TY - JOUR AB - Genetic perturbations that affect bacterial resistance to antibiotics have been characterized genome-wide, but how do such perturbations interact with subsequent evolutionary adaptation to the drug? Here, we show that strong epistasis between resistance mutations and systematically identified genes can be exploited to control spontaneous resistance evolution. We evolved hundreds of Escherichia coli K-12 mutant populations in parallel, using a robotic platform that tightly controls population size and selection pressure. We find a global diminishing-returns epistasis pattern: strains that are initially more sensitive generally undergo larger resistance gains. However, some gene deletion strains deviate from this general trend and curtail the evolvability of resistance, including deletions of genes for membrane transport, LPS biosynthesis, and chaperones. Deletions of efflux pump genes force evolution on inferior mutational paths, not explored in the wild type, and some of these essentially block resistance evolution. This effect is due to strong negative epistasis with resistance mutations. The identified genes and cellular functions provide potential targets for development of adjuvants that may block spontaneous resistance evolution when combined with antibiotics. AU - Lukacisinova, Marta AU - Fernando, Booshini AU - Bollenbach, Mark Tobias ID - 8037 JF - Nature Communications TI - Highly parallel lab evolution reveals that epistasis can curb the evolution of antibiotic resistance VL - 11 ER - TY - JOUR AB - The mitochondrial respiratory chain, formed by five protein complexes, utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains, however, fragmentary due to bottlenecks in understanding redox-driven conformational transitions and their interplay with the hydrated proton pathways. Complex I from Thermus thermophilus encases 16 subunits with nine iron–sulfur clusters, reduced by electrons from NADH. Here, employing the latest crystal structure of T. thermophilus complex I, we have used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron–sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which allosterically couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol form—a design essential for menaquinol release. Remarkably, the barriers to diffusive menaquinone dynamics are lesser than that of the more ubiquitous ubiquinone, and the naphthoquinone headgroup of the former furnishes stronger binding interactions with the pocket, favoring menaquinone for charge transport in T. thermophilus. Our computations are consistent with experimentally validated mutations and hierarchize the key residues into three functional classes, identifying new mutation targets. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the transmembrane subunits are found to be responsible for proton pumping. Put together, the simulations reveal the molecular design principles linking redox reactions to quinone turnover to proton translocation in complex I. AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun Kit AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M. R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 8040 IS - 20 JF - Journal of the American Chemical Society SN - 00027863 TI - Charge transfer and chemo-mechanical coupling in respiratory complex I VL - 142 ER - TY - JOUR AB - When tiny soft ferromagnetic particles are placed along a liquid interface and exposed to a vertical magnetic field, the balance between capillary attraction and magnetic repulsion leads to self-organization into well-defined patterns. Here, we demonstrate experimentally that precessing magnetic fields induce metachronal waves on the periphery of these assemblies, similar to the ones observed in ciliates and some arthropods. The outermost layer of particles behaves like an array of cilia or legs whose sequential movement causes a net and controllable locomotion. This bioinspired many-particle swimming strategy is effective even at low Reynolds number, using only spatially uniform fields to generate the waves. AU - Collard, Ylona AU - Grosjean, Galien M AU - Vandewalle, Nicolas ID - 8036 JF - Communications Physics TI - Magnetically powered metachronal waves induce locomotion in self-assemblies VL - 3 ER - TY - JOUR AB - With decreasing Reynolds number, Re, turbulence in channel flow becomes spatio-temporally intermittent and self-organises into solitary stripes oblique to the mean flow direction. We report here the existence of localised nonlinear travelling wave solutions of the Navier–Stokes equations possessing this obliqueness property. Such solutions are identified numerically using edge tracking coupled with arclength continuation. All solutions emerge in saddle-node bifurcations at values of Re lower than the non-localised solutions. Relative periodic orbit solutions bifurcating from branches of travelling waves have also been computed. A complete parametric study is performed, including their stability, the investigation of their large-scale flow, and the robustness to changes of the numerical domain. AU - Paranjape, Chaitanya S AU - Duguet, Yohann AU - Hof, Björn ID - 8043 JF - Journal of Fluid Mechanics SN - 00221120 TI - Oblique stripe solutions of channel flow VL - 897 ER - TY - GEN AB - The mitochondrial respiratory chain, formed by five protein complexes, utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains, however, fragmentary due to bottlenecks in understanding redox-driven conformational transitions and their interplay with the hydrated proton pathways. Complex I from Thermus thermophilus encases 16 subunits with nine iron–sulfur clusters, reduced by electrons from NADH. Here, employing the latest crystal structure of T. thermophilus complex I, we have used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron–sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which allosterically couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol forma design essential for menaquinol release. Remarkably, the barriers to diffusive menaquinone dynamics are lesser than that of the more ubiquitous ubiquinone, and the naphthoquinone headgroup of the former furnishes stronger binding interactions with the pocket, favoring menaquinone for charge transport in T. thermophilus. Our computations are consistent with experimentally validated mutations and hierarchize the key residues into three functional classes, identifying new mutation targets. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the transmembrane subunits are found to be responsible for proton pumping. Put together, the simulations reveal the molecular design principles linking redox reactions to quinone turnover to proton translocation in complex I. AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M. R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 9326 TI - Charge transfer and chemo-mechanical coupling in respiratory complex I ER - TY - JOUR AB - We consider systems of N bosons in a box of volume one, interacting through a repulsive two-body potential of the form κN3β−1V(Nβx). For all 0<β<1, and for sufficiently small coupling constant κ>0, we establish the validity of Bogolyubov theory, identifying the ground state energy and the low-lying excitation spectrum up to errors that vanish in the limit of large N. AU - Boccato, Chiara AU - Brennecke, Christian AU - Cenatiempo, Serena AU - Schlein, Benjamin ID - 8042 IS - 7 JF - Journal of the European Mathematical Society SN - 14359855 TI - The excitation spectrum of Bose gases interacting through singular potentials VL - 22 ER - TY - GEN AB - Additional analyses of the trajectories AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun Kit AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M.R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 9713 TI - Supporting information ER - TY - GEN AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun Kit AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M.R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 9878 TI - Movies ER - TY - JOUR AB - Background: The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment. Methods: The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo. Results: Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system. Conclusion: We propose that the chemokine axis CCL20–CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy. AU - Hippe, Andreas AU - Braun, Stephan Alexander AU - Oláh, Péter AU - Gerber, Peter Arne AU - Schorr, Anne AU - Seeliger, Stephan AU - Holtz, Stephanie AU - Jannasch, Katharina AU - Pivarcsi, Andor AU - Buhren, Bettina AU - Schrumpf, Holger AU - Kislat, Andreas AU - Bünemann, Erich AU - Steinhoff, Martin AU - Fischer, Jens AU - Lira, Sérgio A. AU - Boukamp, Petra AU - Hevezi, Peter AU - Stoecklein, Nikolas Hendrik AU - Hoffmann, Thomas AU - Alves, Frauke AU - Sleeman, Jonathan AU - Bauer, Thomas AU - Klufa, Jörg AU - Amberg, Nicole AU - Sibilia, Maria AU - Zlotnik, Albert AU - Müller-Homey, Anja AU - Homey, Bernhard ID - 8093 JF - British Journal of Cancer SN - 0007-0920 TI - EGFR/Ras-induced CCL20 production modulates the tumour microenvironment VL - 123 ER - TY - JOUR AB - In the setting of the fractional quantum Hall effect we study the effects of strong, repulsive two-body interaction potentials of short range. We prove that Haldane’s pseudo-potential operators, including their pre-factors, emerge as mathematically rigorous limits of such interactions when the range of the potential tends to zero while its strength tends to infinity. In a common approach the interaction potential is expanded in angular momentum eigenstates in the lowest Landau level, which amounts to taking the pre-factors to be the moments of the potential. Such a procedure is not appropriate for very strong interactions, however, in particular not in the case of hard spheres. We derive the formulas valid in the short-range case, which involve the scattering lengths of the interaction potential in different angular momentum channels rather than its moments. Our results hold for bosons and fermions alike and generalize previous results in [6], which apply to bosons in the lowest angular momentum channel. Our main theorem asserts the convergence in a norm-resolvent sense of the Hamiltonian on the whole Hilbert space, after appropriate energy scalings, to Hamiltonians with contact interactions in the lowest Landau level. AU - Seiringer, Robert AU - Yngvason, Jakob ID - 8091 JF - Journal of Statistical Physics SN - 00224715 TI - Emergence of Haldane pseudo-potentials in systems with short-range interactions VL - 181 ER - TY - JOUR AB - The projection methods with vanilla inertial extrapolation step for variational inequalities have been of interest to many authors recently due to the improved convergence speed contributed by the presence of inertial extrapolation step. However, it is discovered that these projection methods with inertial steps lose the Fejér monotonicity of the iterates with respect to the solution, which is being enjoyed by their corresponding non-inertial projection methods for variational inequalities. This lack of Fejér monotonicity makes projection methods with vanilla inertial extrapolation step for variational inequalities not to converge faster than their corresponding non-inertial projection methods at times. Also, it has recently been proved that the projection methods with vanilla inertial extrapolation step may provide convergence rates that are worse than the classical projected gradient methods for strongly convex functions. In this paper, we introduce projection methods with alternated inertial extrapolation step for solving variational inequalities. We show that the sequence of iterates generated by our methods converges weakly to a solution of the variational inequality under some appropriate conditions. The Fejér monotonicity of even subsequence is recovered in these methods and linear rate of convergence is obtained. The numerical implementations of our methods compared with some other inertial projection methods show that our method is more efficient and outperforms some of these inertial projection methods. AU - Shehu, Yekini AU - Iyiola, Olaniyi S. ID - 8077 JF - Applied Numerical Mathematics SN - 0168-9274 TI - Projection methods with alternating inertial steps for variational inequalities: Weak and linear convergence VL - 157 ER - TY - JOUR AB - In the present work, we report a solution-based strategy to produce crystallographically textured SnSe bulk nanomaterials and printed layers with optimized thermoelectric performance in the direction normal to the substrate. Our strategy is based on the formulation of a molecular precursor that can be continuously decomposed to produce a SnSe powder or printed into predefined patterns. The precursor formulation and decomposition conditions are optimized to produce pure phase 2D SnSe nanoplates. The printed layer and the bulk material obtained after hot press displays a clear preferential orientation of the crystallographic domains, resulting in an ultralow thermal conductivity of 0.55 W m–1 K–1 in the direction normal to the substrate. Such textured nanomaterials present highly anisotropic properties with the best thermoelectric performance in plane, i.e., in the directions parallel to the substrate, which coincide with the crystallographic bc plane of SnSe. This is an unfortunate characteristic because thermoelectric devices are designed to create/harvest temperature gradients in the direction normal to the substrate. We further demonstrate that this limitation can be overcome with the introduction of small amounts of tellurium in the precursor. The presence of tellurium allows one to reduce the band gap and increase both the charge carrier concentration and the mobility, especially the cross plane, with a minimal decrease of the Seebeck coefficient. These effects translate into record out of plane ZT values at 800 K. AU - Zhang, Yu AU - Liu, Yu AU - Xing, Congcong AU - Zhang, Ting AU - Li, Mengyao AU - Pacios, Mercè AU - Yu, Xiaoting AU - Arbiol, Jordi AU - Llorca, Jordi AU - Cadavid, Doris AU - Ibáñez, Maria AU - Cabot, Andreu ID - 8039 IS - 24 JF - ACS Applied Materials and Interfaces TI - Tin selenide molecular precursor for the solution processing of thermoelectric materials and devices VL - 12 ER - TY - JOUR AB - The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn’s disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease. AU - Hillary, Robert F. AU - Trejo-Banos, Daniel AU - Kousathanas, Athanasios AU - Mccartney, Daniel L. AU - Harris, Sarah E. AU - Stevenson, Anna J. AU - Patxot, Marion AU - Ojavee, Sven Erik AU - Zhang, Qian AU - Liewald, David C. AU - Ritchie, Craig W. AU - Evans, Kathryn L. AU - Tucker-Drob, Elliot M. AU - Wray, Naomi R. AU - Mcrae, Allan F. AU - Visscher, Peter M. AU - Deary, Ian J. AU - Robinson, Matthew Richard AU - Marioni, Riccardo E. ID - 8133 IS - 1 JF - Genome Medicine TI - Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults VL - 12 ER - TY - JOUR AB - Mechanistic modeling in neuroscience aims to explain observed phenomena in terms of underlying causes. However, determining which model parameters agree with complex and stochastic neural data presents a significant challenge. We address this challenge with a machine learning tool which uses deep neural density estimators—trained using model simulations—to carry out Bayesian inference and retrieve the full space of parameters compatible with raw data or selected data features. Our method is scalable in parameters and data features and can rapidly analyze new data after initial training. We demonstrate the power and flexibility of our approach on receptive fields, ion channels, and Hodgkin–Huxley models. We also characterize the space of circuit configurations giving rise to rhythmic activity in the crustacean stomatogastric ganglion, and use these results to derive hypotheses for underlying compensation mechanisms. Our approach will help close the gap between data-driven and theory-driven models of neural dynamics. AU - Gonçalves, Pedro J. AU - Lueckmann, Jan-Matthis AU - Deistler, Michael AU - Nonnenmacher, Marcel AU - Öcal, Kaan AU - Bassetto, Giacomo AU - Chintaluri, Chaitanya AU - Podlaski, William F. AU - Haddad, Sara A. AU - Vogels, Tim P AU - Greenberg, David S. AU - Macke, Jakob H. ID - 8127 JF - eLife TI - Training deep neural density estimators to identify mechanistic models of neural dynamics VL - 9 ER - TY - JOUR AB - Cortical areas comprise multiple types of inhibitory interneurons with stereotypical connectivity motifs, but their combined effect on postsynaptic dynamics has been largely unexplored. Here, we analyse the response of a single postsynaptic model neuron receiving tuned excitatory connections alongside inhibition from two plastic populations. Depending on the inhibitory plasticity rule, synapses remain unspecific (flat), become anti-correlated to, or mirror excitatory synapses. Crucially, the neuron’s receptive field, i.e., its response to presynaptic stimuli, depends on the modulatory state of inhibition. When both inhibitory populations are active, inhibition balances excitation, resulting in uncorrelated postsynaptic responses regardless of the inhibitory tuning profiles. Modulating the activity of a given inhibitory population produces strong correlations to either preferred or non-preferred inputs, in line with recent experimental findings showing dramatic context-dependent changes of neurons’ receptive fields. We thus confirm that a neuron’s receptive field doesn’t follow directly from the weight profiles of its presynaptic afferents. AU - Agnes, Everton J. AU - Luppi, Andrea I. AU - Vogels, Tim P ID - 8126 IS - 50 JF - The Journal of Neuroscience TI - Complementary inhibitory weight profiles emerge from plasticity and allow attentional switching of receptive fields VL - 40 ER - TY - JOUR AB - The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1−/− mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity. AU - Salzer, Elisabeth AU - Zoghi, Samaneh AU - Kiss, Máté G. AU - Kage, Frieda AU - Rashkova, Christina AU - Stahnke, Stephanie AU - Haimel, Matthias AU - Platzer, René AU - Caldera, Michael AU - Ardy, Rico Chandra AU - Hoeger, Birgit AU - Block, Jana AU - Medgyesi, David AU - Sin, Celine AU - Shahkarami, Sepideh AU - Kain, Renate AU - Ziaee, Vahid AU - Hammerl, Peter AU - Bock, Christoph AU - Menche, Jörg AU - Dupré, Loïc AU - Huppa, Johannes B. AU - Sixt, Michael K AU - Lomakin, Alexis AU - Rottner, Klemens AU - Binder, Christoph J. AU - Stradal, Theresia E.B. AU - Rezaei, Nima AU - Boztug, Kaan ID - 8132 IS - 49 JF - Science Immunology TI - The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity VL - 5 ER - TY - GEN AB - Additional file 2: Supplementary Tables. The association of pre-adjusted protein levels with biological and technical covariates. Protein levels were adjusted for age, sex, array plate and four genetic principal components (population structure) prior to analyses. Significant associations are emboldened. (Table S1). pQTLs associated with inflammatory biomarker levels from Bayesian penalised regression model (Posterior Inclusion Probability > 95%). (Table S2). All pQTLs associated with inflammatory biomarker levels from ordinary least squares regression model (P < 7.14 × 10− 10). (Table S3). Summary of lambda values relating to ordinary least squares GWAS and EWAS performed on inflammatory protein levels (n = 70) in Lothian Birth Cohort 1936 study. (Table S4). Conditionally significant pQTLs associated with inflammatory biomarker levels from ordinary least squares regression model (P < 7.14 × 10− 10). (Table S5). Comparison of variance explained by ordinary least squares and Bayesian penalised regression models for concordantly identified SNPs. (Table S6). Estimate of heritability for blood protein levels as well as proportion of variance explained attributable to different prior mixtures. (Table S7). Comparison of heritability estimates from Ahsan et al. (maximum likelihood) and Hillary et al. (Bayesian penalised regression). (Table S8). List of concordant SNPs identified by linear model and Bayesian penalised regression and whether they have been previously identified as eQTLs. (Table S9). Bayesian tests of colocalisation for cis pQTLs and cis eQTLs. (Table S10). Sherlock algorithm: Genes whose expression are putatively associated with circulating inflammatory proteins that harbour pQTLs. (Table S11). CpGs associated with inflammatory protein biomarkers as identified by Bayesian model (Bayesian model; Posterior Inclusion Probability > 95%). (Table S12). CpGs associated with inflammatory protein biomarkers as identified by linear model (limma) at P < 5.14 × 10− 10. (Table S13). CpGs associated with inflammatory protein biomarkers as identified by mixed linear model (OSCA) at P < 5.14 × 10− 10. (Table S14). Estimate of variance explained for blood protein levels by DNA methylation as well as proportion of explained attributable to different prior mixtures - BayesR+. (Table S15). Comparison of variance in protein levels explained by genome-wide DNA methylation data by mixed linear model (OSCA) and Bayesian penalised regression model (BayesR+). (Table S16). Variance in circulating inflammatory protein biomarker levels explained by common genetic and methylation data (joint and conditional estimates from BayesR+). Ordered by combined variance explained by genetic and epigenetic data - smallest to largest. Significant results from t-tests comparing distributions for variance explained by methylation or genetics alone versus combined estimate are emboldened. (Table S17). Genetic and epigenetic factors identified by BayesR+ when conditioning on all SNPs and CpGs together. (Table S18). Mendelian Randomisation analyses to assess whether proteins with concordantly identified genetic signals are causally associated with Alzheimer’s disease risk. (Table S19). AU - Hillary, Robert F. AU - Trejo-Banos, Daniel AU - Kousathanas, Athanasios AU - McCartney, Daniel L. AU - Harris, Sarah E. AU - Stevenson, Anna J. AU - Patxot, Marion AU - Ojavee, Sven Erik AU - Zhang, Qian AU - Liewald, David C. AU - Ritchie, Craig W. AU - Evans, Kathryn L. AU - Tucker-Drob, Elliot M. AU - Wray, Naomi R. AU - McRae, Allan F. AU - Visscher, Peter M. AU - Deary, Ian J. AU - Robinson, Matthew Richard AU - Marioni, Riccardo E. ID - 9706 TI - Additional file 2 of multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults ER - TY - JOUR AB - We prove an upper bound on the free energy of a two-dimensional homogeneous Bose gas in the thermodynamic limit. We show that for a2ρ ≪ 1 and βρ ≳ 1, the free energy per unit volume differs from the one of the non-interacting system by at most 4πρ2|lna2ρ|−1(2−[1−βc/β]2+) to leading order, where a is the scattering length of the two-body interaction potential, ρ is the density, β is the inverse temperature, and βc is the inverse Berezinskii–Kosterlitz–Thouless critical temperature for superfluidity. In combination with the corresponding matching lower bound proved by Deuchert et al. [Forum Math. Sigma 8, e20 (2020)], this shows equality in the asymptotic expansion. AU - Mayer, Simon AU - Seiringer, Robert ID - 8134 IS - 6 JF - Journal of Mathematical Physics SN - 00222488 TI - The free energy of the two-dimensional dilute Bose gas. II. Upper bound VL - 61 ER - TY - JOUR AU - Barton, Nicholas H ID - 8112 IS - 1806 JF - Philosophical Transactions of the Royal Society. Series B: Biological Sciences SN - 0962-8436 TI - On the completion of speciation VL - 375 ER - TY - JOUR AB - In mammalian genomes, a subset of genes is regulated by genomic imprinting, resulting in silencing of one parental allele. Imprinting is essential for cerebral cortex development, but prevalence and functional impact in individual cells is unclear. Here, we determined allelic expression in cortical cell types and established a quantitative platform to interrogate imprinting in single cells. We created cells with uniparental chromosome disomy (UPD) containing two copies of either the maternal or the paternal chromosome; hence, imprinted genes will be 2-fold overexpressed or not expressed. By genetic labeling of UPD, we determined cellular phenotypes and transcriptional responses to deregulated imprinted gene expression at unprecedented single-cell resolution. We discovered an unexpected degree of cell-type specificity and a novel function of imprinting in the regulation of cortical astrocyte survival. More generally, our results suggest functional relevance of imprinted gene expression in glial astrocyte lineage and thus for generating cortical cell-type diversity. AU - Laukoter, Susanne AU - Pauler, Florian AU - Beattie, Robert J AU - Amberg, Nicole AU - Hansen, Andi H AU - Streicher, Carmen AU - Penz, Thomas AU - Bock, Christoph AU - Hippenmeyer, Simon ID - 8162 IS - 6 JF - Neuron SN - 0896-6273 TI - Cell-type specificity of genomic imprinting in cerebral cortex VL - 107 ER -