@article{LiLiLinketal.2019, author = {Li, Shan and Li, Xin and Link, Roman and Li, Ren and Deng, Liping and Schuldt, Bernhard and Jiang, Xiaomei and Zhao, Rongjun and Zheng, Jingming and Li, Shuang and Yin, Yafang}, title = {Influence of cambial age and axial height on the spatial patterns of xylem traits in Catalpa bungei, a ring-porous tree species native to China}, series = {Forests}, volume = {10}, journal = {Forests}, number = {8}, issn = {1999-4907}, doi = {10.3390/f10080662}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196297}, year = {2019}, abstract = {Studying how cambial age and axial height affects wood anatomical traits may improve our understanding of xylem hydraulics, heartwood formation and axial growth. Radial strips were collected from six different heights (0-11.3 m) along the main trunk of three Manchurian catalpa (Catalpa bungei) trees, yielding 88 samples. In total, thirteen wood anatomical vessel and fiber traits were observed usinglight microscopy (LM) and scanning electron microscopy (SEM), and linear models were used to analyse the combined effect of axial height, cambial age and their interaction. Vessel diameter differed by about one order of magnitude between early- and latewood, and increased significantly with both cambial age and axial height in latewood, while it was positively affected by cambial age and independent of height in earlywood. Vertical position further had a positive effect on earlywood vessel density, and negative effects on fibre wall thickness, wall thickness to diameter ratio and length. Cambial age had positive effects on the pit membrane diameter and vessel element length, while the annual diameter growth decreased with both cambial age and axial position. In contrast, early- and latewood fiber diameter were unaffected by both cambial age and axial height. We further observed an increasing amount of tyloses from sapwood to heartwood, accompanied by an increase of warty layers and amorphous deposits on cell walls, bordered pit membranes and pit apertures. This study highlights the significant effects of cambial age and vertical position on xylem anatomical traits, and confirms earlier work that cautions to take into account xylem spatial position when interpreting wood anatomical structures, and thus, xylem hydraulic functioning.}, language = {en} } @article{ZhaoYuHuetal.2015, author = {Zhao, De-Wei and Yu, Mang and Hu, Kai and Wang, Wei and Yang, Lei and Wang, Ben-Jie and Gao, Xiao-Hong and Guo, Yong-Ming and Xu, Yong-Qing and Wei, Yu-Shan and Tian, Si-Miao and Yang, Fan and Wang, Nan and Huang, Shi-Bo and Xie, Hui and Wei, Xiao-Wei and Jiang, Hai-Shen and Zang, Yu-Qiang and Ai, Jun and Chen, Yuan-Liang and Lei, Guang-Hua and Li, Yu-Jin and Tian, Geng and Li, Zong-Sheng and Cao, Yong and Ma, Li}, title = {Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey}, series = {Chinese Medical Journal}, volume = {128}, journal = {Chinese Medical Journal}, number = {21}, doi = {10.4103/0366-6999.168017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-138482}, pages = {2843-2850}, year = {2015}, abstract = {Background: Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating disease that represents a significant financial burden for both individuals and healthcare systems. Despite its significance, however, its prevalence in the Chinese general population remains unknown. This study aimed to investigate the prevalence of NONFH and its associated risk factors in the Chinese population. Methods: A nationally representative survey of 30,030 respondents was undertaken from June 2012 to August 2013. All participants underwent a questionnaire investigation, physical examination of hip, and bilateral hip joint X-ray and/or magnetic resonance imaging examination. Blood samples were taken after overnight fasting to test serum total cholesterol, triglyceride, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels. We then used multivariate logistic regression analysis to investigate the associations between various metabolic, demographic, and lifestyle-related variables and NONFH. Results: NONFH was diagnosed in 218 subjects (0.725\%) and the estimated NONFH cases were 8.12 million among Chinese people aged 15 years and over. The prevalence of NONFH was significantly higher in males than in females (1.02\% vs. 0.51\%, \(\chi^2\) = 24.997, P < 0.001). Among NONFH patients, North residents were subjected to higher prevalence of NONFH than that of South residents (0.85\% vs. 0.61\%, \(\chi^2\) = 5.847, P = 0.016). Our multivariate regression analysis showed that high blood levels of triglycerides, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol, male, urban residence, family history of osteonecrosis of the femoral head, heavy smoking, alcohol abuse and glucocorticoid intake, overweight, and obesity were all significantly associated with an increased risk of NONFH. Conclusions: Our findings highlight that NONFH is a significant public health challenge in China and underscore the need for policy measures on the national level. Furthermore, NONFH shares a number of risk factors with atherosclerosis.}, language = {en} } @article{YanHongChenetal.2013, author = {Yan, Yan and Hong, Ni and Chen, Tiansheng and Li, Mingyou and Wang, Tiansu and Guan, Guijun and Qiao, Yongkang and Chen, Songlin and Schartl, Manfred and Li, Chang-Ming and Hong, Yunhan}, title = {p53 Gene Targeting by Homologous Recombination in Fish ES Cells}, series = {PLoS One}, volume = {8}, journal = {PLoS One}, number = {3}, doi = {10.1371/journal.pone.0059400}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133416}, pages = {e59400}, year = {2013}, abstract = {Background: Gene targeting (GT) provides a powerful tool for the generation of precise genetic alterations in embryonic stem (ES) cells to elucidate gene function and create animal models for human diseases. This technology has, however, been limited to mouse and rat. We have previously established ES cell lines and procedures for gene transfer and selection for homologous recombination (HR) events in the fish medaka (Oryzias latipes). Methodology and Principal Findings: Here we report HR-mediated GT in this organism. We designed a GT vector to disrupt the tumor suppressor gene p53 (also known as tp53). We show that all the three medaka ES cell lines, MES1 similar to MES3, are highly proficient for HR, as they produced detectable HR without drug selection. Furthermore, the positive-negative selection (PNS) procedure enhanced HR by similar to 12 folds. Out of 39 PNS-resistant colonies analyzed, 19 (48.7\%) were positive for GT by PCR genotyping. When 11 of the PCR-positive colonies were further analyzed, 6 (54.5\%) were found to be bona fide homologous recombinants by Southern blot analysis, sequencing and fluorescent in situ hybridization. This produces a high efficiency of up to 26.6\% for p53 GT under PNS conditions. We show that p53 disruption and long-term propagation under drug selection conditions do not compromise the pluripotency, as p53-targeted ES cells retained stable growth, undifferentiated phenotype, pluripotency gene expression profile and differentiation potential in vitro and in vivo. Conclusions: Our results demonstrate that medaka ES cells are proficient for HR-mediated GT, offering a first model organism of lower vertebrates towards the development of full ES cell-based GT technology.}, language = {en} } @article{HuangBelharazemLietal.2013, author = {Huang, Bei and Belharazem, Djeda and Li, Li and Kneitz, Susanne and Schnabel, Philipp A. and Rieker, Ralf J. and K{\"o}rner, Daniel and Nix, Wilfried and Schalke, Berthold and M{\"u}ller-Hermelink, Hans Konrad and Ott, German and Rosenwald, Andreas and Str{\"o}bel, Philipp and Marx, Alexander}, title = {Anti-apoptotic signature in thymic squamous cell carcinomas - functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c}, series = {Frontiers in Oncology}, volume = {3}, journal = {Frontiers in Oncology}, number = {316}, doi = {10.3389/fonc.2013.00316}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132214}, year = {2013}, abstract = {The molecular pathogenesis of thymomas and thymic arcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important.This made us re-analyze historic expression data obtained in a spectrumof thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.}, language = {en} } @article{CarstenAGorskiLietal.2011, author = {Carsten A., B{\"o}ger and Gorski, Mathias and Li, Man and Hoffmann, Michael M. and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O'Seaghdha, Conall M. and Kutalik, Zolt{\´a}n and Wichmann, H.-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G. and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andr{\´e} and Hofman, Albert and Beckmann, Jacques S. and Kr{\"a}mer, Bernhard K. and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I. and Heid, Iris M. and Fox, Caroline S. and Kao, W.H.}, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD}, series = {PLoS Genetics}, volume = {7}, journal = {PLoS Genetics}, number = {9}, doi = {10.1371/journal.pgen.1002292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133758}, pages = {e1002292}, year = {2011}, abstract = {Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.}, language = {en} } @article{QiuHeLietal.1993, author = {Qiu, Yueming and He, Li and Li, Jie and Yuan, Shixin and Becker, Charles R. and Landwehr, G.}, title = {Infrared photoconductor fabricated with HgTe/CdTe superlattice grown by molecular beam epitaxy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-37772}, year = {1993}, abstract = {An infrared photoconductor fabricated with a HgTe/CdTe superlattice grown on a GaAs substrate by molecular beam epitaxy is described here for the first time. The growth procedure, device fabrication, and measurement results are described. The results show that the device has relatively high uniformity and 1000 K black-body detectivity 2.4 X 10\(^9\) cm Hz\(^{1/2}\) W\(^{-1}\) . The photoconductivity decay method was used for determining carrier lifetime of the HgTe/CdTe superlattice, the measured lifetime is 12\(\mu\)s at 77 K, which is the longest lifetime ever reported for HgTe/CdTe superlattices and we believe that the increase of lifetime is mainly due to the reduction of dimensions.}, language = {en} } @article{MuellerFiebigWeidaueretal.2013, author = {Mueller, Thomas D. and Fiebig, Juliane E. and Weidauer, Stella E. and Qiu, Li-Yan and Bauer, Markus and Schmieder, Peter and Beerbaum, Monika and Zhang, Jin-Li and Oschkinat, Hartmut and Sebald, Walter}, title = {The Clip-Segment of the von Willebrand Domain 1 of the BMP Modulator Protein Crossveinless 2 Is Preformed}, series = {Molecules}, journal = {Molecules}, doi = {10.3390/molecules181011658}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97196}, year = {2013}, abstract = {Bone Morphogenetic Proteins (BMPs) are secreted protein hormones that act as morphogens and exert essential roles during embryonic development of tissues and organs. Signaling by BMPs occurs via hetero-oligomerization of two types of serine/threonine kinase transmembrane receptors. Due to the small number of available receptors for a large number of BMP ligands ligand-receptor promiscuity presents an evident problem requiring additional regulatory mechanisms for ligand-specific signaling. Such additional regulation is achieved through a plethora of extracellular antagonists, among them members of the Chordin superfamily, that modulate BMP signaling activity by binding. The key-element in Chordin-related antagonists for interacting with BMPs is the von Willebrand type C (VWC) module, which is a small domain of about 50 to 60 residues occurring in many different proteins. Although a structure of the VWC domain of the Chordin-member Crossveinless 2 (CV2) bound to BMP-2 has been determined by X-ray crystallography, the molecular mechanism by which the VWC domain binds BMPs has remained unclear. Here we present the NMR structure of the Danio rerio CV2 VWC1 domain in its unbound state showing that the key features for high affinity binding to BMP-2 is a pre-oriented peptide loop.}, language = {en} } @article{YangYaoLietal.2022, author = {Yang, Xuting and Yao, Wanqiang and Li, Pengfei and Hu, Jinfei and Latifi, Hooman and Kang, Li and Wang, Ningjing and Zhang, Dingming}, title = {Changes of SOC content in China's Shendong coal mining area during 1990-2020 investigated using remote sensing techniques}, series = {Sustainability}, volume = {14}, journal = {Sustainability}, number = {12}, issn = {2071-1050}, doi = {10.3390/su14127374}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278939}, year = {2022}, abstract = {Coal mining, an important human activity, disturbs soil organic carbon (SOC) accumulation and decomposition, eventually affecting terrestrial carbon cycling and the sustainability of human society. However, changes of SOC content and their relation with influential factors in coal mining areas remained unclear. In the study, predictive models of SOC content were developed based on field sampling and Landsat images for different land-use types (grassland, forest, farmland, and bare land) of the largest coal mining area in China (i.e., Shendong). The established models were employed to estimate SOC content across the Shendong mining area during 1990-2020, followed by an investigation into the impacts of climate change and human disturbance on SOC content by a Geo-detector. Results showed that the models produced satisfactory results (R\(^2\) > 0.69, p < 0.05), demonstrating that SOC content over a large coal mining area can be effectively assessed using remote sensing techniques. Results revealed that average SOC content in the study area rose from 5.67 gC·kg\(^{-1}\) in 1990 to 9.23 gC·kg\(^{-1}\) in 2010 and then declined to 5.31 gC·Kg\(^{-1}\) in 2020. This could be attributed to the interaction between the disturbance of soil caused by coal mining and the improvement of eco-environment by land reclamation. Spatially, the SOC content of farmland was the highest, followed by grassland, and that of bare land was the lowest. SOC accumulation was inhibited by coal mining activities, with the effect of high-intensity mining being lower than that of moderate- and low-intensity mining activities. Land use was found to be the strongest individual influencing factor for SOC content changes, while the interaction between vegetation coverage and precipitation exerted the most significant influence on the variability of SOC content. Furthermore, the influence of mining intensity combined with precipitation was 10 times higher than that of mining intensity alone.}, language = {en} } @article{ZhangZhengZhengetal.2019, author = {Zhang, Yonghong and Zheng, Lanlan and Zheng, Yan and Zhou, Chao and Huang, Ping and Xiao, Xiao and Zhao, Yongheng and Hao, Xincai and Hu, Zhubing and Chen, Qinhua and Li, Hongliang and Wang, Xuanbin and Fukushima, Kenji and Wang, Guodong and Li, Chen}, title = {Assembly and Annotation of a Draft Genome of the Medicinal Plant Polygonum cuspidatum}, series = {Frontiers in Plant Science}, volume = {10}, journal = {Frontiers in Plant Science}, issn = {1664-462X}, doi = {10.3389/fpls.2019.01274}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189279}, pages = {1274}, year = {2019}, abstract = {Polygonum cuspidatum (Japanese knotweed, also known as Huzhang in Chinese), a plant that produces bioactive components such as stilbenes and quinones, has long been recognized as important in traditional Chinese herbal medicine. To better understand the biological features of this plant and to gain genetic insight into the biosynthesis of its natural products, we assembled a draft genome of P. cuspidatum using Illumina sequencing technology. The draft genome is ca. 2.56 Gb long, with 71.54\% of the genome annotated as transposable elements. Integrated gene prediction suggested that the P. cuspidatum genome encodes 55,075 functional genes, including 6,776 gene families that are conserved in the five eudicot species examined and 2,386 that are unique to P. cuspidatum. Among the functional genes identified, 4,753 are predicted to encode transcription factors. We traced the gene duplication history of P. cuspidatum and determined that it has undergone two whole-genome duplication events about 65 and 6.6 million years ago. Roots are considered the primary medicinal tissue, and transcriptome analysis identified 2,173 genes that were expressed at higher levels in roots compared to aboveground tissues. Detailed phylogenetic analysis demonstrated expansion of the gene family encoding stilbene synthase and chalcone synthase enzymes in the phenylpropanoid metabolic pathway, which is associated with the biosynthesis of resveratrol, a pharmacologically important stilbene. Analysis of the draft genome identified 7 abscisic acid and water deficit stress-induced protein-coding genes and 14 cysteine-rich transmembrane module genes predicted to be involved in stress responses. The draft de novo genome assembly produced in this study represents a valuable resource for the molecular characterization of medicinal compounds in P. cuspidatum, the improvement of this important medicinal plant, and the exploration of its abiotic stress resistance.}, language = {en} } @article{MitchellLiWeinholdetal.2016, author = {Mitchell, Jonathan S. and Li, Ni and Weinhold, Niels and F{\"o}rsti, Asta and Ali, Mina and van Duin, Mark and Thorleifsson, Gudmar and Johnson, David C. and Chen, Bowang and Halvarsson, Britt-Marie and Gudbjartsson, Daniel F. and Kuiper, Rowan and Stephens, Owen W. and Bertsch, Uta and Broderick, Peter and Campo, Chiara and Einsele, Hermann and Gregory, Walter A. and Gullberg, Urban and Henrion, Marc and Hillengass, Jens and Hoffmann, Per and Jackson, Graham H. and Johnsson, Ellinor and J{\"o}ud, Magnus and Kristinsson, Sigurdur Y. and Lenhoff, Stig and Lenive, Oleg and Mellqvist, Ulf-Henrik and Migliorini, Gabriele and Nahi, Hareth and Nelander, Sven and Nickel, Jolanta and N{\"o}then, Markus M. and Rafnar, Thorunn and Ross, Fiona M. and da Silva Filho, Miguel Inacio and Swaminathan, Bhairavi and Thomsen, Hauke and Turesson, Ingemar and Vangsted, Annette and Vogel, Ulla and Waage, Anders and Walker, Brian A. and Wihlborg, Anna-Karin and Broyl, Annemiek and Davies, Faith E. and Thorsteinsdottir, Unnur and Langer, Christian and Hansson, Markus and Kaiser, Martin and Sonneveld, Pieter and Stefansson, Kari and Morgan, Gareth J. and Goldschmidt, Hartmut and Hemminki, Kari and Nilsson, Bj{\"o}rn and Houlston, Richard S.}, title = {Genome-wide association study identifies multiple susceptibility loci for multiple myeloma}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms12050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165983}, pages = {12050}, year = {2016}, abstract = {Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10-8), 6q21 (rs9372120, P=9.09 × 10-15), 7q36.1 (rs7781265, P=9.71 × 10-9), 8q24.21 (rs1948915, P=4.20 × 10-11), 9p21.3 (rs2811710, P=1.72 × 10-13), 10p12.1 (rs2790457, P=1.77 × 10-8), 16q23.1 (rs7193541, P=5.00 × 10-12) and 20q13.13 (rs6066835, P=1.36 × 10-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.}, language = {en} } @article{LiWinklerPabstetal.2015, author = {Li, Mengxia and Winkler, Beate and Pabst, Thomas and Bley, Thorsten and K{\"o}stler, Herbert and Neubauer, Henning}, title = {Fast MR Imaging of the paediatric abdomen with CAIPIRINHA-accelerated T1w 3D FLASH and with high-resolution T2w HASTE: a study on image quality}, series = {Gastroenterology Research and Practice}, volume = {2015}, journal = {Gastroenterology Research and Practice}, number = {693654}, doi = {10.1155/2015/693654}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149217}, year = {2015}, abstract = {The aim of this study was to explore the applicability of fast MR techniques to routine paediatric abdominopelvic MRI at 1.5 Tesla. "Controlled Aliasing in Parallel Imaging Results in Higher Acceleration-" (CAIPIRINHA-) accelerated contrast-enhanced-T1w 3D FLASH imaging was compared to standard T1w 2D FLASH imaging with breath-holding in 40 paediatric patients and to respiratory-triggered T1w TSE imaging in 10 sedated young children. In 20 nonsedated patients, we compared T2w TIRM to fat-saturated T2w HASTE imaging. Two observers performed an independent and blinded assessment of overall image quality. Acquisition time was reduced by the factor of 15 with CAIPIRINHA-accelerated T1w FLASH and by 7 with T2w HASTE. With CAIPIRINHA and with HASTE, there were significantly less motion artefacts in nonsedated patients. In sedated patients, respiratory-triggered T1w imaging in general showed better image quality. However, satisfactory image quality was achieved with CAIPIRINHA in two sedated patients where respiratory triggering failed. In summary, fast scanning with CAIPIRINHA and HASTE presents a reliable high quality alternative to standard sequences in paediatric abdominal MRI. Paediatric patients, in particular, benefit greatly from fast image acquisition with less breath-hold cycles or shorter sedation.}, language = {en} } @article{SacepeOostingaLietal.2011, author = {Sac{\´e}p{\´e}, Benjamin and Oostinga, Jeroen B. and Li, Jian and Ubaldini, Alberto and Couto, Nuno J. G. and Giannini, Enrico and Morpurgo, Alberto F.}, title = {Gate-tuned normal and superconducting transport at the surface of a topological insulator}, series = {Nature Communications}, volume = {2}, journal = {Nature Communications}, doi = {10.1038/ncomms1586}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140175}, pages = {575, 1-7}, year = {2011}, abstract = {Three-dimensional topological insulators are characterized by the presence of a bandgap in their bulk and gapless Dirac fermions at their surfaces. New physical phenomena originating from the presence of the Dirac fermions are predicted to occur, and to be experimentally accessible via transport measurements in suitably designed electronic devices. Here we study transport through superconducting junctions fabricated on thin Bi2Se3 single crystals, equipped with a gate electrode. In the presence of perpendicular magnetic field B, sweeping the gate voltage enables us to observe the filling of the Dirac fermion Landau levels, whose character evolves continuously from electron- to hole-like. When B=0, a supercurrent appears, whose magnitude can be gate tuned, and is minimum at the charge neutrality point determined from the Landau level filling. Our results demonstrate how gated nano-electronic devices give control over normal and superconducting transport of Dirac fermions at an individual surface of a three-dimensional topological insulators.}, language = {en} } @article{IyengarSedorFreedmanetal.2015, author = {Iyengar, Sudha K. and Sedor, John R. and Freedman, Barry I. and Kao, W. H. Linda and Kretzler, Matthias and Keller, Benjamin J. and Abboud, Hanna E. and Adler, Sharon G. and Best, Lyle G. and Bowden, Donald W. and Burlock, Allison and Chen, Yii-Der Ida and Cole, Shelley A. and Comeau, Mary E. and Curtis, Jeffrey M. and Divers, Jasmin and Drechsler, Christiane and Duggirala, Ravi and Elston, Robert C. and Guo, Xiuqing and Huang, Huateng and Hoffmann, Michael Marcus and Howard, Barbara V. and Ipp, Eli and Kimmel, Paul L. and Klag, Michael J. and Knowler, William C. and Kohn, Orly F. and Leak, Tennille S. and Leehey, David J. and Li, Man and Malhotra, Alka and M{\"a}rz, Winfried and Nair, Viji and Nelson, Robert G. and Nicholas, Susanne B. and O'Brien, Stephen J. and Pahl, Madeleine V. and Parekh, Rulan S. and Pezzolesi, Marcus G. and Rasooly, Rebekah S. and Rotimi, Charles N. and Rotter, Jerome I. and Schelling, Jeffrey R. and Seldin, Michael F. and Shah, Vallabh O. and Smiles, Adam M. and Smith, Michael W. and Taylor, Kent D. and Thameem, Farook and Thornley-Brown, Denyse P. and Truitt, Barbara J. and Wanner, Christoph and Weil, E. Jennifer and Winkler, Cheryl A. and Zager, Philip G. and Igo, Jr, Robert P. and Hanson, Robert L. and Langefeld, Carl D.}, title = {Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: Family Investigation of Nephropathy and Diabetes (FIND)}, series = {PLoS Genetics}, volume = {11}, journal = {PLoS Genetics}, number = {8}, doi = {10.1371/journal.pgen.1005352}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180545}, pages = {e1005352}, year = {2015}, abstract = {Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45\% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10\(^{-9}\)). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10\(^{-8}\)), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.}, language = {en} } @article{ZhangWuLietal.2015, author = {Zhang, Xin and Wu, Wei and Li, Gang and Wen, Lin and Sun, Qing and Ji, An-Chun}, title = {Phase diagram of interacting Fermi gas in spin-orbit coupled square lattices}, series = {New Journal of Physics}, volume = {17}, journal = {New Journal of Physics}, number = {073036}, doi = {10.1088/1367-2630/17/7/073036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151475}, year = {2015}, abstract = {The spin-orbit (SO) coupled optical lattices have attracted considerable interest. In this paper, we investigate the phase diagram of the interacting Fermi gas with Rashba-type spin-orbit coupling (SOC) on a square optical lattice. The phase diagram is investigated in a wide range of atomic interactions and SOC strength within the framework of the cluster dynamical mean-field theory (CDMFT). We show that the interplay between the atomic interactions and SOC results in a rich phase diagram. In the deep Mott insulator regime, the SOC can induce diverse spin ordered phases. Whereas near the metal-insulator transition (MIT), the SOC tends to destroy the conventional antiferromagnetic fluctuations, giving rise to distinctive features of the MIT. Furthermore, the strong fluctuations arising from SOC may destroy the magnetic orders and trigger an order to disorder transition in close proximity of the MIT.}, language = {en} } @article{LiYanThomaleetal.2015, author = {Li, Gang and Yan, Binghai and Thomale, Ronny and Hanke, Werner}, title = {Topological nature and the multiple Dirac cones hidden in Bismuth high-Tc superconductors}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {10435}, doi = {10.1038/srep10435}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148569}, year = {2015}, abstract = {Recent theoretical studies employing density-functional theory have predicted BaBiO\(_{3}\) (when doped with electrons) and YBiO\(_{3}\) to become a topological insulator (TI) with a large topological gap (~0.7 eV). This, together with the natural stability against surface oxidation, makes the Bismuth-Oxide family of special interest for possible applications in quantum information and spintronics. The central question, we study here, is whether the hole-doped Bismuth Oxides, i.e. Ba\(_{1-X}\)K\(_{X}\)BiO\(_{3}\) and BaPb\(_{1-X}\)Bi\(_{X}\)O\(_{3}\), which are "high-Tc" bulk superconducting near 30 K, additionally display in the further vicinity of their Fermi energy E\(_{F}\) a topological gap with a Dirac-type of topological surface state. Our electronic structure calculations predict the K-doped family to emerge as a TI, with a topological gap above E\(_{F}\). Thus, these compounds can become superconductors with hole-doping and potential TIs with additional electron doping. Furthermore, we predict the Bismuth-Oxide family to contain an additional Dirac cone below E\(_{F}\) for further hole doping, which manifests these systems to be candidates for both electron-and hole-doped topological insulators.}, language = {en} } @article{FreyHoubenBroecker2010, author = {Frey, Li­dia M. and Houben, Roland and Br{\"o}cker, Eva-B.}, title = {Pigmentation, Melanocyte Colonization, and p53 Status in Basal Cell Carcinoma}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68283}, year = {2010}, abstract = {Basal cell carcinoma (BCC) is the most common neoplasm in the Caucasian population. Only a fraction of BCC exhibits pigmentation. Lack of melanocyte colonization has been suggested to be due to p53-inactivating mutations in the BCC cells interfering with the p53-proopiomelanocortin pathway and the production of alpha melanocyte-stimulating hormone in the tumor. To evaluate this, we determined tumor pigmentation as well as expression of melan-A and of p53 in 49 BCC tissues bymeans of immunohistochemistry. As expected, we observed a positive relation between tumor pigmentation and melan-A positive intratumoral melanocytes.Melanocyte colonization and, to a lesser extent, p53 overexpression showed intraindividual heterogeneity in larger tumors. p53 overexpression, which is indicative of p53 mutations, was not correlated to melanocyte colonization of BCC. Sequencing of exon 5-8 of the p53 gene in selected BCC cases revealed that colonization by melanocytes and BCC pigmentation is neither ablated by p53 mutations nor generally present in BCCs with wild-type p53.}, subject = {Medizin}, language = {en} } @article{SirenHeldmanDoronetal.1992, author = {Sir{\´e}n, Anna-Leena and Heldman, Eliahu and Doron, David and Yue, Tian-Li and Liu, Yong and Feuerstein, G. and Hallenbeck, JM}, title = {Release of proinflammatory and prothrombbtic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive Wistar-Kyoto rats}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47469}, year = {1992}, abstract = {Background and Purpose: We reported previously that stroke risk factors prepared the brain stem for the development of ischemia and hemorrhage and induced the production of tumor necrosis factor following an intrathecal injection of Iipopolysaccharide, a prototypic monocyte-activating stimulus. This study evaluates whether blood or brain cells of hypertensive rats produce more proinflammatory and prothrombotic mediators than do blood or brain cells of normotensive rats. MethotJs: Levels of tumor necrosis factor, platelet-activating factor, 6-ketoprostaglandin F1a, and thromboxane B2 in the cerebrospinal fluid and blood of spontaneously hypertensive and normotensive Wistar-Kyoto rats were monitored before and after achallenge with Iipopolysaccharide. Results: Little or no activity from these media tors was found in the cerebrospinal fluid or blood of saline-injected control animals. Intravenous administration of Iipopolysaccharide (0.001, 0.1, and 1.8 mg/kg) produced dose-dependent increases in blood levels of all mediators in hypertensive rats. In normotensive rats the levels were less than in hypertensive rats and were not c1early dose-related. When Iipopolysaccharide was injected intracerebroventricularly, more tumor necrosis factor was measured in the cerebrospinal fluid than in the blood, suggesting local synthesis of this cytokine. Levels of tumor necrosis factor and platelet-activating factor in the cerebrospinal fluid were higher in hypertensive than in normotensive rats. The thromboxane A2/prostacyclin ratio was not aItered significantly between the two rat strains. Conclusions: It is suggested that the higher incidence of brain stem ischemia and hemorrhage after the intrathecal injection oflipopolysaccharide in hypertensive rats than in normotensive rats might be related to the higher levels of the two cytotoxic factors tumor necrosis factor and platelet-activating factor produced in response to such challenge.}, subject = {Gehirn}, language = {en} } @article{LeschStoeberBallingetal.1994, author = {Lesch, K. P. and St{\"o}ber, Gerald and Balling, U. and Franzek, Ernst and Li, S. H. and Ross, C. A. and Newman, M. and Beckmann, H. and Riederer, P.}, title = {Triplet repeats in clinical subtypes of schizophrenia: variation at the DRPLA (B37 CAG repeat) locus is not associated with periodic catatonia}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63369}, year = {1994}, abstract = {Clinical evidence for a dominant mode of inheritance and anticipation in periodic catatonia, a distinct subtype of schizophrenia, indicates that genes with triplet repeat expansions or other unstable repetitive elements affecting gene expression may be involved in the etiology of this disorder. Because patients affected with dentatorubral-pallidoluysian atrophy (DRPLA) may present with "schizophrenic" symptoms, we have investigated the DRPLA (B 37 CAG repeat) locus on chromosome 12 in 41 patients with periodic catatonia. The B 37 CAG repeat locus was highly polymorphic but all alleles in both the patient and control group had repeat sizes within the normal range. We conclude that variation at the DRPLA locus is unlikely to be associated with periodic catatonia. The evidence for dominant inheritance and anticipation as well as the high prevalence of human brain genes containing trinucleotide repeats justifies further screening for triplet repeat expansions in periodic catatonia.}, subject = {Schizophrenie}, language = {en} } @phdthesis{Li2015, author = {Li, Han}, title = {Fabrication of Carbon Nanotube Thin Films by Evaporation-Induced Self-Assembly}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123407}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {159}, year = {2015}, abstract = {In summary, we have prepared single-wall carbon nanotube (SWNT) thin films by the method of evaporation-induced self-assembly (EISA). Using the scalable two-plate or lens setups, sorts of different film types or patterns of SWNTs has been successfully fabricated directly from the evaporation of solvents and could be precisely controlled by the concentrations of SWNT in ambient conditions. The special geometry of meniscus as the capillary bridge has not only given rise to a much higher efficiency of fabrication than what previously reported but also allowed us to monitor the pinning and depinning process carefully and further investigate the mechanism underlying the formation of different film morphologies. In contrast with the conventional "stick-slip" model, we have provided the new dynamical pinning and zipping model for the contact line (CL) behavior. By analyzing the motion of CL and varying deposited patterns, the traditionally so-called "stick" state should be treated as a dynamical pinning process due to the interfacial tension contrast between SWNT-covered and bare silicon surface. Besides, the plausible one-step "slip" motion could be dominated by the zipping-like kink propagation. In addition, the experiments with heated substrates at higher temperatures between 30°C and 50 °C have shown that the striped pattern could be fabricated by both much lower SWNT and SDS concentrations than that in room temperature, which is consistent with our model of interfacial tension contrast. In this situation, the deposition rate was increased but the quality of SWNT alignment was undermined because the corresponding moving velocity of SWNT was also too fast for SWNTs to rotate when the evaporative rate was high. The similar results were identified by the SWNT/polymer conjugates dispersed in chloroform under the similar setups and other identical conditions. The typical breathing motion of dynamical pinning and zipping-like propagation for depinning were confirmed by the new suspensions despite that some morphological parameters changed dramatically compared with that from the aqueous solution. For example, the spacing between stripes reached 100 µm ~ 200 µm because the large contact angle contrast between HDMS- and SWNT-covered surface accompanies with the high evaporation rate of chloroform in the pinning and depinning process. Likewise the average CL velocity for fabrication reached around 20 µm/s due to the much higher evaporation rate of chloroform than water. Using alike suspensions, the modified EISA method called dose-controlled floating evaporative self-assembly (DFES) was employed to implement the self-assembly of SWNTs on the water/air interface and then deposit them on solid substrate by directed floating. Although the stripes were fabricated successfully by drops with certain doses and SWNT concentrations, there inevitably existed randomly oriented SWNTs from the water surface that built networks between the stripes containing well-aligned tubes. In order to slow down the evaporation rate and monitor the process detailedly, we used chlorobenzene as the solvent instead of chloroform and find the typical pinning/depinning movement of the CL. A preliminary analysis of the results in terms of chlorobenzene implied that the CL possibly followed the similar pinning/depinning process in consistence with our model with capillary bridge. In the last part of the thesis, the primary research on the optical properties of these stripes of ultrahigh purity semiconducting nanotubes was conducted by fluorescence microscopy and photoluminescence excitation (PLE) spectroscopy. The energy transfer of the photogenerated excitons was confirmed between different tube species with controlled band gaps. In short, the experiments performed in this thesis allowed to gain new insights about the fabrication of large-area SWNT thin films by the cost-effective solution-processed method and most importantly to uncover its intrinsic mechanism as well. Combined with the separation and selection technique like density gradient centrifugation or polyfluorene derivatives assisted method, highly monodisperse semiconducting nanotubes could be deposited into organized, controllable and functional arrays. Beyond the ambient conditions, precise control for the evaporation under preset temperature and vapor pressure could possibly extend the technique to the industry level. Assisted by some other mature techniques such as roll-to-roll printing, the cost-effective method could be widely used in the manufacture of various thin film devices. More complex 2D or even 3D structures could be designed and accomplished by the method for the functional or stretchable requirements. Further research on the fundamental exciton transition and diffusion in different networks or structures of SWNTs will be the significant precondition for the real applications. Looking ahead, from the individual carbon nanotube to its thin film, this promising material with outstanding properties had many challenges to overcome before the real-world applications. Thanks to the availability of pure and well-defined materials, the scalable solution-processed approaches for fabrication of thin films should be able to unlock the potential of carbon nanotubes and exploit them in (opto-)electronic devices in the foreseeing future.}, subject = {Kohlenstoff-Nanor{\"o}hre}, language = {en} } @article{EdgecockCarettaDavenneetal.2013, author = {Edgecock, T. R. and Caretta, O. and Davenne, T. and Densam, C. and Fitton, M. and Kelliher, D. and Loveridge, P. and Machida, S. and Prior, C. and Rogers, C. and Rooney, M. and Thomason, J. and Wilcox, D. and Wildner, E. and Efthymiopoulos, I. and Garoby, R. and Gilardoni, S. and Hansen, C. and Benedetto, E. and Jensen, E. and Kosmicki, A. and Martini, M. and Osborne, J. and Prior, G. and Stora, T. and Melo Mendonca, T. and Vlachoudis, V. and Waaijer, C. and Cupial, P. and Chanc{\´e}, A. and Longhin, A. and Payet, J. and Zito, M. and Baussan, E. and Bobeth, C. and Bouquerel, E. and Dracos, M. and Gaudiot, G. and Lepers, B. and Osswald, F. and Poussot, P. and Vassilopoulos, N. and Wurtz, J. and Zeter, V. and Bielski, J. and Kozien, M. and Lacny, L. and Skoczen, B. and Szybinski, B. and Ustrycka, A. and Wroblewski, A. and Marie-Jeanne, M. and Balint, P. and Fourel, C. and Giraud, J. and Jacob, J. and Lamy, T. and Latrasse, L. and Sortais, P. and Thuillier, T. and Mitrofanov, S. and Loiselet, M. and Keutgen, Th. and Delbar, Th. and Debray, F. and Trophine, C. and Veys, S. and Daversin, C. and Zorin, V. and Izotov, I. and Skalyga, V. and Burt, G. and Dexter, A. C. and Kravchuk, V. L. and Marchi, T. and Cinausero, M. and Gramegna, F. and De Angelis, G. and Prete, G. and Collazuol, G. and Laveder, M. and Mazzocco, M. and Mezzetto, M. and Signorini, C. and Vardaci, E. and Di Nitto, A. and Brondi, A. and La Rana, G. and Migliozzi, P. and Moro, R. and Palladino, V. and Gelli, N. and Berkovits, D. and Hass, M. and Hirsh, T. Y. and Schuhmann, M. and Stahl, A. and Wehner, J. and Bross, A. and Kopp, J. and Neuffer, D. and Wands, R. and Bayes, R. and Laing, A. and Soler, P. and Agarwalla, S. K. and Cervera Villanueva, A. and Donini, A. and Ghosh, T. and G{\´o}mez Cadenas, J. J. and Hern{\´a}ndez, P. and Mart{\´i}n-Albo, J. and Mena, O. and Burguet-Castell, J. and Agostino, L. and Buizza-Avanzini, M. and Marafini, M. and Patzak, T. and Tonazzo, A. and Duchesneau, D. and Mosca, L. and Bogomilov, M. and Karadzhov, Y. and Matev, R. and Tsenov, R. and Akhmedov, E. and Blennow, M. and Lindner, M. and Schwetz, T. and Fern{\´a}ndez Martinez, E. and Maltoni, M. and Men{\´e}ndez, J. and Giunti, C. and Gonz{\´a}lez Garc{\´i}a, M. C. and Salvado, J. and Coloma, P. and Huber, P. and Li, T. and L{\´o}pez Pav{\´o}n, J. and Orme, C. and Pascoli, S. and Meloni, D. and Tang, J. and Winter, W. and Ohlsson, T. and Zhang, H. and Scotto-Lavina, L. and Terranova, F. and Bonesini, M. and Tortora, L. and Alekou, A. and Aslaninejad, M. and Bontoiu, C. and Kurup, A. and Jenner, L. J. and Long, K. and Pasternak, J. and Pozimski, J. and Back, J. J. and Harrison, P. and Beard, K. and Bogacz, A. and Berg, J. S. and Stratakis, D. and Witte, H. and Snopok, P. and Bliss, N. and Cordwell, M. and Moss, A. and Pattalwar, S. and Apollonio, M.}, title = {High intensity neutrino oscillation facilities in Europe}, series = {Physical Review Special Topics-Accelerators and Beams}, volume = {16}, journal = {Physical Review Special Topics-Accelerators and Beams}, number = {2}, doi = {10.1103/PhysRevSTAB.16.021002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126611}, pages = {21002}, year = {2013}, abstract = {The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Frejus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of mu(+) and mu(-) beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular He-6 and Ne-18, also stored in a ring. The far detector is also the MEMPHYS detector in the Frejus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive.}, language = {en} } @article{WangLiKateleetal.2014, author = {Wang, Hui and Li, Min-Yi and Katele, F{\´e}lix Zongwe and Satyanandamurty, Tirumani and Wu, Jun and Bringmann, Gerhard}, title = {Decandrinin, an unprecedented \(C_9\)-spiro-fused 7,8-\( seco-ent\)-abietane from the Godavari mangrove \(Ceriops\ decandra\)}, series = {Beilstein Journal of Organic Chemistry}, volume = {10}, journal = {Beilstein Journal of Organic Chemistry}, issn = {1860-5397}, doi = {10.3762/bjoc.10.23}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119983}, pages = {276-81}, year = {2014}, abstract = {Decandrinin (1), an unprecedented \(C_9\)-spiro-fused 7,8-\(seco-ent\)-abietane, was obtained from the bark of an Indian mangrove, \(Ceriops\ decandra\), collected in the estuary of Godavari, Andhra Pradesh. The constitution and the relative configuration of 1 were determined by HRMS (ESI) and extensive NMR investigations, and the absolute configuration by circular dichroism (CD) and optical-rotatory dispersion (ORD) spectroscopy in combination with quantum-chemical calculations. Decandrinin is the first 7,8-\(seco-ent\)-abietane.}, language = {en} } @article{KadariLuLietal.2014, author = {Kadari, Asifiqbal and Lu, Min and Li, Ming and Sekaran, Thileepan and Thummer, Rajkumar P. and Guyette, Naomi and Chu, Vi and Edenhofer, Frank}, title = {Excision of viral reprogramming cassettes by Cre protein transduction enables rapid, robust and efficient derivation of transgene-free human induced pluripotent stem cells}, series = {Stem Cell Research \& Therapy}, volume = {5}, journal = {Stem Cell Research \& Therapy}, number = {2}, issn = {1757-6512}, doi = {10.1186/scrt435}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120578}, pages = {47}, year = {2014}, abstract = {Integrating viruses represent robust tools for cellular reprogramming; however, the presence of viral transgenes in induced pluripotent stem cells (iPSCs) is deleterious because it holds the risk of insertional mutagenesis leading to malignant transformation. Here, we combine the robustness of lentiviral reprogramming with the efficacy of Cre recombinase protein transduction to derive iPSCs devoid of transgenes. By genome-wide analysis and targeted differentiation towards the cardiomyocyte lineage, we show that transgene-free iPSCs are superior to iPSCs before Cre transduction. Our study provides a simple, rapid and robust protocol for the generation of clinical-grade iPSCs suitable for disease modeling, tissue engineering and cell replacement therapies.}, language = {en} } @article{AgostonLiHaslingeretal.2012, author = {Agoston, Zsuzsa and Li, Naixin and Haslinger, Anja and Wizenmann, Andrea and Schulte, Dorothea}, title = {Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development}, series = {BMC Developmental Biology}, volume = {12}, journal = {BMC Developmental Biology}, number = {10}, doi = {10.1186/1471-213X-12-10}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132626}, year = {2012}, abstract = {Background: During early stages of brain development, secreted molecules, components of intracellular signaling pathways and transcriptional regulators act in positive and negative feed-back or feed-forward loops at the mid-hindbrain boundary. These genetic interactions are of central importance for the specification and subsequent development of the adjacent mid-and hindbrain. Much less, however, is known about the regulatory relationship and functional interaction of molecules that are expressed in the tectal anlage after tectal fate specification has taken place and tectal development has commenced. Results: Here, we provide experimental evidence for reciprocal regulation and subsequent cooperation of the paired-type transcription factors Pax3, Pax7 and the TALE-homeodomain protein Meis2 in the tectal anlage. Using in ovo electroporation of the mesencephalic vesicle of chick embryos we show that (i) Pax3 and Pax7 mutually regulate each other's expression in the mesencephalic vesicle, (ii) Meis2 acts downstream of Pax3/7 and requires balanced expression levels of both proteins, and (iii) Meis2 physically interacts with Pax3 and Pax7. These results extend our previous observation that Meis2 cooperates with Otx2 in tectal development to include Pax3 and Pax7 as Meis2 interacting proteins in the tectal anlage. Conclusion: The results described here suggest a model in which interdependent regulatory loops involving Pax3 and Pax7 in the dorsal mesencephalic vesicle modulate Meis2 expression. Physical interaction with Meis2 may then confer tectal specificity to a wide range of otherwise broadly expressed transcriptional regulators, including Otx2, Pax3 and Pax7.}, language = {en} } @article{MarenholzEsparzaGordilloRueschendorfetal.2015, author = {Marenholz, Ingo and Esparza-Gordillo, Jorge and R{\"u}schendorf, Franz and Bauerfeind, Anja and Strachan, David P. and Spycher, Ben D. and Baurecht, Hansj{\"o}rg and Magaritte-Jeannin, Patricia and S{\"a}{\"a}f, Annika and Kerkhof, Marjan and Ege, Markus and Baltic, Svetlana and Matheson, Melanie C. and Li, Jin and Michel, Sven and Ang, Wei Q. and McArdle, Wendy and Arnold, Andreas and Homuth, Georg and Demenais, Florence and Bouzigon, Emmanuelle and S{\"o}derh{\"a}ll, Cilla and Pershagen, G{\"o}ran and de Jongste, Johan C. and Postma, Dirkje S. and Braun-Fahrl{\"a}nder, Charlotte and Horak, Elisabeth and Ogorodova, Ludmila M. and Puzyrev, Valery P. and Bragina, Elena Yu and Hudson, Thomas J. and Morin, Charles and Duffy, David L. and Marks, Guy B. and Robertson, Colin F. and Montgomery, Grant W. and Musk, Bill and Thompson, Philip J. and Martin, Nicholas G. and James, Alan and Sleiman, Patrick and Toskala, Elina and Rodriguez, Elke and F{\"o}lster-Holst, Regina and Franke, Andre and Lieb, Wolfgang and Gieger, Christian and Heinzmann, Andrea and Rietschel, Ernst and Keil, Thomas and Cichon, Sven and N{\"o}then, Markus M. and Pennel, Craig E. and Sly, Peter D. and Schmidt, Carsten O. and Matanovic, Anja and Schneider, Valentin and Heinig, Matthias and H{\"u}bner, Norbert and Holt, Patrick G. and Lau, Susanne and Kabesch, Michael and Weidinger, Stefan and Hakonarson, Hakon and Ferreira, Manuel A. R. and Laprise, Catherine and Freidin, Maxim B. and Genuneit, Jon and Koppelman, Gerard H. and Mel{\´e}n, Erik and Dizier, Marie-H{\´e}l{\`e}ne and Henderson, A. John and Lee, Young Ae}, title = {Meta-analysis identifies seven susceptibility loci involved in the atopic march}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {8804}, doi = {10.1038/ncomms9804}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139835}, year = {2015}, abstract = {Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.}, language = {en} } @article{MontesCobosLiFischeretal.2015, author = {Montes-Cobos, Elena and Li, Xiao and Fischer, Henrike J. and Sasse, Andr{\´e} and K{\"u}gler, Sebastian and Didi{\´e}, Michael and Toischer, Karl and Fassnacht, Martin and Dressel, Ralf and Reichardt, Holger M.}, title = {Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0143954}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137575}, pages = {e0143954}, year = {2015}, abstract = {Mineralocorticoid receptor (MR) inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox). Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes.}, language = {en} } @article{FanLiChaoetal.2015, author = {Fan, Ben and Li, Lei and Chao, Yanjie and F{\"o}rstner, Konrad and Vogel, J{\"o}rg and Borriss, Rainer and Wu, Xiao-Qin}, title = {dRNA-Seq Reveals Genomewide TSSs and Noncoding RNAs of Plant Beneficial Rhizobacterium Bacillus amyloliquefaciens FZB42}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0142002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-138369}, pages = {e0142002}, year = {2015}, abstract = {Bacillus amyloliquefaciens subsp. plantarum FZB42 is a representative of Gram-positive plant-growth-promoting rhizobacteria (PGPR) that inhabit plant root environments. In order to better understand the molecular mechanisms of bacteria-plant symbiosis, we have systematically analyzed the primary transcriptome of strain FZB42 grown under rhizospheremimicking conditions using differential RNA sequencing (dRNA-seq). Our analysis revealed 4,877 transcription start sites for protein-coding genes, identified genes differentially expressed under different growth conditions, and corrected many previously mis-annotated genes. We also identified a large number of riboswitches and cis-encoded antisense RNAs, as well as trans-encoded small noncoding RNAs that may play important roles in the gene regulation of Bacillus. Overall, our analyses provided a landscape of Bacillus primary transcriptome and improved the knowledge of rhizobacteria-host interactions.}, language = {en} } @article{ZhaoZhangBhuripanyoetal.2013, author = {Zhao, Bo and Zhang, Keya and Bhuripanyo, Karan and Choi, Chan Hee J. and Villhauer, Eric B. and Li, Heng and Zheng, Ning and Kiyokawa, Hiroaki and Schindelin, Hermann and Yin, Jun}, title = {Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {e70312}, issn = {1932-6203}, doi = {10.1371/journal.pone.0070312}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128479}, year = {2013}, abstract = {The C-terminal peptides of ubiquitin (UB) and UB-like proteins (UBLs) play a key role in their recognition by the specific activating enzymes (E1s) to launch their transfer through the respective enzymatic cascades thus modifying cellular proteins. UB and Nedd8, a UBL regulating the activity of cullin-RING UB ligases, only differ by one residue at their C-termini; yet each has its specific E1 for the activation reaction. It has been reported recently that UAE can cross react with Nedd8 to enable its passage through the UB transfer cascade for protein neddylation. To elucidate differences in UB recognition by UAE and NAE, we carried out phage selection of a UB library with randomized C-terminal sequences based on the catalytic formation of UB similar to NAE thioester conjugates. Our results confirmed the previous finding that residue 72 of UB plays a "gate-keeping" role in E1 selectivity. We also found that diverse sequences flanking residue 72 at the UB C-terminus can be accommodated by NAE for activation. Furthermore heptameric peptides derived from the C-terminal sequences of UB variants selected for NAE activation can function as mimics of Nedd8 to form thioester conjugates with NAE and the downstream E2 enzyme Ubc12 in the Nedd8 transfer cascade. Once the peptides are charged onto the cascade enzymes, the full-length Nedd8 protein is effectively blocked from passing through the cascade for the critical modification of cullin. We have thus identified a new class of inhibitors of protein neddylation based on the profiles of the UB C-terminal sequences recognized by NAE.}, language = {en} } @article{SongXiuHuangetal.2011, author = {Song, Ning-Ning and Xiu, Jian-Bo and Huang, Ying and Chen, Jia-Yin and Zhang, Lei and Gutknecht, Lise and Lesch, Klaus Peter and Li, He and Ding, Yu-Qiang}, title = {Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0015998}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133581}, pages = {e15998}, year = {2011}, abstract = {The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreER(T2) mice were generated and crossed with Lmx1b(flox/flox) mice to obtain Pet1-CreER(T2); Lmx1b(flox/flox) mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60\% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2.}, language = {en} } @article{KirylukYifuSannaCherchietal.2012, author = {Kiryluk, Krzysztof and Yifu, Li and Sanna-Cherchi, Simone and Rohanizadegan, Mersedeh and Suzuki, Hitoshi and Eitner, Frank and Snyder, Holly J. and Choi, Murim and Hou, Ping and Scolari, Francesco and Izzi, Claudia and Gigante, Maddalena and Gesualdo, Loreto and Savoldi, Silvana and Amoroso, Antonio and Cusi, Daniele and Zamboli, Pasquale and Julian, Bruce A. and Novak, Jan and Wyatt, Robert J. and Mucha, Krzysztof and Perola, Markus and Kristiansson, Kati and Viktorin, Alexander and Magnusson, Patrik K. and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Stefansson, Kari and Boland, Anne and Metzger, Marie and Thibaudin, Lise and Wanner, Christoph and Jager, Kitty J. and Goto, Shin and Maixnerova, Dita and Karnib, Hussein H. and Nagy, Judit and Panzer, Ulf and Xie, Jingyuan and Chen, Nan and Tesar, Vladimir and Narita, Ichiei and Berthoux, Francois and Floege, J{\"u}rgen and Stengel, Benedicte and Zhang, Hong and Lifton, Richard P. and Gharavi, Ali G.}, title = {Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {6}, doi = {10.1371/journal.pgen.1002765}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130195}, pages = {e1002765}, year = {2012}, abstract = {IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5x10\(^{-32}\) 3x10\(^{-10}\), with heterogeneity detected only at the PSMB9/TAP1 locus (I\(^{-2}\) = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5x10\(^{-4}\)). A seven-SNP genetic risk score, which explained 4.7\% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3x10\(^{-128}\)). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.}, language = {en} } @phdthesis{Li2009, author = {Li, Naixin}, title = {Dorso-ventral Differentiation and Specification of the Mesencephalon in Early Chick Embryos}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-32950}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {The chick midbrain is subdivided into functionally distinct ventral and dorsal domains, tegmentum and optic tectum. In the mature tectum, neurons are organized in layers, while they form discrete nuclei in the tegmentum. An interesting characteristic of the embryonic brain is the development of a large optic tectum, of which the growth becomes obvious at embryonic day 3 (E3). Dorsoventral (DV) specification of the early midbrain should thus play a crucial role for the organization of the neuronal circuitry in optic tectum and tegmentum. In the first part of my thesis, I investigated regional commitment and establishment of cellular differences along the midbrain DV axis. I examined the commitment of gene expression patterns in isolated ventral and dorsal tissue in vivo and in vitro, and studied their cell mixing properties. Explant cultures, and grafting of dorsal midbrain into a ventral environment or vice versa, revealed a gradual increase in the autonomy of region-specific gene regulation between, which was accompanied by a gradual increase in differential adhesive properties from E2 to E3, once the DV axis polarity was fixed. These events happened at a time-point when the majority of midbrain cells are not yet differentiated. Long-term transplantation (6 - 9 days) using quail cells from ventral midbrain as grafts showed the same result. Hence, the results suggest that progressive specification of the midbrain DV axis is accompanied by progressively reduced cell mixing between dorsal and ventral precursors, leading to a partial regionalization of midbrain tissue into autonomous units of precursor cell populations. In the second part I investigated the genes that might be involved in regulating the growth of the tectum. In particular, I focused on the role of Pax7 transcription factor, a paired domain protein. The results suggested that Pax7 was involved in regulating the medial-lateral extension of the tectum. Over expression of Pax7 in dorsal midbrain led to an enlarged tectum accompanied by a raise in cell division, while Pax7 knockdown by shrank caused a reduction in tectum. The overall pattern of neuronal differentiation was not disturbed by an up or down regulation of Pax7. Pax7 also positively regulated Pax3, another pair-ruled gene expressed dorsally. These results suggest that Pax7 very likely together with Pax3 could facilitate or maintain neural cell proliferation in the midbrain at early stages and that a regulation of the size in that region does not influence the neuronal patterning of the developmental field. I further checked the expression and function of a GFPase Rab 23, that was suggested to be involved in the DV patterning in mouse neural tube as a negative regulator of Shh signaling. Overexpression of Rab23 indicated that it facilitated the expression of Pax7 and Pax3 in the neural tube and suppressed ventral genes like Nkx6.1 cell autonomously, however, it did not disturb neuronal patterning. Interestingly, a thorough expression study of Rab 23 during chick early development revealed that Rab23 is already expressed very early and asymmetrically during gastrulation, suggesting a possible role of Rab23 on the left-right determination of Hensen's node. In combination with the result that Rab23 is expressed in the notochord early in development, I assume that both Rab23 and Shh exist in all neural progenitor cells initially, and when their expression patterns separate gradually the neural cells adopt a ventral or dorsal fate according to their location along the dorsoventral axis. The avian embryo is a classic system used widely to investigate questions of vertebrate development. The easy and cheap accessibility of the embryo for in ovo or ex ovo experiments all around the year make it an ideal animal model to work with. The only recently developed method of over expressing genes in specific cells or regions in the chick embryo by electroporation enabled me to study different ways of gene suppression using this way of gene transfection. Thus, I compared the effect of long-hairpin and short hairpin dsRNA in different vectors and antisense morpholino oligonucleotides. The results revealed that all hairpin dsRNA constructs did reduce gene and protein expression often accompanied by morphological changes. Most efficiently were shRNAi constructs cloned into a siRNA-specific vector - pSilencer 1.0-U6. Gene silencing was already well observed 36 hours after transfection. In comparison antisense morpholino oligonucleotides did not show such big gene reduction as the shRNA in pSilencer. Taken together, this methodical research proposes that the shRNA in the pSilencer vector was a good and effective tool to reduce gene and protein expression locally.}, subject = {Differenzierung}, language = {en} } @article{MengSendtnerSmith1995, author = {Meng, Li and Sendtner, Michael and Smith, Austin}, title = {Essential function of LIF receptor in motor neurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-34219}, year = {1995}, abstract = {D EVELOPME'iT and maintenance of the mammalian nervous system is dependent upon neurotrophic cytokines. One class of neurotrophic factor acts through rcccptor complexes involving the lowaffinity leukaemia inhibitor y faclor receptor subunit (LlF-R). Members of this fa mily of cytokines, such as ciliary neurotrophic factor (CNTF) and leukaemia inhibitory factor (LIF), have profound effects on the survival and maintenance of motor neurons, Recently it was reported that mice lacking LlF-R die shortly after birth unlike mice lacking CNTF or LIF which are viable. Here we describe histopathological analyses of lifr mutants tha t reveal a loss > 35\% of facia l motor neurons, 40\% of spinal motor neurons and 50\% of neurons in the nucleus ambiguus. These findings point to the existence of a ligand for LIF-R tha t is required for the normal development of motor neurons in both brainstem nuclei and spinal cord.}, language = {en} } @article{BensaadFavaroLewisetal.2014, author = {Bensaad, Karim and Favaro, Elena and Lewis, Caroline A. and Peck, Barrie and Lord, Simon and Collins, Jennifer M. and Pinnick, Katherine E. and Wigfield, Simon and Buffa, Francesca M. and Li, Ji-Liang and Zhang, Qifeng and Wakelam, Michael J. O. and Karpe, Fredrik and Schulze, Almut and Harris, Adrian L.}, title = {Fatty Acid Uptake and Lipid Storage Induced by HIF-1 alpha Contribute to Cell Growth and Survival after Hypoxia-Reoxygenation}, series = {Cell Reports}, volume = {9}, journal = {Cell Reports}, number = {1}, issn = {2211-1247}, doi = {10.1016/j.celrep.2014.08.056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115162}, pages = {349-365}, year = {2014}, abstract = {An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1 alpha (HIF-1 alpha)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O-2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via beta-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.}, language = {en} } @article{LiWongNongetal.2014, author = {Li, Lei and Wong, Hin-chung and Nong, Wenyan and Cheung, Man Kit and Law, Patrick Tik Wan and Kam, Kai Man and Kwan, Hoi Shan}, title = {Comparative genomic analysis of clinical and environmental strains provides insight into the pathogenicity and evolution of Vibrio parahaemolyticus}, series = {BMC Genomics}, volume = {15}, journal = {BMC Genomics}, number = {1135}, issn = {1471-2164}, doi = {10.1186/1471-2164-15-1135}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118080}, year = {2014}, abstract = {Background: Vibrio parahaemolyticus is a Gram-negative halophilic bacterium. Infections with the bacterium could become systemic and can be life-threatening to immunocompromised individuals. Genome sequences of a few clinical isolates of V. parahaemolyticus are currently available, but the genome dynamics across the species and virulence potential of environmental strains on a genome-scale have not been described before. Results: Here we present genome sequences of four V. parahaemolyticus clinical strains from stool samples of patients and five environmental strains in Hong Kong. Phylogenomics analysis based on single nucleotide polymorphisms revealed a clear distinction between the clinical and environmental isolates. A new gene cluster belonging to the biofilm associated proteins of V. parahaemolyticus was found in clincial strains. In addition, a novel small genomic island frequently found among clinical isolates was reported. A few environmental strains were found harboring virulence genes and prophage elements, indicating their virulence potential. A unique biphenyl degradation pathway was also reported. A database for V. parahaemolyticus (http://kwanlab.bio.cuhk.edu.hk/vp webcite) was constructed here as a platform to access and analyze genome sequences and annotations of the bacterium. Conclusions: We have performed a comparative genomics analysis of clinical and environmental strains of V. parahaemolyticus. Our analyses could facilitate understanding of the phylogenetic diversity and niche adaptation of this bacterium. "}, language = {en} } @article{GrafLiHerrmannetal.2014, author = {Graf, Nicolas and Li, Zhoulei and Herrmann, Ken and Weh, Daniel and Aichler, Michaela and Slawska, Jolanta and Walch, Axel and Peschel, Christian and Schwaiger, Markus and Buck, Andreas K. and Dechow, Tobias and Keller, Ulrich}, title = {Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma}, series = {Oncotargets and Therapy}, volume = {7}, journal = {Oncotargets and Therapy}, doi = {10.2147/OTT.S59314}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117915}, pages = {789-798}, year = {2014}, abstract = {Background: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[F-18] fluorothymidine (FLT). Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects. Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue. Conclusion: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.}, language = {en} } @article{LiSamnickLapaetal.2012, author = {Li, Xiang and Samnick, Samuel and Lapa, Constantin and Israel, Ina and Buck, Andreas K. and Kreissl, Michael C. and Bauer, Wolfgang}, title = {68Ga-DOTATATE PET/CT for the detection of inflammation of large arteries: correlation with18F-FDG, calcium burden and risk factors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76231}, year = {2012}, abstract = {Background: Ga-[1,4,7,10-tetraazacyclododecane-N,N0,N00,N000-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) positron emission tomography (PET) is commonly used for the visualization of somatostatin receptor (SSTR)-positive neuroendocrine tumors. SSTR is also known to be expressed on macrophages, which play a major role in inflammatory processes in the walls of coronary arteries and large vessels. Therefore, imaging SSTR expression has the potential to visualize vulnerable plaques. We assessed 68Ga-DOTATATE accumulation in large vessels in comparison to 18F-2-fluorodeoxyglucose (FDG) uptake, calcified plaques (CPs), and cardiovascular risk factors. Methods: Sixteen consecutive patients with neuroendocrine tumors or thyroid cancer underwent both 68Ga-DOTATATE and 18F-FDG PET/CT for staging or restaging purposes. Detailed clinical data, including common cardiovascular risk factors, were recorded. For a separate assessment, they were divided into a high-risk and a low-risk group. In each patient, we calculated the maximum target-to-background ratio (TBR) of eight arterial segments. The correlation of the TBRmean of both tracers with risk factors including plaque burden was assessed. Results: The mean TBR of 68Ga-DOTATATE in all large arteries correlated significantly with the presence of CPs (r = 0.52; p < 0.05), hypertension (r = 0.60; p < 0.05), age (r = 0.56; p < 0.05), and uptake of 18F-FDG (r = 0.64; p < 0.01). There was one significant correlation between 18F-FDG uptake and hypertension (0.58; p < 0.05). Out of the 37 sites with the highest focal 68Ga-DOTATATE uptake, 16 (43.2\%) also had focal 18F-FDG uptake. Of 39 sites with the highest 18F-FDG uptake, only 11 (28.2\%) had a colocalized 68Ga-DOTATATE accumulation. Conclusions: In this series of cancer patients, we found a stronger association of increased 68Ga-DOTATATE uptake with known risk factors of cardiovascular disease as compared to 18F-FDG, suggesting a potential role for plaque imaging in large arteries. Strikingly, we found that focal uptake of 68Ga-DOTATATE and 18F-FDG does not colocalize in a significant number of lesions.}, subject = {Medizin}, language = {en} } @phdthesis{Li2004, author = {Li, Jie}, title = {Differential effects of neuromelanin and synthetic dopamine melanin on cell lines}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-13588}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2004}, abstract = {xxx}, language = {en} } @phdthesis{Li2014, author = {Li, Xiang}, title = {Molecular imaging of inflammation in atherosclerosis: Preclinical study in Apolipoprotein E-Deficient mice and preliminary evaluation in human using positron emission tomography}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-104622}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2014}, abstract = {Motivation and Aim: Cardiovascular disease has been the leading cause of mortality and morbidity throughout the world. In developed countries, cardiovascular diseases are already responsible for a majority of deaths and will become the pre-eminent health problem worldwide (1,2). Rupture of atherosclerotic plaque accounts for approximately 70\% of fatal acute myocardial infarction and sudden heart deaths. Conventional criterias for the diagnosis of "vulnerable plaques" are calcified nodules, yellow appearance of plaque, a thin cap, a large lipid core, severe luminal stenosis, intraplaque hemorrhage, inflammation, thrombogenicity, and plaque injury (3-5). Noninvasive diagnosis of vulnerable plaque still remains a great challenge and a huge research prospect, which triggered us to investigate the feasibility of PET imaging on the evaluation of atherosclerosis. Nuclear imaging of atherosclerosis， especially co-registered imaging modalities, could provide a promising diagnostic tool including both anatomy and activities to identify vulnerable atherosclerotic plaque or early detection of inflammatory endothelium at risk. Furthermore, the development of specific imaging tracers for clinical applications is also a challenging task. The aim of this work was to assess the potential of novel PET imaging probes associated with intra-plaque inflammation on animal models and in human respectively. Methods In this work, several molecular imaging modalities were employed for evaluation of atherosclerosis. They included Positron emission tomography / Computed tomography (PET/CT) for human studies, and micro-PET, autoradiography and high-resolution magnetic resonance imaging (MRI) for animal studies. Radiotracers for PET imaging included the glucose analogue 18F-Fluorodeoxyglucose (18F-FDG), the somatostatin receptor avide tracer 68Ga-DOTATATE, and the Gallium-68 labeled fucoidan (68Ga-Fucoidan), which was developed as a PET tracer to detect endothelial P-selectin, which overexpressed at early stage of atherosclerosis and endothelial overlying activated plaque. Tracer's capabilities were firstly assessed on cellular level in vitro. Subsequently, Animal studies were conducted in two animal models: 1, Apolipoprotein E (ApoE-/-) mice having severe atherosclerotic plaque; 2, Lipopolysaccharide (LPS) -induced mice for receiving acute vascular inflammation. Corresponding analyses on protein and histological level were conducted as well to confirm our results. In human study, 16 patients with neuroendocrine tumors (NETs) were investigated on imaging vascular inflammation. These patients had undergone both 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT for staging or restaging within 6 weeks. 16 patients were randomized into two groups: high-risk group and low-risk group. Uptake ratio of both tracers from two groups were compared and correlated with common cardiovascular risk factors. Results and Conclusion In murine study, the expression of somatostatin receptor 2, which is the main bio-target of 68Ga-DOTATATE on macrophage/monocyte was confirmed by flow cytometry and immunohistochemistry. Prospectively, high specific accumulation of 68Ga-DOTATATE to the macrophage within the plaques was observed in aorta lesions by autoradiography and by micro-PET. In study with 68Ga-fucoidan, a strong expression of P-selectin on active endothelium overlying on inflamed plaque but weaker on inactive plaques was confirmed. Specific focal uptake of 68Ga-fucoidan were detected at aorta segments by micro-PET, and correlated with high-resolution magnetic resonance imaging (MRI), which was used to characterize the morphology of plaques. 68Ga-fucoidan also showed a greater affinity to active inflamed plaque in comparison of inactive fibrous plaque, which was assessed by autoradiography. Specificity of 68Ga-DOTATATE and 68Ga-fucoidan were confirmed by ex-vivo blocking autoradiography and in vivo blocking PET imaging respectively. In human study, focal uptake of both 18F-FDG and 68Ga-DOTATATE was detected. Analyzing concordance of two tracers' uptake ratio, Out of the 37 sites with highest focal 68Ga-DOTATATE uptake, 16 (43.2\%) also had focal 18F-FDG uptake. Of 39 sites with highest 18F-FDG uptake, only 11 (28.2\%) had a colocalized 68Ga-DOTATATE accumulation. Correlated tracers' uptake and calcium burden and risk factors, Mean target-to-background ratio (TBR) of 68Ga-DOTATATE correlated significantly with the presence of calcified plaques (r=0.52), hypertension (r=0.60), age (r=0.56) and uptake of 18F-FDG (r=0.64). TBRmean of 18F-FDG correlated significantly only with hypertension (r=0.58; p<0.05). Additionally, TBRmean of 68Ga-DOTATATE is significant higher in the high risk group while TBRmean of 18F-FDG is not. In conclusion, we evaluated vascular inflammation of atherosclerosis non-invasively using the two PET tracers: 68Ga-DOTATATE and 68Ga-Fucoidan. 68Ga-DOTATATE show specific affinity to infiltrated macrophage within the plaques. 68Ga-Fucoidan may hold the potential to discriminate between active and inactive atherosclerotic plaques in terms of variant accumulation on different-types of plaques. PET as leading molecular imaging technique provides superiority in assessing cellular activity, which is pivotal for understanding internal activity of atherosclerotic plaques. Since diagnosis of atherosclerosis is a complex and multi-dimensional task. More integrated imaging technology such as PET/MRI, faster imaging algorithm, more efficient radiotracer are required for further development of atherosclerosis imaging,}, subject = {Arteriosklerose}, language = {en} } @phdthesis{Li2013, author = {Li, Xiaoli}, title = {Functional analyses of ES cell pluripotency by inducible knockdown of the Polycomb group protein Pcgf6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-84015}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Polycomb group (PcG) proteins are chromatin modifiers involved in heritable gene repression. Two main PcG complexes have been characterized: Polycomb repressive complex (PRC) 2 is involved in the initiation of gene silencing, whereas PRC1 participates in the stable maintenance of gene repression. Pcgf4 (Polycomb group protein, Bmi1) is one of the most studied PRC1 members with essential functions for embryonic development and adult stem cell self renewal. In embryonic stem cells (ES cells), Pcgf4 is poorly expressed while its paralogs (Pcgf1, Pcgf2, Pcgf3, Pcgf5 and Pcgf6) are expressed at higher levels. The relevance of the Pcgf paralog Pcgf6 for the maintenance of ESC pluripotency has not been addressed so far. My analyses revealed that Pcgf6 was the most expressed Pcgf paralog in undifferentiated ES cells. When ES cells differentiated, gene expression of Pcgf6 strongly declined. To investigate the functions of Pcgf6 in ES cells, we established a doxycycline (dox) inducible shRNA-targeted knockdown system according to publications by Seibler et al. (Seibler et al. 2005; Seibler et al. 2007). Following dox-induced knockdown (KD) of Pcgf6, we observed decreased ES cell colony formation. In parallel, gene expression of pluripotency markers Oct4, Nanog and Sox2 was reduced upon dox-treatment, wheras the expression of mesoderm genes such as T (Brachyury) were up-regulated. Further, microarray analysis revealed de-repression of several spermatogenesis-specic genes upon Pcgf6-KD, suggesting that Pcgf6 may play a role during spermatogenesis. Upon in vitro differentiation, Pcgf6-KD ES cells showed increased hemangioblast formation, paralleled by increased hematopoietic development. In summary, results of this study suggest that Pcgf6 is involved in maintaining ES cell identity by repressing lineage-specific gene expression in undifferentiated ES cells.}, subject = {Embryonale Stammzelle}, language = {en} } @phdthesis{Li2010, author = {Li, Jian-Qiang}, title = {Modulating the expression of enzymes of isoprenoid synthesis: effects on Vgamma9Vdelta2 T cell activation and tumor cell growth}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-46388}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {This study focuses on phosphoantigen specific Vg9Vd2 T cells which only exist in human and non-human primates. This population accounts for 1\%-5\% of peripheral blood T-lymphocytes but their frequency can rise to 50\% of total blood T cells upon infection. Vg9Vd2 T cells can be activated by nonpeptide compounds with critical phosphate moieties which are termed as phosphoantigens. These include isopentenyl pyrophosphate (IPP), a key compound of isoprenoid synthesis in all organisms, and (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), a direct precursor of IPP in DOXP pathway which only exist in eubacteria, plants, apicomplexaen parasites. Its activity as phosphoantigen is at least 1000 fold higher than that of IPP. However, direct structural evidence of phosphoantigen binding to the TCR is missing so far. Moreover, Vg9Vd2 T cells have potent anti-tumor activity e.g. against the B-cell lymphoma Daudi, whose Vg9Vd2 T cell activating properties have been suggested to result from sensing of abnormal intracellular IPP levels by the Vg9Vd2 TCR or Vg9Vd2 TCR binding to other postulated ligands such as an ectopically expressed F1-ATPase or UL-16 binding protein 4 (ULBP4). Aminobisphosphonates and alkymines were hypothesized to activate Vg9Vd2 T cells indirectly by inhibiting the IPP consuming enzyme farnysyl pyrophosphates synthesis (FPPS) although off target effects of these drugs or a direct interaction with the Vg9Vd2 TCR could not be excluded. This thesis presents new approaches for the mechanistic analysis of Vg9Vd2 T cell activation. By employing retroviral transduction of FPPS specific shRNA, it shows that specific shRNA reduces expression of FPPS and is sufficient to convert hematopoietic and non-hematopoietic tumor cell lines into Vg9Vd2 T cell activators. FPPS knockdown cells activated Vg9Vd2 T cells as measured by increased levels of CD69 and CD107a, kill of FPPS knockdown cells and induction of IFN-\&\#947; secretion. The IPP-synthesis-inhibiting drug mevastatin reduced Vg9Vd2 T cell activation by FPPS knockdown cells or aminobisphosphonate treated cells but not activation by the phosphoantigen bromohydrin pyrophosphate (BrHPP). A reduced growth of the FPPS knockdown cells has not been observed which is different to what has been reported for aminobisphosphonate treated cells. Finally, the human B-cell lymphoma RAJI has been transduced with Tetracyclin-inducible FPPS specific shRNA and proven to gain and loose the capacity to activate Vg9Vd2 TCR transductants upon doxycylin provision or removal. Another approach for the analysis of Vg9Vd2 T cell activation is Vg9Vd2 TCR transduced mouse cell lines with specificity for phosphoantigens. In contrast to the previously used Vg9Vd2 TCR transduced Jurkat cells, these cells do not present phosphoantigens, and are therefore specially suited for analysis of phosphoantigen presentation. The response of the new TCR transductants to presumed Vg9Vd2 TCR ligands/activators such as phosphoantigens, aminobisphosphonates or FPPS knockdown cells, depended strongly on the expression of a rat/mouse CD28 molecule by the transductants and its ligation by the (CD80) counter receptor on the ligand-presenting cell. The response is likely to reflect recognition of cognate Vg9Vd2 TCR antigens since mutations in the TCR-\&\#948; chain CDR2 and 3 abolished this response but activation by TCR or CD3 specific antibodies. A major difference between TCR transductants and primary gd T cells, was the lacking response of TCR transductants to Daudi or IPP. In addition their sensitivity to other soluble phosphoantigens was about 100 fold weaker than that of primary cells, stimulation of both cell type to CD80 expressing FPPS knock down or aminobisphosphonates was similar. Finally, the transductants have also been used to analyze effects of over-expression or knockdown of enzymes of isoprenoid synthesis such as 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase or HMGR), mevalonate-5-pyrophosphate decarboxylase (MVD), isopentenyl pyrophosphate isomerase (IDI), geranyl-geranyl pyrophosphate synthase (GGPPS) but no clear effects have been found. In conclusion, this thesis supports the concept of Vg9Vd2 T cells being sensors of a dysregulated isoprenoid metabolism and established new tools to study ligand recognition and TCR mediated activation of this T cell population. These tools will be most useful to address following questions: 1) How does the dysregulation of isoprenoid metabolism affect tumor growth? 2) What is the correlation between the modulation of IPP levels and the Vg9Vd2 TCR binding or expression of other postulated ligands? 3) Are there any mevalonate pathway enzymes other than FPPS and HMGR, which play an important role in Vg9Vd2 T cells activation? 4) What is/are the putative phosphoantigen-presenting molecule(s)?}, subject = {Primaten}, language = {en} } @article{GesslerKoenigArdenetal.1994, author = {Gessler, Manfred and K{\"o}nig, A. and Arden, K. and Grundy, P. and Orkin, S. H. and Sallan, S. and Peters, C. and Ruyle, S. and Mandell, J. and Li, F. and Cavenee, W. and Bruns, G. A.}, title = {Infrequent mutation of the WT1 gene in 77 Wilms' Tumors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-34308}, year = {1994}, abstract = {Homozygous deletions in Wilms' tumor DNA have been a key step in the identification and isolation of the WTI gene. Several additional loci are also postulated to contribute to Wilms' tumor formation. To assess the frequency of WTI alterations we have analyzed the WTI locus in a panel of 77 Wilms' tumors. Eight tumors showed evidence for large deletions of several hundred or thousand kilobasepairs of DNA, some of which were also cytogenetically detected. Additional intragenic mutations were detected using more sensitive SSCP analyses to scan all 10 WTI exons. Most of these result in premature stop codons or missense mutations that inactivate the remaining WTI allele. The overall frequency of WTI alterations detected with these methods is less than 15\%. While some mutations may not be detectable with the methods employed, our results suggest that direct alterations of the WTI gene are present in only a small fraction of Wilms' tumors. Thus, mutations at other Wilms' tumor loci or disturbance of interactions between these genes likely play an important role in Wilms' tumor development.}, language = {en} } @phdthesis{Li2009, author = {Li, Xueqing}, title = {Hydrogen Bond-directed Self-assembly of Perylene Bisimide Organogelators}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-43727}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {Perylene bisimide (PBI) dyes are a widely used class of industrial pigments, and currently have gained significant importance for organic-based electronic and optical devices. Structural modification at the PBI core results in changes of the optical and electronic properties, which enable tailored functions. Moreover, the aggregation behavior of PBIs is alterable and controllable to achieve new materials, among which organogels are of particular interest because of their potential for applications as supramolecular soft materials. In this work, new PBI-based organic gelators were designed, synthesized, and characterized, and the aggregation behaviors under different conditions were intensively studied by various spectroscopic and microscopic methods. In chapter 2, a brief overview is given on the structural and functional features of organogel systems. The definition, formation and reversibility of organogels are introduced. Some examples on dye based organogel are selected, among which PBI-based organogelators reported so far are especially emphasized. Some basic knowledges of supramolecular chirality are also overviewed such as characterization, amplification, and symmetry breaking of the chiral aggregates. According to our former experiences, PBIs tend to form aggregates because the planer aromatic cores interact with one another by pi-pi interaction. In chapter 3, a new PBI molecule is introduced which possesses amide groups between the conjugated core and periphery alkyl chains. It is found that well oriented aggregates are formed by hydrogen bonding and the pi-pi interaction of the cores. These interactions enable the aggregates to grow in one-dimension forming very long fibers, and these fibers further intercross to 3D network structures, e.g., organogels. In comparison to the very few PBI-based gelators reported before, one advantage of this gelator is that, it is more versatile and can gelate a wide range of organic solvents. Moreover, the well-organized fibers that are composed of extended \&\#960;-stacks provide efficient pathways for n-type charge carriers. Interestingly, AFM studies reveal that the PBI molecules form well-defined helical fibers in toluene. Both left-handed (M) and right-handed (P) helicities can be observed without any preference for one handedness because the building block is intrinsically achiral. In chapter 4, we tried to influence the M/P enantiomeric ratio by applying external forces. For example, we utilized chiral solvents to generate chiral aggregates with a preferential handedness. AFM analysis of the helices showed that a enantiomeric ratio of about 60: 40 can be achieved by aggregation in chiral solvents R- or S-limonene. Moreover, the long aggregated fibres can align at macroscopic level in vortex flows upon rotary stirring In chapter 5, bulky tetra-phenoxy groups are introduced in the bay area of the PBI gelator. The conjugated core of the new molecule is now distorted because of the steric hindrance. UV/Vis studies reveal a J-type aggregation in apolar solvents like MCH due to intermolecular pi-pi-stacking and hydrogen-bonding interactions. Microscopic studies reveal formation of columnar aggregates in apolar solvent MCH, thus this molecule lacks the ability to form gels in this solvent, but form highly fluorescent lyotropic mesophases at higher concentration. On the other hand, in polar solvents like acetone and dioxane, participation of the solvent molecules in hydrogen bonding significantly reduced the aggregation propensity but enforced the gel formation. The outstanding fluorescence properties of the dye in both J-aggregated viscous lyotropic mesophases and bulk gel phases suggest very promising applications in photonics, photovoltaics, security printing, or as fluorescent sensors. In chapter 6, we did some studies on combining PBI molecules with inorganic gold nanorods. Gold nanorods were synthesized photochemically. By virtue of the thioacetate functionalized PBIs, the rods were connected end to end to form gold nanochains, which were characterized by absorption spectra and TEM measurement. Such chromophore-nanorod hybrids might be applied to guide electromagnetic radiation based on optical antenna technology.}, subject = {Perylenderivate}, language = {en} } @article{KuaiGongDingetal.2018, author = {Kuai, Yue and Gong, Xin and Ding, Liya and Li, Fang and Lei, Lizhen and Gong, Yuqi and Liu, Qingmeng and Tan, Huajiao and Zhang, Xinxia and Liu, Dongyu and Ren, Guoping and Pan, Hongyang and Shi, Yaoyao and Berberich-Siebelt, Friederike and Ma, Zhengrong and Zhou, Ren}, title = {Wilms' tumor 1-associating protein plays an aggressive role in diffuse large B-cell lymphoma and forms a complex with BCL6 via Hsp90}, series = {Cell Communication and Signaling}, volume = {16}, journal = {Cell Communication and Signaling}, doi = {10.1186/s12964-018-0258-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230168}, year = {2018}, abstract = {Background Wilms' tumor 1-associating protein (WTAP) is a nuclear protein, which is ubiquitously expressed in many tissues. Furthermore, in various types of malignancies WTAP is overexpressed and plays a role as an oncogene. The function of WTAP in diffuse large B-cell lymphoma (DLBCL), however, remains unclear. Methods Immunohistochemistry was applied to evaluate the levels of WTAP expression in DLBCL tissues and normal lymphoid tissues. Overexpression and knock-down of WTAP in DLBCL cell lines, verified on mRNA and protein level served to analyze cell proliferation and apoptosis in DLBCL cell lines by flow cytometry. Finally, co-immunoprecipitation (Co-IP), IP, and GST-pull down assessed the interaction of WTAP with Heat shock protein 90 (Hsp90) and B-cell lymphoma 6 (BCL6) as well as determined the extend of its ubiquitinylation. Results WTAP protein levels were consistently upregulated in DLBCL tissues. WTAP promoted DLBCL cell proliferation and improved the ability to confront apoptosis, while knockdown of WTAP in DLBCL cell lines allowed a significant higher apoptosis rate after treatment with Etoposide, an anti-tumor drug. The stable expression of WTAP was depended on Hsp90. In line, we demonstrated that WTAP could form a complex with BCL6 via Hsp90 in vivo and in vitro. Conclusion WTAP is highly expressed in DLBCL, promoting growth and anti-apoptosis in DLBCL cell lines. WTAP is a client protein of Hsp90 and can appear in a complex with BCL6 and Hsp90 in DLBCL. Down-regulation of WTAP could improve the chemotherapeutic treatments in DLBCL.}, language = {en} } @article{Li2022, author = {Li, Chang-An}, title = {Topological states in two-dimensional Su-Schrieffer-Heeger models}, series = {Frontiers in Physics}, volume = {10}, journal = {Frontiers in Physics}, issn = {2296-424X}, doi = {10.3389/fphy.2022.861242}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267328}, year = {2022}, abstract = {We study the topological properties of the generalized two-dimensional (2D) Su-Schrieffer-Heeger (SSH) models. We show that a pair of Dirac points appear in the Brillouin zone (BZ), consisting a semimetallic phase. Interestingly, the locations of these Dirac points are not pinned to any high-symmetry points of the BZ but tunable by model parameters. Moreover, the merging of two Dirac points undergoes a novel topological phase transition, which leads to either a weak topological insulator or a nodal-line metallic phase. We demonstrate these properties by constructing two specific models, which we referred as type-I and type-II 2D SSH models. The feasible experimental platforms to realize our models are also discussed.}, language = {en} } @article{BousquetFarrellCrooksetal.2016, author = {Bousquet, J. and Farrell, J. and Crooks, G. and Hellings, P. and Bel, E. H. and Bewick, M. and Chavannes, N. H. and Correia de Sousa, J. and Cruz, A. A. and Haahtela, T. and Joos, G. and Khaltaev, N. and Malva, J. and Muraro, A. and Nogues, M. and Palkonen, S. and Pedersen, S. and Robalo-Cordeiro, C. and Samolinski, B. and Strandberg, T. and Valiulis, A. and Yorgancioglu, A. and Zuberbier, T. and Bedbrook, A. and Aberer, W. and Adachi, M. and Agusti, A. and Akdis, C. A. and Akdis, M. and Ankri, J. and Alonso, A. and Annesi-Maesano, I. and Ansotegui, I. J. and Anto, J. M. and Arnavielhe, S. and Arshad, H. and Bai, C. and Baiardini, I. and Bachert, C. and Baigenzhin, A. K. and Barbara, C. and Bateman, E. D. and Begh{\´e}, B. and Ben Kheder, A. and Bennoor, K. S. and Benson, M. and Bergmann, K. C. and Bieber, T. and Bindslev-Jensen, C. and Bjermer, L. and Blain, H. and Blasi, F. and Boner, A. L. and Bonini, M. and Bonini, S. and Bosnic-Anticevitch, S. and Boulet, L. P. and Bourret, R. and Bousquet, P. J. and Braido, F. and Briggs, A. H. and Brightling, C. E. and Brozek, J. and Buhl, R. and Burney, P. G. and Bush, A. and Caballero-Fonseca, F. and Caimmi, D. and Calderon, M. A. and Calverley, P. M. and Camargos, P. A. M. and Canonica, G. W. and Camuzat, T. and Carlsen, K. H. and Carr, W. and Carriazo, A. and Casale, T. and Cepeda Sarabia, A. M. and Chatzi, L. and Chen, Y. Z. and Chiron, R. and Chkhartishvili, E. and Chuchalin, A. G. and Chung, K. F. and Ciprandi, G. and Cirule, I. and Cox, L. and Costa, D. J. and Custovic, A. and Dahl, R. and Dahlen, S. E. and Darsow, U. and De Carlo, G. and De Blay, F. and Dedeu, T. and Deleanu, D. and De Manuel Keenoy, E. and Demoly, P. and Denburg, J. A. and Devillier, P. and Didier, A. and Dinh-Xuan, A. T. and Djukanovic, R. and Dokic, D. and Douagui, H. and Dray, G. and Dubakiene, R. and Durham, S. R. and Dykewicz, M. S. and El-Gamal, Y. and Emuzyte, R. and Fabbri, L. M. and Fletcher, M. and Fiocchi, A. and Fink Wagner, A. and Fonseca, J. and Fokkens, W. J. and Forastiere, F. and Frith, P. and Gaga, M. and Gamkrelidze, A. and Garces, J. and Garcia-Aymerich, J. and Gemicioğlu, B. and Gereda, J. E. and Gonz{\´a}lez Diaz, S. and Gotua, M. and Grisle, I. and Grouse, L. and Gutter, Z. and Guzm{\´a}n, M. A. and Heaney, L. G. and Hellquist-Dahl, B. and Henderson, D. and Hendry, A. and Heinrich, J. and Heve, D. and Horak, F. and Hourihane, J. O'. B. and Howarth, P. and Humbert, M. and Hyland, M. E. and Illario, M. and Ivancevich, J. C. and Jardim, J. R. and Jares, E. J. and Jeandel, C. and Jenkins, C. and Johnston, S. L. and Jonquet, O. and Julge, K. and Jung, K. S. and Just, J. and Kaidashev, I. and Kaitov, M. R. and Kalayci, O. and Kalyoncu, A. F. and Keil, T. and Keith, P. K. and Klimek, L. and Koffi N'Goran, B. and Kolek, V. and Koppelman, G. H. and Kowalski, M. L. and Kull, I. and Kuna, P. and Kvedariene, V. and Lambrecht, B. and Lau, S. and Larenas‑Linnemann, D. and Laune, D. and Le, L. T. T. and Lieberman, P. and Lipworth, B. and Li, J. and Lodrup Carlsen, K. and Louis, R. and MacNee, W. and Magard, Y. and Magnan, A. and Mahboub, B. and Mair, A. and Majer, I. and Makela, M. J. and Manning, P. and Mara, S. and Marshall, G. D. and Masjedi, M. R. and Matignon, P. and Maurer, M. and Mavale‑Manuel, S. and Mel{\´e}n, E. and Melo‑Gomes, E. and Meltzer, E. O. and Menzies‑Gow, A. and Merk, H. and Michel, J. P. and Miculinic, N. and Mihaltan, F. and Milenkovic, B. and Mohammad, G. M. Y. and Molimard, M. and Momas, I. and Montilla‑Santana, A. and Morais‑Almeida, M. and Morgan, M. and M{\"o}sges, R. and Mullol, J. and Nafti, S. and Namazova‑Baranova, L. and Naclerio, R. and Neou, A. and Neffen, H. and Nekam, K. and Niggemann, B. and Ninot, G. and Nyembue, T. D. and O'Hehir, R. E. and Ohta, K. and Okamoto, Y. and Okubo, K. and Ouedraogo, S. and Paggiaro, P. and Pali‑Sch{\"o}ll, I. and Panzner, P. and Papadopoulos, N. and Papi, A. and Park, H. S. and Passalacqua, G. and Pavord, I. and Pawankar, R. and Pengelly, R. and Pfaar, O. and Picard, R. and Pigearias, B. and Pin, I. and Plavec, D. and Poethig, D. and Pohl, W. and Popov, T. A. and Portejoie, F. and Potter, P. and Postma, D. and Price, D. and Rabe, K. F. and Raciborski, F. and Radier Pontal, F. and Repka‑Ramirez, S. and Reitamo, S. and Rennard, S. and Rodenas, F. and Roberts, J. and Roca, J. and Rodriguez Ma{\~n}as, L. and et al,}, title = {Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5)}, series = {Clinical and Translational Allergy}, volume = {6}, journal = {Clinical and Translational Allergy}, number = {29}, doi = {10.1186/s13601-016-0116-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166874}, year = {2016}, abstract = {Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.}, language = {en} } @article{SchuchForstnerRappetal.2021, author = {Schuch, Luise A. and Forstner, Maria and Rapp, Christina K. and Li, Yang and Smith, Desiree E. C. and Mendes, Marisa I. and Delhommel, Florent and Sattler, Michael and Emiralioğlu, Nagehan and Taskiran, Ekim Z. and Orhan, Diclehan and Kiper, Nural and Rohlfs, Meino and Jeske, Tim and Hastreiter, Maximilian and Gerstlauer, Michael and Torrent-Vernetta, Alba and Moreno-Gald{\´o}, Antonio and Kammer, Birgit and Brasch, Frank and Reu-Hofer, Simone and Griese, Matthias}, title = {FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs!}, series = {Clinical Genetics}, volume = {99}, journal = {Clinical Genetics}, number = {6}, doi = {10.1111/cge.13943}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238827}, pages = {789 -- 801}, year = {2021}, abstract = {Aminoacyl-tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non-canonical) functions outside of translation. Bi-allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi-allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl-tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient-derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non-canonical function in FARS1-associated recessive disease.}, language = {en} } @article{LiGuanGaoetal.2020, author = {Li, Ningbo and Guan, Lianwu and Gao, Yanbin and Du, Shitong and Wu, Menghao and Guang, Xingxing and Cong, Xiaodan}, title = {Indoor and outdoor low-cost seamless integrated navigation system based on the integration of INS/GNSS/LIDAR system}, series = {Remote Sensing}, volume = {12}, journal = {Remote Sensing}, number = {19}, issn = {2072-4292}, doi = {10.3390/rs12193271}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216229}, year = {2020}, abstract = {Global Navigation Satellite System (GNSS) provides accurate positioning data for vehicular navigation in open outdoor environment. In an indoor environment, Light Detection and Ranging (LIDAR) Simultaneous Localization and Mapping (SLAM) establishes a two-dimensional map and provides positioning data. However, LIDAR can only provide relative positioning data and it cannot directly provide the latitude and longitude of the current position. As a consequence, GNSS/Inertial Navigation System (INS) integrated navigation could be employed in outdoors, while the indoors part makes use of INS/LIDAR integrated navigation and the corresponding switching navigation will make the indoor and outdoor positioning consistent. In addition, when the vehicle enters the garage, the GNSS signal will be blurred for a while and then disappeared. Ambiguous GNSS satellite signals will lead to the continuous distortion or overall drift of the positioning trajectory in the indoor condition. Therefore, an INS/LIDAR seamless integrated navigation algorithm and a switching algorithm based on vehicle navigation system are designed. According to the experimental data, the positioning accuracy of the INS/LIDAR navigation algorithm in the simulated environmental experiment is 50\% higher than that of the Dead Reckoning (DR) algorithm. Besides, the switching algorithm developed based on the INS/LIDAR integrated navigation algorithm can achieve 80\% success rate in navigation mode switching.}, language = {en} } @article{GrausLiRathjeetal.2023, author = {Graus, Dorothea and Li, Kunkun and Rathje, Jan M. and Ding, Meiqi and Krischke, Markus and M{\"u}ller, Martin J. and Cuin, Tracey Ann and Al-Rasheid, Khaled A. S. and Scherzer, S{\"o}nke and Marten, Irene and Konrad, Kai R. and Hedrich, Rainer}, title = {Tobacco leaf tissue rapidly detoxifies direct salt loads without activation of calcium and SOS signaling}, series = {New Phytologist}, volume = {237}, journal = {New Phytologist}, number = {1}, doi = {10.1111/nph.18501}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312152}, pages = {217 -- 231}, year = {2023}, abstract = {Salt stress is a major abiotic stress, responsible for declining agricultural productivity. Roots are regarded as hubs for salt detoxification, however, leaf salt concentrations may exceed those of roots. How mature leaves manage acute sodium chloride (NaCl) stress is mostly unknown. To analyze the mechanisms for NaCl redistribution in leaves, salt was infiltrated into intact tobacco leaves. It initiated pronounced osmotically-driven leaf movements. Leaf downward movement caused by hydro-passive turgor loss reached a maximum within 2 h. Salt-driven cellular water release was accompanied by a transient change in membrane depolarization but not an increase in cytosolic calcium ion (Ca\(^{2+}\)) level. Nonetheless, only half an hour later, the leaves had completely regained turgor. This recovery phase was characterized by an increase in mesophyll cell plasma membrane hydrogen ion (H\(^{+}\)) pumping, a salt uptake-dependent cytosolic alkalization, and a return of the apoplast osmolality to pre-stress levels. Although, transcript numbers of abscisic acid- and Salt Overly Sensitive pathway elements remained unchanged, salt adaptation depended on the vacuolar H\(^{+}\)/Na\(^{+}\)-exchanger NHX1. Altogether, tobacco leaves can detoxify sodium ions (Na\(^{+}\)) rapidly even under massive salt loads, based on pre-established posttranslational settings and NHX1 cation/H+ antiport activity. Unlike roots, signaling and processing of salt stress in tobacco leaves does not depend on Ca\(^{2+}\) signaling.}, language = {en} } @article{JiangOronClarketal.2016, author = {Jiang, Yuxiang and Oron, Tal Ronnen and Clark, Wyatt T. and Bankapur, Asma R. and D'Andrea, Daniel and Lepore, Rosalba and Funk, Christopher S. and Kahanda, Indika and Verspoor, Karin M. and Ben-Hur, Asa and Koo, Da Chen Emily and Penfold-Brown, Duncan and Shasha, Dennis and Youngs, Noah and Bonneau, Richard and Lin, Alexandra and Sahraeian, Sayed M. E. and Martelli, Pier Luigi and Profiti, Giuseppe and Casadio, Rita and Cao, Renzhi and Zhong, Zhaolong and Cheng, Jianlin and Altenhoff, Adrian and Skunca, Nives and Dessimoz, Christophe and Dogan, Tunca and Hakala, Kai and Kaewphan, Suwisa and Mehryary, Farrokh and Salakoski, Tapio and Ginter, Filip and Fang, Hai and Smithers, Ben and Oates, Matt and Gough, Julian and T{\"o}r{\"o}nen, Petri and Koskinen, Patrik and Holm, Liisa and Chen, Ching-Tai and Hsu, Wen-Lian and Bryson, Kevin and Cozzetto, Domenico and Minneci, Federico and Jones, David T. and Chapman, Samuel and BKC, Dukka and Khan, Ishita K. and Kihara, Daisuke and Ofer, Dan and Rappoport, Nadav and Stern, Amos and Cibrian-Uhalte, Elena and Denny, Paul and Foulger, Rebecca E. and Hieta, Reija and Legge, Duncan and Lovering, Ruth C. and Magrane, Michele and Melidoni, Anna N. and Mutowo-Meullenet, Prudence and Pichler, Klemens and Shypitsyna, Aleksandra and Li, Biao and Zakeri, Pooya and ElShal, Sarah and Tranchevent, L{\´e}on-Charles and Das, Sayoni and Dawson, Natalie L. and Lee, David and Lees, Jonathan G. and Sillitoe, Ian and Bhat, Prajwal and Nepusz, Tam{\´a}s and Romero, Alfonso E. and Sasidharan, Rajkumar and Yang, Haixuan and Paccanaro, Alberto and Gillis, Jesse and Sede{\~n}o-Cort{\´e}s, Adriana E. and Pavlidis, Paul and Feng, Shou and Cejuela, Juan M. and Goldberg, Tatyana and Hamp, Tobias and Richter, Lothar and Salamov, Asaf and Gabaldon, Toni and Marcet-Houben, Marina and Supek, Fran and Gong, Qingtian and Ning, Wei and Zhou, Yuanpeng and Tian, Weidong and Falda, Marco and Fontana, Paolo and Lavezzo, Enrico and Toppo, Stefano and Ferrari, Carlo and Giollo, Manuel and Piovesan, Damiano and Tosatto, Silvio C. E. and del Pozo, Angela and Fern{\´a}ndez, Jos{\´e} M. and Maietta, Paolo and Valencia, Alfonso and Tress, Michael L. and Benso, Alfredo and Di Carlo, Stefano and Politano, Gianfranco and Savino, Alessandro and Rehman, Hafeez Ur and Re, Matteo and Mesiti, Marco and Valentini, Giorgio and Bargsten, Joachim W. and van Dijk, Aalt D. J. and Gemovic, Branislava and Glisic, Sanja and Perovic, Vladmir and Veljkovic, Veljko and Almeida-e-Silva, Danillo C. and Vencio, Ricardo Z. N. and Sharan, Malvika and Vogel, J{\"o}rg and Kansakar, Lakesh and Zhang, Shanshan and Vucetic, Slobodan and Wang, Zheng and Sternberg, Michael J. E. and Wass, Mark N. and Huntley, Rachael P. and Martin, Maria J. and O'Donovan, Claire and Robinson, Peter N. and Moreau, Yves and Tramontano, Anna and Babbitt, Patricia C. and Brenner, Steven E. and Linial, Michal and Orengo, Christine A. and Rost, Burkhard and Greene, Casey S. and Mooney, Sean D. and Friedberg, Iddo and Radivojac, Predrag and Veljkovic, Nevena}, title = {An expanded evaluation of protein function prediction methods shows an improvement in accuracy}, series = {Genome Biology}, volume = {17}, journal = {Genome Biology}, number = {184}, doi = {10.1186/s13059-016-1037-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166293}, year = {2016}, abstract = {Background A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent.}, language = {en} } @article{WuWinklerWieseretal.2015, author = {Wu, Lingdan and Winkler, Markus H. and Wieser, Matthias J. and Andreatta, Marta and Li, Yonghui and Pauli, Paul}, title = {Emotion regulation in heavy smokers: experiential, expressive and physiological consequences of cognitive reappraisal}, series = {Frontiers in Psychology}, volume = {6}, journal = {Frontiers in Psychology}, number = {1555}, doi = {10.3389/fpsyg.2015.01555}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145225}, year = {2015}, abstract = {Emotion regulation dysfunctions are assumed to contribute to the development of tobacco addiction and relapses among smokers attempting to quit. To further examine this hypothesis, the present study compared heavy smokers with non-smokers (NS) in a reappraisal task. Specifically, we investigated whether non-deprived smokers (NDS) and deprived smokers (DS) differ from non-smokers in cognitive emotion regulation and whether there is an association between the outcome of emotion regulation and the cigarette craving. Sixty-five participants (23 non-smokers, 22 NDS, and 20 DS) were instructed to down-regulate emotions by reappraising negative or positive pictorial scenarios. Self-ratings of valence, arousal, and cigarette craving as well as facial electromyography and electroencephalograph activities were measured. Ratings, facial electromyography, and electroencephalograph data indicated that both NDS and DS performed comparably to nonsmokers in regulating emotional responses via reappraisal, irrespective of the valence of pictorial stimuli. Interestingly, changes in cigarette craving were positively associated with regulation of emotional arousal irrespective of emotional valence. These results suggest that heavy smokers are capable to regulate emotion via deliberate reappraisal and smokers' cigarette craving is associated with emotional arousal rather than emotional valence. This study provides preliminary support for the therapeutic use of reappraisal to replace maladaptive emotion-regulation strategies in nicotine addicts.}, language = {en} } @article{KremerKivitzSimonCamposetal.2015, author = {Kremer, Joel M and Kivitz, Alan J and Simon-Campos, Jesus A and Nasonov, Evgeny L and Tony, Hans-Peter and Lee, Soo-Kon and Vlahos, Bonnie and Hammond, Constance and Bukowski, Jack and Li, Huihua and Schulman, Seth L and Raber, Susan and Zuckerman, Andrea and Isaacs, John D}, title = {Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial}, series = {Arthritis Research \& Therapy}, volume = {17}, journal = {Arthritis Research \& Therapy}, number = {95}, doi = {10.1186/s13075-015-0612-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143409}, year = {2015}, abstract = {Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA. Methods: This was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged \(\geq\)18 years with active RA. Patients were randomised 2: 1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib -> placebo); or oral placebo BID in both Periods (placebo. placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft-Gault equation) and SCr; efficacy; and safety. Results: 148 patients were randomised to tofacitinib -> placebo (N = 97) or placebo -> placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8\% (90\% confidence interval [CI]: 2\%, 14\%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study - ratio (tofacitinib -> placebo/placebo -> placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90\% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo -> placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies. Conclusion: Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance.}, language = {en} } @article{LiuChenGaoetal.2017, author = {Liu, Han and Chen, Chunhai and Gao, Zexia and Min, Jiumeng and Gu, Yongming and Jian, Jianbo and Jiang, Xiewu and Cai, Huimin and Ebersberger, Ingo and Xu, Meng and Zhang, Xinhui and Chen, Jianwei and Luo, Wei and Chen, Boxiang and Chen, Junhui and Liu, Hong and Li, Jiang and Lai, Ruifang and Bai, Mingzhou and Wei, Jin and Yi, Shaokui and Wang, Huanling and Cao, Xiaojuan and Zhou, Xiaoyun and Zhao, Yuhua and Wei, Kaijian and Yang, Ruibin and Liu, Bingnan and Zhao, Shancen and Fang, Xiaodong and Schartl, Manfred and Qian, Xueqiao and Wang, Weimin}, title = {The draft genome of blunt snout bream (Megalobrama amblycephala) reveals the development of intermuscular bone and adaptation to herbivorous diet}, series = {GigaScience}, volume = {6}, journal = {GigaScience}, number = {7}, doi = {10.1093/gigascience/gix039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170844}, year = {2017}, abstract = {The blunt snout bream Megalobrama amblycephala is the economically most important cyprinid fish species. As an herbivore, it can be grown by eco-friendly and resource-conserving aquaculture. However, the large number of intermuscular bones in the trunk musculature is adverse to fish meat processing and consumption. As a first towards optimizing this aquatic livestock, we present a 1.116-Gb draft genome of M. amblycephala, with 779.54 Mb anchored on 24 linkage groups. Integrating spatiotemporal transcriptome analyses, we show that intermuscular bone is formed in the more basal teleosts by intramembranous ossification and may be involved in muscle contractibility and coordinating cellular events. Comparative analysis revealed that olfactory receptor genes, especially of the beta type, underwent an extensive expansion in herbivorous cyprinids, whereas the gene for the umami receptor T1R1 was specifically lost in M. amblycephala. The composition of gut microflora, which contributes to the herbivorous adaptation of M. amblycephala, was found to be similar to that of other herbivores. As a valuable resource for the improvement of M. amblycephala livestock, the draft genome sequence offers new insights into the development of intermuscular bone and herbivorous adaptation.}, language = {en} } @article{SanchezMaldonadoMonizDiezterHorstetal.2020, author = {S{\´a}nchez-Maldonado, Jose Manuel and Mo{\~n}iz-D{\´i}ez, Ana and ter Horst, Rob and Campa, Daniele and Cabrera-Serrano, Antonio Jos{\´e} and Mart{\´i}nez-Bueno, Manuel and Garrido-Collado, Mar{\´i}a del Pilar and Hern{\´a}ndez-Mohedo, Francisca and Fern{\´a}ndez-Puerta, Laura and L{\´o}pez-Nevot, Miguel {\´A}ngel and Cunha, Cristina and Gonz{\´a}lez-Sierra, Pedro Antonio and Springer, Jan and Lackner, Michaela and Alcazar-Fuoli, Laura and Fianchi, Luana and Aguado, Jos{\´e} Mar{\´i}a and Pagano, Livio and L{\´o}pez-Fern{\´a}ndez, Elisa and Clavero, Esther and Potenza, Leonardo and Luppi, Mario and Moratalla, Lucia and Solano, Carlos and Sampedro, Antonio and Cuenca-Estrella, Manuel and Lass-Fl{\"o}rl, Cornelia and Canzian, Federico and Loeffler, Juergen and Li, Yang and Einsele, Hermann and Netea, Mihai G. and V{\´a}zquez, Lourdes and Carvalho, Agostinho and Jurado, Manuel and Sainz, Juan}, title = {Polymorphisms within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis: a two-stage case control study in the context of the aspBIOmics consortium}, series = {Journal of Fungi}, volume = {7}, journal = {Journal of Fungi}, number = {1}, issn = {2309-608X}, doi = {10.3390/jof7010004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220107}, year = {2020}, abstract = {Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4\(_{rs7526628T/T}\) genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4\(_{rs7526628T}\) allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2\(_{rs12137965G}\) allele increased the risk of IA by 60\% (p = 0.0017), whereas each copy of the MAPKAPK2\(_{rs17013271T}\) allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2\(_{rs12137965G}\) allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2\(_{rs17013271T}\) allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.}, language = {en} } @article{HellmuthKlingenbergLietal.2021, author = {Hellmuth, Kathrin and Klingenberg, Christian and Li, Qin and Tang, Min}, title = {Multiscale convergence of the inverse problem for chemotaxis in the Bayesian setting}, series = {Computation}, volume = {9}, journal = {Computation}, number = {11}, issn = {2079-3197}, doi = {10.3390/computation9110119}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250216}, year = {2021}, abstract = {Chemotaxis describes the movement of an organism, such as single or multi-cellular organisms and bacteria, in response to a chemical stimulus. Two widely used models to describe the phenomenon are the celebrated Keller-Segel equation and a chemotaxis kinetic equation. These two equations describe the organism's movement at the macro- and mesoscopic level, respectively, and are asymptotically equivalent in the parabolic regime. The way in which the organism responds to a chemical stimulus is embedded in the diffusion/advection coefficients of the Keller-Segel equation or the turning kernel of the chemotaxis kinetic equation. Experiments are conducted to measure the time dynamics of the organisms' population level movement when reacting to certain stimulation. From this, one infers the chemotaxis response, which constitutes an inverse problem. In this paper, we discuss the relation between both the macro- and mesoscopic inverse problems, each of which is associated with two different forward models. The discussion is presented in the Bayesian framework, where the posterior distribution of the turning kernel of the organism population is sought. We prove the asymptotic equivalence of the two posterior distributions.}, language = {en} } @article{MendeLetunicHuertaCepasetal.2017, author = {Mende, Daniel R. and Letunic, Ivica and Huerta-Cepas, Jaime and Li, Simone S. and Forslund, Kristoffer and Sunagawa, Shinichi and Bork, Peer}, title = {proGenomes: a resource for consistent functional and taxonomic annotations of prokaryotic genomes}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {D1}, doi = {10.1093/nar/gkw989}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171987}, pages = {D529-D534}, year = {2017}, abstract = {The availability of microbial genomes has opened many new avenues of research within microbiology. This has been driven primarily by comparative genomics approaches, which rely on accurate and consistent characterization of genomic sequences. It is nevertheless difficult to obtain consistent taxonomic and integrated functional annotations for defined prokaryotic clades. Thus, we developed proGenomes, a resource that provides user-friendly access to currently 25 038 high-quality genomes whose sequences and consistent annotations can be retrieved individually or by taxonomic clade. These genomes are assigned to 5306 consistent and accurate taxonomic species clusters based on previously established methodology. proGenomes also contains functional information for almost 80 million protein-coding genes, including a comprehensive set of general annotations and more focused annotations for carbohydrate-active enzymes and antibiotic resistance genes. Additionally, broad habitat information is provided for many genomes. All genomes and associated information can be downloaded by user-selected clade or multiple habitat-specific sets of representative genomes. We expect that the availability of high-quality genomes with comprehensive functional annotations will promote advances in clinical microbial genomics, functional evolution and other subfields of microbiology. proGenomes is available at http://progenomes.embl.de.}, language = {en} } @article{HollenhorstJurastowNandigamaetal.2020, author = {Hollenhorst, Monika I. and Jurastow, Innokentij and Nandigama, Rajender and Appenzeller, Silke and Li, Lei and Vogel, J{\"o}rg and Wiederhold, Stephanie and Althaus, Mike and Empting, Martin and Altm{\"u}ller, Janine and Hirsch, Anna K. H. and Flockerzi, Veit and Canning, Brendan J. and Saliba, Antoine-Emmanuel and Krasteva-Christ, Gabriela}, title = {Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling}, series = {The FASEB Journal}, volume = {34}, journal = {The FASEB Journal}, number = {1}, doi = {10.1096/fj.201901314RR}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213516}, pages = {316 -- 332}, year = {2020}, abstract = {For protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter "taste" substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca\(^{2+}\)]\(_{i}\) in BC and subsequent ACh-release. ACh-release is regulated in an autocrine manner. While the muscarinic ACh-receptors M3R and M1R are activating, M2R is inhibitory. Paracrine effects of ACh released in response to denatonium included increased [Ca\(^{2+}\)]\(_{i}\) in ciliated cells. Stimulation by denatonium or with Pseudomonas quinolone signaling molecules led to an increase in mucociliary clearance in explanted tracheae that was Trpm5- and M3R-mediated. We show that ACh-release from BC via the bitter taste cascade leads to immediate paracrine protective responses that can be boosted in an autocrine manner. This mechanism represents the initial step for the activation of innate immune responses against pathogens in the airways.}, language = {en} } @article{LiStoecklLukasetal.2020, author = {Li, Shushan and St{\"o}ckl, Sabine and Lukas, Christoph and G{\"o}tz, Julia and Herrmann, Marietta and Federlin, Marianne and Gr{\"a}ssel, Susanne}, title = {hBMSC-Derived Extracellular Vesicles Attenuate IL-1β-Induced Catabolic Effects on OA-Chondrocytes by Regulating Pro-inflammatory Signaling Pathways}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.603598}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219749}, year = {2020}, abstract = {Background: Human bone marrow-derived mesenchymal stromal cells (hBMSCs) provide a promising therapeutic approach in the cell-based therapy of osteoarthritis (OA). However, several disadvantages evolved recently, including immune responses of the host and regulatory hurdles, making it necessary to search for alternative treatment options. Extracellular vesicles (EVs) are released by multiple cell types and tissues into the extracellular microenvironment, acting as message carriers during intercellular communication. Here, we investigate putative protective effects of hBMSC-derived EVs as a cell-free approach, on IL-1β-stimulated chondrocytes obtained from OA-patients. Methods: EVs were harvested from the cell culture supernatant of hBMSCs by a sequential ultracentrifugation process. Western blot, scanning electron microscopy (SEM), and nanoparticle tracking analysis (NTA) were performed to characterize the purified particles as EVs. Intracellular incorporation of EVs, derived from PHK26-labeled hBMSCs, was tested by adding the labeled EVs to human OA chondrocytes (OA-CH), followed by fluorescence microscopy. Chondrocytes were pre-stimulated with IL-1β for 24 h, followed by EVs treatment for 24 h. Subsequently, proliferation, apoptosis, and migration (wound healing) were analyzed via BrdU assay, caspase 3/7 assay, and scratch assay, respectively. With qRT-PCR, the relative expression level of anabolic and catabolic genes was determined. Furthermore, immunofluorescence microscopy and western blot were performed to evaluate the protein expression and phosphorylation levels of Erk1/2, PI3K/Akt, p38, TAK1, and NF-κB as components of pro-inflammatory signaling pathways in OA-CH. Results: EVs from hBMSCs (hBMSC-EVs) promote proliferation and reduce apoptosis of OA-CH and IL-1β-stimulated OA-CH. Moreover, hBMSC-EVs attenuate IL-1β-induced reduction of chondrocyte migration. Furthermore, hBMSC-EVs increase gene expression of PRG4, BCL2, and ACAN (aggrecan) and decrease gene expression of MMP13, ALPL, and IL1ß in OA-CH. Notably, COL2A1, SOX9, BCL2, ACAN, and COMP gene expression levels were significantly increased in IL-1β+ EV groups compared with those IL-1β groups without EVs, whereas the gene expression levels of COLX, IL1B, MMP13, and ALPL were significantly decreased in IL-1β+ EV groups compared to IL-1β groups without EVs. In addition, the phosphorylation status of Erk1/2, PI3K/Akt, p38, TAK1, and NF-κB signaling molecules, induced by IL-1β, is prevented by hBMSC- EVs. Conclusion: EVs derived from hBMSCs alleviated IL-1β-induced catabolic effects on OA-CH via promoting proliferation and migration and reducing apoptosis, probably via downregulation of IL-1ß-activated pro-inflammatory Erk1/2, PI3K/Akt, p38, TAK1, and NF-κB signaling pathways. EVs released from BMSCs may be considered as promising cell-free intervention strategy in cartilage regenerative medicine, avoiding several adverse effects of cell-based regenerative approaches.}, language = {en} } @article{NiedermairLukasLietal.2020, author = {Niedermair, Tanja and Lukas, Christoph and Li, Shushan and St{\"o}ckl, Sabine and Craiovan, Benjamin and Brochhausen, Christoph and Federlin, Marianne and Herrmann, Marietta and Gr{\"a}ssel, Susanne}, title = {Influence of Extracellular Vesicles Isolated From Osteoblasts of Patients With Cox-Arthrosis and/or Osteoporosis on Metabolism and Osteogenic Differentiation of BMSCs}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.615520}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219902}, year = {2020}, abstract = {Background: Studies with extracellular vesicles (EVs), including exosomes, isolated from mesenchymal stem cells (MSC) indicate benefits for the treatment of musculoskeletal pathologies as osteoarthritis (OA) and osteoporosis (OP). However, little is known about intercellular effects of EVs derived from pathologically altered cells that might influence the outcome by counteracting effects from "healthy" MSC derived EVs. We hypothesize, that EVs isolated from osteoblasts of patients with hip OA (coxarthrosis/CA), osteoporosis (OP), or a combination of both (CA/OP) might negatively affect metabolism and osteogenic differentiation of bone-marrow derived (B)MSCs. Methods: Osteoblasts, isolated from bone explants of CA, OP, and CA/OP patients, were compared regarding growth, viability, and osteogenic differentiation capacity. Structural features of bone explants were analyzed via μCT. EVs were isolated from supernatant of na{\"i}ve BMSCs and CA, OP, and CA/OP osteoblasts (osteogenic culture for 35 days). BMSC cultures were stimulated with EVs and subsequently, cell metabolism, osteogenic marker gene expression, and osteogenic differentiation were analyzed. Results: Trabecular bone structure was different between the three groups with lowest number and highest separation in the CA/OP group. Viability and Alizarin red staining increased over culture time in CA/OP osteoblasts whereas growth of osteoblasts was comparable. Alizarin red staining was by trend higher in CA compared to OP osteoblasts after 35 days and ALP activity was higher after 28 and 35 days. Stimulation of BMSC cultures with CA, OP, and CA/OP EVs did not affect proliferation but increased caspase 3/7-activity compared to unstimulated BMSCs. BMSC viability was reduced after stimulation with CA and CA/OP EVs compared to unstimulated BMSCs or stimulation with OP EVs. ALP gene expression and activity were reduced in BMSCs after stimulation with CA, OP, and CA/OP EVs. Stimulation of BMSCs with CA EVs reduced Alizarin Red staining by trend. Conclusion: Stimulation of BMSCs with EVs isolated from CA, OP, and CA/OP osteoblasts had mostly catabolic effects on cell metabolism and osteogenic differentiation irrespective of donor pathology and reflect the impact of tissue microenvironment on cell metabolism. These catabolic effects are important for understanding differences in effects of EVs on target tissues/cells when harnessing them as therapeutic drugs.}, language = {en} } @article{DuLauterbachLietal.2020, author = {Du, Shitong and Lauterbach, Helge A. and Li, Xuyou and Demisse, Girum G. and Borrmann, Dorit and N{\"u}chter, Andreas}, title = {Curvefusion — A Method for Combining Estimated Trajectories with Applications to SLAM and Time-Calibration}, series = {Sensors}, volume = {20}, journal = {Sensors}, number = {23}, issn = {1424-8220}, doi = {10.3390/s20236918}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219988}, year = {2020}, abstract = {Mapping and localization of mobile robots in an unknown environment are essential for most high-level operations like autonomous navigation or exploration. This paper presents a novel approach for combining estimated trajectories, namely curvefusion. The robot used in the experiments is equipped with a horizontally mounted 2D profiler, a constantly spinning 3D laser scanner and a GPS module. The proposed algorithm first combines trajectories from different sensors to optimize poses of the planar three degrees of freedom (DoF) trajectory, which is then fed into continuous-time simultaneous localization and mapping (SLAM) to further improve the trajectory. While state-of-the-art multi-sensor fusion methods mainly focus on probabilistic methods, our approach instead adopts a deformation-based method to optimize poses. To this end, a similarity metric for curved shapes is introduced into the robotics community to fuse the estimated trajectories. Additionally, a shape-based point correspondence estimation method is applied to the multi-sensor time calibration. Experiments show that the proposed fusion method can achieve relatively better accuracy, even if the error of the trajectory before fusion is large, which demonstrates that our method can still maintain a certain degree of accuracy in an environment where typical pose estimation methods have poor performance. In addition, the proposed time-calibration method also achieves high accuracy in estimating point correspondences.}, language = {en} } @article{TruongvanLiMisraetal.2022, author = {Truongvan, Ngoc and Li, Shurong and Misra, Mohit and Kuhn, Monika and Schindelin, Hermann}, title = {Structures of UBA6 explain its dual specificity for ubiquitin and FAT10}, series = {Nature Communications}, volume = {13}, journal = {Nature Communications}, doi = {10.1038/s41467-022-32040-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301161}, year = {2022}, abstract = {The covalent modification of target proteins with ubiquitin or ubiquitin-like modifiers is initiated by E1 activating enzymes, which typically transfer a single modifier onto cognate conjugating enzymes. UBA6 is an unusual E1 since it activates two highly distinct modifiers, ubiquitin and FAT10. Here, we report crystal structures of UBA6 in complex with either ATP or FAT10. In the UBA6-FAT10 complex, the C-terminal domain of FAT10 binds to where ubiquitin resides in the UBA1-ubiquitin complex, however, a switch element ensures the alternate recruitment of either modifier. Simultaneously, the N-terminal domain of FAT10 interacts with the 3-helix bundle of UBA6. Site-directed mutagenesis identifies residues permitting the selective activation of either ubiquitin or FAT10. These results pave the way for studies investigating the activation of either modifier by UBA6 in physiological and pathophysiological settings.}, language = {en} } @article{GoettschBeerenwinkelDengetal.2021, author = {Goettsch, Winfried and Beerenwinkel, Niko and Deng, Li and D{\"o}lken, Lars and Dutilh, Bas E. and Erhard, Florian and Kaderali, Lars and Kleist, Max von and Marquet, Roland and Matthijnssens, Jelle and McCallin, Shawna and McMahon, Dino and Rattei, Thomas and Van Rij, Ronald P. and Robertson, David L. and Schwemmle, Martin and Stern-Ginossar, Noam and Marz, Manja}, title = {ITN—VIROINF: Understanding (harmful) virus-host interactions by linking virology and bioinformatics}, series = {Viruses}, volume = {13}, journal = {Viruses}, number = {5}, issn = {1999-4915}, doi = {10.3390/v13050766}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236687}, year = {2021}, abstract = {Many recent studies highlight the fundamental importance of viruses. Besides their important role as human and animal pathogens, their beneficial, commensal or harmful functions are poorly understood. By developing and applying tailored bioinformatical tools in important virological models, the Marie Skłodowska-Curie Initiative International Training Network VIROINF will provide a better understanding of viruses and the interaction with their hosts. This will open the door to validate methods of improving viral growth, morphogenesis and development, as well as to control strategies against unwanted microorganisms. The key feature of VIROINF is its interdisciplinary nature, which brings together virologists and bioinformaticians to achieve common goals.}, language = {en} } @article{HaringCrandallCarboneetal.2019, author = {Haring, Bernhard and Crandall, Carolyn J and Carbone, Laura and Liu, Simin and Li, Wenjun and Johnson, Karen C and Wactawski-Wende, Jean and Shadyab, Aladdin H and Gass, Margery L and Kamensky, Victor and Cauley, Jane A and Wassertheil-Smoller, Sylvia}, title = {Lipoprotein(a) plasma levels, bone mineral density and risk of hip fracture: a post hoc analysis of the Women's Health Initiative, USA}, series = {BMJ Open}, volume = {9}, journal = {BMJ Open}, doi = {10.1136/bmjopen-2018-027257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201139}, pages = {e027257}, year = {2019}, abstract = {Objectives Elevated Lipoprotein(a) (Lp[a]) is a well-known risk factor for cardiovascular disease. However, its roles in bone metabolism and fracture risk are unclear. We therefore investigated whether plasma Lp(a) levels were associated with bone mineral density (BMD) and incident hip fractures in a large cohort of postmenopausal women. Design Post hoc analysis of data from the Women's Health Initiative (WHI), USA. Setting 40 clinical centres in the USA. Participants The current analytical cohort consisted of 9698 white, postmenopausal women enrolled in the WHI, a national prospective study investigating determinants of chronic diseases including heart disease, breast and colorectal cancers and osteoporotic fractures among postmenopausal women. Recruitment for WHI took place from 1 October 1993 to 31 December 1998. Exposures Plasma Lp(a) levels were measured at baseline. Outcome measures Incident hip fractures were ascertained annually and confirmed by medical records with follow-up through 29 August 2014. BMD at the femoral neck was measured by dual X-ray absorptiometry in a subset of participants at baseline. Statistical analyses Cox proportional hazards and logistic regression models were used to evaluate associations of quartiles of plasma Lp(a) levels with hip fracture events and hip BMD T-score, respectively. Results During a mean follow-up of 13.8 years, 454 incident cases of hip fracture were observed. In analyses adjusting for confounding variables including age, body mass index, history of hysterectomy, smoking, physical activity, diabetes mellitus, general health status, cardiovascular disease, use of menopausal hormone therapy, use of bisphosphonates, calcitonin or selective-oestrogen receptor modulators, baseline dietary and supplemental calcium and vitamin D intake and history of fracture, no significant association of plasma Lp(a) levels with low hip BMD T-score or hip fracture risk was detected. Conclusions These findings suggest that plasma Lp(a) levels are not related to hip BMD T-score or hip fracture events in postmenopausal women.}, language = {en} } @article{RuppertFranzSaratisetal.2017, author = {Ruppert, Manuela and Franz, Mirjam and Saratis, Anastasios and Escarcena, Laura Velo and Hendrich, Oliver and Gooi, Li Ming and Schwenkert, Isabell and Klebes, Ansgar and Scholz, Henrike}, title = {Hangover links nuclear RNA signaling to cAMP regulation via the phosphodiesterase 4d ortholog dunce}, series = {Cell Reports}, volume = {18}, journal = {Cell Reports}, number = {2}, doi = {10.1016/j.celrep.2016.12.048}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171950}, pages = {533-544}, year = {2017}, abstract = {The hangover gene defines a cellular stress pathway that is required for rapid ethanol tolerance in Drosophila melanogaster. To understand how cellular stress changes neuronal function, we analyzed Hangover function on a cellular and neuronal level. We provide evidence that Hangover acts as a nuclear RNA binding protein and we identified the phosphodiesterase 4d ortholog dunce as a target RNA. We generated a transcript-specific dunce mutant that is impaired not only in ethanol tolerance but also in the cellular stress response. At the neuronal level, Dunce and Hangover are required in the same neuron pair to regulate experience-dependent motor output. Within these neurons, two cyclic AMP (cAMP)-dependent mechanisms balance the degree of tolerance. The balance is achieved by feedback regulation of Hangover and dunce transcript levels. This study provides insight into how nuclear Hangover/RNA signaling is linked to the cytoplasmic regulation of cAMP levels and results in neuronal adaptation and behavioral changes.}, language = {en} } @article{HerrmannDiederichsMelniketal.2021, author = {Herrmann, Marietta and Diederichs, Solvig and Melnik, Svitlana and Riegger, Jana and Trivanović, Drenka and Li, Shushan and Jenei-Lanzl, Zsuzsa and Brenner, Rolf E. and Huber-Lang, Markus and Zaucke, Frank and Schildberg, Frank A. and Gr{\"a}ssel, Susanne}, title = {Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.624096}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222882}, year = {2021}, abstract = {The incidence of musculoskeletal diseases is steadily increasing with aging of the population. In the past years, extracellular vesicles (EVs) have gained attention in musculoskeletal research. EVs have been associated with various musculoskeletal pathologies as well as suggested as treatment option. EVs play a pivotal role in communication between cells and their environment. Thereby, the EV cargo is highly dependent on their cellular origin. In this review, we summarize putative mechanisms by which EVs can contribute to musculoskeletal tissue homeostasis, regeneration and disease, in particular matrix remodeling and mineralization, pro-angiogenic effects and immunomodulatory activities. Mesenchymal stromal cells (MSCs) present the most frequently used cell source for EV generation for musculoskeletal applications, and herein we discuss how the MSC phenotype can influence the cargo and thus the regenerative potential of EVs. Induced pluripotent stem cell-derived mesenchymal progenitor cells (iMPs) may overcome current limitations of MSCs, and iMP-derived EVs are discussed as an alternative strategy. In the last part of the article, we focus on therapeutic applications of EVs and discuss both practical considerations for EV production and the current state of EV-based therapies.}, language = {en} } @techreport{AngnideBielitskaBorchertetal.2020, author = {Angnide, Enarile and Bielitska, Iryna and Borchert, Leon and Braun, Louisa and B{\"u}hler, Pascal and Chen, Xinyue and Ho, Katherina and Hofmann, Lena and Kebekus, Melvin and Kubsch, Torbj{\"o}rn and Li, Alexander and Lin, Simon and Mischer, Andreas and Mogus, Mateja and Schmid, Fabian and Schneidawind, Luisa and Voss, Manuela and Wilson, Claire and Wieteska, Filip and Yu, Linda}, title = {Chinese Entanglements in Lower Franconian Business}, editor = {Lindner, Jonas and Fischer, Doris}, doi = {10.25972/OPUS-20987}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209876}, pages = {219}, year = {2020}, abstract = {Using own survey data and interviews, this study analyzes how businesses in Lower Franconia (Unterfranken) are entangled with China. Starting with a bird's-eye-view of the current situation, the study goes on to provide valuable insights from five specific industries. The study shows that a majority of the analyzed firms have some sort of ties to China, be it through Chinese customers, import/export activities, or else.}, subject = {China}, language = {en} } @article{delAlamoLiMunketal.2020, author = {del Alamo, Miguel and Li, Housen and Munk, Axel and Werner, Frank}, title = {Variational Multiscale Nonparametric Regression: Algorithms and Implementation}, series = {Algorithms}, volume = {13}, journal = {Algorithms}, number = {11}, issn = {1999-4893}, doi = {10.3390/a13110296}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219332}, year = {2020}, abstract = {Many modern statistically efficient methods come with tremendous computational challenges, often leading to large-scale optimisation problems. In this work, we examine such computational issues for recently developed estimation methods in nonparametric regression with a specific view on image denoising. We consider in particular certain variational multiscale estimators which are statistically optimal in minimax sense, yet computationally intensive. Such an estimator is computed as the minimiser of a smoothness functional (e.g., TV norm) over the class of all estimators such that none of its coefficients with respect to a given multiscale dictionary is statistically significant. The so obtained multiscale Nemirowski-Dantzig estimator (MIND) can incorporate any convex smoothness functional and combine it with a proper dictionary including wavelets, curvelets and shearlets. The computation of MIND in general requires to solve a high-dimensional constrained convex optimisation problem with a specific structure of the constraints induced by the statistical multiscale testing criterion. To solve this explicitly, we discuss three different algorithmic approaches: the Chambolle-Pock, ADMM and semismooth Newton algorithms. Algorithmic details and an explicit implementation is presented and the solutions are then compared numerically in a simulation study and on various test images. We thereby recommend the Chambolle-Pock algorithm in most cases for its fast convergence. We stress that our analysis can also be transferred to signal recovery and other denoising problems to recover more general objects whenever it is possible to borrow statistical strength from data patches of similar object structure.}, language = {en} } @article{LiDengXieetal.2018, author = {Li, Cong and Deng, Xiaobing and Xie, Xiaowen and Liu, Ying and Friedmann Angeli, Jos{\´e} Pedro and Lai, Luhua}, title = {Activation of Glutathione Peroxidase 4 as a Novel Anti-inflammatory Strategy}, series = {Frontiers in Pharmacology}, volume = {9}, journal = {Frontiers in Pharmacology}, number = {1120}, issn = {1663-9812}, doi = {10.3389/fphar.2018.01120}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195985}, year = {2018}, abstract = {The anti-oxidative enzyme, glutathione peroxidase 4 (GPX4), helps to promote inflammation resolution by eliminating oxidative species produced by the arachidonic acid (AA) metabolic network. Up-regulating its activity has been proposed as a promising strategy for inflammation intervention. In the present study, we aimed to study the effect of GPX4 activator on the AA metabolic network and inflammation related pathways. Using combined computational and experimental screen, we identified a novel compound that can activate the enzyme activity of GPX4 by more than two folds. We further assessed its potential in a series of cellular assays where GPX4 was demonstrated to play a regulatory role. We are able to show that GPX4 activation suppressed inflammatory conditions such as oxidation of AA and NF-κB pathway activation. We further demonstrated that this GPX4 activator can decrease the intracellular ROS level and suppress ferroptosis. Our study suggests that GPX4 activators can be developed as anti-inflammatory or cyto-protective agent in lipid-peroxidation-mediated diseases.}, language = {en} } @article{XuHeKaiseretal.2016, author = {Xu, Li and He, Jianzheng and Kaiser, Andrea and Gr{\"a}ber, Nikolas and Schl{\"a}ger, Laura and Ritze, Yvonne and Scholz, Henrike}, title = {A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0167518}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166762}, pages = {e0167518}, year = {2016}, abstract = {Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling—the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.}, language = {en} } @article{SchmidtHaywardCoelhoetal.2019, author = {Schmidt, Thomas S. B. and Hayward, Matthew R. and Coelho, Luiis P. and Li, Simone S. and Costea, Paul I. and Voigt, Anita Y. and Wirbel, Jakob and Maistrenko, Oleksandr M. and Alves, Renato J. C. and Bergsten, Emma and de Beaufort, Carine and Sobhani, Iradj and Heintz-Buschart, Anna and Sunagawa, Shinichi and Zeller, Georg and Wilmes, Paul and Bork, Peer}, title = {Extensive transmission of microbes along the gastrointestinal tract}, series = {eLife}, volume = {8}, journal = {eLife}, doi = {10.7554/eLife.42693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228954}, pages = {e42693, 1-18}, year = {2019}, abstract = {The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease.}, subject = {Barrier}, language = {en} } @article{LiPradaDaminelietal.2021, author = {Li, Kunkun and Prada, Juan and Damineli, Daniel S. C. and Liese, Anja and Romeis, Tina and Dandekar, Thomas and Feij{\´o}, Jos{\´e} A. and Hedrich, Rainer and Konrad, Kai Robert}, title = {An optimized genetically encoded dual reporter for simultaneous ratio imaging of Ca\(^{2+}\) and H\(^{+}\) reveals new insights into ion signaling in plants}, series = {New Phytologist}, volume = {230}, journal = {New Phytologist}, number = {6}, doi = {10.1111/nph.17202}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239847}, pages = {2292 -- 2310}, year = {2021}, abstract = {Whereas the role of calcium ions (Ca\(^{2+}\)) in plant signaling is well studied, the physiological significance of pH-changes remains largely undefined. Here we developed CapHensor, an optimized dual-reporter for simultaneous Ca\(^{2+}\) and pH ratio-imaging and studied signaling events in pollen tubes (PTs), guard cells (GCs), and mesophyll cells (MCs). Monitoring spatio-temporal relationships between membrane voltage, Ca\(^{2+}\)- and pH-dynamics revealed interconnections previously not described. In tobacco PTs, we demonstrated Ca\(^{2+}\)-dynamics lag behind pH-dynamics during oscillatory growth, and pH correlates more with growth than Ca\(^{2+}\). In GCs, we demonstrated abscisic acid (ABA) to initiate stomatal closure via rapid cytosolic alkalization followed by Ca2+ elevation. Preventing the alkalization blocked GC ABA-responses and even opened stomata in the presence of ABA, disclosing an important pH-dependent GC signaling node. In MCs, a flg22-induced membrane depolarization preceded Ca2+-increases and cytosolic acidification by c. 2 min, suggesting a Ca\(^{2+}\)/pH-independent early pathogen signaling step. Imaging Ca2+ and pH resolved similar cytosol and nuclear signals and demonstrated flg22, but not ABA and hydrogen peroxide to initiate rapid membrane voltage-, Ca\(^{2+}\)- and pH-responses. We propose close interrelation in Ca\(^{2+}\)- and pH-signaling that is cell type- and stimulus-specific and the pH having crucial roles in regulating PT growth and stomata movement.}, language = {en} } @article{HanRenMamtiminetal.2023, author = {Han, Chao and Ren, Pengxuan and Mamtimin, Medina and Kruk, Linus and Sarukhanyan, Edita and Li, Chenyu and Anders, Hans-Joachim and Dandekar, Thomas and Krueger, Irena and Elvers, Margitta and Goebel, Silvia and Adler, Kristin and M{\"u}nch, G{\"o}tz and Gudermann, Thomas and Braun, Attila and Mammadova-Bach, Elmina}, title = {Minimal collagen-binding epitope of glycoprotein VI in human and mouse platelets}, series = {Biomedicines}, volume = {11}, journal = {Biomedicines}, number = {2}, issn = {2227-9059}, doi = {10.3390/biomedicines11020423}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304148}, year = {2023}, abstract = {Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused on site-specific targeting of GPVI. Using computational modeling and bioinformatics, we analyzed collagen- and CRP-binding surfaces of GPVI monomers and dimers, and compared the interacting surfaces with other mammalian GPVI isoforms. We could predict a minimal collagen-binding epitope of GPVI dimer and designed an EA-20 antibody that recognizes a linear epitope of this surface. Using platelets and whole blood samples donated from wild-type and humanized GPVI transgenic mice and also humans, our experimental results show that the EA-20 antibody inhibits platelet adhesion and aggregation in response to collagen and CRP, but not to fibrin. The EA-20 antibody also prevents thrombus formation in whole blood, on the collagen-coated surface, in arterial flow conditions. We also show that EA-20 does not influence GPVI clustering or receptor shedding. Therefore, we propose that blockade of this minimal collagen-binding epitope of GPVI with the EA-20 antibody could represent a new anti-thrombotic approach by inhibiting specific interactions between GPVI and the collagen matrix.}, language = {en} } @article{ZimnyKoobLietal.2022, author = {Zimny, Sebastian and Koob, Dennis and Li, Jingguo and Wimmer, Ralf and Schiergens, Tobias and Nagel, Jutta and Reiter, Florian Paul and Denk, Gerald and Hohenester, Simon}, title = {Hydrophobic bile salts induce pro-fibrogenic proliferation of hepatic stellate cells through PI3K p110 alpha signaling}, series = {Cells}, volume = {11}, journal = {Cells}, number = {15}, issn = {2073-4409}, doi = {10.3390/cells11152344}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281806}, year = {2022}, abstract = {Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis.}, language = {en} } @article{StuehlerKowalewskiReisetal.2022, author = {St{\"u}hler, R. and Kowalewski, A. and Reis, F. and Jungblut, D. and Dominguez, F. and Scharf, B. and Li, G. and Sch{\"a}fer, J. and Hankiewicz, E. M. and Claessen, R.}, title = {Effective lifting of the topological protection of quantum spin Hall edge states by edge coupling}, series = {Nature Communications}, volume = {13}, journal = {Nature Communications}, doi = {10.1038/s41467-022-30996-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300886}, year = {2022}, abstract = {The scientific interest in two-dimensional topological insulators (2D TIs) is currently shifting from a more fundamental perspective to the exploration and design of novel functionalities. Key concepts for the use of 2D TIs in spintronics are based on the topological protection and spin-momentum locking of their helical edge states. In this study we present experimental evidence that topological protection can be (partially) lifted by pairwise coupling of 2D TI edges in close proximity. Using direct wave function mapping via scanning tunneling microscopy/spectroscopy (STM/STS) we compare isolated and coupled topological edges in the 2D TI bismuthene. The latter situation is realized by natural lattice line defects and reveals distinct quasi-particle interference (QPI) patterns, identified as electronic Fabry-P{\´e}rot resonator modes. In contrast, free edges show no sign of any single-particle backscattering. These results pave the way for novel device concepts based on active control of topological protection through inter-edge hybridization for, e.g., electronic Fabry-P{\´e}rot interferometry.}, language = {en} } @article{SauerLiHollWiedenetal.2017, author = {Sauer, Alexander and Li, Mengxia and Holl-Wieden, Annette and Pabst, Thomas and Neubauer, Henning}, title = {Readout-segmented multi-shot diffusion-weighted MRI of the knee joint in patients with juvenile idiopathic arthritis}, series = {Pediatric Rheumatology}, volume = {15}, journal = {Pediatric Rheumatology}, number = {73}, doi = {10.1186/s12969-017-0203-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158095}, year = {2017}, abstract = {Background: Diffusion-weighted MRI has been proposed as a new technique for imaging synovitis without intravenous contrast application. We investigated diagnostic utility of multi-shot readout-segmented diffusion-weighted MRI (multi-shot DWI) for synovial imaging of the knee joint in patients with juvenile idiopathic arthritis (JIA). Methods: Thirty-two consecutive patients with confirmed or suspected JIA (21 girls, median age 13 years) underwent routine 1.5 T MRI with contrast-enhanced T1w imaging (contrast-enhanced MRI) and with multi-shot DWI (RESOLVE, b-values 0-50 and 800 s/mm\(^2\)). Contrast-enhanced MRI, representing the diagnostic standard, and diffusion-weighted images at b = 800 s/mm\(^2\) were separately rated by three independent blinded readers at different levels of expertise for the presence and the degree of synovitis on a modified 5-item Likert scale along with the level of subjective diagnostic confidence. Results: Fourteen (44\%) patients had active synovitis and joint effusion, nine (28\%) patients showed mild synovial enhancement not qualifying for arthritis and another nine (28\%) patients had no synovial signal alterations on contrast-enhanced imaging. Ratings by the 1st reader on contrast-enhanced MRI and on DWI showed substantial agreement (κ = 0.74). Inter-observer-agreement was high for diagnosing, or ruling out, active arthritis of the knee joint on contrast-enhanced MRI and on DWI, showing full agreement between 1st and 2nd reader and disagreement in one case (3\%) between 1st and 3rd reader. In contrast, ratings in cases of absent vs. little synovial inflammation were markedly inconsistent on DWI. Diagnostic confidence was lower on DWI, compared to contrast-enhanced imaging. Conclusion: Multi-shot DWI of the knee joint is feasible in routine imaging and reliably diagnoses, or rules out, active arthritis of the knee joint in paediatric patients without the need of gadolinium-based i.v. contrast injection. Possibly due to "T2w shine-through" artifacts, DWI does not reliably differentiate non-inflamed joints from knee joints with mild synovial irritation.}, language = {en} } @article{RasouliKianiPouyaShabalaetal.2021, author = {Rasouli, Fatemeh and Kiani-Pouya, Ali and Shabala, Lana and Li, Leiting and Tahir, Ayesha and Yu, Min and Hedrich, Rainer and Chen, Zhonghua and Wilson, Richard and Zhang, Heng and Shabala, Sergey}, title = {Salinity effects on guard cell proteome in Chenopodium quinoa}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms22010428}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285625}, year = {2021}, abstract = {Epidermal fragments enriched in guard cells (GCs) were isolated from the halophyte quinoa (Chenopodium quinoa Wild.) species, and the response at the proteome level was studied after salinity treatment of 300 mM NaCl for 3 weeks. In total, 2147 proteins were identified, of which 36\% were differentially expressed in response to salinity stress in GCs. Up and downregulated proteins included signaling molecules, enzyme modulators, transcription factors and oxidoreductases. The most abundant proteins induced by salt treatment were desiccation-responsive protein 29B (50-fold), osmotin-like protein OSML13 (13-fold), polycystin-1, lipoxygenase, alpha-toxin, and triacylglycerol lipase (PLAT) domain-containing protein 3-like (eight-fold), and dehydrin early responsive to dehydration (ERD14) (eight-fold). Ten proteins related to the gene ontology term "response to ABA" were upregulated in quinoa GC; this included aspartic protease, phospholipase D and plastid-lipid-associated protein. Additionally, seven proteins in the sucrose-starch pathway were upregulated in the GC in response to salinity stress, and accumulation of tryptophan synthase and L-methionine synthase (enzymes involved in the amino acid biosynthesis) was observed. Exogenous application of sucrose and tryptophan, L-methionine resulted in reduction in stomatal aperture and conductance, which could be advantageous for plants under salt stress. Eight aspartic proteinase proteins were highly upregulated in GCs of quinoa, and exogenous application of pepstatin A (an inhibitor of aspartic proteinase) was accompanied by higher oxidative stress and extremely low stomatal aperture and conductance, suggesting a possible role of aspartic proteinase in mitigating oxidative stress induced by saline conditions.}, language = {en} } @article{RasouliKianiPouyaLietal.2020, author = {Rasouli, Fatemeh and Kiani-Pouya, Ali and Li, Leiting and Zhang, Heng and Chen, Zhonghua and Hedrich, Rainer and Wilson, Richard and Shabala, Sergey}, title = {Sugar beet (Beta vulgaris) guard cells responses to salinity stress: a proteomic analysis}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {7}, issn = {1422-0067}, doi = {10.3390/ijms21072331}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285765}, year = {2020}, abstract = {Soil salinity is a major environmental constraint affecting crop growth and threatening global food security. Plants adapt to salinity by optimizing the performance of stomata. Stomata are formed by two guard cells (GCs) that are morphologically and functionally distinct from the other leaf cells. These microscopic sphincters inserted into the wax-covered epidermis of the shoot balance CO\(_2\) intake for photosynthetic carbon gain and concomitant water loss. In order to better understand the molecular mechanisms underlying stomatal function under saline conditions, we used proteomics approach to study isolated GCs from the salt-tolerant sugar beet species. Of the 2088 proteins identified in sugar beet GCs, 82 were differentially regulated by salt treatment. According to bioinformatics analysis (GO enrichment analysis and protein classification), these proteins were involved in lipid metabolism, cell wall modification, ATP biosynthesis, and signaling. Among the significant differentially abundant proteins, several proteins classified as "stress proteins" were upregulated, including non-specific lipid transfer protein, chaperone proteins, heat shock proteins, inorganic pyrophosphatase 2, responsible for energized vacuole membrane for ion transportation. Moreover, several antioxidant enzymes (peroxide, superoxidase dismutase) were highly upregulated. Furthermore, cell wall proteins detected in GCs provided some evidence that GC walls were more flexible in response to salt stress. Proteins such as L-ascorbate oxidase that were constitutively high under both control and high salinity conditions may contribute to the ability of sugar beet GCs to adapt to salinity by mitigating salinity-induced oxidative stress.}, language = {en} } @article{HeidrichBauriedlBarquistetal.2017, author = {Heidrich, Nadja and Bauriedl, Saskia and Barquist, Lars and Li, Lei and Schoen, Christoph and Vogel, J{\"o}rg}, title = {The primary transcriptome of Neisseria meningitidis and its interaction with the RNA chaperone Hfq}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {10}, doi = {10.1093/nar/gkx168}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170828}, pages = {6147-6167}, year = {2017}, abstract = {Neisseria meningitidis is a human commensal that can also cause life-threatening meningitis and septicemia. Despite growing evidence for RNA-based regulation in meningococci, their transcriptome structure and output of regulatory small RNAs (sRNAs) are incompletely understood. Using dRNA-seq, we have mapped at single-nucleotide resolution the primary transcriptome of N. meningitidis strain 8013. Annotation of 1625 transcriptional start sites defines transcription units for most protein-coding genes but also reveals a paucity of classical σ70-type promoters, suggesting the existence of activators that compensate for the lack of -35 consensus sequences in N. meningitidis. The transcriptome maps also reveal 65 candidate sRNAs, a third of which were validated by northern blot analysis. Immunoprecipitation with the RNA chaperone Hfq drafts an unexpectedly large post-transcriptional regulatory network in this organism, comprising 23 sRNAs and hundreds of potential mRNA targets. Based on this data, using a newly developed gfp reporter system we validate an Hfq-dependent mRNA repression of the putative colonization factor PrpB by the two trans-acting sRNAs RcoF1/2. Our genome-wide RNA compendium will allow for a better understanding of meningococcal transcriptome organization and riboregulation with implications for colonization of the human nasopharynx.}, language = {en} } @article{HutinLingTarbouriechetal.2022, author = {Hutin, Stephanie and Ling, Wai Li and Tarbouriech, Nicolas and Schoehn, Guy and Grimm, Clemens and Fischer, Utz and Burmeister, Wim P.}, title = {The vaccinia virus DNA helicase structure from combined single-particle cryo-electron microscopy and AlphaFold2 prediction}, series = {Viruses}, volume = {14}, journal = {Viruses}, number = {10}, issn = {1999-4915}, doi = {10.3390/v14102206}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290523}, year = {2022}, abstract = {Poxviruses are large DNA viruses with a linear double-stranded DNA genome circularized at the extremities. The helicase-primase D5, composed of six identical 90 kDa subunits, is required for DNA replication. D5 consists of a primase fragment flexibly attached to the hexameric C-terminal polypeptide (res. 323-785) with confirmed nucleotide hydrolase and DNA-binding activity but an elusive helicase activity. We determined its structure by single-particle cryo-electron microscopy. It displays an AAA+ helicase core flanked by N- and C-terminal domains. Model building was greatly helped by the predicted structure of D5 using AlphaFold2. The 3.9 {\AA} structure of the N-terminal domain forms a well-defined tight ring while the resolution decreases towards the C-terminus, still allowing the fit of the predicted structure. The N-terminal domain is partially present in papillomavirus E1 and polyomavirus LTA helicases, as well as in a bacteriophage NrS-1 helicase domain, which is also closely related to the AAA+ helicase domain of D5. Using the Pfam domain database, a D5_N domain followed by DUF5906 and Pox_D5 domains could be assigned to the cryo-EM structure, providing the first 3D structures for D5_N and Pox_D5 domains. The same domain organization has been identified in a family of putative helicases from large DNA viruses, bacteriophages, and selfish DNA elements.}, language = {en} } @article{WangStoecklLietal.2022, author = {Wang, Chenglong and St{\"o}ckl, Sabine and Li, Shushan and Herrmann, Marietta and Lukas, Christoph and Reinders, Yvonne and Sickmann, Albert and Gr{\"a}ssel, Susanne}, title = {Effects of extracellular vesicles from osteogenic differentiated human BMSCs on osteogenic and adipogenic differentiation capacity of na{\"i}ve human BMSCs}, series = {Cells}, volume = {11}, journal = {Cells}, number = {16}, issn = {2073-4409}, doi = {10.3390/cells11162491}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286112}, year = {2022}, abstract = {Osteoporosis, or steroid-induced osteonecrosis of the hip, is accompanied by increased bone marrow adipogenesis. Such a disorder of adipogenic/osteogenic differentiation, affecting bone-marrow-derived mesenchymal stem cells (BMSCs), contributes to bone loss during aging. Here, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on the osteogenic and adipogenic differentiation capacity of na{\"i}ve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of na{\"i}ve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of na{\"i}ve hBMSCs more effectively than EVs derived from na{\"i}ve hBMSCs (na{\"i}ve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of na{\"i}ve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and na{\"i}ve EVs contained distinct protein profiles, with pro-osteogenic and anti-adipogenic proteins encapsulated in osteogenic EVs. We speculate that osteogenic EVs could serve as an intercellular communication system between bone- and bone-marrow adipose tissue, for transporting osteogenic factors and thus favoring pro-osteogenic processes. Our data may support the theory of an endocrine circuit with the skeleton functioning as a ductless gland.}, language = {en} } @phdthesis{Li2023, author = {Li, Kunkun}, title = {Dissecting the interconnection of Ca\(^{2+}\) and pH signaling in plants with a novel biosensor for dual imaging}, doi = {10.25972/OPUS-24973}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249736}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Calcium ion (Ca2+) and protons (H+) are both regarded as second messengers, participating in plant growth and stress mechanisms. However, H+ signals in plant physiology are less well investigated compared to Ca2+ signals. If interconnections between these two second messengers exist remains to be uncovered because appropriate imaging tools to monitor Ca2+ and H+ simultaneously in the same cell as well as accurate bioinformatics analysis remain to be developed. To overcome this problem and unravel the role and possible interconnection of Ca2+ and H+ in plants, a new biosensor named CapHensor was developed and optimized to visualize intracellular Ca2+ and H+ changes simultaneously and ratiometrically in the same cell. The CapHensor consisted of an optimized green fluorescent pH sensor (PRpHluorin) and an established red fluorescent Ca2+ sensor (R-GECO1) that were combined in one construct via a P2A sequence. A P2A self-cleavage site between the two sensors allowed to express equal amounts but spatially separated sensors, which enabled artifact-free and ratiometric imaging of cellular Ca2+ and pH side-by-side. The function of the CapHensor was verified in pollen tubes, since they possess standing Ca2+ and pH gradients. We found better imaging quality and the signal-to-noise ratio to be enhanced in live-cell imaging when two R-GECO1 proteins were fused in tandem within the CapHensor construct. To guarantee exclusive subcellular localization and avoid mixed signals from different compartments, Nuclear Export Sequence (NES) and Nuclear Localization Sequence (NLS) were used to target PRpHluorin and R-GECO1 to distinct compartments. After optimization and verification its function, CapHensor was successfully expressed in different cell types to investigate the role of Ca2+ and H+ signals to control polar growth of pollen tube, stomatal movement or leaf defense signaling. Results obtained in the past indicated both Ca2+ gradients and pH gradients in pollen tubes play roles in polar growth. However, the role and temporal relationship between the growth process and changes in Ca2+ and pH have not been conclusively resolved. Using CapHensor, I found cytosolic acidification at the tip could promote and alkalization to suppress growth velocity in N. tabacum pollen tubes, indicating that cytosolic H+ concentrations ([H+]cyt) play an important role in regulation pollen tubes growth despite the accompanied changes in cytosolic Ca2+ concentrations ([Ca2+]cyt). Moreover, growth correlated much better with the tip [H+]cyt regime than with the course of the tip [Ca2+]cyt regime. However, surprisingly, tip-focused [Ca2+]cyt andII [H+]cyt oscillations both lagged behind growth oscillations approximately 33 s and 18 s, respectively, asking for a re-evaluation of the role that tip [Ca2+]cyt may play in pollen tube growth. Live-cell CapHensor imaging combined with electrophysiology uncovered that oscillatory membrane depolarization correlated better with tip [H+]cyt oscillations than with tip [Ca2+]cyt oscillations, indicative for a prominent role of [H+]cyt to also control electrogenic membrane transport. Using CapHensor, reading out cellular movement at the same time enabled to provide a precise temporal and spatial resolution of ion signaling events, pointing out a prominent role of [H+]cyt in pollen tube tip growth. For leaf cells, a special CapHensor construct design had to be developed, containing additional NES localization sequences to avoid overlapping of fluorescense signals from the nucleus and the cytosol. Once this was achieved, the role of Ca2+ and pH changes in guard cells, another typical single-cell system was investigated. Cytosolic pH changes have been described in stomatal movement, but the physiological role of pH and the interaction with changing Ca2+ signals were still unexplored. Combining CapHensor with the here developed technique to monitor stomatal movement in parallel, the role of Ca2+ and H+ in stomatal movement was studied in detail and novel aspects were identified. The phytohormone ABA and the bacterial elicitor flagellin (flg22) are typical abiotic and biotic stresses, respectively, to trigger stomatal closure. What kind of Ca2+ and H+ signals by ABA and flg22 are set-off in guard cells and what their temporal relationship and role for stomatal movement is were unknown. Similar [Ca2+]cyt increases were observed upon ABA and flg22 triggered stomatal closure, but [H+]cyt dynamics differed fundamentally. ABA triggered pronounced cytosolic alkalization preceded the [Ca2+]cyt responses significantly by 57 s while stomata started to close ca. 205 s after phytohormone application. With flg22, stomatal closure was accompanied only with a mild cytosolic alkalization but the [Ca2+]cyt response was much more pronounced compared to the ABA effects. Where the cytosolic alkalization originates from was unclear but the vacuole was speculated to contribute in the past. In this thesis, vacuolar pH changes were visualized by the dye BCECF over time, basically displaying exactly the opposite course of the concentration shift in the vacuole than observed in the cytosol. This is indicative for the vacuolar pH dynamics to be coupled strongly to the cytosolic pH changes. In stomatal closure signalling, reactive oxygen species (ROS) were proposed to play a major role, however, only very high concentration of H2O2 (> 200 µM), which resulted in the loss of membrane integrity, induced stomatal closure. Unexpectedly, physiological concentrations of ROS led to cytosolic acidificationIII which was associated with stomatal opening, but not stomatal closure. To study the role of [H+]cyt to steer stomatal movement in detail, extracellular and intracellular pH variations were evoked in N. tabacum guard cells and their behaviour was followed. The results demonstrated cytosolic acidification stimulated stomatal opening while cytosolic alkalization triggered stomatal closure accompanied by [Ca2+]cyt elevations. This demonstrated pH regulation to be an important aspect in stomatal movement and to feed-back on the Ca2+-dynamics. It was remarkable that cytosolic alkalization but not [Ca2+]cyt increase seemed to play a crucial role in stomatal closure, because more pronounced cytosolic alkalization, evoked stronger stomatal closure despite similar [Ca2+]cyt increases. Increases in [Ca2+]cyt, which are discussed as an early stomatal closure signal in the past, could not trigger stomatal closure alone in my experiments, even when extremely strong [Ca2+]cyt signals were triggered. Regarding the interaction between the two second messengers, [Ca2+]cyt and [H+]cyt were negatively correlated most of the times, which was different from pollen tubes showing positive correlation of [Ca2+]cyt and [H+]cyt regimes. [Ca2+]cyt elevations were always associated with a cytosolic alkalization and this relationship could be blocked by the presence of vanadate, a plasma membrane H+-pump blocker, indicating plasma membrane H+-ATPases to contribute to the negative correlation of [Ca2+]cyt and [H+]cyt. To compare with guard cells, cytosolic and nuclear versions of CapHensor were expressed in N. benthamiana mesophyll cells, a multicellular system I investigated. Mesophyll cell responses to the same stimuli as tested in guard cells demonstrated that ABA and H2O2 did not induce any [Ca2+]cyt and [H+]cyt changes while flg22 induced an increase in [Ca2+]cyt and [H+]cyt, which is different from the response in guard cells. I could thus unequivocally demonstrate that guard cells and mesophyll cells do respond differently with [Ca2+]cyt and [H+]cyt changes to the same stimuli, a concept that has been proposed before, but never demonstrated in such detail for plants. Spontaneous Ca2+ oscillations have been observed for a long time in guard cells, but the function or cause is still poorly understood. Two populations of oscillatory guard cells were identified according to their [Ca2+]cyt and [H+]cyt phase relationship in my study. In approximately half of the oscillatory cells, [H+]cyt oscillations preceded [Ca2+]cyt oscillations whereas [Ca2+]cyt was the leading signal in the other half of the guard cells population. Strikingly, natural [H+]cyt oscillations were dampened by ABA but not by flg22. This effect could be well explained by dampening of vacuolar H+ oscillations in the presence of ABA, but not through flg22. Vacuolar pH contributes to spontaneous [H+]cyt oscillations and ABA but not flg22 can block the interdependence of naturalIV [Ca2+]cyt and [H+]cyt signals. To study the role of [Ca2+]cyt oscillations in stomatal movement, solutions containing high and low KCl concentrations were applied aiming to trigger [Ca2+]cyt oscillations. The triggering of [Ca2+]cyt oscillations by this method was established two decades ago leading to the dogma that [Ca2+]cyt increases are the crucial signal for stomatal closure. However, I found stomatal movement by this method was mainly due to osmotic effects rather than [Ca2+]cyt increases. Fortunately, through this methodology, I found a strong correlation between cytosolic pH and the transport of potassium across the plasma membrane and vacuole existed. The plasma membrane H+-ATPases and H+-coupled K+ transporters were identified as the cause of [H+]cyt changes, both very important aspects in stomata physiology that were not visualized experimentally before. Na+ transport is also important for stomatal regulation and leaves generally since salt can be transported from the root to the shoot. Unlike well-described Ca2+- dependent mechanisms in roots, how leaves process salt stress is not at all understood. I applied salt on protoplasts from leaves, mesophyll cells and guard cells and combined live-cell imaging with Vm recordings to understand the transport and signaling for leaf cells to cope with salt stress. In both, mesophyll and guard cells, NaCl did not trigger Ca2+-signals as described for roots but rather triggered Ca2+ peaks when washing salt out. However, membrane depolarization and pronounced alkalinization were very reliably triggered by NaCl, which could presumably act as a signal for detoxification of high salt concentrations. In line with this, I found the vacuolar cation/H+ antiporter NHX1 to play a role in sodium transport, [H+]cyt homeostasis and the control of membrane potential. Overexpression of AtNHX1 enabled to diminish [H+]cyt changes and resulted in a smaller depolarization responses druing NaCl stress. My results thus demonstrated in contrast to roots, leaf cells do not use Ca2+-dependent signalling cascades to deal with salt stress. I could show Na+ and K+ induced [H+]cyt and Vm responses and Cl- transport to only have a minor impact. Summing all my results up briefly, I uncovered pH signals to play important roles to control pollen tube growth, stomatal movement and leaf detoxification upon salt. My results strongly suggested pH changes might be a more important signal than previously thought to steer diverse processes in plants. Using CapHensor in combination with electrophysiology and bioinformatics tools, I discovered distinct interconnections between [Ca2+]cyt and [H+]cyt in different cell types and distinct [Ca2+]cyt and [H+]cyt signals are initiated through diverse stimuli and environmental cues. The CapHensor will be very useful in the future to further investigate the coordinated role of Ca2+ and pH changes in controlling plant physiology.}, subject = {Pflanzen}, language = {en} } @article{CoelhoKultimaCosteaetal.2018, author = {Coelho, Luis Pedro and Kultima, Jens Roat and Costea, Paul Igor and Fournier, Coralie and Pan, Yuanlong and Czarnecki-Maulden, Gail and Hayward, Matthew Robert and Forslund, Sofia K. and Schmidt, Thomas Sebastian Benedikt and Descombes, Patrick and Jackson, Janet R. and Li, Qinghong and Bork, Peer}, title = {Similarity of the dog and human gut microbiomes in gene content and response to diet}, series = {Microbiome}, volume = {6}, journal = {Microbiome}, doi = {10.1186/s40168-018-0450-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223177}, year = {2018}, abstract = {Background Gut microbes influence their hosts in many ways, in particular by modulating the impact of diet. These effects have been studied most extensively in humans and mice. In this work, we used whole genome metagenomics to investigate the relationship between the gut metagenomes of dogs, humans, mice, and pigs. Results We present a dog gut microbiome gene catalog containing 1,247,405 genes (based on 129 metagenomes and a total of 1.9 terabasepairs of sequencing data). Based on this catalog and taxonomic abundance profiling, we show that the dog microbiome is closer to the human microbiome than the microbiome of either pigs or mice. To investigate this similarity in terms of response to dietary changes, we report on a randomized intervention with two diets (high-protein/low-carbohydrate vs. lower protein/higher carbohydrate). We show that diet has a large and reproducible effect on the dog microbiome, independent of breed or sex. Moreover, the responses were in agreement with those observed in previous human studies. Conclusions We conclude that findings in dogs may be predictive of human microbiome results. In particular, a novel finding is that overweight or obese dogs experience larger compositional shifts than lean dogs in response to a high-protein diet.}, language = {en} } @article{LiShanRupprechtetal.2022, author = {Li, Donghai and Shan, Hangyong and Rupprecht, Christoph and Knopf, Heiko and Watanabe, Kenji and Taniguchi, Takashi and Qin, Ying and Tongay, Sefaattin and Nuß, Matthias and Schr{\"o}der, Sven and Eilenberger, Falk and H{\"o}fling, Sven and Schneider, Christian and Brixner, Tobias}, title = {Hybridized exciton-photon-phonon states in a transition-metal-dichalcogenide van-der-Waals heterostructure microcavity}, series = {Physical Review Letters}, journal = {Physical Review Letters}, edition = {accepted version}, issn = {1079-7114}, doi = {10.1103/PhysRevLett.128.087401}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351303}, year = {2022}, abstract = {Excitons in atomically thin transition-metal dichalcogenides (TMDs) have been established as an attractive platform to explore polaritonic physics, owing to their enormous binding energies and giant oscillator strength. Basic spectral features of exciton polaritons in TMD microcavities, thus far, were conventionally explained via two-coupled-oscillator models. This ignores, however, the impact of phonons on the polariton energy structure. Here we establish and quantify the threefold coupling between excitons, cavity photons, and phonons. For this purpose, we employ energy-momentum-resolved photoluminescence and spatially resolved coherent two-dimensional spectroscopy to investigate the spectral properties of a high-quality-factor microcavity with an embedded WSe\(_2\) van-der-Waals heterostructure at room temperature. Our approach reveals a rich multi-branch structure which thus far has not been captured in previous experiments. Simulation of the data reveals hybridized exciton-photon-phonon states, providing new physical insight into the exciton polariton system based on layered TMDs.}, language = {en} }