers with a tip and includes a web browser-based surface providing support for interacting, handwriting, and sketching. The evaluation of the reference implementation based on the OTSS framework identified an average stylus precision of 0.98 mm (SD = 0.54 mm) and an average surface accuracy of 0.60 mm (SD = 0.32 mm) in a seated VR environment. The time for displaying the stylus movement as digital ink on the web browser surface in VR was 79.40 ms on average (SD = 23.26 ms), including the physical controller’s motion-to-photon latency visualized by its virtual representation (M = 42.57 ms, SD = 15.70 ms). The usability evaluation (N = 10) revealed a low task load, high usability, and high user experience. Participants successfully reproduced given shapes and created legible handwriting, indicating that the OTSS and it’s reference implementation is ready for everyday use. We provide source code access to our implementation, including stylus and surface calibration and surface interaction features, making it easy to reuse, extend, adapt and/or replicate previous results (https://go.uniwue.de/hci-otss). KW - virtual reality KW - augmented reality KW - handwriting KW - sketching KW - stylus KW - user interaction KW - usability evaluation KW - passive haptic feedback Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260219 VL - 2 ER - TY - JOUR A1 - Bartl, Andrea A1 - Wenninger, Stephan A1 - Wolf, Erik A1 - Botsch, Mario A1 - Latoschik, Marc Erich T1 - Affordable but not cheap: a case study of the effects of two 3D-reconstruction methods of virtual humans JF - Frontiers in Virtual Reality N2 - Realistic and lifelike 3D-reconstruction of virtual humans has various exciting and important use cases. Our and others’ appearances have notable effects on ourselves and our interaction partners in virtual environments, e.g., on acceptance, preference, trust, believability, behavior (the Proteus effect), and more. Today, multiple approaches for the 3D-reconstruction of virtual humans exist. They significantly vary in terms of the degree of achievable realism, the technical complexities, and finally, the overall reconstruction costs involved. This article compares two 3D-reconstruction approaches with very different hardware requirements. The high-cost solution uses a typical complex and elaborated camera rig consisting of 94 digital single-lens reflex (DSLR) cameras. The recently developed low-cost solution uses a smartphone camera to create videos that capture multiple views of a person. Both methods use photogrammetric reconstruction and template fitting with the same template model and differ in their adaptation to the method-specific input material. Each method generates high-quality virtual humans ready to be processed, animated, and rendered by standard XR simulation and game engines such as Unreal or Unity. We compare the results of the two 3D-reconstruction methods in an immersive virtual environment against each other in a user study. Our results indicate that the virtual humans from the low-cost approach are perceived similarly to those from the high-cost approach regarding the perceived similarity to the original, human-likeness, beauty, and uncanniness, despite significant differences in the objectively measured quality. The perceived feeling of change of the own body was higher for the low-cost virtual humans. Quality differences were perceived more strongly for one’s own body than for other virtual humans. KW - virtual humans KW - 3D-reconstruction methods KW - avatars KW - agents KW - user study Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260492 VL - 2 ER - TY - JOUR A1 - Wienrich, Carolin A1 - Latoschik, Marc Erich T1 - eXtended Artificial Intelligence: New Prospects of Human-AI Interaction Research JF - Frontiers in Virtual Reality N2 - Artificial Intelligence (AI) covers a broad spectrum of computational problems and use cases. Many of those implicate profound and sometimes intricate questions of how humans interact or should interact with AIs. Moreover, many users or future users do have abstract ideas of what AI is, significantly depending on the specific embodiment of AI applications. Human-centered-design approaches would suggest evaluating the impact of different embodiments on human perception of and interaction with AI. An approach that is difficult to realize due to the sheer complexity of application fields and embodiments in reality. However, here XR opens new possibilities to research human-AI interactions. The article’s contribution is twofold: First, it provides a theoretical treatment and model of human-AI interaction based on an XR-AI continuum as a framework for and a perspective of different approaches of XR-AI combinations. It motivates XR-AI combinations as a method to learn about the effects of prospective human-AI interfaces and shows why the combination of XR and AI fruitfully contributes to a valid and systematic investigation of human-AI interactions and interfaces. Second, the article provides two exemplary experiments investigating the aforementioned approach for two distinct AI-systems. The first experiment reveals an interesting gender effect in human-robot interaction, while the second experiment reveals an Eliza effect of a recommender system. Here the article introduces two paradigmatic implementations of the proposed XR testbed for human-AI interactions and interfaces and shows how a valid and systematic investigation can be conducted. In sum, the article opens new perspectives on how XR benefits human-centered AI design and development. KW - human-artificial intelligence interface KW - human-artificial intelligence interaction KW - XR-artificial intelligence continuum KW - XR-artificial intelligence combination KW - research methods KW - human-centered, human-robot KW - recommender system Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260296 VL - 2 ER - TY - JOUR A1 - Wienrich, Carolin A1 - Carolus, Astrid T1 - Development of an Instrument to Measure Conceptualizations and Competencies About Conversational Agents on the Example of Smart Speakers JF - Frontiers in Computer Science N2 - The concept of digital literacy has been introduced as a new cultural technique, which is regarded as essential for successful participation in a (future) digitized world. Regarding the increasing importance of AI, literacy concepts need to be extended to account for AI-related specifics. The easy handling of the systems results in increased usage, contrasting limited conceptualizations (e.g., imagination of future importance) and competencies (e.g., knowledge about functional principles). In reference to voice-based conversational agents as a concrete application of AI, the present paper aims for the development of a measurement to assess the conceptualizations and competencies about conversational agents. In a first step, a theoretical framework of “AI literacy” is transferred to the context of conversational agent literacy. Second, the “conversational agent literacy scale” (short CALS) is developed, constituting the first attempt to measure interindividual differences in the “(il) literate” usage of conversational agents. 29 items were derived, of which 170 participants answered. An explanatory factor analysis identified five factors leading to five subscales to assess CAL: storage and transfer of the smart speaker’s data input; smart speaker’s functional principles; smart speaker’s intelligent functions, learning abilities; smart speaker’s reach and potential; smart speaker’s technological (surrounding) infrastructure. Preliminary insights into construct validity and reliability of CALS showed satisfying results. Third, using the newly developed instrument, a student sample’s CAL was assessed, revealing intermediated values. Remarkably, owning a smart speaker did not lead to higher CAL scores, confirming our basic assumption that usage of systems does not guarantee enlightened conceptualizations and competencies. In sum, the paper contributes to the first insights into the operationalization and understanding of CAL as a specific subdomain of AI-related competencies. KW - artificial intelligence literacy KW - artificial intelligence education KW - voice-based artificial intelligence KW - conversational agents KW - measurement Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260198 VL - 3 ER - TY - JOUR A1 - Wienrich, Carolin A1 - Reitelbach, Clemens A1 - Carolus, Astrid T1 - The Trustworthiness of Voice Assistants in the Context of Healthcare Investigating the Effect of Perceived Expertise on the Trustworthiness of Voice Assistants, Providers, Data Receivers, and Automatic Speech Recognition JF - Frontiers in Computer Science N2 - As an emerging market for voice assistants (VA), the healthcare sector imposes increasing requirements on the users’ trust in the technological system. To encourage patients to reveal sensitive data requires patients to trust in the technological counterpart. In an experimental laboratory study, participants were presented a VA, which was introduced as either a “specialist” or a “generalist” tool for sexual health. In both conditions, the VA asked the exact same health-related questions. Afterwards, participants assessed the trustworthiness of the tool and further source layers (provider, platform provider, automatic speech recognition in general, data receiver) and reported individual characteristics (disposition to trust and disclose sexual information). Results revealed that perceiving the VA as a specialist resulted in higher trustworthiness of the VA and of the provider, the platform provider and automatic speech recognition in general. Furthermore, the provider’s trustworthiness affected the perceived trustworthiness of the VA. Presenting both a theoretical line of reasoning and empirical data, the study points out the importance of the users’ perspective on the assistant. In sum, this paper argues for further analyses of trustworthiness in voice-based systems and its effects on the usage behavior as well as the impact on responsible design of future technology. KW - voice assistant KW - trustworthiness KW - trust KW - anamnesis tool KW - expertise framing (Min5-Max 8) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260209 VL - 3 ER - TY - JOUR A1 - Wienrich, Carolin A1 - Komma, Philipp A1 - Vogt, Stephanie A1 - Latoschik, Marc E. T1 - Spatial Presence in Mixed Realities – Considerations About the Concept, Measures, Design, and Experiments JF - Frontiers in Virtual Reality N2 - Plenty of theories, models, measures, and investigations target the understanding of virtual presence, i.e., the sense of presence in immersive Virtual Reality (VR). Other varieties of the so-called eXtended Realities (XR), e.g., Augmented and Mixed Reality (AR and MR) incorporate immersive features to a lesser degree and continuously combine spatial cues from the real physical space and the simulated virtual space. This blurred separation questions the applicability of the accumulated knowledge about the similarities of virtual presence and presence occurring in other varieties of XR, and corresponding outcomes. The present work bridges this gap by analyzing the construct of presence in mixed realities (MR). To achieve this, the following presents (1) a short review of definitions, dimensions, and measurements of presence in VR, and (2) the state of the art views on MR. Additionally, we (3) derived a working definition of MR, extending the Milgram continuum. This definition is based on entities reaching from real to virtual manifestations at one time point. Entities possess different degrees of referential power, determining the selection of the frame of reference. Furthermore, we (4) identified three research desiderata, including research questions about the frame of reference, the corresponding dimension of transportation, and the dimension of realism in MR. Mainly the relationship between the main aspects of virtual presence of immersive VR, i.e., the place-illusion, and the plausibility-illusion, and of the referential power of MR entities are discussed regarding the concept, measures, and design of presence in MR. Finally, (5) we suggested an experimental setup to reveal the research heuristic behind experiments investigating presence in MR. The present work contributes to the theories and the meaning of and approaches to simulate and measure presence in MR. We hypothesize that research about essential underlying factors determining user experience (UX) in MR simulations and experiences is still in its infancy and hopes this article provides an encouraging starting point to tackle related questions. KW - mixed reality KW - virtual-reality-continuum KW - spatial presence KW - place-illusion KW - plausibility-illusion KW - transportation KW - realism Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260328 VL - 2 ER - TY - JOUR A1 - Glémarec, Yann A1 - Lugrin, Jean-Luc A1 - Bosser, Anne-Gwenn A1 - Collins Jackson, Aryana A1 - Buche, Cédric A1 - Latoschik, Marc Erich T1 - Indifferent or Enthusiastic? Virtual Audiences Animation and Perception in Virtual Reality JF - Frontiers in Virtual Reality N2 - In this paper, we present a virtual audience simulation system for Virtual Reality (VR). The system implements an audience perception model controlling the nonverbal behaviors of virtual spectators, such as facial expressions or postures. Groups of virtual spectators are animated by a set of nonverbal behavior rules representing a particular audience attitude (e.g., indifferent or enthusiastic). Each rule specifies a nonverbal behavior category: posture, head movement, facial expression and gaze direction as well as three parameters: type, frequency and proportion. In a first user-study, we asked participants to pretend to be a speaker in VR and then create sets of nonverbal behaviour parameters to simulate different attitudes. Participants manipulated the nonverbal behaviours of single virtual spectator to match a specific levels of engagement and opinion toward them. In a second user-study, we used these parameters to design different types of virtual audiences with our nonverbal behavior rules and evaluated their perceptions. Our results demonstrate our system’s ability to create virtual audiences with three types of different perceived attitudes: indifferent, critical, enthusiastic. The analysis of the results also lead to a set of recommendations and guidelines regarding attitudes and expressions for future design of audiences for VR therapy and training applications. KW - virtual reality KW - perception KW - nonverbal behavior KW - interaction KW - virtual agent KW - virtual audience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259328 VL - 2 ER - TY - JOUR A1 - Du, Baoguo A1 - Ma, Yuhua A1 - Yáñez‐Serrano, Ana Maria A1 - Arab, Leila A1 - Fasbender, Lukas A1 - Alfarraj, Saleh A1 - Albasher, Gadah A1 - Hedrich, Rainer A1 - White, Philip J. A1 - Werner, Christiane A1 - Rennenberg, Heinz T1 - Physiological responses of date palm (Phoenix dactylifera) seedlings to seawater and flooding JF - New Phytologist N2 - In their natural environment along coast lines, date palms are exposed to seawater inundation and, hence, combined stress by salinity and flooding. To elucidate the consequences of this combined stress on foliar gas exchange and metabolite abundances in leaves and roots, date palm seedlings were exposed to flooding with seawater and its major constituents under controlled conditions. Seawater flooding significantly reduced CO\(_{2}\) assimilation, transpiration and stomatal conductance, but did not affect isoprene emission. A similar effect was observed upon NaCl exposure. By contrast, flooding with distilled water or MgSO\(_{4}\) did not affect CO\(_{2}\)/H\(_{2}\)O gas exchange or stomatal conductance significantly, indicating that neither flooding itself, nor seawater sulfate, contributed greatly to stomatal closure. Seawater exposure increased Na and Cl contents in leaves and roots, but did not affect sulfate contents significantly. Metabolite analyses revealed reduced abundances of foliar compatible solutes, such as sugars and sugar alcohols, whereas nitrogen compounds accumulated in roots. Reduced transpiration upon seawater exposure may contribute to controlling the movement of toxic ions to leaves and, therefore, can be seen as a mechanism to cope with salinity. The present results indicate that date palm seedlings are tolerant towards seawater exposure to some extent, and highly tolerant to flooding. KW - compatible solutes and other metabolites KW - date palm KW - flooding KW - salinity KW - shoot–root interaction KW - stomatal conductance KW - sulfate Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228226 VL - 229 IS - 6 SP - 3318 EP - 3329 ER - TY - JOUR A1 - Atiyas, Izak A1 - Doganoglu, Toker A1 - Inceoglu, Firat T1 - Upstream Competition with Complex and Unobservable Contracts JF - Review of Industrial Organization N2 - This paper examines situations where two vertically integrated firms consider supplying an input to an independent downstream competitor via privately observed contracts. We identify equilibria where competition in the upstream market emerges—the downstream competitor gets supplied—as well as when the downstream firm does not receive the input and is excluded from the market. The likelihood of the outcome in which the downstream firm does not get supplied depends not only on demand parameters, but also on contractual flexibility and observability. We show that when contracts are unobservable, downstream entry will occur less often. Furthermore, our results suggest that permitting contracts that enable the contracting parties to coordinate their behavior in the downstream market may improve welfare by increasing the likelihood that the downstream firm is supplied. KW - collective refusal to supply KW - foreclosure KW - unobservable contracts KW - upstream competition Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241161 VL - 58 ER - TY - JOUR A1 - Seibold, Sebastian A1 - Hothorn, Torsten A1 - Gossner, Martin M. A1 - Simons, Nadja K. A1 - Blüthgen, Nico A1 - Müller, Jörg A1 - Ambarlı, Didem A1 - Ammer, Christian A1 - Bauhus, Jürgen A1 - Fischer, Markus A1 - Habel, Jan C. A1 - Penone, Caterina A1 - Schall, Peter A1 - Schulze, Ernst‐Detlef A1 - Weisser, Wolfgang W. T1 - Insights from regional and short‐term biodiversity monitoring datasets are valuable: a reply to Daskalova et al. 2021 JF - Insect Conservation and Diversity N2 - Reports of major losses in insect biodiversity have stimulated an increasing interest in temporal population changes. Existing datasets are often limited to a small number of study sites, few points in time, a narrow range of land‐use intensities and only some taxonomic groups, or they lack standardised sampling. While new monitoring programs have been initiated, they still cover rather short time periods. Daskalova et al. 2021 (Insect Conservation and Diversity, 14, 1‐18) argue that temporal trends of insect populations derived from short time series are biased towards extreme trends, while their own analysis of an assembly of shorter‐ and longer‐term time series does not support an overall insect decline. With respect to the results of Seibold et al. 2019 (Nature, 574, 671–674) based on a 10‐year multi‐site time series, they claim that the analysis suffers from not accounting for temporal pseudoreplication. Here, we explain why the criticism of missing statistical rigour in the analysis of Seibold et al. (2019) is not warranted. Models that include ‘year’ as random effect, as suggested by Daskalova et al. (2021), fail to detect non‐linear trends and assume that consecutive years are independent samples which is questionable for insect time‐series data. We agree with Daskalova et al. (2021) that the assembly and analysis of larger datasets is urgently needed, but it will take time until such datasets are available. Thus, short‐term datasets are highly valuable, should be extended and analysed continually to provide a more detailed understanding of insect population changes under the influence of global change, and to trigger immediate conservation actions. KW - Arthropod KW - biodiversity KW - insect decline KW - land use KW - time series Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228309 VL - 14 IS - 1 SP - 144 EP - 148 ER - TY - JOUR A1 - Homburg, Annika A1 - Weiß, Christian H. A1 - Frahm, Gabriel A1 - Alwan, Layth C. A1 - Göb, Rainer T1 - Analysis and forecasting of risk in count processes JF - Journal of Risk and Financial Management N2 - Risk measures are commonly used to prepare for a prospective occurrence of an adverse event. If we are concerned with discrete risk phenomena such as counts of natural disasters, counts of infections by a serious disease, or counts of certain economic events, then the required risk forecasts are to be computed for an underlying count process. In practice, however, the discrete nature of count data is sometimes ignored and risk forecasts are calculated based on Gaussian time series models. But even if methods from count time series analysis are used in an adequate manner, the performance of risk forecasting is affected by estimation uncertainty as well as certain discreteness phenomena. To get a thorough overview of the aforementioned issues in risk forecasting of count processes, a comprehensive simulation study was done considering a broad variety of risk measures and count time series models. It becomes clear that Gaussian approximate risk forecasts substantially distort risk assessment and, thus, should be avoided. In order to account for the apparent estimation uncertainty in risk forecasting, we use bootstrap approaches for count time series. The relevance and the application of the proposed approaches are illustrated by real data examples about counts of storm surges and counts of financial transactions. KW - count time series KW - expected shortfall KW - expectiles KW - Gaussian approximation KW - mid quantiles KW - tail conditional expectation KW - value at risk Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236692 SN - 1911-8074 VL - 14 IS - 4 ER - TY - JOUR A1 - Hein, Rebecca M. A1 - Wienrich, Carolin A1 - Latoschik, Marc E. T1 - A systematic review of foreign language learning with immersive technologies (2001-2020) JF - AIMS Electronics and Electrical Engineering N2 - This study provides a systematic literature review of research (2001–2020) in the field of teaching and learning a foreign language and intercultural learning using immersive technologies. Based on 2507 sources, 54 articles were selected according to a predefined selection criteria. The review is aimed at providing information about which immersive interventions are being used for foreign language learning and teaching and where potential research gaps exist. The papers were analyzed and coded according to the following categories: (1) investigation form and education level, (2) degree of immersion, and technology used, (3) predictors, and (4) criterions. The review identified key research findings relating the use of immersive technologies for learning and teaching a foreign language and intercultural learning at cognitive, affective, and conative levels. The findings revealed research gaps in the area of teachers as a target group, and virtual reality (VR) as a fully immersive intervention form. Furthermore, the studies reviewed rarely examined behavior, and implicit measurements related to inter- and trans-cultural learning and teaching. Inter- and transcultural learning and teaching especially is an underrepresented investigation subject. Finally, concrete suggestions for future research are given. The systematic review contributes to the challenge of interdisciplinary cooperation between pedagogy, foreign language didactics, and Human-Computer Interaction to achieve innovative teaching-learning formats and a successful digital transformation. KW - foreign language learning and teaching KW - intercultural learning and teaching KW - immersive technologies KW - education KW - human-computer interaction KW - systematic literature review Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268811 VL - 5 IS - 2 ER - TY - JOUR A1 - Wagner, Nicole A1 - Mott, Kristina A1 - Upcin, Berin A1 - Stegner, David A1 - Schulze, Harald A1 - Ergün, Süleyman T1 - CXCL12-abundant reticular (CAR) cells direct megakaryocyte protrusions across the bone marrow sinusoid wall JF - Cells N2 - Megakaryocytes (MKs) release platelets into the lumen of bone marrow (BM) sinusoids while remaining to reside within the BM. The morphogenetic events of this complex process are still not fully understood. We combined confocal laser scanning microscopy with transmission and serial block-face scanning electron microscopy followed by 3D-reconstruction on mouse BM tissue sections. These analyses revealed that MKs in close vicinity to BM sinusoid (BMS) wall first induce the lateral retraction of CXCL12-abundant reticular (CAR) cells (CAR), followed by basal lamina (BL) degradation enabling direct MK-sinusoidal endothelial cells (SECs) interaction. Subsequently, an endothelial engulfment starts that contains a large MK protrusion. Then, MK protrusions penetrate the SEC, transmigrate into the BMS lumen and form proplatelets that are in direct contact to the SEC surface. Furthermore, such processes are induced on several sites, as observed by 3D reconstructions. Our data demonstrate that MKs in interaction with CAR-cells actively induce BMS wall alterations, including CAR-cell retraction, BL degradation, and SEC engulfment containing a large MK protrusion. This results in SEC penetration enabling the migration of MK protrusion into the BMS lumen where proplatelets that are adherent to the luminal SEC surface are formed and contribute to platelet release into the blood circulation. KW - megakaryocytes KW - microvasculature KW - CXCL12-abundant reticular (CAR)-cells Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234180 SN - 2073-4409 VL - 10 IS - 4 ER -