@unpublished{7783, abstract = {The Drosophila Genetic Reference Panel (DGRP) serves as a valuable resource to better understand the genetic landscapes underlying quantitative traits. However, such DGRP studies have so far only focused on nuclear genetic variants. To address this, we sequenced the mitochondrial genomes of >170 DGRP lines, identifying 229 variants including 21 indels and 7 frameshifts. We used our mitochondrial variation data to identify 12 genetically distinct mitochondrial haplotypes, thus revealing important population structure at the mitochondrial level. We further examined whether this population structure was reflected on the nuclear genome by screening for the presence of potential mito-nuclear genetic incompatibilities in the form of significant genotype ratio distortions (GRDs) between mitochondrial and nuclear variants. In total, we detected a remarkable 1,845 mito-nuclear GRDs, with the highest enrichment observed in a 40 kb region around the gene Sex-lethal (Sxl). Intriguingly, downstream phenotypic analyses did not uncover major fitness effects associated with these GRDs, suggesting that a large number of mito-nuclear GRDs may reflect population structure at the mitochondrial level rather than actual genomic incompatibilities. This is further supported by the GRD landscape showing particular large genomic regions associated with a single mitochondrial haplotype. Next, we explored the functional relevance of the detected mitochondrial haplotypes through an association analysis on a set of 259 assembled, non-correlating DGRP phenotypes. We found multiple significant associations with stress- and metabolism-related phenotypes, including food intake in males. We validated the latter observation by reciprocal swapping of mitochondrial genomes from high food intake DGRP lines to low food intake ones. In conclusion, our study uncovered important mitochondrial population structure and haplotype-specific metabolic variation in the DGRP, thus demonstrating the significance of incorporating mitochondrial haplotypes in geno-phenotype relationship studies.}, author = {Bevers, Roel P.J. and Litovchenko, Maria and Kapopoulou, Adamandia and Braman, Virginie S. and Robinson, Matthew Richard and Auwerx, Johan and Hollis, Brian and Deplancke, Bart}, booktitle = {bioRxiv}, pages = {49}, publisher = {Cold Spring Harbor Laboratory}, title = {{Extensive mitochondrial population structure and haplotype-specific phenotypic variation in the Drosophila Genetic Reference Panel}}, year = {2018}, } @article{6001, abstract = {The concurrent memory reclamation problem is that of devising a way for a deallocating thread to verify that no other concurrent threads hold references to a memory block being deallocated. To date, in the absence of automatic garbage collection, there is no satisfactory solution to this problem; existing tracking methods like hazard pointers, reference counters, or epoch-based techniques like RCU are either prohibitively expensive or require significant programming expertise to the extent that implementing them efficiently can be worthy of a publication. None of the existing techniques are automatic or even semi-automated. In this article, we take a new approach to concurrent memory reclamation. Instead of manually tracking access to memory locations as done in techniques like hazard pointers, or restricting shared accesses to specific epoch boundaries as in RCU, our algorithm, called ThreadScan, leverages operating system signaling to automatically detect which memory locations are being accessed by concurrent threads. Initial empirical evidence shows that ThreadScan scales surprisingly well and requires negligible programming effort beyond the standard use of Malloc and Free.}, author = {Alistarh, Dan-Adrian and Leiserson, William and Matveev, Alexander and Shavit, Nir}, issn = {2329-4949}, journal = {ACM Transactions on Parallel Computing}, number = {4}, publisher = {Association for Computing Machinery}, title = {{ThreadScan: Automatic and scalable memory reclamation}}, doi = {10.1145/3201897}, volume = {4}, year = {2018}, } @inproceedings{7812, abstract = {Deep neural networks (DNNs) continue to make significant advances, solving tasks from image classification to translation or reinforcement learning. One aspect of the field receiving considerable attention is efficiently executing deep models in resource-constrained environments, such as mobile or embedded devices. This paper focuses on this problem, and proposes two new compression methods, which jointly leverage weight quantization and distillation of larger teacher networks into smaller student networks. The first method we propose is called quantized distillation and leverages distillation during the training process, by incorporating distillation loss, expressed with respect to the teacher, into the training of a student network whose weights are quantized to a limited set of levels. The second method, differentiable quantization, optimizes the location of quantization points through stochastic gradient descent, to better fit the behavior of the teacher model. We validate both methods through experiments on convolutional and recurrent architectures. We show that quantized shallow students can reach similar accuracy levels to full-precision teacher models, while providing order of magnitude compression, and inference speedup that is linear in the depth reduction. In sum, our results enable DNNs for resource-constrained environments to leverage architecture and accuracy advances developed on more powerful devices.}, author = {Polino, Antonio and Pascanu, Razvan and Alistarh, Dan-Adrian}, booktitle = {6th International Conference on Learning Representations}, location = {Vancouver, Canada}, title = {{Model compression via distillation and quantization}}, year = {2018}, } @article{7983, abstract = {Feste Alkalicarbonate sind universelle Bestandteile von Passivierungsschichten an Materialien für Interkalationsbatterien, übliche Nebenprodukte in Metall‐O2‐Batterien, und es wird angenommen, dass sie sich reversibel in Metall‐O2 /CO2‐Zellen bilden und zersetzen. In all diesen Kathoden zersetzt sich Li2CO3 zu CO2, sobald es Spannungen >3.8 V vs. Li/Li+ ausgesetzt wird. Beachtenswert ist, dass keine O2‐Entwicklung detektiert wird, wie gemäß der Zersetzungsreaktion 2 Li2CO3 → 4 Li+ + 4 e− + 2 CO2 + O2 zu erwarten wäre. Deswegen war der Verbleib eines der O‐Atome ungeklärt und wurde nicht identifizierten parasitären Reaktionen zugerechnet. Hier zeigen wir, dass hochreaktiver Singulett‐Sauerstoff (1O2) bei der Oxidation von Li2CO3 in einem aprotischen Elektrolyten gebildet und daher nicht als O2 freigesetzt wird. Diese Ergebnisse haben weitreichende Auswirkungen auf die langfristige Zyklisierbarkeit von Batterien: sie untermauern die Wichtigkeit, 1O2 in Metall‐O2‐Batterien zu verhindern, stellen die Möglichkeit einer reversiblen Metall‐O2 /CO2‐Batterie basierend auf einem Carbonat‐Entladeprodukt in Frage und helfen, Grenzflächenreaktivität von Übergangsmetallkathoden mit Li2CO3‐Resten zu erklären.}, author = {Mahne, Nika and Renfrew, Sara E. and McCloskey, Bryan D. and Freunberger, Stefan Alexander}, issn = {0044-8249}, journal = {Angewandte Chemie}, number = {19}, pages = {5627--5631}, publisher = {Wiley}, title = {{Elektrochemische Oxidation von Lithiumcarbonat generiert Singulett-Sauerstoff}}, doi = {10.1002/ange.201802277}, volume = {130}, year = {2018}, } @article{8015, abstract = {The neural code of cortical processing remains uncracked; however, it must necessarily rely on faithful signal propagation between cortical areas. In this issue of Neuron, Joglekar et al. (2018) show that strong inter-areal excitation balanced by local inhibition can enable reliable signal propagation in data-constrained network models of macaque cortex. }, author = {Stroud, Jake P. and Vogels, Tim P}, issn = {0896-6273}, journal = {Neuron}, number = {1}, pages = {8--9}, publisher = {Elsevier}, title = {{Cortical signal propagation: Balance, amplify, transmit}}, doi = {10.1016/j.neuron.2018.03.028}, volume = {98}, year = {2018}, } @article{8073, abstract = {Motor cortex (M1) exhibits a rich repertoire of neuronal activities to support the generation of complex movements. Although recent neuronal-network models capture many qualitative aspects of M1 dynamics, they can generate only a few distinct movements. Additionally, it is unclear how M1 efficiently controls movements over a wide range of shapes and speeds. We demonstrate that modulation of neuronal input–output gains in recurrent neuronal-network models with a fixed architecture can dramatically reorganize neuronal activity and thus downstream muscle outputs. Consistent with the observation of diffuse neuromodulatory projections to M1, a relatively small number of modulatory control units provide sufficient flexibility to adjust high-dimensional network activity using a simple reward-based learning rule. Furthermore, it is possible to assemble novel movements from previously learned primitives, and one can separately change movement speed while preserving movement shape. Our results provide a new perspective on the role of modulatory systems in controlling recurrent cortical activity.}, author = {Stroud, Jake P. and Porter, Mason A. and Hennequin, Guillaume and Vogels, Tim P}, issn = {1097-6256}, journal = {Nature Neuroscience}, number = {12}, pages = {1774--1783}, publisher = {Springer Nature}, title = {{Motor primitives in space and time via targeted gain modulation in cortical networks}}, doi = {10.1038/s41593-018-0276-0}, volume = {21}, year = {2018}, } @article{8231, author = {Fazekas-Singer, Judit and Singer, Josef and Ilieva, Kristina M. and Matz, Miroslawa and Herrmann, Ina and Spillner, Edzard and Karagiannis, Sophia N. and Jensen-Jarolim, Erika}, issn = {0091-6749}, journal = {Journal of Allergy and Clinical Immunology}, number = {3}, pages = {973--976.e11}, publisher = {Elsevier}, title = {{AllergoOncology: Generating a canine anticancer IgE against the epidermal growth factor receptor}}, doi = {10.1016/j.jaci.2018.04.021}, volume = {142}, year = {2018}, } @article{8234, abstract = {Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as ≥2.3-fold higher accumulation of FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1) poor conservation of target expression in xenografts and (2) unfavorable pharmacokinetics of FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using FE@SUPPY.}, author = {Balber, T. and Singer, Judit and Berroterán-Infante, N. and Dumanic, M. and Fetty, L. and Fazekas-Singer, J. and Vraka, C. and Nics, L. and Bergmann, M. and Pallitsch, K. and Spreitzer, H. and Wadsak, W. and Hacker, M. and Jensen-Jarolim, E. and Viernstein, H. and Mitterhauser, M.}, issn = {1555-4309}, journal = {Contrast Media & Molecular Imaging}, publisher = {Hindawi}, title = {{Preclinical in vitro and in vivo evaluation of [18F]FE@SUPPY for cancer PET imaging: Limitations of a xenograft model for colorectal cancer}}, doi = {10.1155/2018/1269830}, volume = {2018}, year = {2018}, } @article{8232, abstract = {Anti-epidermal growth factor receptor (EGFR) antibody therapy is used in EGFR expressing cancers including lung, colon, head and neck, and bladder cancers, however results have been modest. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate which is activated by NIR light. NIR-PIT is in clinical trials in patients with recurrent head and neck cancers using cetuximab-IR700 as the conjugate. However, its use has otherwise been restricted to mouse models. This is an effort to explore larger animal models with NIR-PIT. We describe the use of a recombinant canine anti-EGFR monoclonal antibody (mAb), can225IgG, conjugated to the photo-absorber, IR700DX, in three EGFR expressing canine transitional cell carcinoma (TCC) cell lines as a prelude to possible canine clinical studies. Can225-IR700 conjugate showed specific binding and cell-specific killing after NIR-PIT on EGFR expressing cells in vitro. In the in vivo study, can225-IR700 conjugate demonstrated accumulation of the fluorescent conjugate with high tumor-to-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of can225-IR700 i.v. only; (3) NIR light exposure only; (4) 100 μg of can225-IR700 i.v., NIR light exposure. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.001 vs. other groups) in the treatment groups. In conclusion, NIR-PIT with can225-IR700 is a promising treatment for canine EGFR-expressing cancers, including invasive transitional cell carcinoma in pet dogs, that could provide a pathway to translation to humans.}, author = {Nagaya, Tadanobu and Okuyama, Shuhei and Ogata, Fusa and Maruoka, Yasuhiro and Knapp, Deborah W. and Karagiannis, Sophia N. and Fazekas-Singer, Judit and Choyke, Peter L. and LeBlanc, Amy K. and Jensen-Jarolim, Erika and Kobayashi, Hisataka}, issn = {1949-2553}, journal = {Oncotarget}, pages = {19026--19038}, publisher = {Impact Journals}, title = {{Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody}}, doi = {10.18632/oncotarget.24876}, volume = {9}, year = {2018}, } @article{8233, abstract = {The M2a subtype of macrophages plays an important role in human immunoglobulin E (IgE-mediated allergies) and other Th2 type immune reactions. In contrast, very little is known about these cells in the dog. Here we describe an in vitro method to activate canine histiocytic DH82 cells and primary canine monocyte-derived macrophages (MDMs) toward the M2a macrophages using human cytokines. For a side-by-side comparison, we compared the canine cells to human MDMs, and the human monocytic cell line U937 activated towards M1 and M2a cells on the cellular and molecular level. In analogy to activated human M2a cells, canine M2a, differentiated from both DH82 and MDMs, showed an increase in CD206 surface receptor expression compared to M1. Interestingly, canine M2a, but not M1 derived from MDM, upregulated the high-affinity IgE receptor (FcεRI). Transcription levels of M2a-associated genes (IL10, CCL22, TGFβ, CD163) showed a diverse pattern between the human and dog species, whereas M1 genes (IDO1, CXCL11, IL6, TNF-α) were similarly upregulated in canine and human M1 cells (cell lines and MDMs). We suggest that our novel in vitro method will be suitable in comparative allergology studies focussing on macrophages.}, author = {Herrmann, Ina and Gotovina, Jelena and Fazekas-Singer, Judit and Fischer, Michael B. and Hufnagl, Karin and Bianchini, Rodolfo and Jensen-Jarolim, Erika}, issn = {0145-305X}, journal = {Developmental & Comparative Immunology}, number = {5}, pages = {118--127}, publisher = {Elsevier}, title = {{Canine macrophages can like human macrophages be in vitro activated toward the M2a subtype relevant in allergy}}, doi = {10.1016/j.dci.2018.01.005}, volume = {82}, year = {2018}, }