@article{LinzBrandsKertelsetal.2021, author = {Linz, Christian and Brands, Roman C. and Kertels, Olivia and Dierks, Alexander and Brumberg, Joachim and Gerhard-Hartmann, Elena and Hartmann, Stefan and Schirbel, Andreas and Serfling, Sebastian and Zhi, Yingjun and Buck, Andreas K. and K{\"u}bler, Alexander and Hohm, Julian and Lapa, Constantin and Kircher, Malte}, title = {Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity - initial experience and comparison to [18F]FDG PET/CT and MRI}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {48}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, doi = {10.1007/s00259-021-05422-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369331}, pages = {3951-3960}, year = {2021}, abstract = {Purpose While [18F]-fluorodeoxyglucose ([18F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-na{\"i}ve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [18F]FDG and [68Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUVmax) and peak (SUVpeak) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [18F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([18F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3\% vs. 87.5\%; P = 0.32) and specificity (93.3\% vs. 81.3\%; P = 0.16) to [18F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.}, language = {en} } @article{LinzBrandsHerterichetal.2021, author = {Linz, Christian and Brands, Roman C. and Herterich, Theresia and Hartmann, Stefan and M{\"u}ller-Richter, Urs and K{\"u}bler, Alexander C. and Haug, Lukas and Kertels, Olivia and Bley, Thorsten A. and Dierks, Alexander and Buck, Andreas K. and Lapa, Constantin and Brumberg, Joachim}, title = {Accuracy of 18-F Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Imaging in Primary Staging of Squamous Cell Carcinoma of the Oral Cavity}, series = {JAMA Network Open}, volume = {4}, journal = {JAMA Network Open}, doi = {10.1001/jamanetworkopen.2021.7083}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369313}, year = {2021}, abstract = {Importance Squamous cell carcinoma (SCC) of the oral cavity is one of the most common tumor entities worldwide. Precise initial staging is necessary to determine a diagnosis, treatment, and prognosis. Objective To examine the diagnostic accuracy of preoperative 18-F fluorodeoxyglucose (FDG) positron emission tomographic/computed tomographic (PET/CT) imaging in detecting cervical lymph node metastases. Design, Setting, and Participants This prospective diagnostic study was performed at a single tertiary reference center between June 1, 2013, and January 31, 2016. Data were analyzed from April 7, 2018, through May 31, 2019. Observers of the FDG PET/CT imaging were blinded to patients' tumor stage. A total of 150 treatment-naive patients with clinical suspicion of SCC of the oral cavity were enrolled. Exposures All patients underwent FDG PET/CT imaging before local tumor resection with selective or complete neck dissection. Main Outcomes and Measures The accuracy of FDG PET/CT in localizing primary tumor, lymph node, and distant metastases was tested. Histopathologic characteristics of the tissue samples served as the standard of reference. Results Of the 150 patients enrolled, 135 patients (74 [54.8\%] men) with a median age of 63 years (range, 23-88 years) met the inclusion criteria (histopathologically confirmed primary SCC of the oral cavity/level-based histopathologic assessment of the resected lymph nodes). Thirty-six patients (26.7\%) in the study cohort had neck metastases. Use of FDG PET/CT detected cervical lymph node metastasis with 83.3\% sensitivity (95\% CI, 71.2\%-95.5\%) and 84.8\% specificity (95\% CI, 77.8\%-91.9\%) and had a negative predictive value of 93.3\% (95\% CI, 88.2\%-98.5\%). The specificity was higher than for contrast-enhanced cervical CT imaging (67.0\%; 95\% CI, 57.4\%-76.7\%; P < .01) and cervical magnetic resonance imaging (62.6\%; 95\% CI, 52.7\%-72.6\%; P < .001). Ipsilateral lymph node metastasis in left- or right-sided primary tumor sites was detected with 78.6\% sensitivity (95\% CI, 63.4\%-93.8\%) and 83.1\% specificity (95\% CI, 75.1\%-91.2\%), and contralateral metastatic involvement was detected with 66.7\% sensitivity (95\% CI, 28.9\%-100.0\%) and 98.6\% specificity (95\% CI, 95.9\%-100.0\%). No distant metastases were observed. Conclusions and Relevance In this study, FDG PET/CT imaging had a high negative predictive value in detecting cervical lymph node metastasis in patients with newly diagnosed, treatment-naive SCC of the oral cavity. Routine clinical use of FDG PET/CT might lead to a substantial reduction of treatment-related morbidity in most patients.}, language = {en} } @article{LinzHohlLangetal.2021, author = {Linz, Benedikt and Hohl, Mathias and Lang, Lisa and Wong, Dickson W. L. and Nickel, Alexander G. and De La Torre, Carolina and Sticht, Carsten and Wirth, Klaus and Boor, Peter and Maack, Christoph and Speer, Thimoteus and Jespersen, Thomas and Schotten, Ulrich and Sanders, Prashanthan and B{\"o}hm, Michael and Linz, Dominik}, title = {Repeated exposure to transient obstructive sleep apnea-related conditions causes an atrial fibrillation substrate in a chronic rat model}, series = {Heart Rhythm}, volume = {18}, journal = {Heart Rhythm}, doi = {10.1016/j.hrthm.2020.10.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369298}, pages = {455-464}, year = {2021}, abstract = {Background High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways. Objective We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate. Methods INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2\% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS). Results INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0\% ± 0.5\% vs CTR 5.1\% ± 0.3\%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033). Conclusion Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development.}, language = {en} } @article{LinhoffSandrockKadleretal.2021, author = {Linhoff, Lena and Sandrock, Alexander and Kadler, Matthias and Els{\"a}sser, Dominik and Rhode, Wolfgang}, title = {Excluding possible sites of high-energy emission in 3C 84}, series = {Monthly Notices of the Royal Astronomical Society}, volume = {500}, journal = {Monthly Notices of the Royal Astronomical Society}, doi = {10.1093/mnras/staa3521}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369287}, pages = {4671-4677}, year = {2021}, abstract = {The FR-I galaxy 3C 84, that is identified with the misaligned blazar NGC 1275, is well known as one of the very few radio galaxies emitting gamma-rays in the TeV range. Yet, the gamma-ray emission region cannot be pinpointed and the responsible mechanisms are still unclear. We calculate the optical absorption depth of high-energy photons in the broad-line region of 3C 84 depending on their energy and distance to the central black hole. Based on these calculations, a lower limit on the distance of the emission region from the central black hole can be derived. These lower limits are estimated for two broad-line region geometries (shell and ring) and two states of the source, the low state in 2016 October-December and a flare state in 2017 January. For the shell geometry, we can place the emission region outside the Ly α radius. For the ring geometry and the low flux activity, the minimal distance between the black hole, and the gamma-ray emission region is close to the Ly α radius. In the case of the flaring state (ring geometry), the results are not conclusive. Our results exclude the region near the central black hole as the origin of the gamma-rays detected by Fermi-LAT and Major Atmospheric Gamma-Ray Imaging Cherenkov. With these findings, we can constrain the theoretical models of acceleration mechanisms and compare the possible emission region to the source's morphology resolved by radio images from the Very Long Baseline Array.}, language = {en} } @article{LiebersDuellFitzgeraldetal.2021, author = {Liebers, Nora and Duell, Johannes and Fitzgerald, Donnacha and Kerkhoff, Andrea and Noerenberg, Daniel and Kaebisch, Eva and Acker, Fabian and Fuhrmann, Stephan and Leng, Corinna and Welslau, Manfred and Chemnitz, Jens and Middeke, Jan-Moritz and Weber, Thomas and Holtick, Udo and Trappe, Ralf and Pfannes, Roald and Liersch, Ruediger and Spoer, Christian and Fuxius, Stefan and Gebauer, Niklas and Caill{\´e}, L{\´e}andra and Geer, Thomas and Koenecke, Christian and Keller, Ulrich and Claus, Rainer and Mougiakakos, Dimitrios and Mayer, Stephanie and Huettmann, Andreas and Pott, Christiane and Trummer, Arne and Wulf, Gerald and Brunnberg, Uta and Bullinger, Lars and Hess, Georg and Mueller-Tidow, Carsten and Glass, Bertram and Lenz, Georg and Dreger, Peter and Dietrich, Sascha}, title = {Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas}, series = {Blood Advances}, volume = {5}, journal = {Blood Advances}, doi = {10.1182/bloodadvances.2020004155}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369173}, pages = {2707-2716}, year = {2021}, abstract = {The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1\%. The 6-month progression-free survival and overall survival (OS) was 27.7\% and 49.6\%, respectively. In the bridging cohort, 51.2\% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9\% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40\%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.}, language = {en} } @article{LiangCostanzaPrutschetal.2021, author = {Liang, Huan-Chang and Costanza, Mariantonia and Prutsch, Nicole and Zimmerman, Mark W. and Gurnhofer, Elisabeth and Montes-Mojarro, Ivonne A. and Abraham, Brian J. and Prokoph, Nina and Stoiber, Stefan and Tangermann, Simone and Lobello, Cosimo and Oppelt, Jan and Anagnostopoulos, Ioannis and Hielscher, Thomas and Pervez, Shahid and Klapper, Wolfram and Zammarchi, Francesca and Silva, Daniel-Adriano and Garcia, K. Christopher and Baker, David and Janz, Martin and Schleussner, Nikolai and Fend, Falko and Posp{\´i}šilov{\´a}, Š{\´a}rka and Janikov{\´a}, Andrea and Wallwitz, Jacqueline and Stoiber, Dagmar and Simonitsch-Klupp, Ingrid and Cerroni, Lorenzo and Pileri, Stefano and de Leval, Laurence and Sibon, David and Fataccioli, Virginie and Gaulard, Philippe and Assaf, Chalid and Kn{\"o}rr, Fabian and Damm-Welk, Christine and Woessmann, Wilhelm and Turner, Suzanne D. and Look, A. Thomas and Mathas, Stephan and Kenner, Lukas and Merkel, Olaf}, title = {Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma}, series = {Nature Communications}, volume = {12}, journal = {Nature Communications}, doi = {10.1038/s41467-021-25379-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371581}, year = {2021}, abstract = {Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.}, language = {en} } @article{LiKuhnZukowskaKasprzyketal.2021, author = {Li, Yuanyue and Kuhn, Michael and Zukowska-Kasprzyk, Joanna and Hennrich, Marco L. and Kastritis, Panagiotis L. and O'Reilly, Francis J. and Phapale, Prasad and Beck, Martin and Gavin, Anne-Claude and Bork, Peer}, title = {Coupling proteomics and metabolomics for the unsupervised identification of protein-metabolite interactions in Chaetomium thermophilum}, series = {PLOS ONE}, volume = {16}, journal = {PLOS ONE}, doi = {10.1371/journal.pone.0254429}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364299}, year = {2021}, abstract = {Protein-metabolite interactions play an important role in the cell's metabolism and many methods have been developed to screen them in vitro. However, few methods can be applied at a large scale and not alter biological state. Here we describe a proteometabolomic approach, using chromatography to generate cell fractions which are then analyzed with mass spectrometry for both protein and metabolite identification. Integrating the proteomic and metabolomic analyses makes it possible to identify protein-bound metabolites. Applying the concept to the thermophilic fungus Chaetomium thermophilum, we predict 461 likely protein-metabolite interactions, most of them novel. As a proof of principle, we experimentally validate a predicted interaction between the ribosome and isopentenyl adenine.}, language = {en} } @article{LiSanchoChungetal.2021, author = {Li, Wenhong and Sancho, Ana and Chung, Wen-Lu and Vinik, Yaron and Groll, J{\"u}rgen and Zick, Yehiel and Medalia, Ohad and Bershadsky, Alexander D. and Benjamin, Geiger}, title = {Differential cellular responses to adhesive interactions with galectin-8- and fibronectin-coated substrates}, series = {Journal of Cell Science}, volume = {134}, journal = {Journal of Cell Science}, doi = {10.1242/jcs.252221}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364286}, year = {2021}, abstract = {The mechanisms underlying the cellular response to extracellular matrices (ECMs) that consist of multiple adhesive ligands are still poorly understood. Here, we address this topic by monitoring specific cellular responses to two different extracellular adhesion molecules - the main integrin ligand fibronectin and galectin-8, a lectin that binds β-galactoside residues - as well as to mixtures of the two proteins. Compared with cell spreading on fibronectin, cell spreading on galectin-8-coated substrates resulted in increased projected cell area, more-pronounced extension of filopodia and, yet, the inability to form focal adhesions and stress fibers. These differences can be partially reversed by experimental manipulations of small G-proteins of the Rho family and their downstream targets, such as formins, the Arp2/3 complex and Rho kinase. We also show that the physical adhesion of cells to galectin-8 was stronger than adhesion to fibronectin. Notably, galectin-8 and fibronectin differently regulate cell spreading and focal adhesion formation, yet act synergistically to upregulate the number and length of filopodia. The physiological significance of the coherent cellular response to a molecularly complex matrix is discussed. This article has an associated First Person interview with the first author of the paper.}, language = {en} } @article{LiStoecklLukasetal.2021, author = {Li, Shushan and St{\"o}ckl, Sabine and Lukas, Christoph and Herrmann, Marietta and Brochhausen, Christoph and K{\"o}nig, Matthias A. and Johnstone, Brian and Gr{\"a}ssel, Susanne}, title = {Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1β-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p}, series = {Stem Cell Research \& Therapy}, volume = {12}, journal = {Stem Cell Research \& Therapy}, doi = {10.1186/s13287-021-02317-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364237}, year = {2021}, abstract = {Background Curcumin has anti-inflammatory effects and qualifies as a potential candidate for the treatment of osteoarthritis (OA). However, curcumin has limited bioavailability. Extracellular vesicles (EVs) are released by multiple cell types and act as molecule carrier during intercellular communication. We assume that EVs can maintain bioavailability and stability of curcumin after encapsulation. Here, we evaluated modulatory effects of curcumin-primed human (h)BMSC-derived EVs (Cur-EVs) on IL-1β stimulated human osteoarthritic chondrocytes (OA-CH). Methods CellTiter-Blue Viability- (CTB), Caspase 3/7-, and live/dead assays were used to determine range of cytotoxic curcumin concentrations for hBMSC and OA-CH. Cur-EVs and control EVs were harvested from cell culture supernatants of hBMSC by ultracentrifugation. Western blotting (WB), transmission electron microscopy, and nanoparticle tracking analysis were performed to characterize the EVs. The intracellular incorporation of EVs derived from PHK26 labeled and curcumin-primed or control hBMSC was tested by adding the labeled EVs to OA-CH cultures. OA-CH were pre-stimulated with IL-1β, followed by Cur-EV and control EV treatment for 24 h and subsequent analysis of viability, apoptosis, and migration (scratch assay). Relative expression of selected anabolic and catabolic genes was assessed with qRT-PCR. Furthermore, WB was performed to evaluate phosphorylation of Erk1/2, PI3K/Akt, and p38MAPK in OA-CH. The effect of hsa-miR-126-3p expression on IL-1β-induced OA-CH was determined using CTB-, Caspase 3/7-, live/dead assays, and WB. Results Cur-EVs promoted viability and reduced apoptosis of IL-1β-stimulated OA-CH and attenuated IL-1β-induced inhibition of migration. Furthermore, Cur-EVs increased gene expression of BCL2, ACAN, SOX9, and COL2A1 and decreased gene expression of IL1B, IL6, MMP13, and COL10A1 in IL-1β-stimulated OA-CH. In addition, phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK, induced by IL-1β, is prevented by Cur-EVs. Cur-EVs increased IL-1β-reduced expression of hsa-miR-126-3p and hsa-miR-126-3p mimic reversed the effects of IL-1β. Conclusion Cur-EVs alleviated IL-1β-induced catabolic effects on OA-CH by promoting viability and migration, reducing apoptosis and phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK thereby modulating pro-inflammatory signaling pathways. Treatment of OA-CH with Cur-EVs is followed by upregulation of expression of hsa-miR-126-3p which is involved in modulation of anabolic response of OA-CH. EVs may be considered as promising drug delivery vehicles of curcumin helping to alleviate OA.}, language = {en} } @article{LiZhangFanetal.2021, author = {Li, Ming and Zhang, Rui and Fan, Guangyi and Xu, Wenteng and Zhou, Qian and Wang, Lei and Li, Wensheng and Pang, Zunfang and Yu, Mengjun and Liu, Qun and Liu, Xin and Schartl, Manfred and Chen, Songlin}, title = {Reconstruction of the Origin of a Neo-Y Sex Chromosome and Its Evolution in the Spotted Knifejaw, Oplegnathus punctatus}, series = {Molecular Biology and Evolution}, volume = {38}, journal = {Molecular Biology and Evolution}, doi = {10.1093/molbev/msab056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-364215}, pages = {2615-2626}, year = {2021}, abstract = {Sex chromosomes are a peculiar constituent of the genome because the evolutionary forces that fix the primary sex-determining gene cause genic degeneration and accumulation of junk DNA in the heterogametic partner. One of the most spectacular phenomena in sex chromosome evolution is the occurrence of neo-Y chromosomes, which lead to X1X2Y sex-determining systems. Such neo-sex chromosomes are critical for understanding the processes of sex chromosome evolution because they rejuvenate their total gene content. We assembled the male and female genomes at the chromosome level of the spotted knifejaw (Oplegnathus punctatus), which has a cytogenetically recognized neo-Y chromosome. The full assembly and annotation of all three sex chromosomes allowed us to reconstruct their evolutionary history. Contrary to other neo-Y chromosomes, the fusion to X2 is quite ancient, estimated at 48 Ma. Despite its old age and being even older in the X1 homologous region which carries a huge inversion that occurred as early as 55-48 Ma, genetic degeneration of the neo-Y appears to be only moderate. Transcriptomic analysis showed that sex chromosomes harbor 87 genes, which may serve important functions in the testis. The accumulation of such male-beneficial genes, a large inversion on the X1 homologous region and fusion to X2 appear to be the main drivers of neo-Y evolution in the spotted knifejaw. The availability of high-quality assemblies of the neo-Y and both X chromosomes make this fish an ideal model for a better understanding of the variability of sex determination mechanisms and of sex chromosome evolution.}, language = {en} } @article{LiNagyLiuetal.2021, author = {Li, Jinlin and Nagy, Noemi and Liu, Jiangnan and Gupta, Soham and Frisan, Teresa and Hennig, Thomas and Cameron, Donald P. and Baranello, Laura and Masucci, Maria G.}, title = {The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection}, series = {PLOS Pathogens}, volume = {17}, journal = {PLOS Pathogens}, doi = {10.1371/journal.ppat.1009954}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363841}, year = {2021}, abstract = {Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and deubiquitinated TOP2, and stabilized SUMOy-lated TOP2 trapped in cleavage complexes (TOP2ccs), which halted the DNA damage response to TOP2-induced double strand DNA breaks and promoted cell survival. Induction of the productive virus cycle in epithelial and lymphoid cell lines carrying recombinant EBV encoding the active enzyme was accompanied by TOP2 deubiquitination, accumulation of TOP2ccs and resistance to Etoposide toxicity. The protective effect of BPLF1 was dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair. These findings highlight a previously unrecognized function of BPLF1 in supporting a non-proteolytic pathway for TOP2ccs debulking that favors cell survival and virus production.}, language = {en} } @article{LiTrovatelloDalConteetal.2021, author = {Li, Donghai and Trovatello, Chiara and Dal Conte, Stefano and Nuß, Matthias and Soavi, Giancarlo and Wang, Gang and Ferrari, Andrea C. and Cerullo, Giulio and Brixner, Tobias}, title = {Exciton-phonon coupling strength in single-layer MoSe2 at room temperature}, series = {Nature Communications}, volume = {12}, journal = {Nature Communications}, doi = {10.1038/s41467-021-20895-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363837}, year = {2021}, abstract = {Single-layer transition metal dichalcogenides are at the center of an ever increasing research effort both in terms of fundamental physics and applications. Exciton-phonon coupling plays a key role in determining the (opto)electronic properties of these materials. However, the exciton-phonon coupling strength has not been measured at room temperature. Here, we use two-dimensional micro-spectroscopy to determine exciton-phonon coupling of single-layer MoSe2. We detect beating signals as a function of waiting time induced by the coupling between A excitons and A′1 optical phonons. Analysis of beating maps combined with simulations provides the exciton-phonon coupling. We get a Huang-Rhys factor ~1, larger than in most other inorganic semiconductor nanostructures. Our technique offers a unique tool to measure exciton-phonon coupling also in other heterogeneous semiconducting systems, with a spatial resolution ~260 nm, and provides design-relevant parameters for the development of optoelectronic devices.}, language = {en} } @article{LewisHabringerKircheretal.2021, author = {Lewis, Richard and Habringer, Stefan and Kircher, Malte and Hefter, Maike and Peuker, Caroline Anna and Werner, Rudolf and Ademaj-Kospiri, Val{\"e}za and G{\"a}ble, Alexander and Weber, Wolfgang and Wester, Hans-J{\"u}rgen and Buck, Andreas and Herhaus, Peter and Lapa, Constantin and Keller, Ulrich}, title = {Investigation of spleen CXCR4 expression by [68Ga]Pentixafor PET in a cohort of 145 solid cancer patients}, series = {EJNMMI Research}, volume = {11}, journal = {EJNMMI Research}, doi = {10.1186/s13550-021-00822-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363820}, year = {2021}, abstract = {Background The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([68Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed. Results We investigated the hypothesis that enhanced spleen [68Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [68Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [68Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [68Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [68Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer. Conclusion Spleen [68Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [68Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities.}, language = {en} } @article{LevitisGouldvan PraagGauetal.2021, author = {Levitis, Elizabeth and Gould van Praag, Cassandra D and Gau, R{\´e}mi and Heunis, Stephan and DuPre, Elizabeth and Kiar, Gregory and Bottenhorn, Katherine L and Glatard, Tristan and Nikolaidis, Aki and Whitaker, Kirstie Jane and Mancini, Matteo and Niso, Guiomar and Afyouni, Soroosh and Alonso-Ortiz, Eva and Appelhoff, Stefan and Arnatkeviciute, Aurina and Atay, Selim Melvin and Auer, Tibor and Baracchini, Giulia and Bayer, Johanna M M and Beauvais, Michael J S and Bijsterbosch, Janine D and Bilgin, Isil P and Bollmann, Saskia and Bollmann, Steffen and Botvinik-Nezer, Rotem and Bright, Molly G and Calhoun, Vince D and Chen, Xiao and Chopra, Sidhant and Chuan-Peng, Hu and Close, Thomas G and Cookson, Savannah L and Craddock, R Cameron and De La Vega, Alejandro and De Leener, Benjamin and Demeter, Damion V and Di Maio, Paola and Dickie, Erin W and Eickhoff, Simon B and Esteban, Oscar and Finc, Karolina and Frigo, Matteo and Ganesan, Saampras and Ganz, Melanie and Garner, Kelly G and Garza-Villarreal, Eduardo A and Gonzalez-Escamilla, Gabriel and Goswami, Rohit and Griffiths, John D and Grootswagers, Tijl and Guay, Samuel and Guest, Olivia and Handwerker, Daniel A and Herholz, Peer and Heuer, Katja and Huijser, Dorien C and Iacovella, Vittorio and Joseph, Michael J E and Karakuzu, Agah and Keator, David B and Kobeleva, Xenia and Kumar, Manoj and Laird, Angela R and Larson-Prior, Linda J and Lautarescu, Alexandra and Lazari, Alberto and Legarreta, Jon Haitz and Li, Xue-Ying and Lv, Jinglei and Mansour L., Sina and Meunier, David and Moraczewski, Dustin and Nandi, Tulika and Nastase, Samuel A and Nau, Matthias and Noble, Stephanie and Norgaard, Martin and Obungoloch, Johnes and Oostenveld, Robert and Orchard, Edwina R and Pinho, Ana Lu{\´i}sa and Poldrack, Russell A and Qiu, Anqi and Raamana, Pradeep Reddy and Rokem, Ariel and Rutherford, Saige and Sharan, Malvika and Shaw, Thomas B and Syeda, Warda T and Testerman, Meghan M and Toro, Roberto and Valk, Sofie L and Van Den Bossche, Sofie and Varoquaux, Ga{\"e}l and V{\´a}ša, František and Veldsman, Michele and Vohryzek, Jakub and Wagner, Adina S and Walsh, Reubs J and White, Tonya and Wong, Fu-Te and Xie, Xihe and Yan, Chao-Gan and Yang, Yu-Fang and Yee, Yohan and Zanitti, Gaston E and Van Gulick, Ana E and Duff, Eugene and Maumet, Camille}, title = {Centering inclusivity in the design of online conferences—An OHBM-Open Science perspective}, series = {GigaScience}, volume = {10}, journal = {GigaScience}, doi = {10.1093/gigascience/giab051}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371574}, pages = {1-14}, year = {2021}, abstract = {As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume.}, language = {en} } @article{LetunicBork2021, author = {Letunic, Ivica and Bork, Peer}, title = {Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic tree display and annotation}, series = {Nucleic Acids Research}, volume = {49}, journal = {Nucleic Acids Research}, doi = {10.1093/nar/gkab301}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363803}, pages = {W293-W296}, year = {2021}, abstract = {The Interactive Tree Of Life (https://itol.embl.de) is an online tool for the display, manipulation and annotation of phylogenetic and other trees. It is freely available and open to everyone. iTOL version 5 introduces a completely new tree display engine, together with numerous new features. For example, a new dataset type has been added (MEME motifs), while annotation options have been expanded for several existing ones. Node metadata display options have been extended and now also support non-numerical categorical values, as well as multiple values per node. Direct manual annotation is now available, providing a set of basic drawing and labeling tools, allowing users to draw shapes, labels and other features by hand directly onto the trees. Support for tree and dataset scales has been extended, providing fine control over line and label styles. Unrooted tree displays can now use the equal-daylight algorithm, proving a much greater display clarity. The user account system has been streamlined and expanded with new navigation options and currently handles >1 million trees from >70 000 individual users.}, language = {en} } @article{LeichSchrederPischimarovetal.2021, author = {Leich, Ellen and Schreder, Martin and Pischimarov, Jordan and St{\"u}hmer, Thorsten and Steinbrunn, Torsten and Rudelius, Martina and Br{\"u}nnert, Daniela and Chatterjee, Manik and Langer, Christian and Keppler, Sarah and Heredia-Guerrero, Sofia Catalina and Einsele, Hermann and Knop, Stefan and Bargou, Ralf Christian and Rosenwald, Andreas}, title = {Novel molecular subgroups within the context of receptor tyrosine kinase and adhesion signalling in multiple myeloma}, series = {Blood Cancer Journal}, volume = {11}, journal = {Blood Cancer Journal}, doi = {10.1038/s41408-021-00442-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363410}, year = {2021}, abstract = {No abstract available.}, language = {en} } @article{LeichMaierBombenetal.2021, author = {Leich, Ellen and Maier, Claudia and Bomben, Riccardo and Vit, Filippo and Bosi, Alessandro and Horn, Heike and Gattei, Valter and Ott, German and Rosenwald, Andreas and Zam{\`o}, Alberto}, title = {Follicular lymphoma subgroups with and without t(14;18) differ in their N-glycosylation pattern and IGHV usage}, series = {Blood Advances}, volume = {5}, journal = {Blood Advances}, doi = {10.1182/bloodadvances.2021005081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363378}, pages = {4890-4900}, year = {2021}, abstract = {We previously reported that t(14;18)-negative follicular lymphomas (FL) show a clear reduction of newly acquired N-glycosylation sites (NANGS) in immunoglobulin genes. We therefore aimed to investigate in-depth the occurrence of NANGS in a larger cohort of t(14;18)-positive and t(14;18)-negative FL, including early (I/II) and advanced (III/IV) stage treatment-naive and relapsed tumors. The clonotype was determined by using a next-generation sequencing approach in a series of 68 FL with fresh frozen material [36 t(14;18) positive and 32 t(14;18) negative]. The frequency of NANGS differed considerably between t(14;18)-positive and t(14;18)-negative FL stage III/IV, but no difference was observed among t(14;18)-positive and t(14;18)-negative FL stage I/II. The introduction of NANGS in all t(14;18)-negative clinical subgroups occurred significantly more often in the FR3 region. Moreover, t(14;18)-negative treatment-naive FL, specifically those with NANGS, showed a strong bias for IGHV4-34 usage compared with t(14;18)-positive treatment-naive cases with NANGS; IGHV4-34 usage was never recorded in relapsed FL. In conclusion, subgroups of t(14;18)-negative FL might use different mechanisms of B-cell receptor stimulation compared with the lectin-mediated binding described in t(14;18)-positive FL, including responsiveness to autoantigens as indicated by biased IGHV4-34 usage and strong NANGS enrichment in FR3.}, language = {en} } @article{LehnertPrausseHuennigeretal.2021, author = {Lehnert, Teresa and Prauße, Maria T. E. and H{\"u}nniger, Kerstin and Praetorius, Jan-Philipp and Kurzai, Oliver and Figge, Marc Thilo}, title = {Comparative assessment of immune evasion mechanisms in human whole-blood infection assays by a systems biology approach}, series = {PLOS ONE}, volume = {16}, journal = {PLOS ONE}, doi = {10.1371/journal.pone.0249372}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363343}, year = {2021}, abstract = {Computer simulations of mathematical models open up the possibility of assessing hypotheses generated by experiments on pathogen immune evasion in human whole-blood infection assays. We apply an interdisciplinary systems biology approach in which virtual infection models implemented for the dissection of specific immune mechanisms are combined with experimental studies to validate or falsify the respective hypotheses. Focusing on the assessment of mechanisms that enable pathogens to evade the immune response in the early time course of a whole-blood infection, the least-square error (LSE) as a measure for the quantitative agreement between the theoretical and experimental kinetics is combined with the Akaike information criterion (AIC) as a measure for the model quality depending on its complexity. In particular, we compare mathematical models with three different types of pathogen immune evasion as well as all their combinations: (i) spontaneous immune evasion, (ii) evasion mediated by immune cells, and (iii) pre-existence of an immune-evasive pathogen subpopulation. For example, by testing theoretical predictions in subsequent imaging experiments, we demonstrate that the simple hypothesis of having a subpopulation of pre-existing immune-evasive pathogens can be ruled out. Furthermore, in this study we extend our previous whole-blood infection assays for the two fungal pathogens Candida albicans and C. glabrata by the bacterial pathogen Staphylococcus aureus and calibrated the model predictions to the time-resolved experimental data for each pathogen. Our quantitative assessment generally reveals that models with a lower number of parameters are not only scored with better AIC values, but also exhibit lower values for the LSE. Furthermore, we describe in detail model-specific and pathogen-specific patterns in the kinetics of cell populations that may be measured in future experiments to distinguish and pinpoint the underlying immune mechanisms.}, language = {en} } @article{LehnertLeonhardtTimmeetal.2021, author = {Lehnert, Teresa and Leonhardt, Ines and Timme, Sandra and Thomas-R{\"u}ddel, Daniel and Bloos, Frank and Sponholz, Christoph and Kurzai, Oliver and Figge, Marc Thilo and H{\"u}nniger, Kerstin}, title = {Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, doi = {10.1038/s41598-021-91362-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363337}, year = {2021}, abstract = {The assessment of a patient's immune function is critical in many clinical situations. In complex clinical immune dysfunction like sepsis, which results from a loss of immune homeostasis due to microbial infection, a plethora of pro- and anti-inflammatory stimuli may occur consecutively or simultaneously. Thus, any immunomodulatory therapy would require in-depth knowledge of an individual patient's immune status at a given time. Whereas lab-based immune profiling often relies solely on quantification of cell numbers, we used an ex vivo whole-blood infection model in combination with biomathematical modeling to quantify functional parameters of innate immune cells in blood from patients undergoing cardiac surgery. These patients experience a well-characterized inflammatory insult, which results in mitigation of the pathogen-specific response patterns towards Staphylococcus aureus and Candida albicans that are characteristic of healthy people and our patients at baseline. This not only interferes with the elimination of these pathogens from blood, but also selectively augments the escape of C. albicans from phagocytosis. In summary, our model could serve as a valuable functional immune assay for recording and evaluating innate responses to infection.}, language = {en} } @article{LehmannJorgensenFratzetal.2021, author = {Lehmann, Julian and J{\o}rgensen, Morten E. and Fratz, Stefanie and M{\"u}ller, Heike M. and Kusch, Jana and Scherzer, S{\"o}nke and Navarro-Retamal, Carlos and Mayer, Dominik and B{\"o}hm, Jennifer and Konrad, Kai R. and Terpitz, Ulrich and Dreyer, Ingo and Mueller, Thomas D. and Sauer, Markus and Hedrich, Rainer and Geiger, Dietmar and Maierhofer, Tobias}, title = {Acidosis-induced activation of anion channel SLAH3 in the flooding-related stress response of Arabidopsis}, series = {Current Biology}, volume = {31}, journal = {Current Biology}, doi = {10.1016/j.cub.2021.06.018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363320}, pages = {3575-3585}, year = {2021}, abstract = {Plants, as sessile organisms, gained the ability to sense and respond to biotic and abiotic stressors to survive severe changes in their environments. The change in our climate comes with extreme dry periods but also episodes of flooding. The latter stress condition causes anaerobiosis-triggered cytosolic acidosis and impairs plant function. The molecular mechanism that enables plant cells to sense acidity and convey this signal via membrane depolarization was previously unknown. Here, we show that acidosis-induced anion efflux from Arabidopsis (Arabidopsis thaliana) roots is dependent on the S-type anion channel AtSLAH3. Heterologous expression of SLAH3 in Xenopus oocytes revealed that the anion channel is directly activated by a small, physiological drop in cytosolic pH. Acidosis-triggered activation of SLAH3 is mediated by protonation of histidine 330 and 454. Super-resolution microscopy analysis showed that the increase in cellular proton concentration switches SLAH3 from an electrically silent channel dimer into its active monomeric form. Our results show that, upon acidification, protons directly switch SLAH3 to its open configuration, bypassing kinase-dependent activation. Moreover, under flooding conditions, the stress response of Arabidopsis wild-type (WT) plants was significantly higher compared to SLAH3 loss-of-function mutants. Our genetic evidence of SLAH3 pH sensor function may guide the development of crop varieties with improved stress tolerance.}, language = {en} }