@article{BrinkerHeklerEnketal.2019, author = {Brinker, Titus J. and Hekler, Achim and Enk, Alexander H. and Berking, Carola and Haferkamp, Sebastian and Hauschild, Axel and Weichenthal, Michael and Klode, Joachim and Schadendorf, Dirk and Holland-Letz, Tim and von Kalle, Christof and Fr{\"o}hling, Stefan and Schilling, Bastian and Utikal, Jochen S.}, title = {Deep neural networks are superior to dermatologists in melanoma image classification}, series = {European Journal of Cancer}, volume = {119}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2019.05.023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220539}, pages = {11-17}, year = {2019}, abstract = {Background Melanoma is the most dangerous type of skin cancer but is curable if detected early. Recent publications demonstrated that artificial intelligence is capable in classifying images of benign nevi and melanoma with dermatologist-level precision. However, a statistically significant improvement compared with dermatologist classification has not been reported to date. Methods For this comparative study, 4204 biopsy-proven images of melanoma and nevi (1:1) were used for the training of a convolutional neural network (CNN). New techniques of deep learning were integrated. For the experiment, an additional 804 biopsy-proven dermoscopic images of melanoma and nevi (1:1) were randomly presented to dermatologists of nine German university hospitals, who evaluated the quality of each image and stated their recommended treatment (19,296 recommendations in total). Three McNemar's tests comparing the results of the CNN's test runs in terms of sensitivity, specificity and overall correctness were predefined as the main outcomes. Findings The respective sensitivity and specificity of lesion classification by the dermatologists were 67.2\% (95\% confidence interval [CI]: 62.6\%-71.7\%) and 62.2\% (95\% CI: 57.6\%-66.9\%). In comparison, the trained CNN achieved a higher sensitivity of 82.3\% (95\% CI: 78.3\%-85.7\%) and a higher specificity of 77.9\% (95\% CI: 73.8\%-81.8\%). The three McNemar's tests in 2 × 2 tables all reached a significance level of p < 0.001. This significance level was sustained for both subgroups. Interpretation For the first time, automated dermoscopic melanoma image classification was shown to be significantly superior to both junior and board-certified dermatologists (p < 0.001).}, language = {en} } @article{BrinkerHeklerHauschildetal.2019, author = {Brinker, Titus J. and Hekler, Achim and Hauschild, Axel and Berking, Carola and Schilling, Bastian and Enk, Alexander H. and Haferkamp, Sebastian and Karoglan, Ante and von Kalle, Christof and Weichenthal, Michael and Sattler, Elke and Schadendorf, Dirk and Gaiser, Maria R. and Klode, Joachim and Utikal, Jochen S.}, title = {Comparing artificial intelligence algorithms to 157 German dermatologists: the melanoma classification benchmark}, series = {European Journal of Cancer}, volume = {111}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2018.12.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220569}, pages = {30-37}, year = {2019}, abstract = {Background Several recent publications have demonstrated the use of convolutional neural networks to classify images of melanoma at par with board-certified dermatologists. However, the non-availability of a public human benchmark restricts the comparability of the performance of these algorithms and thereby the technical progress in this field. Methods An electronic questionnaire was sent to dermatologists at 12 German university hospitals. Each questionnaire comprised 100 dermoscopic and 100 clinical images (80 nevi images and 20 biopsy-verified melanoma images, each), all open-source. The questionnaire recorded factors such as the years of experience in dermatology, performed skin checks, age, sex and the rank within the university hospital or the status as resident physician. For each image, the dermatologists were asked to provide a management decision (treat/biopsy lesion or reassure the patient). Main outcome measures were sensitivity, specificity and the receiver operating characteristics (ROC). Results Total 157 dermatologists assessed all 100 dermoscopic images with an overall sensitivity of 74.1\%, specificity of 60.0\% and an ROC of 0.67 (range = 0.538-0.769); 145 dermatologists assessed all 100 clinical images with an overall sensitivity of 89.4\%, specificity of 64.4\% and an ROC of 0.769 (range = 0.613-0.9). Results between test-sets were significantly different (P < 0.05) confirming the need for a standardised benchmark. Conclusions We present the first public melanoma classification benchmark for both non-dermoscopic and dermoscopic images for comparing artificial intelligence algorithms with diagnostic performance of 145 or 157 dermatologists. Melanoma Classification Benchmark should be considered as a reference standard for white-skinned Western populations in the field of binary algorithmic melanoma classification.}, language = {en} } @article{LinkPaouneskouVelkovaetal.2018, author = {Link, Jana and Paouneskou, Dimitra and Velkova, Maria and Daryabeigi, Anahita and Laos, Triin and Labella, Sara and Barroso, Consuelo and Pacheco Pi{\~n}ol, Sarai and Montoya, Alex and Kramer, Holger and Woglar, Alexander and Baudrimont, Antoine and Markert, Sebastian Mathias and Stigloher, Christian and Martinez-Perez, Enrique and Dammermann, Alexander and Alsheimer, Manfred and Zetka, Monique and Jantsch, Verena}, title = {Transient and Partial Nuclear Lamina Disruption Promotes Chromosome Movement in Early Meiotic Prophase}, series = {Developmental Cell}, volume = {45}, journal = {Developmental Cell}, doi = {10.1016/j.devcel.2018.03.018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236901}, pages = {212-225}, year = {2018}, abstract = {Meiotic chromosome movement is important for the pairwise alignment of homologous chromosomes, which is required for correct chromosome segregation. Movement is driven by cytoplasmic forces, transmitted to chromosome ends by nuclear membrane-spanning proteins. In animal cells, lamins form a prominent scaffold at the nuclear periphery, yet the role lamins play in meiotic chromosome movement is unclear. We show that chromosome movement correlates with reduced lamin association with the nuclear rim, which requires lamin phosphorylation at sites analogous to those that open lamina network crosslinks in mitosis. Failure to remodel the lamina results in delayed meiotic entry, altered chromatin organization, unpaired or interlocked chromosomes, and slowed chromosome movement. The remodeling kinases are delivered to lamins via chromosome ends coupled to the nuclear envelope, potentially enabling crosstalk between the lamina and chromosomal events. Thus, opening the lamina network plays a role in modulating contacts between chromosomes and the nuclear periphery during meiosis.}, language = {en} } @article{TesfamariamJakobWoeckeletal.2019, author = {Tesfamariam, Y. and Jakob, T. and W{\"o}ckel, A. and Adams, A. and Weigl, A. and Monsef, I. and Kuhr, K. and Skoetz, N.}, title = {Adjuvant bisphosphonates or RANK-ligand inhibitors for patients with breast cancer and bone metastases: A systematic review and network meta-analysis}, series = {Critical Reviews in Oncology / Hematology}, volume = {137}, journal = {Critical Reviews in Oncology / Hematology}, doi = {10.1016/j.critrevonc.2019.02.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240827}, pages = {1-8}, year = {2019}, abstract = {Bone-modifying agents like bisphosphonates and receptor activator of nuclear factor kappaβ ligand (RANK-L) inhibitors are used as supportive treatments in breast cancer patients with bone metastases to prevent skeletal-related events (SREs). Due to missing head-to-head comparisons, a network meta-analysis was performed to provide a hierarchy of these therapeutic options. Through a systematic literature search, 21 randomized controlled trials (RCTs) that fulfilled the inclusion criteria were identified. To prevent SREs, the ranking through P-scores showed denosumab (RR: 0.62; 95\%CI: 0.50-0.76), zoledronic acid (RR: 0.72; 95\%CI: 0.61-0.84) and pamidronate (RR: 0.76; 95\%CI: 0.67-0.85) to be significantly superior to placebo. Due to insufficient or heterogeneous data, overall survival, quality of life, pain response and adverse events were not able to be analyzed within the network. Although data were sparse on adverse events, the risk of significant adverse events appeared low. The results of this review can therefore be used to formulate clinical studies more precisely in order to standardise and focus on patient-relevant outcomes.}, language = {en} } @article{MooijvanWijkBeusenetal.2019, author = {Mooij, Wolf M and van Wijk, Dianneke and Beusen, Arthur HW and Brederveld, Robert J and Chang, Manqi and Cobben, Marleen MP and DeAngelis, Don L and Downing, Andrea S and Green, Pamela and Gsell, Alena S and Huttunen, Inese and Janse, Jan H and Janssen, Annette BG and Hengeveld, Geerten M and Kong, Xiangzhen and Kramer, Lilith and Kuiper, Jan J and Langan, Simon J and Nolet, Bart A and Nuijten, Rascha JM and Strokal, Maryna and Troost, Tineke A and van Dam, Anne A and Teurlincx, Sven}, title = {Modeling water quality in the Anthropocene: directions for the next-generation aquatic ecosystem models}, series = {Current Opinion in Environmental Sustainability}, volume = {36}, journal = {Current Opinion in Environmental Sustainability}, doi = {10.1016/j.cosust.2018.10.012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224173}, pages = {85-95}, year = {2019}, abstract = {"Everything changes and nothing stands still" (Heraclitus). Here we review three major improvements to freshwater aquatic ecosystem models — and ecological models in general — as water quality scenario analysis tools towards a sustainable future. To tackle the rapid and deeply connected dynamics characteristic of the Anthropocene, we argue for the inclusion of eco-evolutionary, novel ecosystem and social-ecological dynamics. These dynamics arise from adaptive responses in organisms and ecosystems to global environmental change and act at different integration levels and different time scales. We provide reasons and means to incorporate each improvement into aquatic ecosystem models. Throughout this study we refer to Lake Victoria as a microcosm of the evolving novel social-ecological systems of the Anthropocene. The Lake Victoria case clearly shows how interlinked eco-evolutionary, novel ecosystem and social-ecological dynamics are, and demonstrates the need for transdisciplinary research approaches towards global sustainability.}, language = {en} } @article{KieferTrumppSchaitzetal.2019, author = {Kiefer, Markus and Trumpp, Natalie M. and Schaitz, Caroline and Reuss, Heiko and Kunde, Wilfried}, title = {Attentional modulation of masked semantic priming by visible and masked task cues}, series = {Cognition}, volume = {187}, journal = {Cognition}, doi = {10.1016/j.cognition.2019.02.013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325751}, pages = {62-77}, year = {2019}, abstract = {In contrast to classical theories of cognitive control, recent evidence suggests that cognitive control and unconscious automatic processing influence each other. First, masked semantic priming, an index of unconscious automatic processing, depends on attention to semantics induced by a previously executed task. Second, cognitive control operations (e.g., implementation of task sets indicating how to process a particular stimulus) can be activated by masked task cues, presented outside awareness. In this study, we combined both lines of research. We investigated in three experiments whether induction tasks and presentation of visible or masked task cues, which signal subsequent semantic or perceptual tasks but do not require induction task execution, comparably modulate masked semantic priming. In line with previous research, priming was consistently larger following execution of a semantic rather than a perceptual induction task. However, we observed in experiment 1 (masked letter cues) a reversed priming pattern following task cues (larger priming following cues signaling perceptual tasks) compared to induction tasks. Experiment 2 (visible letter cues) and experiment 3 (visible color cues) showed that this reversed priming pattern depended only on apriori associations between task cues and task elements (task set dominance), but neither on awareness nor on the verbal or non-verbal format of the cues. These results indicate that task cues have the power to modulate subsequent masked semantic priming through attentional mechanisms. Task-set dominance conceivably affects the time course of task set activation and inhibition in response to task cues and thus the direction of their modulatory effects on priming.}, language = {en} } @article{GerberKoenigFendtetal.2019, author = {Gerber, Bertram and K{\"o}nig, Christian and Fendt, Markus and Andreatta, Marta and Romanos, Marcel and Pauli, Paul and Yarali, Ayse}, title = {Timing-dependent valence reversal: a principle of reinforcement processing and its possible implications}, series = {Current Opinion in Behavioral Sciences}, volume = {26}, journal = {Current Opinion in Behavioral Sciences}, doi = {10.1016/j.cobeha.2018.12.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232933}, pages = {114-120}, year = {2019}, abstract = {Punishment feels bad, but relief upon its termination feels good. As a consequence of such timing-dependent valence reversal, memories of opposite valence can result from associating stimulus A with, for example, the occurrence of punishment (A-) versus punishment termination (-A): A- training results in aversive memory, but -A training in appetitive memory (corresponding effects exist for reward occurrence and termination). Whereas learning through the occurrence of punishment is well studied, much less is known about learning through its termination. Current research investigates how dopaminergic system function contributes to these processes in Drosophila, rats and humans. We argue that dopamine-related psychopathology may entail distortions in learning through punishment termination, and that this may contribute, for example, to non-suicidal self-injury or post-traumatic stress disorder.}, language = {en} } @article{ColungaHayworthKressetal.2019, author = {Colunga, Thomas and Hayworth, Miranda and Kreß, Sebastian and Reynolds, David M. and Chen, Luoman and Nazor, Kristopher L. and Baur, Johannes and Singh, Amar M. and Loring, Jeanne F. and Metzger, Marco and Dalton, Stephen}, title = {Human Pluripotent Stem Cell-Derived Multipotent Vascular Progenitors of the Mesothelium Lineage Have Utility in Tissue Engineering and Repair}, series = {Cell Reports}, volume = {26}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2019.02.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223217}, pages = {2566-2579}, year = {2019}, abstract = {In this report we describe a human pluripotent stem cell-derived vascular progenitor (MesoT) cell of the mesothelium lineage. MesoT cells are multipotent and generate smooth muscle cells, endothelial cells, and pericytes and self-assemble into vessel-like networks in vitro. MesoT cells transplanted into mechanically damaged neonatal mouse heart migrate into the injured tissue and contribute to nascent coronary vessels in the repair zone. When seeded onto decellularized vascular scaffolds, MesoT cells differentiate into the major vascular lineages and self-assemble into vasculature capable of supporting peripheral blood flow following transplantation. These findings demonstrate in vivo functionality and the potential utility of MesoT cells in vascular engineering applications.}, language = {en} } @article{ChhatbarDetjeGrabskietal.2018, author = {Chhatbar, Chintan and Detje, Claudia N. and Grabski, Elena and Borst, Katharina and Spanier, Julia and Ghita, Luca and Elliott, David A. and Jord{\~a}o, Marta Joana Costa and Mueller, Nora and Sutton, James and Prajeeth, Chittappen K. and Gudi, Viktoria and Klein, Michael A. and Prinz, Marco and Bradke, Frank and Stangel, Martin and Kalinke, Ulrich}, title = {Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis}, series = {Cell Reports}, volume = {25}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2018.09.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222456}, pages = {118-129}, year = {2018}, abstract = {In sterile neuroinflammation, a pathological role is proposed for microglia, whereas in viral encephalitis, their function is not entirely clear. Many viruses exploit the odorant system and enter the CNS via the olfactory bulb (OB). Upon intranasal vesicular stomatitis virus instillation, we show an accumulation of activated microglia and monocytes in the OB. Depletion of microglia during encephalitis results in enhanced virus spread and increased lethality. Activation, proliferation, and accumulation of microglia are regulated by type I IFN receptor signaling of neurons and astrocytes, but not of microglia. Morphological analysis of myeloid cells shows that type I IFN receptor signaling of neurons has a stronger impact on the activation of myeloid cells than of astrocytes. Thus, in the infected CNS, the cross talk among neurons, astrocytes, and microglia is critical for full microglia activation and protection from lethal encephalitis.}, language = {en} } @article{KuschBornscheinLorethetal.2018, author = {Kusch, Valentin and Bornschein, Grit and Loreth, Desiree and Bank, Julia and Jordan, Johannes and Baur, David and Watanabe, Masahiko and Kulik, Akos and Heckmann, Manfred and Eilers, Jens and Schmidt, Hartmut}, title = {Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors}, series = {Cell Reports}, volume = {22}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2018.02.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233468}, pages = {1965-1973}, year = {2018}, abstract = {Spatial relationships between Cav channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Cav2.1 and Cav2.2 channels, alters the localization of Cav2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca2+-channel pharmacology in electrophysiological and two-photon Ca2+ imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca2+ influx through Cav2.1 and Cav2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Cav2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Cav2.1 and Cav2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains.}, language = {en} }