@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}, } @article{8265, abstract = {Genome rearrangements have played an important role in the evolution of Yersinia pestis from its progenitor Yersinia pseudotuberculosis. Traditional phylogenetic trees for Y. pestis based on sequence comparison have short internal branches and low bootstrap supports as only a small number of nucleotide substitutions have occurred. On the other hand, even a small number of genome rearrangements may resolve topological ambiguities in a phylogenetic tree. We reconstructed phylogenetic trees based on genome rearrangements using several popular approaches such as Maximum likelihood for Gene Order and the Bayesian model of genome rearrangements by inversions. We also reconciled phylogenetic trees for each of the three CRISPR loci to obtain an integrated scenario of the CRISPR cassette evolution. Analysis of contradictions between the obtained evolutionary trees yielded numerous parallel inversions and gain/loss events. Our data indicate that an integrated analysis of sequence-based and inversion-based trees enhances the resolution of phylogenetic reconstruction. In contrast, reconstructions of strain relationships based on solely CRISPR loci may not be reliable, as the history is obscured by large deletions, obliterating the order of spacer gains. Similarly, numerous parallel gene losses preclude reconstruction of phylogeny based on gene content.}, author = {Bochkareva, Olga and Dranenko, Natalia O. and Ocheredko, Elena S. and Kanevsky, German M. and Lozinsky, Yaroslav N. and Khalaycheva, Vera A. and Artamonova, Irena I. and Gelfand, Mikhail S.}, issn = {2167-8359}, journal = {PeerJ}, publisher = {PeerJ}, title = {{Genome rearrangements and phylogeny reconstruction in Yersinia pestis}}, doi = {10.7717/peerj.4545}, volume = {6}, year = {2018}, } @inproceedings{8297, abstract = {Designing a secure permissionless distributed ledger (blockchain) that performs on par with centralized payment processors, such as Visa, is a challenging task. Most existing distributed ledgers are unable to scale-out, i.e., to grow their totalprocessing capacity with the number of validators; and those that do, compromise security or decentralization. We present OmniLedger, a novel scale-out distributed ledger that preserves longterm security under permissionless operation. It ensures security and correctness by using a bias-resistant public-randomness protocol for choosing large, statistically representative shards that process transactions, and by introducing an efficient crossshard commit protocol that atomically handles transactions affecting multiple shards. OmniLedger also optimizes performance via parallel intra-shard transaction processing, ledger pruning via collectively-signed state blocks, and low-latency “trust-butverify” validation for low-value transactions. An evaluation ofour experimental prototype shows that OmniLedger’s throughput scales linearly in the number of active validators, supporting Visa-level workloads and beyond, while confirming typical transactions in under two seconds.}, author = {Kokoris Kogias, Eleftherios and Jovanovic, Philipp and Gasser, Linus and Gailly, Nicolas and Syta, Ewa and Ford, Bryan}, booktitle = {2018 IEEE Symposium on Security and Privacy}, isbn = {9781538643532}, issn = {2375-1207}, location = {San Francisco, CA, United States}, pages = {583--598}, publisher = {IEEE}, title = {{OmniLedger: A secure, scale-out, decentralized ledger via sharding}}, doi = {10.1109/sp.2018.000-5}, year = {2018}, } @unpublished{8547, abstract = {The cerebral cortex contains multiple hierarchically organized areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have quantitatively investigated the neuronal output of individual progenitor cells in the ventricular zone of the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. We found that individual cortical progenitor cells show a high degree of stochasticity and generate pyramidal cell lineages that adopt a wide range of laminar configurations. Mathematical modelling these lineage data suggests that a small number of progenitor cell populations, each generating pyramidal cells following different stochastic developmental programs, suffice to generate the heterogenous complement of pyramidal cell lineages that collectively build the complex cytoarchitecture of the neocortex.}, author = {Llorca, Alfredo and Ciceri, Gabriele and Beattie, Robert J and Wong, Fong K. and Diana, Giovanni and Serafeimidou, Eleni and Fernández-Otero, Marian and Streicher, Carmen and Arnold, Sebastian J. and Meyer, Martin and Hippenmeyer, Simon and Maravall, Miguel and Marín, Oscar}, booktitle = {bioRxiv}, publisher = {Cold Spring Harbor Laboratory}, title = {{Heterogeneous progenitor cell behaviors underlie the assembly of neocortical cytoarchitecture}}, doi = {10.1101/494088}, year = {2018}, }