@article{1137, abstract = {RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.}, author = {Salzer, Elisabeth and Çaǧdaş, Deniz and Hons, Miroslav and Mace, Emily and Garncarz, Wojciech and Petronczki, Oezlem and Platzer, René and Pfajfer, Laurène and Bilic, Ivan and Ban, Sol and Willmann, Katharina and Mukherjee, Malini and Supper, Verena and Hsu, Hsiangting and Banerjee, Pinaki and Sinha, Papiya and Mcclanahan, Fabienne and Zlabinger, Gerhard and Pickl, Winfried and Gribben, John and Stockinger, Hannes and Bennett, Keiryn and Huppa, Johannes and Dupré, Loï̈C and Sanal, Özden and Jäger, Ulrich and Sixt, Michael K and Tezcan, Ilhan and Orange, Jordan and Boztug, Kaan}, journal = {Nature Immunology}, number = {12}, pages = {1352 -- 1360}, publisher = {Nature Publishing Group}, title = {{RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics}}, doi = {10.1038/ni.3575}, volume = {17}, year = {2016}, } @inproceedings{1138, abstract = {Automata with monitor counters, where the transitions do not depend on counter values, and nested weighted automata are two expressive automata-theoretic frameworks for quantitative properties. For a well-studied and wide class of quantitative functions, we establish that automata with monitor counters and nested weighted automata are equivalent. We study for the first time such quantitative automata under probabilistic semantics. We show that several problems that are undecidable for the classical questions of emptiness and universality become decidable under the probabilistic semantics. We present a complete picture of decidability for such automata, and even an almost-complete picture of computational complexity, for the probabilistic questions we consider. © 2016 ACM.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Otop, Jan}, booktitle = {Proceedings of the 31st Annual ACM/IEEE Symposium}, location = {New York, NY, USA}, pages = {76 -- 85}, publisher = {IEEE}, title = {{Quantitative automata under probabilistic semantics}}, doi = {10.1145/2933575.2933588}, year = {2016}, } @inproceedings{1140, abstract = {Given a model of a system and an objective, the model-checking question asks whether the model satisfies the objective. We study polynomial-time problems in two classical models, graphs and Markov Decision Processes (MDPs), with respect to several fundamental -regular objectives, e.g., Rabin and Streett objectives. For many of these problems the best-known upper bounds are quadratic or cubic, yet no super-linear lower bounds are known. In this work our contributions are two-fold: First, we present several improved algorithms, and second, we present the first conditional super-linear lower bounds based on widely believed assumptions about the complexity of CNF-SAT and combinatorial Boolean matrix multiplication. A separation result for two models with respect to an objective means a conditional lower bound for one model that is strictly higher than the existing upper bound for the other model, and similarly for two objectives with respect to a model. Our results establish the following separation results: (1) A separation of models (graphs and MDPs) for disjunctive queries of reachability and Büchi objectives. (2) Two kinds of separations of objectives, both for graphs and MDPs, namely, (2a) the separation of dual objectives such as Streett/Rabin objectives, and (2b) the separation of conjunction and disjunction of multiple objectives of the same type such as safety, Büchi, and coBüchi. In summary, our results establish the first model and objective separation results for graphs and MDPs for various classical -regular objectives. Quite strikingly, we establish conditional lower bounds for the disjunction of objectives that are strictly higher than the existing upper bounds for the conjunction of the same objectives. © 2016 ACM.}, author = {Chatterjee, Krishnendu and Dvoák, Wolfgang and Henzinger, Monika H and Loitzenbauer, Veronika}, booktitle = {Proceedings of the 31st Annual ACM/IEEE Symposium on Logic in Computer Science}, location = {New York, NY, USA}, pages = {197 -- 206}, publisher = {IEEE}, title = {{Model and objective separation with conditional lower bounds: disjunction is harder than conjunction}}, doi = {10.1145/2933575.2935304}, year = {2016}, } @article{1142, abstract = {Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.}, author = {Martins, Rui and Maier, Julia and Gorki, Anna and Huber, Kilian and Sharif, Omar and Starkl, Philipp and Saluzzo, Simona and Quattrone, Federica and Gawish, Riem and Lakovits, Karin and Aichinger, Michael and Radic Sarikas, Branka and Lardeau, Charles and Hladik, Anastasiya and Korosec, Ana and Brown, Markus and Vaahtomeri, Kari and Duggan, Michelle and Kerjaschki, Dontscho and Esterbauer, Harald and Colinge, Jacques and Eisenbarth, Stephanie and Decker, Thomas and Bennett, Keiryn and Kubicek, Stefan and Sixt, Michael K and Superti Furga, Giulio and Knapp, Sylvia}, journal = {Nature Immunology}, number = {12}, pages = {1361 -- 1372}, publisher = {Nature Publishing Group}, title = {{Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions}}, doi = {10.1038/ni.3590}, volume = {17}, year = {2016}, } @article{1143, abstract = {We study the ground state of a dilute Bose gas in a scaling limit where the Gross-Pitaevskii functional emerges. This is a repulsive nonlinear Schrödinger functional whose quartic term is proportional to the scattering length of the interparticle interaction potential. We propose a new derivation of this limit problem, with a method that bypasses some of the technical difficulties that previous derivations had to face. The new method is based on a combination of Dyson\'s lemma, the quantum de Finetti theorem and a second moment estimate for ground states of the effective Dyson Hamiltonian. It applies equally well to the case where magnetic fields or rotation are present.}, author = {Nam, Phan and Rougerie, Nicolas and Seiringer, Robert}, journal = {Analysis and PDE}, number = {2}, pages = {459 -- 485}, publisher = {Mathematical Sciences Publishers}, title = {{Ground states of large bosonic systems: The gross Pitaevskii limit revisited}}, doi = {10.2140/apde.2016.9.459}, volume = {9}, year = {2016}, } @article{100, abstract = {We introduce a scheme for preparation, manipulation, and read out of Majorana zero modes in semiconducting wires with mesoscopic superconducting islands. Our approach synthesizes recent advances in materials growth with tools commonly used in quantum-dot experiments, including gate control of tunnel barriers and Coulomb effects, charge sensing, and charge pumping. We outline a sequence of milestones interpolating between zero-mode detection and quantum computing that includes (1) detection of fusion rules for non-Abelian anyons using either proximal charge sensors or pumped current, (2) validation of a prototype topological qubit, and (3) demonstration of non-Abelian statistics by braiding in a branched geometry. The first two milestones require only a single wire with two islands, and additionally enable sensitive measurements of the system\'s excitation gap, quasiparticle poisoning rates, residual Majorana zero-mode splittings, and topological-qubit coherence times. These pre-braiding experiments can be adapted to other manipulation and read out schemes as well.}, author = {Aasen, David and Hell, Michael and Mishmash, Ryan and Higginbotham, Andrew P and Danon, Jeroen and Leijnse, Martin and Jespersen, Thomas and Folk, Joshua and Marcs, Charles and Flensberg, Karsten and Alicea, Jason}, journal = {Physical Review X}, number = {3}, publisher = {American Physical Society}, title = {{Milestones toward Majorana-based quantum computing}}, doi = {10.1103/PhysRevX.6.031016}, volume = {6}, year = {2016}, } @article{101, abstract = {Majorana zero modes are quasiparticle excitations in condensed matter systems that have been proposed as building blocks of fault-tolerant quantum computers. They are expected to exhibit non-Abelian particle statistics, in contrast to the usual statistics of fermions and bosons, enabling quantum operations to be performed by braiding isolated modes around one another. Quantum braiding operations are topologically protected insofar as these modes are pinned near zero energy, with the departure from zero expected to be exponentially small as the modes become spatially separated. Following theoretical proposals, several experiments have identified signatures of Majorana modes in nanowires with proximity-induced superconductivity and atomic chains, with small amounts of mode splitting potentially explained by hybridization of Majorana modes. Here, we use Coulomb-blockade spectroscopy in an InAs nanowire segment with epitaxial aluminium, which forms a proximity-induced superconducting Coulomb island (a â ∼ Majorana islandâ (tm)) that is isolated from normal-metal leads by tunnel barriers, to measure the splitting of near-zero-energy Majorana modes. We observe exponential suppression of energy splitting with increasing wire length. For short devices of a few hundred nanometres, sub-gap state energies oscillate as the magnetic field is varied, as is expected for hybridized Majorana modes. Splitting decreases by a factor of about ten for each half a micrometre of increased wire length. For devices longer than about one micrometre, transport in strong magnetic fields occurs through a zero-energy state that is energetically isolated from a continuum, yielding uniformly spaced Coulomb-blockade conductance peaks, consistent with teleportation via Majorana modes. Our results help to explain the trivial-to-topological transition in finite systems and to quantify the scaling of topological protection with end-mode separation.}, author = {Albrecht, S M and Higginbotham, Andrew P and Jespersen, Thomas and Madsen, Morten and Kuemmeth, Ferdinand and Nygård, Jesper and Krogstrup, Peter and Marcus, Charles}, journal = {Nature}, number = {7593}, pages = {206 -- 209}, publisher = {Nature Publishing Group}, title = {{Exponential protection of zero modes in Majorana islands}}, doi = {10.1038/nature17162}, volume = {531}, year = {2016}, } @article{102, abstract = {Recent experiments have produced mounting evidence of Majorana zero modes in nanowire-superconductor hybrids. Signatures of an expected topological phase transition accompanying the onset of these modes nevertheless remain elusive. We investigate a fundamental question concerning this issue: Do well-formed Majorana modes necessarily entail a sharp phase transition in these setups? Assuming reasonable parameters, we argue that finite-size effects can dramatically smooth this putative transition into a crossover, even in systems large enough to support well-localized Majorana modes. We propose overcoming such finite-size effects by examining the behavior of low-lying excited states through tunneling spectroscopy. In particular, the excited-state energies exhibit characteristic field and density dependence, and scaling with system size, that expose an approaching topological phase transition. We suggest several experiments for extracting the predicted behavior. As a useful byproduct, the protocols also allow one to measure the wire's spin-orbit coupling directly in its superconducting environment.}, author = {Mishmash, Ryan and Aasen, David and Higginbotham, Andrew P and Alicea, Jason}, journal = {Physical Review B}, number = {24}, publisher = {American Physical Society}, title = {{Approaching a topological phase transition in Majorana nanowires}}, doi = {10.1103/PhysRevB.93.245404}, volume = {93}, year = {2016}, } @article{10376, abstract = {Nucleation processes are at the heart of a large number of phenomena, from cloud formation to protein crystallization. A recently emerging area where nucleation is highly relevant is the initiation of filamentous protein self-assembly, a process that has broad implications in many research areas ranging from medicine to nanotechnology. As such, spontaneous nucleation of protein fibrils has received much attention in recent years with many theoretical and experimental studies focusing on the underlying physical principles. In this paper we make a step forward in this direction and explore the early time behaviour of filamentous protein growth in the context of nucleation theory. We first provide an overview of the thermodynamics and kinetics of spontaneous nucleation of protein filaments in the presence of one relevant degree of freedom, namely the cluster size. In this case, we review how key kinetic observables, such as the reaction order of spontaneous nucleation, are directly related to the physical size of the critical nucleus. We then focus on the increasingly prominent case of filament nucleation that includes a conformational conversion of the nucleating building-block as an additional slow step in the nucleation process. Using computer simulations, we study the concentration dependence of the nucleation rate. We find that, under these circumstances, the reaction order of spontaneous nucleation with respect to the free monomer does no longer relate to the overall physical size of the nucleating aggregate but rather to the portion of the aggregate that actively participates in the conformational conversion. Our results thus provide a novel interpretation of the common kinetic descriptors of protein filament formation, including the reaction order of the nucleation step or the scaling exponent of lag times, and put into perspective current theoretical descriptions of protein aggregation.}, author = {Šarić, Anđela and Michaels, Thomas C. T. and Zaccone, Alessio and Knowles, Tuomas P. J. and Frenkel, Daan}, issn = {1089-7690}, journal = {The Journal of Chemical Physics}, keywords = {physical and theoretical chemistry, general physics and astronomy}, number = {21}, publisher = {American Institute of Physics}, title = {{Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation}}, doi = {10.1063/1.4965040}, volume = {145}, year = {2016}, } @article{10377, abstract = {The interplay of membrane proteins is vital for many biological processes, such as cellular transport, cell division, and signal transduction between nerve cells. Theoretical considerations have led to the idea that the membrane itself mediates protein self-organization in these processes through minimization of membrane curvature energy. Here, we present a combined experimental and numerical study in which we quantify these interactions directly for the first time. In our experimental model system we control the deformation of a lipid membrane by adhering colloidal particles. Using confocal microscopy, we establish that these membrane deformations cause an attractive interaction force leading to reversible binding. The attraction extends over 2.5 times the particle diameter and has a strength of three times the thermal energy (−3.3 kBT). Coarse-grained Monte-Carlo simulations of the system are in excellent agreement with the experimental results and prove that the measured interaction is independent of length scale. Our combined experimental and numerical results reveal membrane curvature as a common physical origin for interactions between any membrane-deforming objects, from nanometre-sized proteins to micrometre-sized particles.}, author = {van der Wel, Casper and Vahid, Afshin and Šarić, Anđela and Idema, Timon and Heinrich, Doris and Kraft, Daniela J.}, issn = {2045-2322}, journal = {Scientific Reports}, keywords = {multidisciplinary}, number = {1}, publisher = {Springer Nature}, title = {{Lipid membrane-mediated attraction between curvature inducing objects}}, doi = {10.1038/srep32825}, volume = {6}, year = {2016}, } @article{10378, abstract = {The ability of biological molecules to replicate themselves is the foundation of life, requiring a complex cellular machinery. However, a range of aberrant processes involve the self-replication of pathological protein structures without any additional assistance. One example is the autocatalytic generation of pathological protein aggregates, including amyloid fibrils, involved in neurodegenerative disorders. Here, we use computer simulations to identify the necessary requirements for the self-replication of fibrillar assemblies of proteins. We establish that a key physical determinant for this process is the affinity of proteins for the surfaces of fibrils. We find that self-replication can take place only in a very narrow regime of inter-protein interactions, implying a high level of sensitivity to system parameters and experimental conditions. We then compare our theoretical predictions with kinetic and biosensor measurements of fibrils formed from the Aβ peptide associated with Alzheimer’s disease. Our results show a quantitative connection between the kinetics of self-replication and the surface coverage of fibrils by monomeric proteins. These findings reveal the fundamental physical requirements for the formation of supra-molecular structures able to replicate themselves, and shed light on mechanisms in play in the proliferation of protein aggregates in nature.}, author = {Šarić, Anđela and Buell, Alexander K. and Meisl, Georg and Michaels, Thomas C. T. and Dobson, Christopher M. and Linse, Sara and Knowles, Tuomas P. J. and Frenkel, Daan}, issn = {1745-2481}, journal = {Nature Physics}, keywords = {general physics and astronomy}, number = {9}, pages = {874--880}, publisher = {Springer Nature}, title = {{Physical determinants of the self-replication of protein fibrils}}, doi = {10.1038/nphys3828}, volume = {12}, year = {2016}, } @article{10380, abstract = {Using non-equilibrium molecular dynamics simulations, it has been recently demonstrated that water molecules align in response to an imposed temperature gradient, resulting in an effective electric field. Here, we investigate how thermally induced fields depend on the underlying treatment of long-ranged interactions. For the short-ranged Wolf method and Ewald summation, we find the peak strength of the field to range between 2 × 107 and 5 × 107 V/m for a temperature gradient of 5.2 K/Å. Our value for the Wolf method is therefore an order of magnitude lower than the literature value [J. A. Armstrong and F. Bresme, J. Chem. Phys. 139, 014504 (2013); J. Armstrong et al., J. Chem. Phys. 143, 036101 (2015)]. We show that this discrepancy can be traced back to the use of an incorrect kernel in the calculation of the electrostatic field. More seriously, we find that the Wolf method fails to predict correct molecular orientations, resulting in dipole densities with opposite sign to those computed using Ewald summation. By considering two different multipole expansions, we show that, for inhomogeneous polarisations, the quadrupole contribution can be significant and even outweigh the dipole contribution to the field. Finally, we propose a more accurate way of calculating the electrostatic potential and the field. In particular, we show that averaging the microscopic field analytically to obtain the macroscopic Maxwell field reduces the error bars by up to an order of magnitude. As a consequence, the simulation times required to reach a given statistical accuracy decrease by up to two orders of magnitude.}, author = {Wirnsberger, P. and Fijan, D. and Šarić, Anđela and Neumann, M. and Dellago, C. and Frenkel, D.}, issn = {1089-7690}, journal = {The Journal of Chemical Physics}, keywords = {physical and theoretical chemistry, general physics and astronomy}, number = {22}, publisher = {American Institute of Physics}, title = {{Non-equilibrium simulations of thermally induced electric fields in water}}, doi = {10.1063/1.4953036}, volume = {144}, year = {2016}, } @article{10381, abstract = {We study phase behaviour of lipid-bilayer vesicles functionalised by ligand–receptor complexes made of synthetic DNA by introducing a modelling framework and a dedicated experimental platform. In particular, we perform Monte Carlo simulations that combine a coarse grained description of the lipid bilayer with state of art analytical models for multivalent ligand–receptor interactions. Using density of state calculations, we derive the partition function in pairs of vesicles and compute the number of ligand–receptor bonds as a function of temperature. Numerical results are compared to microscopy and fluorimetry experiments on large unilamellar vesicles decorated by DNA linkers carrying complementary overhangs. We find that vesicle aggregation is suppressed when the total number of linkers falls below a threshold value. Within the model proposed here, this is due to the higher configurational costs required to form inter-vesicle bridges as compared to intra-vesicle loops, which are in turn related to membrane deformability. Our findings and our numerical/experimental methodologies are applicable to the rational design of liposomes used as functional materials and drug delivery applications, as well as to study inter-membrane interactions in living systems, such as cell adhesion.}, author = {Bachmann, Stephan Jan and Kotar, Jurij and Parolini, Lucia and Šarić, Anđela and Cicuta, Pietro and Di Michele, Lorenzo and Mognetti, Bortolo Matteo}, issn = {1744-6848}, journal = {Soft Matter}, keywords = {condensed matter physics, general chemistry}, number = {37}, pages = {7804--7817}, publisher = {Royal Society of Chemistry}, title = {{Melting transition in lipid vesicles functionalised by mobile DNA linkers}}, doi = {10.1039/c6sm01515h}, volume = {12}, year = {2016}, } @article{21101, abstract = {It has previously been shown that the use of racemic mixtures of naturally chiral macromolecules such as protein and DNA can significantly aid the crystallogenesis process, thereby addressing one of the major bottlenecks to structure determination by X-ray crystallographic methods—that of crystal growth. Although previous studies have provided convincing evidence of the applicability of the racemic crystallization technique to DNA through the study of well-characterized DNA structures, we sought to apply this method to a historically challenging DNA sequence. For this purpose we chose a non-self-complementary DNA duplex containing the biologically-relevant Pribnow box consensus sequence ‘TATAAT’. Four racemic crystal structures of this previously un-crystallizable DNA target are reported (with resolutions in the range of 1.65–2.3 Å), with further crystallographic studies and structural analysis providing insight into the racemic crystallization process as well as structural details of this highly pertinent DNA sequence.}, author = {Mandal, Pradeep K and Collie, Gavin W. and Srivastava, Suresh C. and Kauffmann, Brice and Huc, Ivan}, issn = {1362-4962}, journal = {Nucleic Acids Research}, number = {12}, pages = {5936--5943}, publisher = {Oxford University Press}, title = {{Structure elucidation of the Pribnow box consensus promoter sequence by racemic DNA crystallography}}, doi = {10.1093/nar/gkw367}, volume = {44}, year = {2016}, } @article{1552, abstract = {Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR. Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings.}, author = {Qi, Qin and Toll Riera, Macarena and Heilbron, Karl and Preston, Gail and Maclean, R Craig}, journal = {Proceedings of the Royal Society of London Series B Biological Sciences}, number = {1822}, publisher = {Royal Society, The}, title = {{The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa}}, doi = {10.1098/rspb.2015.2452}, volume = {283}, year = {2016}, } @article{1599, abstract = {The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis. }, author = {Kiermaier, Eva and Moussion, Christine and Veldkamp, Christopher and Gerardy Schahn, Rita and De Vries, Ingrid and Williams, Larry and Chaffee, Gary and Phillips, Andrew and Freiberger, Friedrich and Imre, Richard and Taleski, Deni and Payne, Richard and Braun, Asolina and Förster, Reinhold and Mechtler, Karl and Mühlenhoff, Martina and Volkman, Brian and Sixt, Michael K}, journal = {Science}, number = {6269}, pages = {186 -- 190}, publisher = {American Association for the Advancement of Science}, title = {{Polysialylation controls dendritic cell trafficking by regulating chemokine recognition}}, doi = {10.1126/science.aad0512}, volume = {351}, year = {2016}, } @article{1608, abstract = {We show that the Anderson model has a transition from localization to delocalization at exactly 2 dimensional growth rate on antitrees with normalized edge weights which are certain discrete graphs. The kinetic part has a one-dimensional structure allowing a description through transfer matrices which involve some Schur complement. For such operators we introduce the notion of having one propagating channel and extend theorems from the theory of one-dimensional Jacobi operators that relate the behavior of transfer matrices with the spectrum. These theorems are then applied to the considered model. In essence, in a certain energy region the kinetic part averages the random potentials along shells and the transfer matrices behave similar as for a one-dimensional operator with random potential of decaying variance. At d dimensional growth for d>2 this effective decay is strong enough to obtain absolutely continuous spectrum, whereas for some uniform d dimensional growth with d<2 one has pure point spectrum in this energy region. At exactly uniform 2 dimensional growth also some singular continuous spectrum appears, at least at small disorder. As a corollary we also obtain a change from singular spectrum (d≤2) to absolutely continuous spectrum (d≥3) for random operators of the type rΔdr+λ on ℤd, where r is an orthogonal radial projection, Δd the discrete adjacency operator (Laplacian) on ℤd and λ a random potential. }, author = {Sadel, Christian}, journal = {Annales Henri Poincare}, number = {7}, pages = {1631 -- 1675}, publisher = {Birkhäuser}, title = {{Anderson transition at 2 dimensional growth rate on antitrees and spectral theory for operators with one propagating channel}}, doi = {10.1007/s00023-015-0456-3}, volume = {17}, year = {2016}, } @article{1612, abstract = {We prove that whenever A is a 3-conservative relational structure with only binary and unary relations,then the algebra of polymorphisms of A either has no Taylor operation (i.e.,CSP(A)is NP-complete),or it generates an SD(∧) variety (i.e.,CSP(A)has bounded width).}, author = {Kazda, Alexandr}, journal = {Algebra Universalis}, number = {1}, pages = {75 -- 84}, publisher = {Springer}, title = {{CSP for binary conservative relational structures}}, doi = {10.1007/s00012-015-0358-8}, volume = {75}, year = {2016}, } @article{1613, abstract = {In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer's disease (AD) have been often failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells. In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD.}, author = {Mungenast, Alison and Siegert, Sandra and Tsai, Li}, journal = {Molecular and Cellular Neuroscience}, pages = {13 -- 31}, publisher = {Academic Press}, title = {{Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells}}, doi = {doi:10.1016/j.mcn.2015.11.010}, volume = {73}, year = {2016}, } @article{1616, abstract = {The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high-resolution whole-cell patch-clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ∼3–6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input-output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input-output transformation.}, author = {Kowalski, Janina and Gan, Jian and Jonas, Peter M and Pernia-Andrade, Alejandro}, issn = {1098-1063}, journal = {Hippocampus}, number = {5}, pages = {668 -- 682}, publisher = {Wiley}, title = {{Intrinsic membrane properties determine hippocampal differential firing pattern in vivo in anesthetized rats}}, doi = {10.1002/hipo.22550}, volume = {26}, year = {2016}, }