@article{MelfsenRomanosJansetal.2021, author = {Melfsen, Siebke and Romanos, Marcel and Jans, Thomas and Walitza, Susanne}, title = {Betrayed by the nervous system: a comparison group study to investigate the 'unsafe world' model of selective mutism}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, doi = {10.1007/s00702-021-02404-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370681}, pages = {1433-1443}, year = {2021}, abstract = {The study presented in the following verifies some assumptions of the novel 'unsafe world' model of selective mutism (SM). According to this model, SM is a stress reaction to situations erroneously experienced via cognition without awareness as 'unsafe'. It assumes a high sensitivity to unsafety, whereby the nervous system triggers dissociation or freeze mode at relatively low thresholds. We examine whether there is a correlation between SM, sensory-processing sensitivity and dissociation. We compared a sample of 28 children and adolescents with SM (mean age 12.66 years; 18 females) to 33 controls without SM (mean age 12.45 years; 21 females). Both groups were compared using a medical history sheet, the 'Selective Mutism Questionnaire' (SMQ), a 'Checklist for Speaking Behaviour' (CheckS), the 'Highly Sensitive Person Scale' (HSPS), the 'Child Dissociative Checklist' (CDC), the 'Adolescent Dissociative Experience Scale' (A-DES) and the 'Social Phobia and Anxiety Inventory for Children' (SPAIK). Appropriate parametric and non-parametric tests were conducted to examine differences between groups. The results indicate that sensory-processing sensitivity was significantly higher in the group of children and adolescents with SM [X2(1) = 7.224, p = 0.0007; d = 1.092]. Furthermore, dissociative symptoms were more common in children and adolescents with SM than in controls [F(1, 33) = 13.004, p = 0.001; d = 0.986]. The results indicate that sensory-processing sensitivity and dissociation are important factors of SM that may hold important implications for the treatment.}, language = {en} } @article{OPUS4-31406, title = {Search for heavy long-lived multicharged particles in proton-proton collisions at √\(s\)=13 TeV using the ATLAS detector}, series = {Physical Review D}, volume = {99}, journal = {Physical Review D}, number = {5}, organization = {The ATLAS Collaboration}, doi = {10.1103/PhysRevD.99.052003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314061}, pages = {1-26}, year = {2019}, abstract = {A search for heavy long-lived multicharged particles is performed using the ATLAS detector at the LHC. Data with an integrated luminosity of 36.1 fb(-1) collected in 2015 and 2016 from proton-proton collisions at root s = 13 TeV are examined. Particles producing anomalously high ionization, consistent with long-lived massive particles with electric charges from vertical bar q vertical bar = 2e to vertical bar q vertical bar = 7e, are searched for. No events are observed, and 95\% confidence level cross-section upper limits are interpreted as lower mass limits for a Drell-Yan production model. Multicharged particles with masses between 50 and 980-1220 GeV (depending on their electric charge) are excluded.}, language = {en} } @article{MansourSolimanShehabetal.2017, author = {Mansour, Ahmed M. and Soliman, Fatma A. and Shehab, Ola R. and Abdel-Ghani, Nour T.}, title = {Photodegradation of sulfadiazine catalyzed by p-benzoquinones and picric acid: application to charge transfer complexes}, series = {RSC Advances}, volume = {7}, journal = {RSC Advances}, number = {63}, doi = {10.1039/c7ra05433e}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181507}, pages = {39989-39996}, year = {2017}, abstract = {As the treatment of effluents containing the antibiotic drug sulfadiazine (SZ) is one of the challenging problems in the field of environmental chemistry, it is essential to determine the concentration of SZ by a rapid and accurate method and then find a suitable method to degrade the assayed products into harmless chemicals. The color of the charge transfer (CT) complexes developed from the reaction of SZ with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), chloranilic acid (CHL) and picric acid (PA) was used to determine the concentration of SZ at 528, 510 and 410 nm, respectively. The Lambert-Beer's law is obeyed in the ranges of 6.80-68.06, 13.61-136.12 and 6.80-27.22 μg mL\(^{-1}\) for DDQ, CHL and PA complexes. The photolysis of SZ → DDQ in presence of sodium nitrite at 256 nm leads to faster degradation of SZ compared with the control experiments. This was simply spectrophotometrically followed by a decrease in the intensity of the CT band. The effect of some additives such as oxalic acid, and hematite nano particles was studied. For comparison, other π-acceptor reagents such as CHL and PA were used. About 80\% of SZ is degraded in 45 min upon the illumination of SZ → DDQ at 256 nm, whereas 90 min is required in the case of CHL and PA to attain the same degradation limit.}, language = {en} } @article{SharmaKhairnarMadunicetal.2017, author = {Sharma, Piyush and Khairnar, Vishal and Madunic, Ivana Vrhovac and Singh, Yogesh and Pandyra, Aleksandra and Salker, Madhuri S. and Koepsell, Hermann and Sabolic, Ivan and Lang, Florian and Lang, Pilipp A. and Lang, Karl S.}, title = {SGLT1 deficiency turns listeria infection into a lethal disease in mice}, series = {Cellular Physiology and Biochemistry}, volume = {42}, journal = {Cellular Physiology and Biochemistry}, number = {4}, doi = {10.1159/000479197}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181496}, pages = {1358-1365}, year = {2017}, abstract = {Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na\(^+\)-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose oncentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x10\(^4\) CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1\(^{-/-}\) mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection.}, language = {en} } @article{MaGulbinsEdwardsetal.2017, author = {Ma, Jie and Gulbins, Erich and Edwards, Michael J. and Caldwell, Charles C. and Fraunholz, Martin and Becker, Katrin Anne}, title = {Staphylococcus aureus α-toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides}, series = {Cellular Physiology and Biochemistry}, volume = {43}, journal = {Cellular Physiology and Biochemistry}, number = {6}, doi = {10.1159/000484296}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181481}, pages = {2170-2184}, year = {2017}, abstract = {Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines.}, language = {en} } @article{WangZhangBaietal.2017, author = {Wang, Yiwen and Zhang, Zhen and Bai, Liying and Lin, Chongde and Osinsky, Roman and Hewig, Johannes}, title = {Ingroup/outgroup membership modulates fairness consideration: neural signatures from ERPs and EEG oscillations}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/srep39827}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181461}, year = {2017}, abstract = {Previous studies have shown that ingroup/outgroup membership influences individual's fairness considerations. However, it is not clear yet how group membership influences brain activity when a recipient evaluates the fairness of asset distribution. In this study, subjects participated as recipients in an Ultimatum Game with alleged members of both an experimentally induced ingroup and outgroup. They either received extremely unequal, moderately unequal, or equal offers from proposers while electroencephalogram was recorded. Behavioral results showed that the acceptance rates for unequal offers were higher when interacting with ingroup partners than with outgroup partners. Analyses of event related potentials revealed that proposers' group membership modulated offer evaluation at earlier processing stages. Feedback-related negativity was more negative for extremely and moderately unequal offers compared to equal offers in the ingroup interaction whereas it did not show differential responses to different offers in the outgroup interaction. Analyses of event related oscillations revealed that the theta power (4-6 Hz) was larger for moderately unequal offers than equal offers in the ingroup interaction whereas it did not show differential responses to different offers in the outgroup interaction. Thus, early mechanisms of fairness evaluation are strongly modulated by the ingroup/outgroup membership of the interaction partner.}, language = {en} } @article{ScheunertCohenKullocketal.2017, author = {Scheunert, Gunther and Cohen, Sidney R. and Kullock, Ren{\´e} and McCarron, Ryan and Rechev, Katya and Kaplan-Ashiri, Ifat and Bitton, Ora and Dawson, Paul and Hecht, Bert and Oron, Dan}, title = {Grazing-incidence optical magnetic recording with super-resolution}, series = {Beilstein Journal of Nanotechnology}, volume = {8}, journal = {Beilstein Journal of Nanotechnology}, doi = {10.3762/bjnano.8.4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181457}, pages = {28-37}, year = {2017}, abstract = {Heat-assisted magnetic recording (HAMR) is often considered the next major step in the storage industry: it is predicted to increase the storage capacity, the read/write speed and the data lifetime of future hard disk drives. However, despite more than a decade of development work, the reliability is still a prime concern. Featuring an inherently fragile surface-plasmon resonator as a highly localized heat source, as part of a near-field transducer (NFT), the current industry concepts still fail to deliver drives with sufficient lifetime. This study presents a method to aid conventional NFT-designs by additional grazing-incidence laser illumination, which may open an alternative route to high-durability HAMR. Magnetic switching is demonstrated on consumer-grade CoCrPt perpendicular magnetic recording media using a green and a near-infrared diode laser. Sub-500 nm magnetic features are written in the absence of a NFT in a moderate bias field of only μ0H = 0.3 T with individual laser pulses of 40 mW power and 50 ns duration with a laser spot size of 3 μm (short axis) at the sample surface - six times larger than the magnetic features. Herein, the presence of a nanoscopic object, i.e., the tip of an atomic force microscope in the focus of the laser at the sample surface, has no impact on the recorded magnetic features - thus suggesting full compatibility with NFT-HAMR.}, language = {en} } @article{SzklarczykMorrisCooketal.2017, author = {Szklarczyk, Damian and Morris, John H. and Cook, Helen and Kuhn, Michael and Wyder, Stefan and Simonovic, Milan and Santos, Aalberto and Doncheva, Nadezhda T. and Roth, Alexander and Bork, Peer and Jensen, Lars J. and von Mering, Christian}, title = {The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {D1}, doi = {10.1093/nar/gkw937}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181445}, pages = {D362-D368}, year = {2017}, abstract = {A system-wide understanding of cellular function requires knowledge of all functional interactions between the expressed proteins. The STRING database aims to collect and integrate this information, by consolidating known and predicted protein-protein association data for a large number of organisms. The associations in STRING include direct (physical) interactions, as well as indirect (functional) interactions, as long as both are specific and biologically meaningful. Apart from collecting and reassessing available experimental data on protein-protein interactions, and importing known pathways and protein complexes from curated databases, interaction predictions are derived from the following sources: (i) systematic co-expression analysis, (ii) detection of shared selective signals across genomes, (iii) automated text-mining of the scientific literature and (iv) computational transfer of interaction knowledge between organisms based on gene orthology. In the latest version 10.5 of STRING, the biggest changes are concerned with data dissemination: the web frontend has been completely redesigned to reduce dependency on outdated browser technologies, and the database can now also be queried from inside the popular Cytoscape software framework. Further improvements include automated background analysis of user inputs for functional enrichments, and streamlined download options. The STRING resource is available online, at http://string-db.org/.}, language = {en} } @article{RheeChoiKimetal.2017, author = {Rhee, Jae-Sung and Choi, Beom-Soon and Kim, Jaebum and Kim, Bo-Mi and Lee, Young-Mi and Kim, Il-Chan and Kanamori, Akira and Choi, Ik-Young and Schartl, Manfred and Lee, Jae-Seong}, title = {Diversity, distribution, and significance of transposable elements in the genome of the only selfing hermaphroditic vertebrate Kryptolebias marmoratus}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/srep40121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181329}, year = {2017}, abstract = {The Kryptolebias marmoratus is unique because it is the only selffertilizing hermaphroditic vertebrate, known to date. It primarily reproduces by internal self-fertilization in a mixed ovary/testis gonad. Here, we report on a high-quality genome assembly for the K. marmoratus South Korea (SK) strain highlighting the diversity and distribution of transposable elements (TEs). We find that K. marmoratus genome maintains number and composition of TEs. This can be an important genomic attribute promoting genome recombination in this selfing fish, while, in addition to a mixed mating strategy, it may also represent a mechanism contributing to the evolutionary adaptation to ecological pressure of the species. Future work should help clarify this point further once genomic information is gathered for other taxa of the family Rivulidae that do not self-fertilize. We provide a valuable genome resource that highlights the potential impact of TEs on the genome evolution of a fish species with an uncommon life cycle.}, language = {en} } @phdthesis{Reichelt2024, author = {Reichelt, Niklas}, title = {Exploring the natural variation of heat-dependent metabolic rearrangements in \(Arabidopsis\) \(thaliana\) to identify genes involved in thermotolerance}, doi = {10.25972/OPUS-37132}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371324}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Climate change and associated extreme weather events are a threat not only for agricultural yields but the plant kingdom in general. Therefore, there is a great necessity to better understand the plants' intrinsic mechanisms to combat heat stress. The plant heat stress response already has been investigated in many studies, including the role of HSFA1 transcription factors as the central regulators. Other aspects such as the initial perception of heat and the role of heat-induced changes in plant metabolism are rather unknown. In this thesis, the natural variation of 250 different accessions of Arabidopsis thaliana was investigated regarding the temperature-dependent accumulation of raffinose and triacylglycerols. A connection between these phenotypes and respective genotypes was established using genome-wide association studies. As a result, the candidate gene TREHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1), was identified. Enzymatic TPS1 is responsible for the synthesis of trehalose 6-phosphate (T6P), which serves as an indicator and regulator of sucrose homeostasis. Subsequent analyses using tps1 tilling mutants demonstrated a link between T6P metabolism and an increased accumulation of various soluble carbohydrates and starch, including raffinose both under control conditions and during heat exposure. Furthermore, the mutant lines displayed enhanced thermotolerance and survival rates following long-term heat stress. Transcriptome analyses, however, did not show any difference in the regulation of canonical heat stress-associated genes. Instead, genes related to photosynthesis were overrepresented among the differentially upregulated genes in tps1 tilling lines during heat exposure. In this work, a direct connection of T6P signaling, sucrose homeostasis, and thermotolerance is shown for the first time. In a second project, two Arabidopsis thaliana accessions (Oberursel-0, accession ID: 7276; Nieps-0, accession ID: 7268) showing distinct capacities to acquire short-term thermotolerance were compared to identify the putative causative regulators or mechanisms that lead to the different levels of thermotolerance. An examination of the transcriptomes of 7268 and 7276 showed that several hundreds of genes were already differentially regulated within 10 minutes of exposure to 32 °C or 34 °C. Among these, several genes associated with sulfur metabolism were more highly induced in the more thermotolerant accession 7268. However, experimental as well as genetic manipulation of sulfur availability and metabolism did not result in altered thermotolerance. In addition to sulfur-related genes, most of the canonical heat stress-associated genes were more highly expressed in 7268 than in 7276. While we could not identify a causative regulator or mechanism of differential thermotolerances, the data strongly suggests that 7268 either has a higher overall sensitivity, i.e., the heat stress response is initiated at lower temperatures, or stronger overall heat stress response when exposed to a certain elevated temperature.}, subject = {Schmalwand }, language = {en} } @article{MegyDownesMorelKoppetal.2021, author = {Megy, Karyn and Downes, Kate and Morel-Kopp, Marie-Christine and Bastida, Jos{\´e} M. and Brooks, Shannon and Bury, Loredana and Leinoe, Eva and Gomez, Keith and Morgan, Neil V. and Othman, Maha and Ouwehand, Willem H. and Perez Botero, Juliana and Rivera, Jos{\´e} and Schulze, Harald and Tr{\´e}gou{\"e}t, David-Alexandre and Freson, Kathleen}, title = {GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis}, series = {Journal of Thrombosis and Haemostasis}, volume = {19}, journal = {Journal of Thrombosis and Haemostasis}, doi = {10.1111/jth.15459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370602}, pages = {2612-2617}, year = {2021}, abstract = {The implementation of high-throughput sequencing (HTS) technologies in research and diagnostic laboratories has linked many new genes to rare bleeding, thrombotic, and platelet disorders (BTPD), and revealed multiple genetic variants linked to those disorders, many of them being of uncertain pathogenicity when considering the accepted evidence (variant consequence, frequency in control datasets, number of reported patients, prediction models, and functional assays). The sequencing effort has also resulted in resources for gathering disease-causing variants associated with specific genes, but for BTPD, such well-curated databases exist only for a few genes. On the other hand, submissions by individuals or diagnostic laboratories to the variant database ClinVar are hampered by the lack of a submission process tailored to capture the specific features of hemostatic diseases. As we move toward the implementation of HTS in the diagnosis of BTPD, the Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis has developed and tested a REDCap-based interface, aimed at the community, to submit curated genetic variants for diagnostic-grade BTPD genes. Here, we describe the use of the interface and the initial submission of 821 variants from 30 different centers covering 14 countries. This open-access variant resource will be shared with the community to improve variant classification and regular bulk data transfer to ClinVar.}, language = {en} } @article{MaynardRostaingSchaeferetal.2021, author = {Maynard, Stephanie A and Rostaing, Philippe and Schaefer, Natascha and Gemin, Olivier and Candat, Adrien and Dumoulin, Andr{\´e}a and Villmann, Carmen and Triller, Antoine and Specht, Christian G}, title = {Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses}, series = {eLife}, volume = {10}, journal = {eLife}, doi = {10.7554/eLife.74441}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370504}, year = {2021}, abstract = {Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far, the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy. We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains, and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.}, language = {en} } @article{MaulanaKromidasWallstabeetal.2021, author = {Maulana, Tengku Ibrahim and Kromidas, Elena and Wallstabe, Lars and Cipriano, Madalena and Alb, Miriam and Zaupa, C{\´e}cile and Hudecek, Michael and Fogal, Birgit and Loskill, Peter}, title = {Immunocompetent cancer-on-chip models to assess immuno-oncology therapy}, series = {Advanced Drug Delivery Reviews}, volume = {173}, journal = {Advanced Drug Delivery Reviews}, doi = {10.1016/j.addr.2021.03.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370493}, pages = {281-305}, year = {2021}, abstract = {The advances in cancer immunotherapy come with several obstacles, limiting its widespread use and benefits so far only to a small subset of patients. One of the underlying challenges remains to be the lack of representative nonclinical models that translate to human immunity and are able to predict clinical efficacy and safety outcomes. In recent years, immunocompetent Cancer-on-Chip models emerge as an alternative human-based platform that enables the integration and manipulation of complex tumor microenvironment. In this review, we discuss novel opportunities offered by Cancer-on-Chip models to advance (mechanistic) immuno-oncology research, ranging from design flexibility to multimodal analysis approaches. We then exemplify their (potential) applications for the research and development of adoptive cell therapy, immune checkpoint therapy, cytokine therapy, oncolytic virus, and cancer vaccines.}, language = {en} } @article{MateosDimopoulosCavoetal.2021, author = {Mateos, Maria-Victoria and Dimopoulos, Meletios A. and Cavo, Michele and Suzuki, Kenshi and Knop, Stefan and Doyen, Chantal and Lucio, Paulo and Nagy, Zsolt and Pour, Ludek and Grosicki, Sebastian and Crepaldi, Andre and Liberati, Anna Marina and Campbell, Philip and Yoon, Sung-Soo and Iosava, Genadi and Fujisaki, Tomoaki and Garg, Mamta and Iida, Shinsuke and Blad{\´e}, Joan and Ukropec, Jon and Pei, Huiling and Van Rampelbergh, Rian and Kudva, Anupa and Qi, Ming and San-Miguel, Jesus}, title = {Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE}, series = {Clinical Lymphoma, Myeloma \& Leukemia}, volume = {21}, journal = {Clinical Lymphoma, Myeloma \& Leukemia}, doi = {10.1016/j.clml.2021.06.005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370456}, pages = {785-798}, year = {2021}, abstract = {Background In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status. Patients and Methods Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients. Results Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4\%) were nonfrail (D-VMP, 187 [53.4\%]; VMP, 204 [57.3\%]) and 315 (44.6\%) were frail (163 [46.6\%]; 152 [42.7\%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6\% vs. 74.5\%), frail (71.4\% vs. 59.0\%). Improved greater than or equal to complete response and minimal residual disease (10-5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2\% [D-VMP] and 42.4\% [VMP]; frail: 41.3\% and 34.4\%) and thrombocytopenia (nonfrail: 32.8\% and 36.9\%; frail: 36.9\% and 39.1\%). Conclusion Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.}, language = {en} } @article{MatarranzGhoshKandanellietal.2021, author = {Matarranz, Beatriz and Ghosh, Goutam and Kandanelli, Ramesh and Sampedro, Angel and Kartha, Kalathil K. and Fern{\´a}ndez, Gustavo}, title = {Understanding the role of conjugation length on the self-assembly behaviour of oligophenyleneethynylenes}, series = {Chemical Communications}, volume = {57}, journal = {Chemical Communications}, doi = {10.1039/d1cc01054a}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370444}, pages = {4890-4893}, year = {2021}, abstract = {Oligophenyleneethynylenes (OPEs) are prominent building blocks with exciting optical and supramolecular properties. However, their generally small spectroscopic changes upon aggregation make the analysis of their self-assembly challenging, especially in the absence of additional hydrogen bonds. Herein, by investigating a series of OPEs of increasing size, we have unravelled the role of the conjugation length on the self-assembly properties of OPEs.}, language = {en} } @article{MasiasCernaVelazcoJonesPerezetal.2021, author = {Masias, J. and Cerna-Velazco, N. and Jones-P{\´e}rez, J. and Porod, W.}, title = {Resolving a challenging supersymmetric low-scale seesaw scenario at the ILC}, series = {Physical Review D}, volume = {103}, journal = {Physical Review D}, doi = {10.1103/PhysRevD.103.115028}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370328}, year = {2021}, abstract = {We investigate a scenario inspired by natural supersymmetry, where neutrino data is explained within a low-scale seesaw scenario. For this the minimal supersymmetric Standard Model is extended by adding light right-handed neutrinos and their superpartners, the R-sneutrinos. Moreover, we consider the lightest neutralinos to be Higgsino-like. We first update a previous analysis and assess to which extent does existing LHC data constrain the allowed slepton masses. Here we find scenarios where sleptons with masses as low as 175 GeV are consistent with existing data. However, we also show that the upcoming run will either discover or rule out sleptons with masses of 300 GeV, even for these challenging scenarios. We then take a scenario which is on the borderline of observability of the upcoming LHC run assuming a luminosity of 300 fb(-1). We demonstrate that a prospective international e(+)e(-) linear collider with a center of mass energy of 1 TeV will be able to discover sleptons in scenarios which are difficult for the LHC. Moreover, we also show that a measurement of the spectrum will be possible within 1-3 percent accuracy.}, language = {en} } @article{MartinezLenzSchindleretal.2021, author = {Martinez, Simon and Lenz, J{\"u}rgen and Schindler, Hans and Wendler, Willi and Rues, Stefan and Schweizerhof, Karl and Terebesi, Sophia and Giannakopoulos, Nikolaos Nikitas and Schmitter, Marc}, title = {Clinical Data-Driven Finite Element Analysis of the Kinetics of Chewing Cycles in Order to Optimize Occlusal Reconstructions}, series = {Computer Modeling in Engineering \& Sciences}, volume = {129}, journal = {Computer Modeling in Engineering \& Sciences}, doi = {10.32604/cmes.2021.017422}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370318}, pages = {1259-1281}, year = {2021}, abstract = {The occlusal design plays a decisive role in the fabrication of dental restorations. Dentists and dental technicians depend on mechanical simulations of mandibular movement that are as accurate as possible, in particular, to produce interference-free yet chewing-efficient dental restorations. For this, kinetic data must be available, i.e., movements and deformations under the influence of forces and stresses. In the present study, so-called functional data were collected from healthy volunteers to provide consistent information for proper kinetics. For the latter purpose, biting and chewing forces, electrical muscle activity and jaw movements were registered synchronously, and individual magnetic resonance tomograms (MRI) were prepared. The acquired data were then added to a large complex finite element model of the complete masticatory system using the functional information obtained and individual anatomical geometries so that the kinetics of the chewing process and teeth grinding could be realistically simulated. This allows developing algorithms that optimize computer-aided manufacturing of dental prostheses close to occlusion. In this way, a failure-free function of the dental prosthesis can be guaranteed and its damage during usage can be reduced or prevented even including endosseous implants.}, language = {en} } @article{MaronHaggenmuellervonKalleetal.2021, author = {Maron, Roman C. and Haggenm{\"u}ller, Sarah and von Kalle, Christof and Utikal, Jochen S. and Meier, Friedegund and Gellrich, Frank F. and Hauschild, Axel and French, Lars E. and Schlaak, Max and Ghoreschi, Kamran and Kutzner, Heinz and Heppt, Markus V. and Haferkamp, Sebastian and Sondermann, Wiebke and Schadendorf, Dirk and Schilling, Bastian and Hekler, Achim and Krieghoff-Henning, Eva and Kather, Jakob N. and Fr{\"o}hling, Stefan and Lipka, Daniel B. and Brinker, Titus J.}, title = {Robustness of convolutional neural networks in recognition of pigmented skin lesions}, series = {European Journal of Cancer}, volume = {145}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2020.11.020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370245}, pages = {81-91}, year = {2021}, abstract = {Background A basic requirement for artificial intelligence (AI)-based image analysis systems, which are to be integrated into clinical practice, is a high robustness. Minor changes in how those images are acquired, for example, during routine skin cancer screening, should not change the diagnosis of such assistance systems. Objective To quantify to what extent minor image perturbations affect the convolutional neural network (CNN)-mediated skin lesion classification and to evaluate three possible solutions for this problem (additional data augmentation, test-time augmentation, anti-aliasing). Methods We trained three commonly used CNN architectures to differentiate between dermoscopic melanoma and nevus images. Subsequently, their performance and susceptibility to minor changes ('brittleness') was tested on two distinct test sets with multiple images per lesion. For the first set, image changes, such as rotations or zooms, were generated artificially. The second set contained natural changes that stemmed from multiple photographs taken of the same lesions. Results All architectures exhibited brittleness on the artificial and natural test set. The three reviewed methods were able to decrease brittleness to varying degrees while still maintaining performance. The observed improvement was greater for the artificial than for the natural test set, where enhancements were minor. Conclusions Minor image changes, relatively inconspicuous for humans, can have an effect on the robustness of CNNs differentiating skin lesions. By the methods tested here, this effect can be reduced, but not fully eliminated. Thus, further research to sustain the performance of AI classifiers is needed to facilitate the translation of such systems into the clinic.}, language = {en} } @article{MarcuSchlosserKeuppetal.2021, author = {Marcu, Ana and Schlosser, Andreas and Keupp, Anne and Trautwein, Nico and Johann, Pascal and W{\"o}lfl, Matthias and Lager, Johanna and Monoranu, Camelia Maria and Walz, Juliane S and Henkel, Lisa M and Krauß, J{\"u}rgen and Ebinger, Martin and Schuhmann, Martin and Thomale, Ulrich Wilhelm and Pietsch, Torsten and Klinker, Erdwine and Schlegel, Paul G and Oyen, Florian and Reisner, Yair and Rammensee, Hans-Georg and Eyrich, Matthias}, title = {Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors}, series = {Journal for ImmunoTherapy of Cancer}, volume = {9}, journal = {Journal for ImmunoTherapy of Cancer}, doi = {10.1136/jitc-2021-003404}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370214}, year = {2021}, abstract = {Background Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. Methods Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. Results Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80\% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50\% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. Conclusions These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.}, language = {en} } @article{MarcuBichmannKuchenbeckeretal.2021, author = {Marcu, Ana and Bichmann, Leon and Kuchenbecker, Leon and Kowalewski, Daniel Johannes and Freudenmann, Lena Katharina and Backert, Linus and M{\"u}hlenbruch, Lena and Szolek, Andr{\´a}s and L{\"u}bke, Maren and Wagner, Philipp and Engler, Tobias and Matovina, Sabine and Wang, Jian and Hauri-Hohl, Mathias and Martin, Roland and Kapolou, Konstantina and Walz, Juliane Sarah and Velz, Julia and Moch, Holger and Regli, Luca and Silginer, Manuela and Weller, Michael and L{\"o}ffler, Markus W. and Erhard, Florian and Schlosser, Andreas and Kohlbacher, Oliver and Stevanović, Stefan and Rammensee, Hans-Georg and Neidert, Marian Christoph}, title = {HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy}, series = {Journal for ImmunoTherapy of Cancer}, volume = {9}, journal = {Journal for ImmunoTherapy of Cancer}, doi = {10.1136/jitc-2020-002071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370160}, year = {2021}, abstract = {Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level. Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing. Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference. Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org .}, language = {en} }