@article{7287, abstract = {Passivation layers on electrode materials are ubiquitous in nonaqueous battery chemistries and strongly govern performance and lifetime. They comprise breakdown products of the electrolyte including carbonate, alkyl carbonates, alkoxides, carboxylates, and polymers. Parasitic chemistry in metal–O2 batteries forms similar products and is tied to the deviation of the O2 balance from the ideal stoichiometry during formation/decomposition of alkaline peroxides or superoxides. Accurate and integral quantification of carbonaceous species and peroxides or superoxides in battery electrodes remains, however, elusive. We present a refined procedure to quantify them accurately and sensitively by pointing out and rectifying pitfalls of previous procedures. Carbonaceous compounds are differentiated into inorganic and organic ones. We combine mass and UV–vis spectrometry to quantify evolved O2 and complexed peroxide and CO2 evolved from carbonaceous compounds by acid treatment and Fenton’s reaction. The capabilities of the method are exemplified by means of Li–O2 and Na–O2 cathodes, graphite anodes, and LiNi0.8Co0.15Al0.05O2 cathodes.}, author = {Schafzahl, Bettina and Mourad, Eléonore and Schafzahl, Lukas and Petit, Yann K. and Raju, Anjana R. and Thotiyl, Musthafa Ottakam and Wilkening, Martin and Slugovc, Christian and Freunberger, Stefan Alexander}, issn = {2380-8195}, journal = {ACS Energy Letters}, number = {1}, pages = {170--176}, publisher = {ACS}, title = {{Quantifying total superoxide, peroxide, and carbonaceous compounds in metal–O2 batteries and the solid electrolyte interphase}}, doi = {10.1021/acsenergylett.7b01111}, volume = {3}, year = {2018}, } @article{7285, abstract = {Hydrogelation, the self-assembly of molecules into soft, water-loaded networks, is one way to bridge the structural gap between single molecules and functional materials. The potential of hydrogels, such as those based on perylene bisimides, lies in their chemical, physical, optical, and electronic properties, which are governed by the supramolecular structure of the gel. However, the structural motifs and their precise role for long-range conductivity are yet to be explored. Here, we present a comprehensive structural picture of a perylene bisimide hydrogel, suggesting that its long-range conductivity is limited by charge transfer between electronic backbones. We reveal nanocrystalline ribbon-like structures as the electronic and structural backbone units between which charge transfer is mediated by polar solvent bridges. We exemplify this effect with sensing, where exposure to polar vapor enhances conductivity by 5 orders of magnitude, emphasizing the crucial role of the interplay between structural motif and surrounding medium for the rational design of devices based on nanocrystalline hydrogels.}, author = {Burian, Max and Rigodanza, Francesco and Demitri, Nicola and D̵ord̵ević, Luka and Marchesan, Silvia and Steinhartova, Tereza and Letofsky-Papst, Ilse and Khalakhan, Ivan and Mourad, Eléonore and Freunberger, Stefan Alexander and Amenitsch, Heinz and Prato, Maurizio and Syrgiannis, Zois}, issn = {1936-0851}, journal = {ACS Nano}, number = {6}, pages = {5800--5806}, publisher = {ACS}, title = {{Inter-backbone charge transfer as prerequisite for long-range conductivity in perylene bisimide hydrogels}}, doi = {10.1021/acsnano.8b01689}, volume = {12}, year = {2018}, } @inproceedings{7407, abstract = {Proofs of space (PoS) [Dziembowski et al., CRYPTO'15] are proof systems where a prover can convince a verifier that he "wastes" disk space. PoS were introduced as a more ecological and economical replacement for proofs of work which are currently used to secure blockchains like Bitcoin. In this work we investigate extensions of PoS which allow the prover to embed useful data into the dedicated space, which later can be recovered. Our first contribution is a security proof for the original PoS from CRYPTO'15 in the random oracle model (the original proof only applied to a restricted class of adversaries which can store a subset of the data an honest prover would store). When this PoS is instantiated with recent constructions of maximally depth robust graphs, our proof implies basically optimal security. As a second contribution we show three different extensions of this PoS where useful data can be embedded into the space required by the prover. Our security proof for the PoS extends (non-trivially) to these constructions. We discuss how some of these variants can be used as proofs of catalytic space (PoCS), a notion we put forward in this work, and which basically is a PoS where most of the space required by the prover can be used to backup useful data. Finally we discuss how one of the extensions is a candidate construction for a proof of replication (PoR), a proof system recently suggested in the Filecoin whitepaper. }, author = {Pietrzak, Krzysztof Z}, booktitle = {10th Innovations in Theoretical Computer Science Conference (ITCS 2019)}, isbn = {978-3-95977-095-8}, issn = {1868-8969}, location = {San Diego, CA, United States}, pages = {59:1--59:25}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Proofs of catalytic space}}, doi = {10.4230/LIPICS.ITCS.2019.59}, volume = {124}, year = {2018}, } @article{7717, abstract = {Background: DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals. Methods: We performed a longitudinal analysis to quantify the variation in the rate of change of DNA methylation between individuals using whole blood DNA methylation array profiles collected at 2–4 time points (N = 2894) in 954 individuals (67–90 years). Results: After stringent quality control, we identified 1507 DNA methylation CpG sites (rsCpGs) with statistically significant variation in the rate of change (random slope) of DNA methylation among individuals in a mixed linear model analysis. Genes in the vicinity of these rsCpGs were found to be enriched in Homeobox transcription factors and the Wnt signalling pathway, both of which are related to ageing processes. Furthermore, we investigated the SNP effect on the random slope. We found that 4 out of 1507 rsCpGs had one significant (P < 5 × 10−8/1507) SNP effect and 343 rsCpGs had at least one SNP effect (436 SNP-probe pairs) reaching genome-wide significance (P < 5 × 10−8). Ninety-five percent of the significant (P < 5 × 10−8) SNPs are on different chromosomes from their corresponding probes. Conclusions: We identified CpG sites that have variability in the rate of change of DNA methylation between individuals, and our results suggest a genetic basis of this variation. Genes around these CpG sites have been reported to be involved in the ageing process.}, author = {Zhang, Qian and Marioni, Riccardo E and Robinson, Matthew Richard and Higham, Jon and Sproul, Duncan and Wray, Naomi R and Deary, Ian J and McRae, Allan F and Visscher, Peter M}, issn = {1756-994X}, journal = {Genome Medicine}, number = {1}, publisher = {Springer Nature}, title = {{Genotype effects contribute to variation in longitudinal methylome patterns in older people}}, doi = {10.1186/s13073-018-0585-7}, volume = {10}, year = {2018}, } @article{7712, abstract = {Male pattern baldness (MPB) is a sex-limited, age-related, complex trait. We study MPB genetics in 205,327 European males from the UK Biobank. Here we show that MPB is strongly heritable and polygenic, with pedigree-heritability of 0.62 (SE = 0.03) estimated from close relatives, and SNP-heritability of 0.39 (SE = 0.01) from conventionally-unrelated males. We detect 624 near-independent genome-wide loci, contributing SNP-heritability of 0.25 (SE = 0.01), of which 26 X-chromosome loci explain 11.6%. Autosomal genetic variance is enriched for common variants and regions of lower linkage disequilibrium. We identify plausible genetic correlations between MPB and multiple sex-limited markers of earlier puberty, increased bone mineral density (rg = 0.15) and pancreatic β-cell function (rg = 0.12). Correlations with reproductive traits imply an effect on fitness, consistent with an estimated linear selection gradient of -0.018 per MPB standard deviation. Overall, we provide genetic insights into MPB: a phenotype of interest in its own right, with value as a model sex-limited, complex trait.}, author = {Yap, Chloe X. and Sidorenko, Julia and Wu, Yang and Kemper, Kathryn E. and Yang, Jian and Wray, Naomi R. and Robinson, Matthew Richard and Visscher, Peter M.}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Dissection of genetic variation and evidence for pleiotropy in male pattern baldness}}, doi = {10.1038/s41467-018-07862-y}, volume = {9}, year = {2018}, } @article{7716, abstract = {Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait.}, author = {Maier, Robert M. and Zhu, Zhihong and Lee, Sang Hong and Trzaskowski, Maciej and Ruderfer, Douglas M. and Stahl, Eli A. and Ripke, Stephan and Wray, Naomi R. and Yang, Jian and Visscher, Peter M. and Robinson, Matthew Richard}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Improving genetic prediction by leveraging genetic correlations among human diseases and traits}}, doi = {10.1038/s41467-017-02769-6}, volume = {9}, year = {2018}, } @article{7714, abstract = {Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer’s disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative).}, author = {Zhu, Zhihong and Zheng, Zhili and Zhang, Futao and Wu, Yang and Trzaskowski, Maciej and Maier, Robert and Robinson, Matthew Richard and McGrath, John J. and Visscher, Peter M. and Wray, Naomi R. and Yang, Jian}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Causal associations between risk factors and common diseases inferred from GWAS summary data}}, doi = {10.1038/s41467-017-02317-2}, volume = {9}, year = {2018}, } @article{7713, abstract = {There are mean differences in complex traits among global human populations. We hypothesize that part of the phenotypic differentiation is due to natural selection. To address this hypothesis, we assess the differentiation in allele frequencies of trait-associated SNPs among African, Eastern Asian, and European populations for ten complex traits using data of large sample size (up to ~405,000). We show that SNPs associated with height (P=2.46×10−5), waist-to-hip ratio (P=2.77×10−4), and schizophrenia (P=3.96×10−5) are significantly more differentiated among populations than matched “control” SNPs, suggesting that these trait-associated SNPs have undergone natural selection. We further find that SNPs associated with height (P=2.01×10−6) and schizophrenia (P=5.16×10−18) show significantly higher variance in linkage disequilibrium (LD) scores across populations than control SNPs. Our results support the hypothesis that natural selection has shaped the genetic differentiation of complex traits, such as height and schizophrenia, among worldwide populations.}, author = {Guo, Jing and Wu, Yang and Zhu, Zhihong and Zheng, Zhili and Trzaskowski, Maciej and Zeng, Jian and Robinson, Matthew Richard and Visscher, Peter M. and Yang, Jian}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Global genetic differentiation of complex traits shaped by natural selection in humans}}, doi = {10.1038/s41467-018-04191-y}, volume = {9}, year = {2018}, } @article{7721, abstract = {The availability of genome-wide genetic data on hundreds of thousands of people has led to an equally rapid growth in methodologies available to analyse these data. While the motivation for undertaking genome-wide association studies (GWAS) is identification of genetic markers associated with complex traits, once generated these data can be used for many other analyses. GWAS have demonstrated that complex traits exhibit a highly polygenic genetic architecture, often with shared genetic risk factors across traits. New methods to analyse data from GWAS are increasingly being used to address a diverse set of questions about the aetiology of complex traits and diseases, including psychiatric disorders. Here, we give an overview of some of these methods and present examples of how they have contributed to our understanding of psychiatric disorders. We consider: (i) estimation of the extent of genetic influence on traits, (ii) uncovering of shared genetic control between traits, (iii) predictions of genetic risk for individuals, (iv) uncovering of causal relationships between traits, (v) identifying causal single-nucleotide polymorphisms and genes or (vi) the detection of genetic heterogeneity. This classification helps organise the large number of recently developed methods, although some could be placed in more than one category. While some methods require GWAS data on individual people, others simply use GWAS summary statistics data, allowing novel well-powered analyses to be conducted at a low computational burden.}, author = {Maier, R. M. and Visscher, P. M. and Robinson, Matthew Richard and Wray, N. R.}, issn = {0033-2917}, journal = {Psychological Medicine}, number = {7}, pages = {1055--1067}, publisher = {Cambridge University Press}, title = {{Embracing polygenicity: A review of methods and tools for psychiatric genetics research}}, doi = {10.1017/s0033291717002318}, volume = {48}, year = {2018}, } @article{7754, abstract = {Creating a selective gel that filters particles based on their interactions is a major goal of nanotechnology, with far-reaching implications from drug delivery to controlling assembly pathways. However, this is particularly difficult when the particles are larger than the gel’s characteristic mesh size because such particles cannot passively pass through the gel. Thus, filtering requires the interacting particles to transiently reorganize the gel’s internal structure. While significant advances, e.g., in DNA engineering, have enabled the design of nano-materials with programmable interactions, it is not clear what physical principles such a designer gel could exploit to achieve selective permeability. We present an equilibrium mechanism where crosslink binding dynamics are affected by interacting particles such that particle diffusion is enhanced. In addition to revealing specific design rules for manufacturing selective gels, our results have the potential to explain the origin of selective permeability in certain biological materials, including the nuclear pore complex.}, author = {Goodrich, Carl Peter and Brenner, Michael P. and Ribbeck, Katharina}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Enhanced diffusion by binding to the crosslinks of a polymer gel}}, doi = {10.1038/s41467-018-06851-5}, volume = {9}, year = {2018}, } @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}, } @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}, } @article{8262, abstract = {Background: The genus Burkholderia consists of species that occupy remarkably diverse ecological niches. Its best known members are important pathogens, B. mallei and B. pseudomallei, which cause glanders and melioidosis, respectively. Burkholderia genomes are unusual due to their multichromosomal organization, generally comprised of 2-3 chromosomes. Results: We performed integrated genomic analysis of 127 Burkholderia strains. The pan-genome is open with the saturation to be reached between 86,000 and 88,000 genes. The reconstructed rearrangements indicate a strong avoidance of intra-replichore inversions that is likely caused by selection against the transfer of large groups of genes between the leading and the lagging strands. Translocated genes also tend to retain their position in the leading or the lagging strand, and this selection is stronger for large syntenies. Integrated reconstruction of chromosome rearrangements in the context of strains phylogeny reveals parallel rearrangements that may indicate inversion-based phase variation and integration of new genomic islands. In particular, we detected parallel inversions in the second chromosomes of B. pseudomallei with breakpoints formed by genes encoding membrane components of multidrug resistance complex, that may be linked to a phase variation mechanism. Two genomic islands, spreading horizontally between chromosomes, were detected in the B. cepacia group. Conclusions: This study demonstrates the power of integrated analysis of pan-genomes, chromosome rearrangements, and selection regimes. Non-random inversion patterns indicate selective pressure, inversions are particularly frequent in a recent pathogen B. mallei, and, together with periods of positive selection at other branches, may indicate adaptation to new niches. One such adaptation could be a possible phase variation mechanism in B. pseudomallei.}, author = {Bochkareva, Olga and Moroz, Elena V. and Davydov, Iakov I. and Gelfand, Mikhail S.}, issn = {1471-2164}, journal = {BMC Genomics}, publisher = {Springer Nature}, title = {{Genome rearrangements and selection in multi-chromosome bacteria Burkholderia spp.}}, doi = {10.1186/s12864-018-5245-1}, volume = {19}, year = {2018}, }