TY - DATA AB - This .zip File contains the transport data for "Non-topological zero bias peaks in full-shell nanowires induced by flux tunable Andreev states" by M. Valentini, et. al. The measurements were done using Labber Software and the data is stored in the hdf5 file format. Instructions of how to read the data are in "Notebook_Valentini.pdf". AU - Valentini, Marco ID - 9389 TI - Research data for "Non-topological zero bias peaks in full-shell nanowires induced by flux tunable Andreev states" ER - TY - JOUR AB - Hole gases in planar germanium can have high mobilities in combination with strong spin-orbit interaction and electrically tunable g factors, and are therefore emerging as a promising platform for creating hybrid superconductor-semiconductor devices. A key challenge towards hybrid Ge-based quantum technologies is the design of high-quality interfaces and superconducting contacts that are robust against magnetic fields. In this work, by combining the assets of aluminum, which provides good contact to the Ge, and niobium, which has a significant superconducting gap, we demonstrate highly transparent low-disordered JoFETs with relatively large ICRN products that are capable of withstanding high magnetic fields. We furthermore demonstrate the ability of phase-biasing individual JoFETs, opening up an avenue to explore topological superconductivity in planar Ge. The persistence of superconductivity in the reported hybrid devices beyond 1.8 T paves the way towards integrating spin qubits and proximity-induced superconductivity on the same chip. AU - Aggarwal, Kushagra AU - Hofmann, Andrea C AU - Jirovec, Daniel AU - Prieto Gonzalez, Ivan AU - Sammak, Amir AU - Botifoll, Marc AU - Martí-Sánchez, Sara AU - Veldhorst, Menno AU - Arbiol, Jordi AU - Scappucci, Giordano AU - Danon, Jeroen AU - Katsaros, Georgios ID - 10559 IS - 2 JF - Physical Review Research KW - general engineering SN - 2643-1564 TI - Enhancement of proximity-induced superconductivity in a planar Ge hole gas VL - 3 ER - TY - JOUR AB - While sexual reproduction is widespread among many taxa, asexual lineages have repeatedly evolved from sexual ancestors. Despite extensive research on the evolution of sex, it is still unclear whether this switch represents a major transition requiring major molecular reorganization, and how convergent the changes involved are. In this study, we investigated the phylogenetic relationship and patterns of gene expression of sexual and asexual lineages of Eurasian Artemia brine shrimp, to assess how gene expression patterns are affected by the transition to asexuality. We find only a few genes that are consistently associated with the evolution of asexuality, suggesting that this shift may not require an extensive overhauling of the meiotic machinery. While genes with sex-biased expression have high rates of expression divergence within Eurasian Artemia, neither female- nor male-biased genes appear to show unusual evolutionary patterns after sexuality is lost, contrary to theoretical expectations. AU - Huylmans, Ann K AU - Macon, Ariana AU - Hontoria, Francisco AU - Vicoso, Beatriz ID - 10166 IS - 1959 JF - Proceedings of the Royal Society B: Biological Sciences KW - asexual reproduction KW - parthenogenesis KW - sex-biased genes KW - sexual conflict KW - automixis KW - crustaceans SN - 0962-8452 TI - Transitions to asexuality and evolution of gene expression in Artemia brine shrimp VL - 288 ER - TY - DATA AB - Here are the research data underlying the publication " Effects of fine-scale population structure on inbreeding in a long-term study of snapdragons (Antirrhinum majus)." Further information are summed up in the README document. AU - Surendranadh, Parvathy AU - Arathoon, Louise S AU - Baskett, Carina AU - Field, David AU - Pickup, Melinda AU - Barton, Nicholas H ID - 9192 TI - Effects of fine-scale population structure on the distribution of heterozygosity in a long-term study of Antirrhinum majus ER - TY - DATA AU - Vicoso, Beatriz ID - 9949 TI - Data from Hyulmans et al 2021, "Transitions to asexuality and evolution of gene expression in Artemia brine shrimp" ER - TY - JOUR AB - Phenomenological relations such as Ohm’s or Fourier’s law have a venerable history in physics but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial “growth laws,” which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts drug interactions like antagonism or synergy solely from responses to individual drugs. We provide analytical results for limiting cases, which agree well with numerical results. We systematically refine the model by including direct physical interactions of different antibiotics on the ribosome. In a limiting case, our model provides a mechanistic underpinning for recent predictions of higher-order interactions that were derived using entropy maximization. We further refine the model to include the effects of antibiotics that mimic starvation and the presence of resistance genes. We describe the impact of a starvation-mimicking antibiotic on drug interactions analytically and verify it experimentally. Our extended model suggests a change in the type of drug interaction that depends on the strength of resistance, which challenges established rescaling paradigms. We experimentally show that the presence of unregulated resistance genes can lead to altered drug interaction, which agrees with the prediction of the model. While minimal, the model is readily adaptable and opens the door to predicting interactions of second and higher-order in a broad range of biological systems. AU - Kavcic, Bor AU - Tkačik, Gašper AU - Bollenbach, Tobias ID - 8997 JF - PLOS Computational Biology KW - Modelling and Simulation KW - Genetics KW - Molecular Biology KW - Antibiotics KW - Drug interactions SN - 1553-7358 TI - Minimal biophysical model of combined antibiotic action VL - 17 ER - TY - JOUR AB - Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks (GRNs) remains a major challenge. Here, we use a well-defined synthetic GRN to study in Escherichia coli how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one GRN with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Transcriptional read-through is the main molecular mechanism that places one transcriptional unit (TU) within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual TUs, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of GRNs. AU - Nagy-Staron, Anna A AU - Tomasek, Kathrin AU - Caruso Carter, Caroline AU - Sonnleitner, Elisabeth AU - Kavcic, Bor AU - Paixão, Tiago AU - Guet, Calin C ID - 9283 JF - eLife KW - Genetics and Molecular Biology SN - 2050-084X TI - Local genetic context shapes the function of a gene regulatory network VL - 10 ER - TY - JOUR AB - We introduce a novel technique to automatically decompose an input object’s volume into a set of parts that can be represented by two opposite height fields. Such decomposition enables the manufacturing of individual parts using two-piece reusable rigid molds. Our decomposition strategy relies on a new energy formulation that utilizes a pre-computed signal on the mesh volume representing the accessibility for a predefined set of extraction directions. Thanks to this novel formulation, our method allows for efficient optimization of a fabrication-aware partitioning of volumes in a completely automatic way. We demonstrate the efficacy of our approach by generating valid volume partitionings for a wide range of complex objects and physically reproducing several of them. AU - Alderighi, Thomas AU - Malomo, Luigi AU - Bickel, Bernd AU - Cignoni, Paolo AU - Pietroni, Nico ID - 10184 IS - 6 JF - ACM Transactions on Graphics SN - 0730-0301 TI - Volume decomposition for two-piece rigid casting VL - 40 ER - TY - JOUR AB - The Massively Parallel Computation (MPC) model is an emerging model that distills core aspects of distributed and parallel computation, developed as a tool to solve combinatorial (typically graph) problems in systems of many machines with limited space. Recent work has focused on the regime in which machines have sublinear (in n, the number of nodes in the input graph) space, with randomized algorithms presented for the fundamental problems of Maximal Matching and Maximal Independent Set. However, there have been no prior corresponding deterministic algorithms. A major challenge underlying the sublinear space setting is that the local space of each machine might be too small to store all edges incident to a single node. This poses a considerable obstacle compared to classical models in which each node is assumed to know and have easy access to its incident edges. To overcome this barrier, we introduce a new graph sparsification technique that deterministically computes a low-degree subgraph, with the additional property that solving the problem on this subgraph provides significant progress towards solving the problem for the original input graph. Using this framework to derandomize the well-known algorithm of Luby [SICOMP’86], we obtain O(log Δ + log log n)-round deterministic MPC algorithms for solving the problems of Maximal Matching and Maximal Independent Set with O(nɛ) space on each machine for any constant ɛ > 0. These algorithms also run in O(log Δ) rounds in the closely related model of CONGESTED CLIQUE, improving upon the state-of-the-art bound of O(log 2Δ) rounds by Censor-Hillel et al. [DISC’17]. AU - Czumaj, Artur AU - Davies, Peter AU - Parter, Merav ID - 9541 IS - 2 JF - ACM Transactions on Algorithms SN - 1549-6325 TI - Graph sparsification for derandomizing massively parallel computation with low space VL - 17 ER - TY - JOUR AB - We investigate the effect of coupling between translational and internal degrees of freedom of composite quantum particles on their localization in a random potential. We show that entanglement between the two degrees of freedom weakens localization due to the upper bound imposed on the inverse participation ratio by purity of a quantum state. We perform numerical calculations for a two-particle system bound by a harmonic force in a 1D disordered lattice and a rigid rotor in a 2D disordered lattice. We illustrate that the coupling has a dramatic effect on localization properties, even with a small number of internal states participating in quantum dynamics. AU - Suzuki, Fumika AU - Lemeshko, Mikhail AU - Zurek, Wojciech H. AU - Krems, Roman V. ID - 10134 IS - 16 JF - Physical Review Letters KW - General Physics and Astronomy SN - 0031-9007 TI - Anderson localization of composite particles VL - 127 ER - TY - CONF AB - We introduce a new graph problem, the token dropping game, and we show how to solve it efficiently in a distributed setting. We use the token dropping game as a tool to design an efficient distributed algorithm for stable orientations and more generally for locally optimal semi-matchings. The prior work by Czygrinow et al. (DISC 2012) finds a stable orientation in O(Δ^5) rounds in graphs of maximum degree Δ, while we improve it to O(Δ^4) and also prove a lower bound of Ω(Δ). For the more general problem of locally optimal semi-matchings, the prior upper bound is O(S^5) and our new algorithm runs in O(C · S^4) rounds, which is an improvement for C = o(S); here C and S are the maximum degrees of customers and servers, respectively. AU - Brandt, Sebastian AU - Keller, Barbara AU - Rybicki, Joel AU - Suomela, Jukka AU - Uitto, Jara ID - 9678 SN - 9781450380706 T2 - Annual ACM Symposium on Parallelism in Algorithms and Architectures TI - Efficient load-balancing through distributed token dropping ER - TY - JOUR AB - We consider the following dynamic load-balancing process: given an underlying graph G with n nodes, in each step t≥ 0, one unit of load is created, and placed at a randomly chosen graph node. In the same step, the chosen node picks a random neighbor, and the two nodes balance their loads by averaging them. We are interested in the expected gap between the minimum and maximum loads at nodes as the process progresses, and its dependence on n and on the graph structure. Variants of the above graphical balanced allocation process have been studied previously by Peres, Talwar, and Wieder [Peres et al., 2015], and by Sauerwald and Sun [Sauerwald and Sun, 2015]. These authors left as open the question of characterizing the gap in the case of cycle graphs in the dynamic case, where weights are created during the algorithm’s execution. For this case, the only known upper bound is of 𝒪(n log n), following from a majorization argument due to [Peres et al., 2015], which analyzes a related graphical allocation process. In this paper, we provide an upper bound of 𝒪 (√n log n) on the expected gap of the above process for cycles of length n. We introduce a new potential analysis technique, which enables us to bound the difference in load between k-hop neighbors on the cycle, for any k ≤ n/2. We complement this with a "gap covering" argument, which bounds the maximum value of the gap by bounding its value across all possible subsets of a certain structure, and recursively bounding the gaps within each subset. We provide analytical and experimental evidence that our upper bound on the gap is tight up to a logarithmic factor. AU - Alistarh, Dan-Adrian AU - Nadiradze, Giorgi AU - Sabour, Amirmojtaba ID - 8286 JF - Algorithmica SN - 0178-4617 TI - Dynamic averaging load balancing on cycles ER - TY - THES AB - This thesis is the result of the research carried out by the author during his PhD at IST Austria between 2017 and 2021. It mainly focuses on the Fröhlich polaron model, specifically to its regime of strong coupling. This model, which is rigorously introduced and discussed in the introduction, has been of great interest in condensed matter physics and field theory for more than eighty years. It is used to describe an electron interacting with the atoms of a solid material (the strength of this interaction is modeled by the presence of a coupling constant α in the Hamiltonian of the system). The particular regime examined here, which is mathematically described by considering the limit α →∞, displays many interesting features related to the emergence of classical behavior, which allows for a simplified effective description of the system under analysis. The properties, the range of validity and a quantitative analysis of the precision of such classical approximations are the main object of the present work. We specify our investigation to the study of the ground state energy of the system, its dynamics and its effective mass. For each of these problems, we provide in the introduction an overview of the previously known results and a detailed account of the original contributions by the author. AU - Feliciangeli, Dario ID - 9733 SN - 2663-337X TI - The polaron at strong coupling ER - TY - JOUR AB - As the size and complexity of models and datasets grow, so does the need for communication-efficient variants of stochastic gradient descent that can be deployed to perform parallel model training. One popular communication-compression method for data-parallel SGD is QSGD (Alistarh et al., 2017), which quantizes and encodes gradients to reduce communication costs. The baseline variant of QSGD provides strong theoretical guarantees, however, for practical purposes, the authors proposed a heuristic variant which we call QSGDinf, which demonstrated impressive empirical gains for distributed training of large neural networks. In this paper, we build on this work to propose a new gradient quantization scheme, and show that it has both stronger theoretical guarantees than QSGD, and matches and exceeds the empirical performance of the QSGDinf heuristic and of other compression methods. AU - Ramezani-Kebrya, Ali AU - Faghri, Fartash AU - Markov, Ilya AU - Aksenov, Vitalii AU - Alistarh, Dan-Adrian AU - Roy, Daniel M. ID - 9571 IS - 114 JF - Journal of Machine Learning Research SN - 15324435 TI - NUQSGD: Provably communication-efficient data-parallel SGD via nonuniform quantization VL - 22 ER - TY - JOUR AB - The synaptotrophic hypothesis posits that synapse formation stabilizes dendritic branches, yet this hypothesis has not been causally tested in vivo in the mammalian brain. Presynaptic ligand cerebellin-1 (Cbln1) and postsynaptic receptor GluD2 mediate synaptogenesis between granule cells and Purkinje cells in the molecular layer of the cerebellar cortex. Here we show that sparse but not global knockout of GluD2 causes under-elaboration of Purkinje cell dendrites in the deep molecular layer and overelaboration in the superficial molecular layer. Developmental, overexpression, structure-function, and genetic epistasis analyses indicate that dendrite morphogenesis defects result from competitive synaptogenesis in a Cbln1/GluD2-dependent manner. A generative model of dendritic growth based on competitive synaptogenesis largely recapitulates GluD2 sparse and global knockout phenotypes. Our results support the synaptotrophic hypothesis at initial stages of dendrite development, suggest a second mode in which cumulative synapse formation inhibits further dendrite growth, and highlight the importance of competition in dendrite morphogenesis. AU - Takeo, Yukari H. AU - Shuster, S. Andrew AU - Jiang, Linnie AU - Hu, Miley AU - Luginbuhl, David J. AU - Rülicke, Thomas AU - Contreras, Ximena AU - Hippenmeyer, Simon AU - Wagner, Mark J. AU - Ganguli, Surya AU - Luo, Liqun ID - 8544 IS - 4 JF - Neuron TI - GluD2- and Cbln1-mediated competitive synaptogenesis shapes the dendritic arbors of cerebellar Purkinje cells VL - 109 ER - TY - GEN AB - We provide a definition of the effective mass for the classical polaron described by the Landau-Pekar equations. It is based on a novel variational principle, minimizing the energy functional over states with given (initial) velocity. The resulting formula for the polaron's effective mass agrees with the prediction by Landau and Pekar. AU - Feliciangeli, Dario AU - Rademacher, Simone Anna Elvira AU - Seiringer, Robert ID - 9791 T2 - arXiv TI - The effective mass problem for the Landau-Pekar equations ER - TY - JOUR AB - Normative theories and statistical inference provide complementary approaches for the study of biological systems. A normative theory postulates that organisms have adapted to efficiently solve essential tasks, and proceeds to mathematically work out testable consequences of such optimality; parameters that maximize the hypothesized organismal function can be derived ab initio, without reference to experimental data. In contrast, statistical inference focuses on efficient utilization of data to learn model parameters, without reference to any a priori notion of biological function, utility, or fitness. Traditionally, these two approaches were developed independently and applied separately. Here we unify them in a coherent Bayesian framework that embeds a normative theory into a family of maximum-entropy “optimization priors.” This family defines a smooth interpolation between a data-rich inference regime (characteristic of “bottom-up” statistical models), and a data-limited ab inito prediction regime (characteristic of “top-down” normative theory). We demonstrate the applicability of our framework using data from the visual cortex, and argue that the flexibility it affords is essential to address a number of fundamental challenges relating to inference and prediction in complex, high-dimensional biological problems. AU - Mlynarski, Wiktor F AU - Hledik, Michal AU - Sokolowski, Thomas R AU - Tkačik, Gašper ID - 7553 IS - 7 JF - Neuron TI - Statistical analysis and optimality of neural systems VL - 109 ER - TY - CONF AB - We consider the problem of estimating a signal from measurements obtained via a generalized linear model. We focus on estimators based on approximate message passing (AMP), a family of iterative algorithms with many appealing features: the performance of AMP in the high-dimensional limit can be succinctly characterized under suitable model assumptions; AMP can also be tailored to the empirical distribution of the signal entries, and for a wide class of estimation problems, AMP is conjectured to be optimal among all polynomial-time algorithms. However, a major issue of AMP is that in many models (such as phase retrieval), it requires an initialization correlated with the ground-truth signal and independent from the measurement matrix. Assuming that such an initialization is available is typically not realistic. In this paper, we solve this problem by proposing an AMP algorithm initialized with a spectral estimator. With such an initialization, the standard AMP analysis fails since the spectral estimator depends in a complicated way on the design matrix. Our main contribution is a rigorous characterization of the performance of AMP with spectral initialization in the high-dimensional limit. The key technical idea is to define and analyze a two-phase artificial AMP algorithm that first produces the spectral estimator, and then closely approximates the iterates of the true AMP. We also provide numerical results that demonstrate the validity of the proposed approach. AU - Mondelli, Marco AU - Venkataramanan, Ramji ED - Banerjee, Arindam ED - Fukumizu, Kenji ID - 10598 SN - 2640-3498 T2 - Proceedings of The 24th International Conference on Artificial Intelligence and Statistics TI - Approximate message passing with spectral initialization for generalized linear models VL - 130 ER - TY - JOUR AB - This paper aims to obtain a strong convergence result for a Douglas–Rachford splitting method with inertial extrapolation step for finding a zero of the sum of two set-valued maximal monotone operators without any further assumption of uniform monotonicity on any of the involved maximal monotone operators. Furthermore, our proposed method is easy to implement and the inertial factor in our proposed method is a natural choice. Our method of proof is of independent interest. Finally, some numerical implementations are given to confirm the theoretical analysis. AU - Shehu, Yekini AU - Dong, Qiao-Li AU - Liu, Lu-Lu AU - Yao, Jen-Chih ID - 8196 JF - Optimization and Engineering SN - 1389-4420 TI - New strong convergence method for the sum of two maximal monotone operators VL - 22 ER - TY - JOUR AB - In the worldwide endeavor for disruptive quantum technologies, germanium is emerging as a versatile material to realize devices capable of encoding, processing, or transmitting quantum information. These devices leverage special properties of the germanium valence-band states, commonly known as holes, such as their inherently strong spin-orbit coupling and the ability to host superconducting pairing correlations. In this Review, we initially introduce the physics of holes in low-dimensional germanium structures with key insights from a theoretical perspective. We then examine the material science progress underpinning germanium-based planar heterostructures and nanowires. We review the most significant experimental results demonstrating key building blocks for quantum technology, such as an electrically driven universal quantum gate set with spin qubits in quantum dots and superconductor-semiconductor devices for hybrid quantum systems. We conclude by identifying the most promising prospects toward scalable quantum information processing. AU - Scappucci, Giordano AU - Kloeffel, Christoph AU - Zwanenburg, Floris A. AU - Loss, Daniel AU - Myronov, Maksym AU - Zhang, Jian-Jun AU - Franceschi, Silvano De AU - Katsaros, Georgios AU - Veldhorst, Menno ID - 8911 JF - Nature Reviews Materials TI - The germanium quantum information route VL - 6 ER - TY - JOUR AB - Canonical parametrisations of classical confocal coordinate systems are introduced and exploited to construct non-planar analogues of incircular (IC) nets on individual quadrics and systems of confocal quadrics. Intimate connections with classical deformations of quadrics that are isometric along asymptotic lines and circular cross-sections of quadrics are revealed. The existence of octahedral webs of surfaces of Blaschke type generated by asymptotic and characteristic lines that are diagonally related to lines of curvature is proved theoretically and established constructively. Appropriate samplings (grids) of these webs lead to three-dimensional extensions of non-planar IC nets. Three-dimensional octahedral grids composed of planes and spatially extending (checkerboard) IC-nets are shown to arise in connection with systems of confocal quadrics in Minkowski space. In this context, the Laguerre geometric notion of conical octahedral grids of planes is introduced. The latter generalise the octahedral grids derived from systems of confocal quadrics in Minkowski space. An explicit construction of conical octahedral grids is presented. The results are accompanied by various illustrations which are based on the explicit formulae provided by the theory. AU - Akopyan, Arseniy AU - Bobenko, Alexander I. AU - Schief, Wolfgang K. AU - Techter, Jan ID - 8338 JF - Discrete and Computational Geometry SN - 0179-5376 TI - On mutually diagonal nets on (confocal) quadrics and 3-dimensional webs VL - 66 ER - TY - JOUR AB - We design fast deterministic algorithms for distance computation in the Congested Clique model. Our key contributions include: A (2+ϵ)-approximation for all-pairs shortest paths in O(log2n/ϵ) rounds on unweighted undirected graphs. With a small additional additive factor, this also applies for weighted graphs. This is the first sub-polynomial constant-factor approximation for APSP in this model. A (1+ϵ)-approximation for multi-source shortest paths from O(n−−√) sources in O(log2n/ϵ) rounds on weighted undirected graphs. This is the first sub-polynomial algorithm obtaining this approximation for a set of sources of polynomial size. Our main techniques are new distance tools that are obtained via improved algorithms for sparse matrix multiplication, which we leverage to construct efficient hopsets and shortest paths. Furthermore, our techniques extend to additional distance problems for which we improve upon the state-of-the-art, including diameter approximation, and an exact single-source shortest paths algorithm for weighted undirected graphs in O~(n1/6) rounds. AU - Censor-Hillel, Keren AU - Dory, Michal AU - Korhonen, Janne AU - Leitersdorf, Dean ID - 7939 JF - Distributed Computing SN - 0178-2770 TI - Fast approximate shortest paths in the congested clique VL - 34 ER - TY - JOUR AB - We consider the following setting: suppose that we are given a manifold M in Rd with positive reach. Moreover assume that we have an embedded simplical complex A without boundary, whose vertex set lies on the manifold, is sufficiently dense and such that all simplices in A have sufficient quality. We prove that if, locally, interiors of the projection of the simplices onto the tangent space do not intersect, then A is a triangulation of the manifold, that is, they are homeomorphic. AU - Boissonnat, Jean-Daniel AU - Dyer, Ramsay AU - Ghosh, Arijit AU - Lieutier, Andre AU - Wintraecken, Mathijs ID - 8248 JF - Discrete and Computational Geometry SN - 0179-5376 TI - Local conditions for triangulating submanifolds of Euclidean space VL - 66 ER - TY - JOUR AB - All vertebrates have a spinal cord with dimensions and shape specific to their species. Yet how species‐specific organ size and shape are achieved is a fundamental unresolved question in biology. The formation and sculpting of organs begins during embryonic development. As it develops, the spinal cord extends in anterior–posterior direction in synchrony with the overall growth of the body. The dorsoventral (DV) and apicobasal lengths of the spinal cord neuroepithelium also change, while at the same time a characteristic pattern of neural progenitor subtypes along the DV axis is established and elaborated. At the basis of these changes in tissue size and shape are biophysical determinants, such as the change in cell number, cell size and shape, and anisotropic tissue growth. These processes are controlled by global tissue‐scale regulators, such as morphogen signaling gradients as well as mechanical forces. Current challenges in the field are to uncover how these tissue‐scale regulatory mechanisms are translated to the cellular and molecular level, and how regulation of distinct cellular processes gives rise to an overall defined size. Addressing these questions will help not only to achieve a better understanding of how size is controlled, but also of how tissue size is coordinated with the specification of pattern. AU - Kuzmicz-Kowalska, Katarzyna AU - Kicheva, Anna ID - 7883 JF - Wiley Interdisciplinary Reviews: Developmental Biology SN - 17597684 TI - Regulation of size and scale in vertebrate spinal cord development ER - TY - JOUR AB - We investigate a sheaf-theoretic interpretation of stratification learning from geometric and topological perspectives. Our main result is the construction of stratification learning algorithms framed in terms of a sheaf on a partially ordered set with the Alexandroff topology. We prove that the resulting decomposition is the unique minimal stratification for which the strata are homogeneous and the given sheaf is constructible. In particular, when we choose to work with the local homology sheaf, our algorithm gives an alternative to the local homology transfer algorithm given in Bendich et al. (Proceedings of the 23rd Annual ACM-SIAM Symposium on Discrete Algorithms, pp. 1355–1370, ACM, New York, 2012), and the cohomology stratification algorithm given in Nanda (Found. Comput. Math. 20(2), 195–222, 2020). Additionally, we give examples of stratifications based on the geometric techniques of Breiding et al. (Rev. Mat. Complut. 31(3), 545–593, 2018), illustrating how the sheaf-theoretic approach can be used to study stratifications from both topological and geometric perspectives. This approach also points toward future applications of sheaf theory in the study of topological data analysis by illustrating the utility of the language of sheaf theory in generalizing existing algorithms. AU - Brown, Adam AU - Wang, Bei ID - 7905 JF - Discrete and Computational Geometry SN - 0179-5376 TI - Sheaf-theoretic stratification learning from geometric and topological perspectives VL - 65 ER - TY - JOUR AB - We consider large non-Hermitian real or complex random matrices X with independent, identically distributed centred entries. We prove that their local eigenvalue statistics near the spectral edge, the unit circle, coincide with those of the Ginibre ensemble, i.e. when the matrix elements of X are Gaussian. This result is the non-Hermitian counterpart of the universality of the Tracy–Widom distribution at the spectral edges of the Wigner ensemble. AU - Cipolloni, Giorgio AU - Erdös, László AU - Schröder, Dominik J ID - 8601 JF - Probability Theory and Related Fields SN - 01788051 TI - Edge universality for non-Hermitian random matrices ER - TY - JOUR AB - In this paper, we introduce a relaxed CQ method with alternated inertial step for solving split feasibility problems. We give convergence of the sequence generated by our method under some suitable assumptions. Some numerical implementations from sparse signal and image deblurring are reported to show the efficiency of our method. AU - Shehu, Yekini AU - Gibali, Aviv ID - 7925 JF - Optimization Letters SN - 1862-4472 TI - New inertial relaxed method for solving split feasibilities VL - 15 ER - TY - JOUR AB - Eukaryotic DNA-binding proteins operate in the context of chromatin, where nucleosomes are the elementary building blocks. Nucleosomal DNA is wrapped around a histone core, thereby rendering a large fraction of the DNA surface inaccessible to DNA-binding proteins. Nevertheless, first responders in DNA repair and sequence-specific transcription factors bind DNA target sites obstructed by chromatin. While early studies examined protein binding to histone-free DNA, it is only now beginning to emerge how DNA sequences are interrogated on nucleosomes. These readout strategies range from the release of nucleosomal DNA from histones, to rotational/translation register shifts of the DNA motif, and nucleosome-specific DNA binding modes that differ from those observed on naked DNA. Since DNA motif engagement on nucleosomes strongly depends on position and orientation, we argue that motif location and nucleosome positioning co-determine protein access to DNA in transcription and DNA repair. AU - Michael, Alicia AU - Thomä, Nicolas H. ID - 15151 IS - 14 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - Reading the chromatinized genome VL - 184 ER - TY - JOUR AB - Rigorous investigation of synaptic transmission requires analysis of unitary synaptic events by simultaneous recording from presynaptic terminals and postsynaptic target neurons. However, this has been achieved at only a limited number of model synapses, including the squid giant synapse and the mammalian calyx of Held. Cortical presynaptic terminals have been largely inaccessible to direct presynaptic recording, due to their small size. Here, we describe a protocol for improved subcellular patch-clamp recording in rat and mouse brain slices, with the synapse in a largely intact environment. Slice preparation takes ~2 h, recording ~3 h and post hoc morphological analysis 2 d. Single presynaptic hippocampal mossy fiber terminals are stimulated minimally invasively in the bouton-attached configuration, in which the cytoplasmic content remains unperturbed, or in the whole-bouton configuration, in which the cytoplasmic composition can be precisely controlled. Paired pre–postsynaptic recordings can be integrated with biocytin labeling and morphological analysis, allowing correlative investigation of synapse structure and function. Paired recordings can be obtained from mossy fiber terminals in slices from both rats and mice, implying applicability to genetically modified synapses. Paired recordings can also be performed together with axon tract stimulation or optogenetic activation, allowing comparison of unitary and compound synaptic events in the same target cell. Finally, paired recordings can be combined with spontaneous event analysis, permitting collection of miniature events generated at a single identified synapse. In conclusion, the subcellular patch-clamp techniques detailed here should facilitate analysis of biophysics, plasticity and circuit function of cortical synapses in the mammalian central nervous system. AU - Vandael, David H AU - Okamoto, Yuji AU - Borges Merjane, Carolina AU - Vargas Barroso, Victor M AU - Suter, Benjamin AU - Jonas, Peter M ID - 9438 IS - 6 JF - Nature Protocols SN - 17542189 TI - Subcellular patch-clamp techniques for single-bouton stimulation and simultaneous pre- and postsynaptic recording at cortical synapses VL - 16 ER - TY - THES AB - Blood – this is what animals use to heal wounds fast and efficient. Plants do not have blood circulation and their cells cannot move. However, plants have evolved remarkable capacities to regenerate tissues and organs preventing further damage. In my PhD research, I studied the wound healing in the Arabidopsis root. I used a UV laser to ablate single cells in the root tip and observed the consequent wound healing. Interestingly, the inner adjacent cells induced a division plane switch and subsequently adopted the cell type of the killed cell to replace it. We termed this form of wound healing “restorative divisions”. This initial observation triggered the questions of my PhD studies: How and why do cells orient their division planes, how do they feel the wound and why does this happen only in inner adjacent cells. For answering these questions, I used a quite simple experimental setup: 5 day - old seedlings were stained with propidium iodide to visualize cell walls and dead cells; ablation was carried out using a special laser cutter and a confocal microscope. Adaptation of the novel vertical microscope system made it possible to observe wounds in real time. This revealed that restorative divisions occur at increased frequency compared to normal divisions. Additionally, the major plant hormone auxin accumulates in wound adjacent cells and drives the expression of the wound-stress responsive transcription factor ERF115. Using this as a marker gene for wound responses, we found that an important part of wound signalling is the sensing of the collapse of the ablated cell. The collapse causes a radical pressure drop, which results in strong tissue deformations. These deformations manifest in an invasion of the now free spot specifically by the inner adjacent cells within seconds, probably because of higher pressure of the inner tissues. Long-term imaging revealed that those deformed cells continuously expand towards the wound hole and that this is crucial for the restorative division. These wound-expanding cells exhibit an abnormal, biphasic polarity of microtubule arrays before the division. Experiments inhibiting cell expansion suggest that it is the biphasic stretching that induces those MT arrays. Adapting the micromanipulator aspiration system from animal scientists at our institute confirmed the hypothesis that stretching influences microtubule stability. In conclusion, this shows that microtubules react to tissue deformation and this facilitates the observed division plane switch. This puts mechanical cues and tensions at the most prominent position for explaining the growth and wound healing properties of plants. Hence, it shines light onto the importance of understanding mechanical signal transduction. AU - Hörmayer, Lukas ID - 9992 SN - 2663-337X TI - Wound healing in the Arabidopsis root meristem ER - TY - JOUR AB - Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks. AU - Guzmán, José AU - Schlögl, Alois AU - Espinoza Martinez, Claudia AU - Zhang, Xiaomin AU - Suter, Benjamin AU - Jonas, Peter M ID - 10816 IS - 12 JF - Nature Computational Science KW - general medicine SN - 2662-8457 TI - How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network VL - 1 ER - TY - COMP AB - Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)–dentate gyrus (DG)–CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC–DG–CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC–PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC–CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks. AU - Guzmán, José AU - Schlögl, Alois AU - Espinoza Martinez, Claudia AU - Zhang, Xiaomin AU - Suter, Benjamin AU - Jonas, Peter M ID - 10110 TI - How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex–dentate gyrus–CA3 network ER - TY - GEN AB - Although much is known about how single neurons in the hippocampus represent an animal’s position, how cell-cell interactions contribute to spatial coding remains poorly understood. Using a novel statistical estimator and theoretical modeling, both developed in the framework of maximum entropy models, we reveal highly structured cell-to-cell interactions whose statistics depend on familiar vs. novel environment. In both conditions the circuit interactions optimize the encoding of spatial information, but for regimes that differ in the signal-to-noise ratio of their spatial inputs. Moreover, the topology of the interactions facilitates linear decodability, making the information easy to read out by downstream circuits. These findings suggest that the efficient coding hypothesis is not applicable only to individual neuron properties in the sensory periphery, but also to neural interactions in the central brain. AU - Nardin, Michele AU - Csicsvari, Jozsef L AU - Tkačik, Gašper AU - Savin, Cristina ID - 10077 T2 - bioRxiv TI - The structure of hippocampal CA1 interactions optimizes spatial coding across experience ER - TY - JOUR AB - Aprotic alkali metal–O2 batteries face two major obstacles to their chemistry occurring efficiently, the insulating nature of the formed alkali superoxides/peroxides and parasitic reactions that are caused by the highly reactive singlet oxygen (1O2). Redox mediators are recognized to be key for improving rechargeability. However, it is unclear how they affect 1O2 formation, which hinders strategies for their improvement. Here we clarify the mechanism of mediated peroxide and superoxide oxidation and thus explain how redox mediators either enhance or suppress 1O2 formation. We show that charging commences with peroxide oxidation to a superoxide intermediate and that redox potentials above ~3.5 V versus Li/Li+ drive 1O2 evolution from superoxide oxidation, while disproportionation always generates some 1O2. We find that 1O2 suppression requires oxidation to be faster than the generation of 1O2 from disproportionation. Oxidation rates decrease with growing driving force following Marcus inverted-region behaviour, establishing a region of maximum rate. AU - Petit, Yann K. AU - Mourad, Eléonore AU - Prehal, Christian AU - Leypold, Christian AU - Windischbacher, Andreas AU - Mijailovic, Daniel AU - Slugovc, Christian AU - Borisov, Sergey M. AU - Zojer, Egbert AU - Brutti, Sergio AU - Fontaine, Olivier AU - Freunberger, Stefan Alexander ID - 9250 IS - 5 JF - Nature Chemistry KW - General Chemistry KW - General Chemical Engineering SN - 1755-4330 TI - Mechanism of mediated alkali peroxide oxidation and triplet versus singlet oxygen formation VL - 13 ER - TY - THES AB - Cytoplasmic reorganizations are essential for morphogenesis. In large cells like oocytes, these reorganizations become crucial in patterning the oocyte for later stages of embryonic development. Ascidians oocytes reorganize their cytoplasm (ooplasm) in a spectacular manner. Ooplasmic reorganization is initiated at fertilization with the contraction of the actomyosin cortex along the animal-vegetal axis of the oocyte, driving the accumulation of cortical endoplasmic reticulum (cER), maternal mRNAs associated to it and a mitochondria-rich subcortical layer – the myoplasm – in a region of the vegetal pole termed contraction pole (CP). Here we have used the species Phallusia mammillata to investigate the changes in cell shape that accompany these reorganizations and the mechanochemical mechanisms underlining CP formation. We report that the length of the animal-vegetal (AV) axis oscillates upon fertilization: it first undergoes a cycle of fast elongation-lengthening followed by a slow expansion of mainly the vegetal pole (VP) of the cell. We show that the fast oscillation corresponds to a dynamic polarization of the actin cortex as a result of a fertilization-induced increase in cortical tension in the oocyte that triggers a rupture of the cortex at the animal pole and the establishment of vegetal-directed cortical flows. These flows are responsible for the vegetal accumulation of actin causing the VP to flatten. We find that the slow expansion of the VP, leading to CP formation, correlates with a relaxation of the vegetal cortex and that the myoplasm plays a role in the expansion. We show that the myoplasm is a solid-like layer that buckles under compression forces arising from the contracting actin cortex at the VP. Straightening of the myoplasm when actin flows stops, facilitates the expansion of the VP and the CP. Altogether, our results present a previously unrecognized role for the myoplasm in ascidian ooplasmic segregation. AU - Caballero Mancebo, Silvia ID - 9623 SN - 2663-337X TI - Fertilization-induced deformations are controlled by the actin cortex and a mitochondria-rich subcortical layer in ascidian oocytes ER - TY - JOUR AB - Cytoplasm is a gel-like crowded environment composed of various macromolecules, organelles, cytoskeletal networks, and cytosol. The structure of the cytoplasm is highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules are restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the crowded nature of the cytoplasm at the microscopic scale, large-scale reorganization of the cytoplasm is essential for important cellular functions, such as cell division and polarization. How such mesoscale reorganization of the cytoplasm is achieved, especially for large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, is only beginning to be understood. In this review, we will discuss recent advances in elucidating the molecular, cellular, and biophysical mechanisms by which the cytoskeleton drives cytoplasmic reorganization across different scales, structures, and species. AU - Shamipour, Shayan AU - Caballero Mancebo, Silvia AU - Heisenberg, Carl-Philipp J ID - 9006 IS - 2 JF - Developmental Cell SN - 15345807 TI - Cytoplasm's got moves VL - 56 ER - TY - JOUR AB - De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs. AU - Morandell, Jasmin AU - Schwarz, Lena A AU - Basilico, Bernadette AU - Tasciyan, Saren AU - Dimchev, Georgi A AU - Nicolas, Armel AU - Sommer, Christoph M AU - Kreuzinger, Caroline AU - Dotter, Christoph AU - Knaus, Lisa AU - Dobler, Zoe AU - Cacci, Emanuele AU - Schur, Florian KM AU - Danzl, Johann G AU - Novarino, Gaia ID - 9429 IS - 1 JF - Nature Communications KW - General Biochemistry KW - Genetics and Molecular Biology TI - Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development VL - 12 ER - TY - THES AB - Quantum information and computation has become a vast field paved with opportunities for researchers and investors. As large multinational companies and international funds are heavily investing in quantum technologies it is still a question which platform is best suited for the task of realizing a scalable quantum processor. In this work we investigate hole spins in Ge quantum wells. These hold great promise as they possess several favorable properties: a small effective mass, a strong spin-orbit coupling, long relaxation time and an inherent immunity to hyperfine noise. All these characteristics helped Ge hole spin qubits to evolve from a single qubit to a fully entangled four qubit processor in only 3 years. Here, we investigated a qubit approach leveraging the large out-of-plane g-factors of heavy hole states in Ge quantum dots. We found this qubit to be reproducibly operable at extremely low magnetic field and at large speeds while maintaining coherence. This was possible because large differences of g-factors in adjacent dots can be achieved in the out-of-plane direction. In the in-plane direction the small g-factors, on the other hand, can be altered very effectively by the confinement potentials. Here, we found that this can even lead to a sign change of the g-factors. The resulting g-factor difference alters the dynamics of the system drastically and produces effects typically attributed to a spin-orbit induced spin-flip term. The investigations carried out in this thesis give further insights into the possibilities of holes in Ge and reveal new physical properties that need to be considered when designing future spin qubit experiments. AU - Jirovec, Daniel ID - 10058 KW - qubits KW - quantum computing KW - holes SN - 2663-337X TI - Singlet-Triplet qubits and spin-orbit interaction in 2-dimensional Ge hole gases ER - TY - JOUR AB - Spin qubits are considered to be among the most promising candidates for building a quantum processor. Group IV hole spin qubits have moved into the focus of interest due to the ease of operation and compatibility with Si technology. In addition, Ge offers the option for monolithic superconductor-semiconductor integration. Here we demonstrate a hole spin qubit operating at fields below 10 mT, the critical field of Al, by exploiting the large out-of-plane hole g-factors in planar Ge and by encoding the qubit into the singlet-triplet states of a double quantum dot. We observe electrically controlled X and Z-rotations with tunable frequencies exceeding 100 MHz and dephasing times of 1μs which we extend beyond 15μs with echo techniques. These results show that Ge hole singlet triplet qubits outperform their electronic Si and GaAs based counterparts in speed and coherence, respectively. In addition, they are on par with Ge single spin qubits, but can be operated at much lower fields underlining their potential for on chip integration with superconducting technologies. AU - Jirovec, Daniel AU - Hofmann, Andrea C AU - Ballabio, Andrea AU - Mutter, Philipp M. AU - Tavani, Giulio AU - Botifoll, Marc AU - Crippa, Alessandro AU - Kukucka, Josip AU - Sagi, Oliver AU - Martins, Frederico AU - Saez Mollejo, Jaime AU - Prieto Gonzalez, Ivan AU - Borovkov, Maksim AU - Arbiol, Jordi AU - Chrastina, Daniel AU - Isella, Giovanni AU - Katsaros, Georgios ID - 8909 IS - 8 JF - Nature Materials SN - 1476-1122 TI - A singlet triplet hole spin qubit in planar Ge VL - 20 ER - TY - THES AB - Accumulation of interstitial fluid (IF) between embryonic cells is a common phenomenon in vertebrate embryogenesis. Unlike other model systems, where these accumulations coalesce into a large central cavity – the blastocoel, in zebrafish, IF is more uniformly distributed between the deep cells (DC) before the onset of gastrulation. This is likely due to the presence of a large extraembryonic structure – the yolk cell (YC) at the position where the blastocoel typically forms in other model organisms. IF has long been speculated to play a role in tissue morphogenesis during embryogenesis, but direct evidence supporting such function is still sparse. Here we show that the relocalization of IF to the interface between the YC and DC/epiblast is critical for axial mesendoderm (ME) cell protrusion formation and migration along this interface, a key process in embryonic axis formation. We further demonstrate that axial ME cell migration and IF relocalization engage in a positive feedback loop, where axial ME migration triggers IF accumulation ahead of the advancing axial ME tissue by mechanically compressing the overlying epiblast cell layer. Upon compression, locally induced flow relocalizes the IF through the porous epiblast tissue resulting in an IF accumulation ahead of the leading axial ME. This IF accumulation, in turn, promotes cell protrusion formation and migration of the leading axial ME cells, thereby facilitating axial ME extension. Our findings reveal a central role of dynamic IF relocalization in orchestrating germ layer morphogenesis during gastrulation. AU - Huljev, Karla ID - 9397 SN - 2663-337X TI - Coordinated spatiotemporal reorganization of interstitial fluid is required for axial mesendoderm migration in zebrafish gastrulation ER - TY - GEN AB - The potential of Si and SiGe-based devices for the scaling of quantum circuits is tainted by device variability. Each device needs to be tuned to operation conditions. We give a key step towards tackling this variability with an algorithm that, without modification, is capable of tuning a 4-gate Si FinFET, a 5-gate GeSi nanowire and a 7-gate SiGe heterostructure double quantum dot device from scratch. We achieve tuning times of 30, 10, and 92 minutes, respectively. The algorithm also provides insight into the parameter space landscape for each of these devices. These results show that overarching solutions for the tuning of quantum devices are enabled by machine learning. AU - Severin, B. AU - Lennon, D. T. AU - Camenzind, L. C. AU - Vigneau, F. AU - Fedele, F. AU - Jirovec, Daniel AU - Ballabio, A. AU - Chrastina, D. AU - Isella, G. AU - Kruijf, M. de AU - Carballido, M. J. AU - Svab, S. AU - Kuhlmann, A. V. AU - Braakman, F. R. AU - Geyer, S. AU - Froning, F. N. M. AU - Moon, H. AU - Osborne, M. A. AU - Sejdinovic, D. AU - Katsaros, Georgios AU - Zumbühl, D. M. AU - Briggs, G. A. D. AU - Ares, N. ID - 10066 T2 - arXiv TI - Cross-architecture tuning of silicon and SiGe-based quantum devices using machine learning ER - TY - JOUR AB - The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b, and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation. AU - Bhandari, Pradeep AU - Vandael, David H AU - Fernández-Fernández, Diego AU - Fritzius, Thorsten AU - Kleindienst, David AU - Önal, Hüseyin C AU - Montanaro-Punzengruber, Jacqueline-Claire AU - Gassmann, Martin AU - Jonas, Peter M AU - Kulik, Akos AU - Bettler, Bernhard AU - Shigemoto, Ryuichi AU - Koppensteiner, Peter ID - 9437 JF - eLife TI - GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals VL - 10 ER - TY - THES AB - Left-right asymmetries can be considered a fundamental organizational principle of the vertebrate central nervous system. The hippocampal CA3-CA1 pyramidal cell synaptic connection shows an input-side dependent asymmetry where the hemispheric location of the presynaptic CA3 neuron determines the synaptic properties. Left-input synapses terminating on apical dendrites in stratum radiatum have a higher density of NMDA receptor subunit GluN2B, a lower density of AMPA receptor subunit GluA1 and smaller areas with less often perforated PSDs. On the other hand, left-input synapses terminating on basal dendrites in stratum oriens have lower GluN2B densities than right-input ones. Apical and basal synapses further employ different signaling pathways involved in LTP. SDS-digested freeze-fracture replica labeling can visualize synaptic membrane proteins with high sensitivity and resolution, and has been used to reveal the asymmetry at the electron microscopic level. However, it requires time-consuming manual demarcation of the synaptic surface for quantitative measurements. To facilitate the analysis of replica labeling, I first developed a software named Darea, which utilizes deep-learning to automatize this demarcation. With Darea I characterized the synaptic distribution of NMDA and AMPA receptors as well as the voltage-gated Ca2+ channels in CA1 stratum radiatum and oriens. Second, I explored the role of GluN2B and its carboxy-terminus in the establishment of input-side dependent hippocampal asymmetry. In conditional knock-out mice lacking GluN2B expression in CA1 and GluN2B-2A swap mice, where GluN2B carboxy-terminus was exchanged to that of GluN2A, no significant asymmetries of GluN2B, GluA1 and PSD area were detected. We further discovered a previously unknown functional asymmetry of GluN2A, which was also lost in the swap mouse. These results demonstrate that GluN2B carboxy-terminus plays a critical role in normal formation of input-side dependent asymmetry. AU - Kleindienst, David ID - 9562 SN - 2663-337X TI - 2B or not 2B: Hippocampal asymmetries mediated by NMDA receptor subunit GluN2B C-terminus and high-throughput image analysis by Deep-Learning ER - TY - THES AB - In this thesis, we consider several of the most classical and fundamental problems in static analysis and formal verification, including invariant generation, reachability analysis, termination analysis of probabilistic programs, data-flow analysis, quantitative analysis of Markov chains and Markov decision processes, and the problem of data packing in cache management. We use techniques from parameterized complexity theory, polyhedral geometry, and real algebraic geometry to significantly improve the state-of-the-art, in terms of both scalability and completeness guarantees, for the mentioned problems. In some cases, our results are the first theoretical improvements for the respective problems in two or three decades. AU - Goharshady, Amir Kafshdar ID - 8934 SN - 2663-337X TI - Parameterized and algebro-geometric advances in static program analysis ER - TY - THES AB - Bacteria-host interactions represent a continuous trade-off between benefit and risk. Thus, the host immune response is faced with a non-trivial problem – accommodate beneficial commensals and remove harmful pathogens. This is especially difficult as molecular patterns, such as lipopolysaccharide or specific surface organelles such as pili, are conserved in both, commensal and pathogenic bacteria. Type 1 pili, tightly regulated by phase variation, are considered an important virulence factor of pathogenic bacteria as they facilitate invasion into host cells. While invasion represents a de facto passive mechanism for pathogens to escape the host immune response, we demonstrate a fundamental role of type 1 pili as active modulators of the innate and adaptive immune response. AU - Tomasek, Kathrin ID - 10307 SN - 2663-337X TI - Pathogenic Escherichia coli hijack the host immune response ER - TY - GEN AB - A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host’s immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on dendritic cells as a previously undescribed binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of pathogenic bacteria to CD14 lead to reduced dendritic cell migration and blunted expression of co-stimulatory molecules, both rate-limiting factors of T cell activation. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn’s disease. AU - Tomasek, Kathrin AU - Leithner, Alexander F AU - Glatzová, Ivana AU - Lukesch, Michael S. AU - Guet, Calin C AU - Sixt, Michael K ID - 10316 T2 - bioRxiv TI - Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14 ER - TY - JOUR AB - Availability of the essential macronutrient nitrogen in soil plays a critical role in plant growth, development, and impacts agricultural productivity. Plants have evolved different strategies for sensing and responding to heterogeneous nitrogen distribution. Modulation of root system architecture, including primary root growth and branching, is among the most essential plant adaptions to ensure adequate nitrogen acquisition. However, the immediate molecular pathways coordinating the adjustment of root growth in response to distinct nitrogen sources, such as nitrate or ammonium, are poorly understood. Here, we show that growth as manifested by cell division and elongation is synchronized by coordinated auxin flux between two adjacent outer tissue layers of the root. This coordination is achieved by nitrate‐dependent dephosphorylation of the PIN2 auxin efflux carrier at a previously uncharacterized phosphorylation site, leading to subsequent PIN2 lateralization and thereby regulating auxin flow between adjacent tissues. A dynamic computer model based on our experimental data successfully recapitulates experimental observations. Our study provides mechanistic insights broadening our understanding of root growth mechanisms in dynamic environments. AU - Ötvös, Krisztina AU - Marconi, Marco AU - Vega, Andrea AU - O’Brien, Jose AU - Johnson, Alexander J AU - Abualia, Rashed AU - Antonielli, Livio AU - Montesinos López, Juan C AU - Zhang, Yuzhou AU - Tan, Shutang AU - Cuesta, Candela AU - Artner, Christina AU - Bouguyon, Eleonore AU - Gojon, Alain AU - Friml, Jiří AU - Gutiérrez, Rodrigo A. AU - Wabnik, Krzysztof T AU - Benková, Eva ID - 9010 IS - 3 JF - EMBO Journal SN - 02614189 TI - Modulation of plant root growth by nitrogen source-defined regulation of polar auxin transport VL - 40 ER - TY - JOUR AB - Nitrate commands genome-wide gene expression changes that impact metabolism, physiology, plant growth, and development. In an effort to identify new components involved in nitrate responses in plants, we analyze the Arabidopsis thaliana root phosphoproteome in response to nitrate treatments via liquid chromatography coupled to tandem mass spectrometry. 176 phosphoproteins show significant changes at 5 or 20 min after nitrate treatments. Proteins identified by 5 min include signaling components such as kinases or transcription factors. In contrast, by 20 min, proteins identified were associated with transporter activity or hormone metabolism functions, among others. The phosphorylation profile of NITRATE TRANSPORTER 1.1 (NRT1.1) mutant plants was significantly altered as compared to wild-type plants, confirming its key role in nitrate signaling pathways that involves phosphorylation changes. Integrative bioinformatics analysis highlights auxin transport as an important mechanism modulated by nitrate signaling at the post-translational level. We validated a new phosphorylation site in PIN2 and provide evidence that it functions in primary and lateral root growth responses to nitrate. AU - Vega, Andrea AU - Fredes, Isabel AU - O’Brien, José AU - Shen, Zhouxin AU - Ötvös, Krisztina AU - Abualia, Rashed AU - Benková, Eva AU - Briggs, Steven P. AU - Gutiérrez, Rodrigo A. ID - 9913 IS - 9 JF - EMBO Reports SN - 1469-221X TI - Nitrate triggered phosphoproteome changes and a PIN2 phosphosite modulating root system architecture VL - 22 ER - TY - THES AB - Nitrogen is an essential macronutrient determining plant growth, development and affecting agricultural productivity. Root, as a hub that perceives and integrates local and systemic signals on the plant’s external and endogenous nitrogen resources, communicates with other plant organs to consolidate their physiology and development in accordance with actual nitrogen balance. Over the last years, numerous studies demonstrated that these comprehensive developmental adaptations rely on the interaction between pathways controlling nitrogen homeostasis and hormonal networks acting globally in the plant body. However, molecular insights into how the information about the nitrogen status is translated through hormonal pathways into specific developmental output are lacking. In my work, I addressed so far poorly understood mechanisms underlying root-to-shoot communication that lead to a rapid re-adjustment of shoot growth and development after nitrate provision. Applying a combination of molecular, cell, and developmental biology approaches, genetics and grafting experiments as well as hormonal analytics, I identified and characterized an unknown molecular framework orchestrating shoot development with a root nitrate sensory system. AU - Abualia, Rashed ID - 10303 SN - 2663-337X TI - Role of hormones in nitrate regulated growth ER - TY - THES AB - The brain is one of the largest and most complex organs and it is composed of billions of neurons that communicate together enabling e.g. consciousness. The cerebral cortex is the largest site of neural integration in the central nervous system. Concerted radial migration of newly born cortical projection neurons, from their birthplace to their final position, is a key step in the assembly of the cerebral cortex. The cellular and molecular mechanisms regulating radial neuronal migration in vivo are however still unclear. Recent evidence suggests that distinct signaling cues act cell-autonomously but differentially at certain steps during the overall migration process. Moreover, functional analysis of genetic mosaics (mutant neurons present in wild-type/heterozygote environment) using the MADM (Mosaic Analysis with Double Markers) analyses in comparison to global knockout also indicate a significant degree of non-cell-autonomous and/or community effects in the control of cortical neuron migration. The interactions of cell-intrinsic (cell-autonomous) and cell-extrinsic (non-cell-autonomous) components are largely unknown. In part of this thesis work we established a MADM-based experimental strategy for the quantitative analysis of cell-autonomous gene function versus non-cell-autonomous and/or community effects. The direct comparison of mutant neurons from the genetic mosaic (cell-autonomous) to mutant neurons in the conditional and/or global knockout (cell-autonomous + non-cell-autonomous) allows to quantitatively analyze non-cell-autonomous effects. Such analysis enable the high-resolution analysis of projection neuron migration dynamics in distinct environments with concomitant isolation of genomic and proteomic profiles. Using these experimental paradigms and in combination with computational modeling we show and characterize the nature of non-cell-autonomous effects to coordinate radial neuron migration. Furthermore, this thesis discusses recent developments in neurodevelopment with focus on neuronal polarization and non-cell-autonomous mechanisms in neuronal migration. AU - Hansen, Andi H ID - 9962 KW - Neuronal migration KW - Non-cell-autonomous KW - Cell-autonomous KW - Neurodevelopmental disease SN - 2663-337X TI - Cell-autonomous gene function and non-cell-autonomous effects in radial projection neuron migration ER - TY - JOUR AB - Thermalization is the inevitable fate of many complex quantum systems, whose dynamics allow them to fully explore the vast configuration space regardless of the initial state---the behaviour known as quantum ergodicity. In a quest for experimental realizations of coherent long-time dynamics, efforts have focused on ergodicity-breaking mechanisms, such as integrability and localization. The recent discovery of persistent revivals in quantum simulators based on Rydberg atoms have pointed to the existence of a new type of behaviour where the system rapidly relaxes for most initial conditions, while certain initial states give rise to non-ergodic dynamics. This collective effect has been named ”quantum many-body scarring’by analogy with a related form of weak ergodicity breaking that occurs for a single particle inside a stadium billiard potential. In this Review, we provide a pedagogical introduction to quantum many-body scars and highlight the emerging connections with the semiclassical quantization of many-body systems. We discuss the relation between scars and more general routes towards weak violations of ergodicity due to embedded algebras and non-thermal eigenstates, and highlight possible applications of scars in quantum technology. AU - Serbyn, Maksym AU - Abanin, Dmitry A. AU - Papić, Zlatko ID - 9428 IS - 6 JF - Nature Physics TI - Quantum many-body scars and weak breaking of ergodicity VL - 17 ER - TY - JOUR AB - Auxin is a major plant growth regulator, but current models on auxin perception and signaling cannot explain the whole plethora of auxin effects, in particular those associated with rapid responses. A possible candidate for a component of additional auxin perception mechanisms is the AUXIN BINDING PROTEIN 1 (ABP1), whose function in planta remains unclear. Here we combined expression analysis with gain- and loss-of-function approaches to analyze the role of ABP1 in plant development. ABP1 shows a broad expression largely overlapping with, but not regulated by, transcriptional auxin response activity. Furthermore, ABP1 activity is not essential for the transcriptional auxin signaling. Genetic in planta analysis revealed that abp1 loss-of-function mutants show largely normal development with minor defects in bolting. On the other hand, ABP1 gain-of-function alleles show a broad range of growth and developmental defects, including root and hypocotyl growth and bending, lateral root and leaf development, bolting, as well as response to heat stress. At the cellular level, ABP1 gain-of-function leads to impaired auxin effect on PIN polar distribution and affects BFA-sensitive PIN intracellular aggregation. The gain-of-function analysis suggests a broad, but still mechanistically unclear involvement of ABP1 in plant development, possibly masked in abp1 loss-of-function mutants by a functional redundancy. AU - Gelová, Zuzana AU - Gallei, Michelle C AU - Pernisová, Markéta AU - Brunoud, Géraldine AU - Zhang, Xixi AU - Glanc, Matous AU - Li, Lanxin AU - Michalko, Jaroslav AU - Pavlovicova, Zlata AU - Verstraeten, Inge AU - Han, Huibin AU - Hajny, Jakub AU - Hauschild, Robert AU - Čovanová, Milada AU - Zwiewka, Marta AU - Hörmayer, Lukas AU - Fendrych, Matyas AU - Xu, Tongda AU - Vernoux, Teva AU - Friml, Jiří ID - 8931 JF - Plant Science KW - Agronomy and Crop Science KW - Plant Science KW - Genetics KW - General Medicine SN - 0168-9452 TI - Developmental roles of auxin binding protein 1 in Arabidopsis thaliana VL - 303 ER - TY - JOUR AB - The phytohormone auxin and its directional transport through tissues are intensively studied. However, a mechanistic understanding of auxin-mediated feedback on endocytosis and polar distribution of PIN auxin transporters remains limited due to contradictory observations and interpretations. Here, we used state-of-the-art methods to reexamine the auxin effects on PIN endocytic trafficking. We used high auxin concentrations or longer treatments versus lower concentrations and shorter treatments of natural (IAA) and synthetic (NAA) auxins to distinguish between specific and nonspecific effects. Longer treatments of both auxins interfere with Brefeldin A-mediated intracellular PIN2 accumulation and also with general aggregation of endomembrane compartments. NAA treatment decreased the internalization of the endocytic tracer dye, FM4-64; however, NAA treatment also affected the number, distribution, and compartment identity of the early endosome/trans-Golgi network (EE/TGN), rendering the FM4-64 endocytic assays at high NAA concentrations unreliable. To circumvent these nonspecific effects of NAA and IAA affecting the endomembrane system, we opted for alternative approaches visualizing the endocytic events directly at the plasma membrane (PM). Using Total Internal Reflection Fluorescence (TIRF) microscopy, we saw no significant effects of IAA or NAA treatments on the incidence and dynamics of clathrin foci, implying that these treatments do not affect the overall endocytosis rate. However, both NAA and IAA at low concentrations rapidly and specifically promoted endocytosis of photo-converted PIN2 from the PM. These analyses identify a specific effect of NAA and IAA on PIN2 endocytosis, thus contributing to its polarity maintenance and furthermore illustrate that high auxin levels have nonspecific effects on trafficking and endomembrane compartments. AU - Narasimhan, Madhumitha AU - Gallei, Michelle C AU - Tan, Shutang AU - Johnson, Alexander J AU - Verstraeten, Inge AU - Li, Lanxin AU - Rodriguez Solovey, Lesia AU - Han, Huibin AU - Himschoot, E AU - Wang, R AU - Vanneste, S AU - Sánchez-Simarro, J AU - Aniento, F AU - Adamowski, Maciek AU - Friml, Jiří ID - 9287 IS - 2 JF - Plant Physiology SN - 0032-0889 TI - Systematic analysis of specific and nonspecific auxin effects on endocytosis and trafficking VL - 186 ER - TY - THES AB - Plant motions occur across a wide spectrum of timescales, ranging from seed dispersal through bursting (milliseconds) and stomatal opening (minutes) to long-term adaptation of gross architecture. Relatively fast motions include water-driven growth as exemplified by root cell expansion under abiotic/biotic stresses or during gravitropism. A showcase is a root growth inhibition in 30 seconds triggered by the phytohormone auxin. However, the cellular and molecular mechanisms are still largely unknown. This thesis covers the studies about this topic as follows. By taking advantage of microfluidics combined with live imaging, pharmaceutical tools, and transgenic lines, we examined the kinetics of and causal relationship among various auxininduced rapid cellular changes in root growth, apoplastic pH, cytosolic Ca2+, cortical microtubule (CMT) orientation, and vacuolar morphology. We revealed that CMT reorientation and vacuolar constriction are the consequence of growth itself instead of responding directly to auxin. In contrast, auxin induces apoplast alkalinization to rapidly inhibit root growth in 30 seconds. This auxin-triggered apoplast alkalinization results from rapid H+- influx that is contributed by Ca2+ inward channel CYCLIC NUCLEOTIDE-GATED CHANNEL 14 (CNGC14)-dependent Ca2+ signaling. To dissect which auxin signaling mediates the rapid apoplast alkalinization, we combined microfluidics and genetic engineering to verify that TIR1/AFB receptors conduct a non-transcriptional regulation on Ca2+ and H+ -influx. This non-canonical pathway is mostly mediated by the cytosolic portion of TIR1/AFB. On the other hand, we uncovered, using biochemical and phospho-proteomic analysis, that auxin cell surface signaling component TRANSMEMBRANE KINASE 1 (TMK1) plays a negative role during auxin-trigger apoplast alkalinization and root growth inhibition through directly activating PM H+ -ATPases. Therefore, we discovered that PM H+ -ATPases counteract instead of mediate the auxintriggered rapid H+ -influx, and that TIR1/AFB and TMK1 regulate root growth antagonistically. This opposite effect of TIR1/AFB and TMK1 is consistent during auxin-induced hypocotyl elongation, leading us to explore the relation of two signaling pathways. Assisted with biochemistry and fluorescent imaging, we verified for the first time that TIR1/AFB and TMK1 can interact with each other. The ability of TIR1/AFB binding to membrane lipid provides a basis for the interaction of plasma membrane- and cytosol-localized proteins. Besides, transgenic analysis combined with genetic engineering and biochemistry showed that vi they do function in the same pathway. Particularly, auxin-induced TMK1 increase is TIR1/AFB dependent, suggesting TIR1/AFB regulation on TMK1. Conversely, TMK1 also regulates TIR1/AFB protein levels and thus auxin canonical signaling. To follow the study of rapid growth regulation, we analyzed another rapid growth regulator, signaling peptide RALF1. We showed that RALF1 also triggers a rapid and reversible growth inhibition caused by H + influx, highly resembling but not dependent on auxin. Besides, RALF1 promotes auxin biosynthesis by increasing expression of auxin biosynthesis enzyme YUCCAs and thus induces auxin signaling in ca. 1 hour, contributing to the sustained RALF1-triggered growth inhibition. These studies collectively contribute to understanding rapid regulation on plant cell growth, novel auxin signaling pathway as well as auxin-peptide crosstalk. AU - Li, Lanxin ID - 10083 SN - 2663-337X TI - Rapid cell growth regulation in Arabidopsis ER - TY - JOUR AB - Auxin plays a dual role in growth regulation and, depending on the tissue and concentration of the hormone, it can either promote or inhibit division and expansion processes in plants. Recent studies have revealed that, beyond transcriptional reprogramming, alternative auxincontrolled mechanisms regulate root growth. Here, we explored the impact of different concentrations of the synthetic auxin NAA that establish growth-promoting and -repressing conditions on the root tip proteome and phosphoproteome, generating a unique resource. From the phosphoproteome data, we pinpointed (novel) growth regulators, such as the RALF34-THE1 module. Our results, together with previously published studies, suggest that auxin, H+-ATPases, cell wall modifications and cell wall sensing receptor-like kinases are tightly embedded in a pathway regulating cell elongation. Furthermore, our study assigned a novel role to MKK2 as a regulator of primary root growth and a (potential) regulator of auxin biosynthesis and signalling, and suggests the importance of the MKK2 Thr31 phosphorylation site for growth regulation in the Arabidopsis root tip. AU - Nikonorova, N AU - Murphy, E AU - Fonseca de Lima, CF AU - Zhu, S AU - van de Cotte, B AU - Vu, LD AU - Balcerowicz, D AU - Li, Lanxin AU - Kong, X AU - De Rop, G AU - Beeckman, T AU - Friml, Jiří AU - Vissenberg, K AU - Morris, PC AU - Ding, Z AU - De Smet, I ID - 10015 JF - Cells KW - primary root KW - (phospho)proteomics KW - auxin KW - (receptor) kinase SN - 2073-4409 TI - The Arabidopsis root tip (phospho)proteomes at growth-promoting versus growth-repressing conditions reveal novel root growth regulators VL - 10 ER - TY - GEN AB - Growth regulation tailors plant development to its environment. A showcase is response to gravity, where shoots bend up and roots down1. This paradox is based on opposite effects of the phytohormone auxin, which promotes cell expansion in shoots, while inhibiting it in roots via a yet unknown cellular mechanism2. Here, by combining microfluidics, live imaging, genetic engineering and phospho-proteomics in Arabidopsis thaliana, we advance our understanding how auxin inhibits root growth. We show that auxin activates two distinct, antagonistically acting signalling pathways that converge on the rapid regulation of the apoplastic pH, a causative growth determinant. Cell surface-based TRANSMEMBRANE KINASE1 (TMK1) interacts with and mediates phosphorylation and activation of plasma membrane H+-ATPases for apoplast acidification, while intracellular canonical auxin signalling promotes net cellular H+-influx, causing apoplast alkalinisation. The simultaneous activation of these two counteracting mechanisms poises the root for a rapid, fine-tuned growth modulation while navigating complex soil environment. AU - Li, Lanxin AU - Verstraeten, Inge AU - Roosjen, Mark AU - Takahashi, Koji AU - Rodriguez Solovey, Lesia AU - Merrin, Jack AU - Chen, Jian AU - Shabala, Lana AU - Smet, Wouter AU - Ren, Hong AU - Vanneste, Steffen AU - Shabala, Sergey AU - De Rybel, Bert AU - Weijers, Dolf AU - Kinoshita, Toshinori AU - Gray, William M. AU - Friml, Jiří ID - 10095 SN - 2693-5015 T2 - Research Square TI - Cell surface and intracellular auxin signalling for H+-fluxes in root growth ER - TY - THES AB - Indirect reciprocity in evolutionary game theory is a prominent mechanism for explaining the evolution of cooperation among unrelated individuals. In contrast to direct reciprocity, which is based on individuals meeting repeatedly, and conditionally cooperating by using their own experiences, indirect reciprocity is based on individuals’ reputations. If a player helps another, this increases the helper’s public standing, benefitting them in the future. This lets cooperation in the population emerge without individuals having to meet more than once. While the two modes of reciprocity are intertwined, they are difficult to compare. Thus, they are usually studied in isolation. Direct reciprocity can maintain cooperation with simple strategies, and is robust against noise even when players do not remember more than their partner’s last action. Meanwhile, indirect reciprocity requires its successful strategies, or social norms, to be more complex. Exhaustive search previously identified eight such norms, called the “leading eight”, which excel at maintaining cooperation. However, as the first result of this thesis, we show that the leading eight break down once we remove the fundamental assumption that information is synchronized and public, such that everyone agrees on reputations. Once we consider a more realistic scenario of imperfect information, where reputations are private, and individuals occasionally misinterpret or miss observations, the leading eight do not promote cooperation anymore. Instead, minor initial disagreements can proliferate, fragmenting populations into subgroups. In a next step, we consider ways to mitigate this issue. We first explore whether introducing “generosity” can stabilize cooperation when players use the leading eight strategies in noisy environments. This approach of modifying strategies to include probabilistic elements for coping with errors is known to work well in direct reciprocity. However, as we show here, it fails for the more complex norms of indirect reciprocity. Imperfect information still prevents cooperation from evolving. On the other hand, we succeeded to show in this thesis that modifying the leading eight to use “quantitative assessment”, i.e. tracking reputation scores on a scale beyond good and bad, and making overall judgments of others based on a threshold, is highly successful, even when noise increases in the environment. Cooperation can flourish when reputations are more nuanced, and players have a broader understanding what it means to be “good.” Finally, we present a single theoretical framework that unites the two modes of reciprocity despite their differences. Within this framework, we identify a novel simple and successful strategy for indirect reciprocity, which can cope with noisy environments and has an analogue in direct reciprocity. We can also analyze decision making when different sources of information are available. Our results help highlight that for sustaining cooperation, already the most simple rules of reciprocity can be sufficient. AU - Schmid, Laura ID - 10293 SN - 2663-337X TI - Evolution of cooperation via (in)direct reciprocity under imperfect information ER - TY - JOUR AB - Indirect reciprocity is a mechanism for the evolution of cooperation based on social norms. This mechanism requires that individuals in a population observe and judge each other’s behaviors. Individuals with a good reputation are more likely to receive help from others. Previous work suggests that indirect reciprocity is only effective when all relevant information is reliable and publicly available. Otherwise, individuals may disagree on how to assess others, even if they all apply the same social norm. Such disagreements can lead to a breakdown of cooperation. Here we explore whether the predominantly studied ‘leading eight’ social norms of indirect reciprocity can be made more robust by equipping them with an element of generosity. To this end, we distinguish between two kinds of generosity. According to assessment generosity, individuals occasionally assign a good reputation to group members who would usually be regarded as bad. According to action generosity, individuals occasionally cooperate with group members with whom they would usually defect. Using individual-based simulations, we show that the two kinds of generosity have a very different effect on the resulting reputation dynamics. Assessment generosity tends to add to the overall noise and allows defectors to invade. In contrast, a limited amount of action generosity can be beneficial in a few cases. However, even when action generosity is beneficial, the respective simulations do not result in full cooperation. Our results suggest that while generosity can favor cooperation when individuals use the most simple strategies of reciprocity, it is disadvantageous when individuals use more complex social norms. AU - Schmid, Laura AU - Shati, Pouya AU - Hilbe, Christian AU - Chatterjee, Krishnendu ID - 9997 IS - 1 JF - Scientific Reports KW - Multidisciplinary TI - The evolution of indirect reciprocity under action and assessment generosity VL - 11 ER - TY - JOUR AB - Direct and indirect reciprocity are key mechanisms for the evolution of cooperation. Direct reciprocity means that individuals use their own experience to decide whether to cooperate with another person. Indirect reciprocity means that they also consider the experiences of others. Although these two mechanisms are intertwined, they are typically studied in isolation. Here, we introduce a mathematical framework that allows us to explore both kinds of reciprocity simultaneously. We show that the well-known ‘generous tit-for-tat’ strategy of direct reciprocity has a natural analogue in indirect reciprocity, which we call ‘generous scoring’. Using an equilibrium analysis, we characterize under which conditions either of the two strategies can maintain cooperation. With simulations, we additionally explore which kind of reciprocity evolves when members of a population engage in social learning to adapt to their environment. Our results draw unexpected connections between direct and indirect reciprocity while highlighting important differences regarding their evolvability. AU - Schmid, Laura AU - Chatterjee, Krishnendu AU - Hilbe, Christian AU - Nowak, Martin A. ID - 9402 IS - 10 JF - Nature Human Behaviour TI - A unified framework of direct and indirect reciprocity VL - 5 ER - TY - JOUR AB - Elastic bending of initially flat slender elements allows the realization and economic fabrication of intriguing curved shapes. In this work, we derive an intuitive but rigorous geometric characterization of the design space of plane elastic rods with variable stiffness. It enables designers to determine which shapes are physically viable with active bending by visual inspection alone. Building on these insights, we propose a method for efficiently designing the geometry of a flat elastic rod that realizes a target equilibrium curve, which only requires solving a linear program. We implement this method in an interactive computational design tool that gives feedback about the feasibility of a design, and computes the geometry of the structural elements necessary to realize it within an instant. The tool also offers an iterative optimization routine that improves the fabricability of a model while modifying it as little as possible. In addition, we use our geometric characterization to derive an algorithm for analyzing and recovering the stability of elastic curves that would otherwise snap out of their unstable equilibrium shapes by buckling. We show the efficacy of our approach by designing and manufacturing several physical models that are assembled from flat elements. AU - Hafner, Christian AU - Bickel, Bernd ID - 9817 IS - 4 JF - ACM Transactions on Graphics KW - Computing methodologies KW - shape modeling KW - modeling and simulation KW - theory of computation KW - computational geometry KW - mathematics of computing KW - mathematical optimization SN - 0730-0301 TI - The design space of plane elastic curves VL - 40 ER - TY - THES AB - Plants maintain the capacity to develop new organs e.g. lateral roots post-embryonically throughout their whole life and thereby flexibly adapt to ever-changing environmental conditions. Plant hormones auxin and cytokinin are the main regulators of the lateral root organogenesis. Additionally to their solo activities, the interaction between auxin and cytokinin plays crucial role in fine-tuning of lateral root development and growth. In particular, cytokinin modulates auxin distribution within the developing lateral root by affecting the endomembrane trafficking of auxin transporter PIN1 and promoting its vacuolar degradation (Marhavý et al., 2011, 2014). This effect is independent of transcription and translation. Therefore, it suggests novel, non-canonical cytokinin activity occuring possibly on the posttranslational level. Impact of cytokinin and other plant hormones on auxin transporters (including PIN1) on the posttranslational level is described in detail in the introduction part of this thesis in a form of a review (Semeradova et al., 2020). To gain insights into the molecular machinery underlying cytokinin effect on the endomembrane trafficking in the plant cell, in particular on the PIN1 degradation, we conducted two large proteomic screens: 1) Identification of cytokinin binding proteins using chemical proteomics. 2) Monitoring of proteomic and phosphoproteomic changes upon cytokinin treatment. In the first screen, we identified DYNAMIN RELATED PROTEIN 2A (DRP2A). We found that DRP2A plays a role in cytokinin regulated processes during the plant growth and that cytokinin treatment promotes destabilization of DRP2A protein. However, the role of DRP2A in the PIN1 degradation remains to be elucidated. In the second screen, we found VACUOLAR PROTEIN SORTING 9A (VPS9A). VPS9a plays crucial role in plant’s response to cytokin and in cytokinin mediated PIN1 degradation. Altogether, we identified proteins, which bind to cytokinin and proteins that in response to cytokinin exhibit significantly changed abundance or phosphorylation pattern. By combining information from these two screens, we can pave our way towards understanding of noncanonical cytokinin effects. AU - Semerádová, Hana ID - 10135 SN - 2663-337X TI - Molecular mechanisms of the cytokinin-regulated endomembrane trafficking to coordinate plant organogenesis ER - TY - THES AB - Most real-world flows are multiphase, yet we know little about them compared to their single-phase counterparts. Multiphase flows are more difficult to investigate as their dynamics occur in large parameter space and involve complex phenomena such as preferential concentration, turbulence modulation, non-Newtonian rheology, etc. Over the last few decades, experiments in particle-laden flows have taken a back seat in favour of ever-improving computational resources. However, computers are still not powerful enough to simulate a real-world fluid with millions of finite-size particles. Experiments are essential not only because they offer a reliable way to investigate real-world multiphase flows but also because they serve to validate numerical studies and steer the research in a relevant direction. In this work, we have experimentally investigated particle-laden flows in pipes, and in particular, examined the effect of particles on the laminar-turbulent transition and the drag scaling in turbulent flows. For particle-laden pipe flows, an earlier study [Matas et al., 2003] reported how the sub-critical (i.e., hysteretic) transition that occurs via localised turbulent structures called puffs is affected by the addition of particles. In this study, in addition to this known transition, we found a super-critical transition to a globally fluctuating state with increasing particle concentration. At the same time, the Newtonian-type transition via puffs is delayed to larger Reynolds numbers. At an even higher concentration, only the globally fluctuating state is found. The dynamics of particle-laden flows are hence determined by two competing instabilities that give rise to three flow regimes: Newtonian-type turbulence at low, a particle-induced globally fluctuating state at high, and a coexistence state at intermediate concentrations. The effect of particles on turbulent drag is ambiguous, with studies reporting drag reduction, no net change, and even drag increase. The ambiguity arises because, in addition to particle concentration, particle shape, size, and density also affect the net drag. Even similar particles might affect the flow dissimilarly in different Reynolds number and concentration ranges. In the present study, we explored a wide range of both Reynolds number and concentration, using spherical as well as cylindrical particles. We found that the spherical particles do not reduce drag while the cylindrical particles are drag-reducing within a specific Reynolds number interval. The interval strongly depends on the particle concentration and the relative size of the pipe and particles. Within this interval, the magnitude of drag reduction reaches a maximum. These drag reduction maxima appear to fall onto a distinct power-law curve irrespective of the pipe diameter and particle concentration, and this curve can be considered as the maximum drag reduction asymptote for a given fibre shape. Such an asymptote is well known for polymeric flows but had not been identified for particle-laden flows prior to this work. AU - Agrawal, Nishchal ID - 9728 KW - Drag Reduction KW - Transition to Turbulence KW - Multiphase Flows KW - particle Laden Flows KW - Complex Flows KW - Experiments KW - Fluid Dynamics SN - 2663-337X TI - Transition to turbulence and drag reduction in particle-laden pipe flows ER - TY - JOUR AB - Biological membranes can dramatically accelerate the aggregation of normally soluble protein molecules into amyloid fibrils and alter the fibril morphologies, yet the molecular mechanisms through which this accelerated nucleation takes place are not yet understood. Here, we develop a coarse-grained model to systematically explore the effect that the structural properties of the lipid membrane and the nature of protein–membrane interactions have on the nucleation rates of amyloid fibrils. We identify two physically distinct nucleation pathways—protein-rich and lipid-rich—and quantify how the membrane fluidity and protein–membrane affinity control the relative importance of those molecular pathways. We find that the membrane’s susceptibility to reshaping and being incorporated into the fibrillar aggregates is a key determinant of its ability to promote protein aggregation. We then characterize the rates and the free-energy profile associated with this heterogeneous nucleation process, in which the surface itself participates in the aggregate structure. Finally, we compare quantitatively our data to experiments on membrane-catalyzed amyloid aggregation of α-synuclein, a protein implicated in Parkinson’s disease that predominately nucleates on membranes. More generally, our results provide a framework for understanding macromolecular aggregation on lipid membranes in a broad biological and biotechnological context. AU - Krausser, Johannes AU - Knowles, Tuomas P. J. AU - Šarić, Anđela ID - 10336 IS - 52 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Physical mechanisms of amyloid nucleation on fluid membranes VL - 117 ER - TY - JOUR AB - The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high-avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across. AU - Tian, Xiaohe AU - Leite, Diana M. AU - Scarpa, Edoardo AU - Nyberg, Sophie AU - Fullstone, Gavin AU - Forth, Joe AU - Matias, Diana AU - Apriceno, Azzurra AU - Poma, Alessandro AU - Duro-Castano, Aroa AU - Vuyyuru, Manish AU - Harker-Kirschneck, Lena AU - Šarić, Anđela AU - Zhang, Zhongping AU - Xiang, Pan AU - Fang, Bin AU - Tian, Yupeng AU - Luo, Lei AU - Rizzello, Loris AU - Battaglia, Giuseppe ID - 10342 IS - 48 JF - Science Advances KW - multidisciplinary SN - 2375-2548 TI - On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias VL - 6 ER - TY - JOUR AB - In this study, we investigate the role of the surface patterning of nanostructures for cell membrane reshaping. To accomplish this, we combine an evolutionary algorithm with coarse-grained molecular dynamics simulations and explore the solution space of ligand patterns on a nanoparticle that promote efficient and reliable cell uptake. Surprisingly, we find that in the regime of low ligand number the best-performing structures are characterized by ligands arranged into long one-dimensional chains that pattern the surface of the particle. We show that these chains of ligands provide particles with high rotational freedom and they lower the free energy barrier for membrane crossing. Our approach reveals a set of nonintuitive design rules that can be used to inform artificial nanoparticle construction and the search for inhibitors of viral entry. AU - Forster, Joel C. AU - Krausser, Johannes AU - Vuyyuru, Manish R. AU - Baum, Buzz AU - Šarić, Anđela ID - 10344 IS - 22 JF - Physical Review Letters SN - 0031-9007 TI - Exploring the design rules for efficient membrane-reshaping nanostructures VL - 125 ER - TY - JOUR AB - Tracing the motion of macromolecules, viruses, and nanoparticles adsorbed onto cell membranes is currently the most direct way of probing the complex dynamic interactions behind vital biological processes, including cell signalling, trafficking, and viral infection. The resulting trajectories are usually consistent with some type of anomalous diffusion, but the molecular origins behind the observed anomalous behaviour are usually not obvious. Here we use coarse-grained molecular dynamics simulations to help identify the physical mechanisms that can give rise to experimentally observed trajectories of nanoscopic objects moving on biological membranes. We find that diffusion on membranes of high fluidities typically results in normal diffusion of the adsorbed nanoparticle, irrespective of the concentration of receptors, receptor clustering, or multivalent interactions between the particle and membrane receptors. Gel-like membranes on the other hand result in anomalous diffusion of the particle, which becomes more pronounced at higher receptor concentrations. This anomalous diffusion is characterised by local particle trapping in the regions of high receptor concentrations and fast hopping between such regions. The normal diffusion is recovered in the limit where the gel membrane is saturated with receptors. We conclude that hindered receptor diffusivity can be a common reason behind the observed anomalous diffusion of viruses, vesicles, and nanoparticles adsorbed on cell and model membranes. Our results enable direct comparison with experiments and offer a new route for interpreting motility experiments on cell membranes. AU - Debets, V. E. AU - Janssen, L. M. C. AU - Šarić, Anđela ID - 10341 IS - 47 JF - Soft Matter KW - condensed matter physics KW - general chemistry SN - 1744-683X TI - Characterising the diffusion of biological nanoparticles on fluid and cross-linked membranes VL - 16 ER - TY - JOUR AB - One of the most robust examples of self-assembly in living organisms is the formation of collagen architectures. Collagen type I molecules are a crucial component of the extracellular matrix, where they self-assemble into fibrils of well-defined axial striped patterns. This striped fibrillar pattern is preserved across the animal kingdom and is important for the determination of cell phenotype, cell adhesion, and tissue regulation and signaling. The understanding of the physical processes that determine such a robust morphology of self-assembled collagen fibrils is currently almost completely missing. Here, we develop a minimal coarse-grained computational model to identify the physical principles of the assembly of collagen-mimetic molecules. We find that screened electrostatic interactions can drive the formation of collagen-like filaments of well-defined striped morphologies. The fibril axial pattern is determined solely by the distribution of charges on the molecule and is robust to the changes in protein concentration, monomer rigidity, and environmental conditions. We show that the striped fibrillar pattern cannot be easily predicted from the interactions between two monomers but is an emergent result of multibody interactions. Our results can help address collagen remodeling in diseases and aging and guide the design of collagen scaffolds for biotechnological applications. AU - Hafner, Anne E. AU - Gyori, Noemi G. AU - Bench, Ciaran A. AU - Davis, Luke K. AU - Šarić, Anđela ID - 10346 IS - 9 JF - Biophysical Journal KW - biophysics SN - 0006-3495 TI - Modeling fibrillogenesis of collagen-mimetic molecules VL - 119 ER - TY - JOUR AB - The misfolding and aberrant aggregation of proteins into fibrillar structures is a key factor in some of the most prevalent human diseases, including diabetes and dementia. Low molecular weight oligomers are thought to be a central factor in the pathology of these diseases, as well as critical intermediates in the fibril formation process, and as such have received much recent attention. Moreover, on-pathway oligomeric intermediates are potential targets for therapeutic strategies aimed at interrupting the fibril formation process. However, a consistent framework for distinguishing on-pathway from off-pathway oligomers has hitherto been lacking and, in particular, no consensus definition of on- and off-pathway oligomers is available. In this paper, we argue that a non-binary definition of oligomers' contribution to fibril-forming pathways may be more informative and we suggest a quantitative framework, in which each oligomeric species is assigned a value between 0 and 1 describing its relative contribution to the formation of fibrils. First, we clarify the distinction between oligomers and fibrils, and then we use the formalism of reaction networks to develop a general definition for on-pathway oligomers, that yields meaningful classifications in the context of amyloid formation. By applying these concepts to Monte Carlo simulations of a minimal aggregating system, and by revisiting several previous studies of amyloid oligomers in light of our new framework, we demonstrate how to perform these classifications in practice. For each oligomeric species we obtain the degree to which it is on-pathway, highlighting the most effective pharmaceutical targets for the inhibition of amyloid fibril formation. AU - Dear, Alexander J. AU - Meisl, Georg AU - Šarić, Anđela AU - Michaels, Thomas C. T. AU - Kjaergaard, Magnus AU - Linse, Sara AU - Knowles, Tuomas P. J. ID - 10350 IS - 24 JF - Chemical Science KW - general chemistry SN - 2041-6520 TI - Identification of on- and off-pathway oligomers in amyloid fibril formation VL - 11 ER - TY - JOUR AB - Sulfolobus acidocaldarius is the closest experimentally tractable archaeal relative of eukaryotes and, despite lacking obvious cyclin-dependent kinase and cyclin homologs, has an ordered eukaryote-like cell cycle with distinct phases of DNA replication and division. Here, in exploring the mechanism of cell division in S. acidocaldarius, we identify a role for the archaeal proteasome in regulating the transition from the end of one cell cycle to the beginning of the next. Further, we identify the archaeal ESCRT-III homolog, CdvB, as a key target of the proteasome and show that its degradation triggers division by allowing constriction of the CdvB1:CdvB2 ESCRT-III division ring. These findings offer a minimal mechanism for ESCRT-III–mediated membrane remodeling and point to a conserved role for the proteasome in eukaryotic and archaeal cell cycle control. AU - Tarrason Risa, Gabriel AU - Hurtig, Fredrik AU - Bray, Sian AU - Hafner, Anne E. AU - Harker-Kirschneck, Lena AU - Faull, Peter AU - Davis, Colin AU - Papatziamou, Dimitra AU - Mutavchiev, Delyan R. AU - Fan, Catherine AU - Meneguello, Leticia AU - Arashiro Pulschen, Andre AU - Dey, Gautam AU - Culley, Siân AU - Kilkenny, Mairi AU - Souza, Diorge P. AU - Pellegrini, Luca AU - de Bruin, Robertus A. M. AU - Henriques, Ricardo AU - Snijders, Ambrosius P. AU - Šarić, Anđela AU - Lindås, Ann-Christin AU - Robinson, Nicholas P. AU - Baum, Buzz ID - 10349 IS - 6504 JF - Science KW - multidisciplinary SN - 0036-8075 TI - The proteasome controls ESCRT-III–mediated cell division in an archaeon VL - 369 ER - TY - JOUR AB - Understanding the mechanism of action of compounds capable of inhibiting amyloid-fibril formation is critical to the development of potential therapeutics against protein-misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates, and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of amyloid-aggregation inhibition that reveals the fundamental thermodynamic and kinetic signatures characterizing effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimization of inhibitors of amyloid-fibril formation, revealing in particular the important role of on-rates in the binding of the inhibitors. AU - Michaels, Thomas C. T. AU - Šarić, Anđela AU - Meisl, Georg AU - Heller, Gabriella T. AU - Curk, Samo AU - Arosio, Paolo AU - Linse, Sara AU - Dobson, Christopher M. AU - Vendruscolo, Michele AU - Knowles, Tuomas P. J. ID - 10347 IS - 39 JF - Proceedings of the National Academy of Sciences KW - multidisciplinary SN - 0027-8424 TI - Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors VL - 117 ER - TY - JOUR AB - Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer’s disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach that combines theory, experiment and simulation, we reveal, in molecular detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases. AU - Michaels, Thomas C. T. AU - Šarić, Anđela AU - Curk, Samo AU - Bernfur, Katja AU - Arosio, Paolo AU - Meisl, Georg AU - Dear, Alexander J. AU - Cohen, Samuel I. A. AU - Dobson, Christopher M. AU - Vendruscolo, Michele AU - Linse, Sara AU - Knowles, Tuomas P. J. ID - 10351 IS - 5 JF - Nature Chemistry KW - general chemical engineering KW - general chemistry SN - 1755-4330 TI - Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide VL - 12 ER - TY - JOUR AB - The endosomal sorting complex required for transport-III (ESCRT-III) catalyzes membrane fission from within membrane necks, a process that is essential for many cellular functions, from cell division to lysosome degradation and autophagy. How it breaks membranes, though, remains unknown. Here, we characterize a sequential polymerization of ESCRT-III subunits that, driven by a recruitment cascade and by continuous subunit-turnover powered by the ATPase Vps4, induces membrane deformation and fission. During this process, the exchange of Vps24 for Did2 induces a tilt in the polymer-membrane interface, which triggers transition from flat spiral polymers to helical filament to drive the formation of membrane protrusions, and ends with the formation of a highly constricted Did2-Ist1 co-polymer that we show is competent to promote fission when bound on the inside of membrane necks. Overall, our results suggest a mechanism of stepwise changes in ESCRT-III filament structure and mechanical properties via exchange of the filament subunits to catalyze ESCRT-III activity. AU - Pfitzner, Anna-Katharina AU - Mercier, Vincent AU - Jiang, Xiuyun AU - Moser von Filseck, Joachim AU - Baum, Buzz AU - Šarić, Anđela AU - Roux, Aurélien ID - 10348 IS - 5 JF - Cell KW - general biochemistry KW - genetics and molecular biology SN - 0092-8674 TI - An ESCRT-III polymerization sequence drives membrane deformation and fission VL - 182 ER - TY - JOUR AB - In the nuclear pore complex, intrinsically disordered nuclear pore proteins (FG Nups) form a selective barrier for transport into and out of the cell nucleus, in a way that remains poorly understood. The collective FG Nup behavior has long been conceptualized either as a polymer brush, dominated by entropic and excluded-volume (repulsive) interactions, or as a hydrogel, dominated by cohesive (attractive) interactions between FG Nups. Here we compare mesoscale computational simulations with a wide range of experimental data to demonstrate that FG Nups are at the crossover point between these two regimes. Specifically, we find that repulsive and attractive interactions are balanced, resulting in morphologies and dynamics that are close to those of ideal polymer chains. We demonstrate that this property of FG Nups yields sufficient cohesion to seal the transport barrier, and yet maintains fast dynamics at the molecular scale, permitting the rapid polymer rearrangements needed for transport events. AU - Davis, Luke K. AU - Ford, Ian J. AU - Šarić, Anđela AU - Hoogenboom, Bart W. ID - 10352 IS - 2 JF - Physical Review E SN - 2470-0045 TI - Intrinsically disordered nuclear pore proteins show ideal-polymer morphologies and dynamics VL - 101 ER - TY - JOUR AB - Experiments have suggested that bacterial mechanosensitive channels separate into 2D clusters, the role of which is unclear. By developing a coarse-grained computer model we find that clustering promotes the channel closure, which is highly dependent on the channel concentration and membrane stress. This behaviour yields a tightly regulated gating system, whereby at high tensions channels gate individually, and at lower tensions the channels spontaneously aggregate and inactivate. We implement this positive feedback into the model for cell volume regulation, and find that the channel clustering protects the cell against excessive loss of cytoplasmic content. AU - Paraschiv, Alexandru AU - Hegde, Smitha AU - Ganti, Raman AU - Pilizota, Teuta AU - Šarić, Anđela ID - 10353 IS - 4 JF - Physical Review Letters KW - general physics and astronomy SN - 0031-9007 TI - Dynamic clustering regulates activity of mechanosensitive membrane channels VL - 124 ER - TY - GEN AB - Data storage and retrieval systems, methods, and computer-readable media utilize a cryptographically verifiable data structure that facilitates verification of a transaction in a decentralized peer-to-peer environment using multi-hop backwards and forwards links. Backward links are cryptographic hashes of past records. Forward links are cryptographic signatures of future records that are added retroactively to records once the target block has been appended to the data structure. AU - Ford, Bryan AU - Gasse, Linus AU - Kokoris Kogias, Eleftherios AU - Jovanovic, Philipp ID - 10557 TI - Cryptographically verifiable data structure having multi-hop forward and backwards links and associated systems and methods ER - TY - JOUR AB - Magnetism typically arises from the joint effect of Fermi statistics and repulsive Coulomb interactions, which favours ground states with non-zero electron spin. As a result, controlling spin magnetism with electric fields—a longstanding technological goal in spintronics and multiferroics1,2—can be achieved only indirectly. Here we experimentally demonstrate direct electric-field control of magnetic states in an orbital Chern insulator3,4,5,6, a magnetic system in which non-trivial band topology favours long-range order of orbital angular momentum but the spins are thought to remain disordered7,8,9,10,11,12,13,14. We use van der Waals heterostructures consisting of a graphene monolayer rotationally faulted with respect to a Bernal-stacked bilayer to realize narrow and topologically non-trivial valley-projected moiré minibands15,16,17. At fillings of one and three electrons per moiré unit cell within these bands, we observe quantized anomalous Hall effects18 with transverse resistance approximately equal to h/2e2 (where h is Planck’s constant and e is the charge on the electron), which is indicative of spontaneous polarization of the system into a single-valley-projected band with a Chern number equal to two. At a filling of three electrons per moiré unit cell, we find that the sign of the quantum anomalous Hall effect can be reversed via field-effect control of the chemical potential; moreover, this transition is hysteretic, which we use to demonstrate non-volatile electric-field-induced reversal of the magnetic state. A theoretical analysis19 indicates that the effect arises from the topological edge states, which drive a change in sign of the magnetization and thus a reversal in the favoured magnetic state. Voltage control of magnetic states can be used to electrically pattern non-volatile magnetic-domain structures hosting chiral edge states, with applications ranging from reconfigurable microwave circuit elements to ultralow-power magnetic memories. AU - Polshyn, Hryhoriy AU - Zhu, J. AU - Kumar, M. A. AU - Zhang, Y. AU - Yang, F. AU - Tschirhart, C. L. AU - Serlin, M. AU - Watanabe, K. AU - Taniguchi, T. AU - MacDonald, A. H. AU - Young, A. F. ID - 10618 IS - 7836 JF - Nature KW - multidisciplinary SN - 0028-0836 TI - Electrical switching of magnetic order in an orbital Chern insulator VL - 588 ER - TY - GEN AB - The understanding of material systems with strong electron-electron interactions is the central problem in modern condensed matter physics. Despite this, the essential physics of many of these materials is still not understood and we have no overall perspective on their properties. Moreover, we have very little ability to make predictions in this class of systems. In this manuscript we share our personal views of what the major open problems are in correlated electron systems and we discuss some possible routes to make progress in this rich and fascinating field. This manuscript is the result of the vigorous discussions and deliberations that took place at Johns Hopkins University during a three-day workshop January 27, 28, and 29, 2020 that brought together six senior scientists and 46 more junior scientists. Our hope, is that the topics we have presented will provide inspiration for others working in this field and motivation for the idea that significant progress can be made on very hard problems if we focus our collective energies. AU - Alexandradinata, A AU - Armitage, N.P. AU - Baydin, Andrey AU - Bi, Wenli AU - Cao, Yue AU - Changlani, Hitesh J. AU - Chertkov, Eli AU - da Silva Neto, Eduardo H. AU - Delacretaz, Luca AU - El Baggari, Ismail AU - Ferguson, G.M. AU - Gannon, William J. AU - Ghorashi, Sayed Ali Akbar AU - Goodge, Berit H. AU - Goulko, Olga AU - Grissonnache, G. AU - Hallas, Alannah AU - Hayes, Ian M. AU - He, Yu AU - Huang, Edwin W. AU - Kogar, Anshu AU - Kumah, Divine AU - Lee, Jong Yeon AU - Legros, A. AU - Mahmood, Fahad AU - Maximenko, Yulia AU - Pellatz, Nick AU - Polshyn, Hryhoriy AU - Sarkar, Tarapada AU - Scheie, Allen AU - Seyler, Kyle L. AU - Shi, Zhenzhong AU - Skinner, Brian AU - Steinke, Lucia AU - Thirunavukkuarasu, K. AU - Trevisan, Thaís Victa AU - Vogl, Michael AU - Volkov, Pavel A. AU - Wang, Yao AU - Wang, Yishu AU - Wei, Di AU - Wei, Kaya AU - Yang, Shuolong AU - Zhang, Xian AU - Zhang, Ya-Hui AU - Zhao, Liuyan AU - Zong, Alfred ID - 10650 T2 - arXiv TI - The future of the correlated electron problem ER - TY - CONF AB - We propose a neural information processing system obtained by re-purposing the function of a biological neural circuit model to govern simulated and real-world control tasks. Inspired by the structure of the nervous system of the soil-worm, C. elegans, we introduce ordinary neural circuits (ONCs), defined as the model of biological neural circuits reparameterized for the control of alternative tasks. We first demonstrate that ONCs realize networks with higher maximum flow compared to arbitrary wired networks. We then learn instances of ONCs to control a series of robotic tasks, including the autonomous parking of a real-world rover robot. For reconfiguration of the purpose of the neural circuit, we adopt a search-based optimization algorithm. Ordinary neural circuits perform on par and, in some cases, significantly surpass the performance of contemporary deep learning models. ONC networks are compact, 77% sparser than their counterpart neural controllers, and their neural dynamics are fully interpretable at the cell-level. AU - Hasani, Ramin AU - Lechner, Mathias AU - Amini, Alexander AU - Rus, Daniela AU - Grosu, Radu ID - 10673 SN - 2640-3498 T2 - Proceedings of the 37th International Conference on Machine Learning TI - A natural lottery ticket winner: Reinforcement learning with ordinary neural circuits ER - TY - CONF AB - High quality graphene heterostructures host an array of fractional quantum Hall isospin ferromagnets with diverse spin and valley orders. While a variety of phase transitions have been observed, disentangling the isospin phase diagram of these states is hampered by the absence of direct probes of spin and valley order. I will describe nonlocal transport measurements based on launching spin waves from a gate defined lateral heterojunction, performed in ultra-clean Corbino geometry graphene devices. At high magnetic fields, we find that the spin-wave transport signal is detected in all FQH states between ν = 0 and 1; however, between ν = 1 and 2 only odd numerator FQH states show finite nonlocal transport, despite the identical ground state spin polarizations in odd- and even numerator states. The results reveal that the neutral spin-waves are both spin and sublattice polarized making them a sensitive probe of ground state sublattice structure. Armed with this understanding, we use nonlocal transport signal to a magnetic field tuned isospin phase transition, showing that the emergent even denominator state at ν = 1/2 in monolayer graphene is indeed a multicomponent state featuring equal populations on each sublattice. AU - Zhou, Haoxin AU - Polshyn, Hryhoriy AU - Tanaguchi, Takashi AU - Watanabe, Kenji AU - Young, Andrea ID - 10693 IS - 1 SN - 0003-0503 T2 - APS March Meeting 2020 TI - Sublattice resolved spin wave transport through graphene fractional quantum Hall states as a probe of isospin order VL - 65 ER - TY - CONF AB - This is the second of three talks describing the observation and characterization of a ferromagnetic moiré heterostructure based on twisted bilayer graphene aligned to hexagonal boron nitride. I will compare the qualitative and quantitative features of this observed quantum anomalous Hall state to traditional systems engineered from thin film (Bi,Sb)2Te3 topological insulators. In particular, we find that the measured electronic energy gap of ~30K is several times higher than the Curie temperature, consistent with a lack of disorder associated with magnetic dopants. In this system, the quantization arises from spontaneous ferromagnetic polarization into a single spin and valley moiré subband, which is topological despite the lack of spin orbit coupling. I will also discuss the observation of current induced switching, which allows the magnetic state of the heterostructure to be controllably reversed with currents as small as a few nanoamperes. AU - Serlin, Marec AU - Tschirhart, Charles AU - Polshyn, Hryhoriy AU - Zhang, Yuxuan AU - Zhu, Jiacheng AU - Huber, Martin E. AU - Balents, Leon AU - Watanabe, Kenji AU - Tanaguchi, Takashi AU - Young, Andrea ID - 10698 IS - 1 T2 - APS March Meeting 2020 TI - Intrinsic quantized anomalous Hall effect in a moiré heterostructure, part II: Temperature dependence and current switching VL - 65 ER - TY - CONF AB - This is the third of three talks describing the observation and characterization of a ferromagnetic moiré heterostructure based on twisted bilayer graphene aligned to hexagonal boron nitride. In this segment I will present scanning probe magnetometry data acquired using a nanoSQUID-on-tip microscope, which provides ~150 nm spatial resolution and a field sensitivity of ~10 nT/rtHz. We study the distribution of magnetic domains within the device as a function of density, magnetic field training, and DC current. Our data allow us to constrain the magnitude of the orbital magnetic moment of the electrons in the QAH state. Comparison with simultaneously acquired transport data allows us to precisely correlate single domain dynamics with discrete jumps in the observed anomalous Hall signal. AU - Tschirhart, Charles AU - Serlin, Marec AU - Polshyn, Hryhoriy AU - Zhang, Yuxuan AU - Zhu, Jiacheng AU - Balents, Leon AU - Huber, Martin E. AU - Watanabe, Kenji AU - Tanaguchi, Takashi AU - Young, Andrea ID - 10699 IS - 1 SN - 0003-0503 T2 - APS March Meeting 2020 TI - Intrinsic quantized anomalous Hall effect in a moiré heterostructure, part III: Scanning probe magnetometry VL - 65 ER - TY - CONF AB - We report the observation of a quantized anomalous Hall effect in a moiré heterostructure consisting of twisted bilayer graphene aligned to an encapsulating hBN substrate. The effect occurs at a density of 3 electrons per superlattice unit cell, where we observe magnetic hysteresis and a Hall resistance quantized to within 0.1% of the resistance quantum at temperatures as high as 3K. In this first of 3 talks, I will describe the fabrication procedure for our device as well as basic transport characterization measurements. I will introduce the phenomenology of twisted bilayer graphene and present evidence for hBN alignment as manifested in the hierarchy of symmetry-breaking gaps and anomalous magnetoresistance. AU - Zhang, Yuxuan AU - Serlin, Marec AU - Tschirhart, Charles AU - Polshyn, Hryhoriy AU - Zhu, Jiacheng AU - Balents, Leon AU - Huber, Martin E. AU - Taniguchi, Takashi AU - Watanabe, Kenji AU - Young, Andrea ID - 10697 IS - 1 T2 - APS March Meeting 2020 TI - Intrinsic quantized anomalous Hall effect in a moiré heterostructure, part I: Device fabrication and transport VL - 65 ER - TY - CONF AB - We experimentally investigate twisted van der Waals heterostructures of monolayer graphene rotated with respect to a bernal stacked graphene bilayer. We report transport measurements for devices with twist angles between 0.9 and 1.4°. The electric field allows efficient tuning of the width, isolation and the topology of the moiré bands in this system. By comparing magnetoresistance measurements to numerical simulations, we develop an understanding of the band structure. Finally, we observe correlated states at half- and quarter-fillings, which arise when narrow moire sublattice band is isolated by energy gaps from dispersive bands. We investigate the effects of in-plane and out-of-plane magnetic field on these states and discuss the implication for their spin- and valley- polarization. AU - Polshyn, Hryhoriy AU - Zhu, Jihang AU - Kumar, Manish AU - Taniguchi, Takashi AU - Watanabe, Kenji AU - MacDonald, Allan AU - Young, Andrea ID - 10696 IS - 1 SN - 0003-0503 T2 - APS March Meeting 2020 TI - Correlated states and tunable topological bands in twisted monolayer-bilayer graphene heterostructures VL - 65 ER - TY - JOUR AB - Partially filled Landau levels host competing electronic orders. For example, electron solids may prevail close to integer filling of the Landau levels before giving way to fractional quantum Hall liquids at higher carrier density1,2. Here, we report the observation of an electron solid with non-collinear spin texture in monolayer graphene, consistent with solidification of skyrmions3—topological spin textures characterized by quantized electrical charge4,5. We probe the spin texture of the solids using a modified Corbino geometry that allows ferromagnetic magnons to be launched and detected6,7. We find that magnon transport is highly efficient when one Landau level is filled (ν=1), consistent with quantum Hall ferromagnetic spin polarization. However, even minimal doping immediately quenches the magnon signal while leaving the vanishing low-temperature charge conductivity unchanged. Our results can be understood by the formation of a solid of charged skyrmions near ν=1, whose non-collinear spin texture leads to rapid magnon decay. Data near fractional fillings show evidence of several fractional skyrmion solids, suggesting that graphene hosts a highly tunable landscape of coupled spin and charge orders. AU - Zhou, Haoxin AU - Polshyn, Hryhoriy AU - Taniguchi, Takashi AU - Watanabe, Kenji AU - Young, Andrea F. ID - 10701 IS - 2 JF - Nature Physics SN - 1745-2473 TI - Skyrmion solids in monolayer graphene VL - 16 ER - TY - JOUR AB - Aging of the circulatory system correlates with the pathogenesis of a large spectrum of diseases. However, it is largely unknown which factors drive the age-dependent or pathological decline of the vasculature and how vascular defects relate to tissue aging. The goal of the study is to design a multianalytical approach to identify how the cellular microenvironment (i.e., fibroblasts) and serum from healthy donors of different ages or Alzheimer disease (AD) patients can modulate the functionality of organ-specific vascular endothelial cells (VECs). Long-living human microvascular networks embedding VECs and fibroblasts from skin biopsies are generated. RNA-seq, secretome analyses, and microfluidic assays demonstrate that fibroblasts from young donors restore the functionality of aged endothelial cells, an effect also achieved by serum from young donors. New biomarkers of vascular aging are validated in human biopsies and it is shown that young serum induces angiopoietin-like-4, which can restore compromised vascular barriers. This strategy is then employed to characterize transcriptional/functional changes induced on the blood–brain barrier by AD serum, demonstrating the importance of PTP4A3 in the regulation of permeability. Features of vascular degeneration during aging and AD are recapitulated, and a tool to identify novel biomarkers that can be exploited to develop future therapeutics modulating vascular function is established. AU - Bersini, Simone AU - Arrojo e Drigo, Rafael AU - Huang, Ling AU - Shokhirev, Maxim N. AU - HETZER, Martin W ID - 11056 IS - 5 JF - Advanced Biosystems KW - General Biochemistry KW - Genetics and Molecular Biology KW - Biomedical Engineering KW - Biomaterials SN - 2366-7478 TI - Transcriptional and functional changes of the human microvasculature during physiological aging and Alzheimer disease VL - 4 ER - TY - JOUR AB - Vascular dysfunctions are a common feature of multiple age-related diseases. However, modeling healthy and pathological aging of the human vasculature represents an unresolved experimental challenge. Here, we generated induced vascular endothelial cells (iVECs) and smooth muscle cells (iSMCs) by direct reprogramming of healthy human fibroblasts from donors of different ages and Hutchinson-Gilford Progeria Syndrome (HGPS) patients. iVECs induced from old donors revealed upregulation of GSTM1 and PALD1, genes linked to oxidative stress, inflammation and endothelial junction stability, as vascular aging markers. A functional assay performed on PALD1 KD VECs demonstrated a recovery in vascular permeability. We found that iSMCs from HGPS donors overexpressed bone morphogenetic protein (BMP)−4, which plays a key role in both vascular calcification and endothelial barrier damage observed in HGPS. Strikingly, BMP4 concentrations are higher in serum from HGPS vs. age-matched mice. Furthermore, targeting BMP4 with blocking antibody recovered the functionality of the vascular barrier in vitro, hence representing a potential future therapeutic strategy to limit cardiovascular dysfunction in HGPS. These results show that iVECs and iSMCs retain disease-related signatures, allowing modeling of vascular aging and HGPS in vitro. AU - Bersini, Simone AU - Schulte, Roberta AU - Huang, Ling AU - Tsai, Hannah AU - HETZER, Martin W ID - 11055 JF - eLife KW - General Immunology and Microbiology KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Medicine KW - General Neuroscience SN - 2050-084X TI - Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome VL - 9 ER - TY - JOUR AB - In recent years, the nuclear pore complex (NPC) has emerged as a key player in genome regulation and cellular homeostasis. New discoveries have revealed that the NPC has multiple cellular functions besides mediating the molecular exchange between the nucleus and the cytoplasm. In this review, we discuss non-transport aspects of the NPC focusing on the NPC-genome interaction, the extreme longevity of the NPC proteins, and NPC dysfunction in age-related diseases. The examples summarized herein demonstrate that the NPC, which first evolved to enable the biochemical communication between the nucleus and the cytoplasm, now doubles as the gatekeeper of cellular identity and aging. AU - Cho, Ukrae H. AU - HETZER, Martin W ID - 11054 IS - 6 JF - Neuron KW - General Neuroscience SN - 0896-6273 TI - Nuclear periphery takes center stage: The role of nuclear pore complexes in cell identity and aging VL - 106 ER - TY - JOUR AB - During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications. Combined with EU-RNA-seq and Hi-C analyses, we found that during prometaphase, promoters, enhancers, and insulators retain H3K4me3 and H3K4me1, while losing H3K27ac. Enhancers globally retaining mitotic H3K4me1 or locally retaining mitotic H3K27ac are associated with cell type-specific genes and their transcription factors for rapid transcriptional activation. As cells exit mitosis, promoters regain H3K27ac, which correlates with transcriptional reactivation. Insulators also gain H3K27ac and CCCTC-binding factor (CTCF) in anaphase/telophase. This increase of H3K27ac in anaphase/telophase is required for posttranscriptional activation and may play a role in the establishment of topologically associating domains (TADs). Together, our results suggest that the genome is reorganized in a sequential order, in which histone methylations occur first in prometaphase, histone acetylation, and CTCF in anaphase/telophase, transcription in cytokinesis, and long-range chromatin interactions in early G1. We thus provide insights into the histone modification landscape that allows faithful reestablishment of the transcriptional program and TADs during cell division. AU - Kang, Hyeseon AU - Shokhirev, Maxim N. AU - Xu, Zhichao AU - Chandran, Sahaana AU - Dixon, Jesse R. AU - HETZER, Martin W ID - 11057 IS - 13-14 JF - Genes & Development KW - Developmental Biology KW - Genetics SN - 0890-9369 TI - Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation VL - 34 ER - TY - JOUR AB - Nucleoporin 93 (Nup93) expression inversely correlates with the survival of triple-negative breast cancer patients. However, our knowledge of Nup93 function in breast cancer besides its role as structural component of the nuclear pore complex is not understood. Combination of functional assays and genetic analyses suggested that chromatin interaction of Nup93 partially modulates the expression of genes associated with actin cytoskeleton remodeling and epithelial to mesenchymal transition, resulting in impaired invasion of triple-negative, claudin-low breast cancer cells. Nup93 depletion induced stress fiber formation associated with reduced cell migration/proliferation and impaired expression of mesenchymal-like genes. Silencing LIMCH1, a gene responsible for actin cytoskeleton remodeling and up-regulated upon Nup93 depletion, partially restored the invasive phenotype of cancer cells. Loss of Nup93 led to significant defects in tumor establishment/propagation in vivo, whereas patient samples revealed that high Nup93 and low LIMCH1 expression correlate with late tumor stage. Our approach identified Nup93 as contributor of triple-negative, claudin-low breast cancer cell invasion and paves the way to study the role of nuclear envelope proteins during breast cancer tumorigenesis. AU - Bersini, Simone AU - Lytle, Nikki K AU - Schulte, Roberta AU - Huang, Ling AU - Wahl, Geoffrey M AU - HETZER, Martin W ID - 11058 IS - 1 JF - Life Science Alliance KW - Health KW - Toxicology and Mutagenesis KW - Plant Science KW - Biochemistry KW - Genetics and Molecular Biology (miscellaneous) KW - Ecology SN - 2575-1077 TI - Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling VL - 3 ER - TY - JOUR AB - Context. The Lyα emitter (LAE) fraction, XLAE, is a potentially powerful probe of the evolution of the intergalactic neutral hydrogen gas fraction. However, uncertainties in the measurement of XLAE are still under debate. Aims. Thanks to deep data obtained with the integral field spectrograph Multi Unit Spectroscopic Explorer (MUSE), we can measure the evolution of the LAE fraction homogeneously over a wide redshift range of z ≈ 3–6 for UV-faint galaxies (down to UV magnitudes of M1500 ≈ −17.75). This is a significantly fainter range than in former studies (M1500 ≤ −18.75) and it allows us to probe the bulk of the population of high-redshift star-forming galaxies. Methods. We constructed a UV-complete photometric-redshift sample following UV luminosity functions and measured the Lyα emission with MUSE using the latest (second) data release from the MUSE Hubble Ultra Deep Field Survey. Results. We derived the redshift evolution of XLAE for M1500 ∈ [ − 21.75; −17.75] for the first time with a equivalent width range EW(Lyα) ≥ 65 Å and found low values of XLAE ≲ 30% at z ≲ 6. The best-fit linear relation is XLAE = 0.07+0.06−0.03z − 0.22+0.12−0.24. For M1500 ∈ [ − 20.25; −18.75] and EW(Lyα) ≥ 25 Å, our XLAE values are consistent with those in the literature within 1σ at z ≲ 5, but our median values are systematically lower than reported values over the whole redshift range. In addition, we do not find a significant dependence of XLAE on M1500 for EW(Lyα) ≥ 50 Å at z ≈ 3–4, in contrast with previous work. The differences in XLAE mainly arise from selection biases for Lyman Break Galaxies (LBGs) in the literature: UV-faint LBGs are more easily selected if they have strong Lyα emission, hence XLAE is biased towards higher values when those samples are used. Conclusions. Our results suggest either a lower increase of XLAE towards z ≈ 6 than previously suggested, or even a turnover of XLAE at z ≈ 5.5, which may be the signature of a late or patchy reionization process. We compared our results with predictions from a cosmological galaxy evolution model. We find that a model with a bursty star formation (SF) can reproduce our observed LAE fractions much better than models where SF is a smooth function of time. AU - Kusakabe, Haruka AU - Blaizot, Jérémy AU - Garel, Thibault AU - Verhamme, Anne AU - Bacon, Roland AU - Richard, Johan AU - Hashimoto, Takuya AU - Inami, Hanae AU - Conseil, Simon AU - Guiderdoni, Bruno AU - Drake, Alyssa B. AU - Christian Herenz, Edmund AU - Schaye, Joop AU - Oesch, Pascal AU - Matthee, Jorryt J AU - Anna Marino, Raffaella AU - Borello Schmidt, Kasper AU - Pelló, Roser AU - Maseda, Michael AU - Leclercq, Floriane AU - Kerutt, Josephine AU - Mahler, Guillaume ID - 11503 JF - Astronomy & Astrophysics KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - dark ages / reionization / first stars / early Universe / cosmology: observations / galaxies: evolution / galaxies: high-redshift / intergalactic medium SN - 0004-6361 TI - The MUSE Hubble Ultra Deep Field Survey: XIV. Evolution of the Lyα emitter fraction from z = 3 to z = 6 VL - 638 ER - TY - JOUR AB - We present spatially resolved maps of six individually-detected Lyman α haloes (LAHs) as well as a first statistical analysis of the Lyman α (Lyα) spectral signature in the circum-galactic medium of high-redshift star-forming galaxies (−17.5 >  MUV >  −21.5) using the Multi-Unit Spectroscopic Explorer. Our resolved spectroscopic analysis of the LAHs reveals significant intrahalo variations of the Lyα line profile. Using a three-dimensional two-component model for the Lyα emission, we measured the full width at half maximum (FWHM), the peak velocity shift, and the asymmetry of the Lyα line in the core and in the halo of 19 galaxies. We find that the Lyα line shape is statistically different in the halo compared to the core (in terms of width, peak wavelength, and asymmetry) for ≈40% of our galaxies. Similarly to object-by-object based studies and a recent resolved study using lensing, we find a correlation between the peak velocity shift and the width of the Lyα line both at the interstellar and circum-galactic scales. This trend has been predicted by radiative transfer simulations of galactic winds as a result of resonant scattering in outflows. While there is a lack of correlation between the spectral properties and the spatial scale lengths of our LAHs, we find a correlation between the width of the line in the LAH and the halo flux fraction. Interestingly, UV bright galaxies (MUV <  −20) show broader, more redshifted, and less asymmetric Lyα lines in their haloes. The most significant correlation found is for the FWHM of the line and the UV continuum slope of the galaxy, suggesting that the redder galaxies have broader Lyα lines. The generally broad and red line shapes found in the halo component suggest that the Lyα haloes are powered either by scattering processes through an outflowing medium, fluorescent emission from outflowing cold clumps of gas, or a mix of both. Considering the large diversity of the Lyα line profiles observed in our sample and the lack of strong correlation, the interpretation of our results is still broadly open and underlines the need for realistic spatially resolved models of the LAHs. AU - Leclercq, Floriane AU - Bacon, Roland AU - Verhamme, Anne AU - Garel, Thibault AU - Blaizot, Jérémy AU - Brinchmann, Jarle AU - Cantalupo, Sebastiano AU - Claeyssens, Adélaïde AU - Conseil, Simon AU - Contini, Thierry AU - Hashimoto, Takuya AU - Herenz, Edmund Christian AU - Kusakabe, Haruka AU - Marino, Raffaella Anna AU - Maseda, Michael AU - Matthee, Jorryt J AU - Mitchell, Peter AU - Pezzulli, Gabriele AU - Richard, Johan AU - Schmidt, Kasper Borello AU - Wisotzki, Lutz ID - 11504 JF - Astronomy & Astrophysics KW - Space and Planetary Science KW - Astronomy and Astrophysics galaxies: high-redshift / galaxies: formation / galaxies: evolution / cosmology: observations SN - 0004-6361 TI - The MUSE Hubble Ultra Deep field survey: XIII. Spatially resolved spectral properties of Lyman α haloes around star-forming galaxies at z > 3 VL - 635 ER - TY - JOUR AB - We investigated the ultraviolet (UV) spectral properties of faint Lyman-α emitters (LAEs) in the redshift range 2.9 ≤ z ≤ 4.6, and we provide material to prepare future observations of the faint Universe. We used data from the MUSE Hubble Ultra Deep Survey to construct mean rest-frame spectra of continuum-faint (median MUV of −18 and down to MUV of −16), low stellar mass (median value of 108.4 M⊙ and down to 107 M⊙) LAEs at redshift z ≳ 3. We computed various averaged spectra of LAEs, subsampled on the basis of their observational (e.g., Lyα strength, UV magnitude and spectral slope) and physical (e.g., stellar mass and star-formation rate) properties. We searched for UV spectral features other than Lyα, such as higher ionization nebular emission lines and absorption features. We successfully observed the O III]λ1666 and [C III]λ1907+C III]λ1909 collisionally excited emission lines and the He IIλ1640 recombination feature, as well as the resonant C IVλλ1548,1551 doublet either in emission or P-Cygni. We compared the observed spectral properties of the different mean spectra and find the emission lines to vary with the observational and physical properties of the LAEs. In particular, the mean spectra of LAEs with larger Lyα equivalent widths, fainter UV magnitudes, bluer UV spectral slopes, and lower stellar masses show the strongest nebular emission. The line ratios of these lines are similar to those measured in the spectra of local metal-poor galaxies, while their equivalent widths are weaker compared to the handful of extreme values detected in individual spectra of z >  2 galaxies. This suggests that weak UV features are likely ubiquitous in high z, low-mass, and faint LAEs. We publicly released the stacked spectra, as they can serve as empirical templates for the design of future observations, such as those with the James Webb Space Telescope and the Extremely Large Telescope. AU - Feltre, Anna AU - Maseda, Michael V. AU - Bacon, Roland AU - Pradeep, Jayadev AU - Leclercq, Floriane AU - Kusakabe, Haruka AU - Wisotzki, Lutz AU - Hashimoto, Takuya AU - Schmidt, Kasper B. AU - Blaizot, Jeremy AU - Brinchmann, Jarle AU - Boogaard, Leindert AU - Cantalupo, Sebastiano AU - Carton, David AU - Inami, Hanae AU - Kollatschny, Wolfram AU - Marino, Raffaella A. AU - Matthee, Jorryt J AU - Nanayakkara, Themiya AU - Richard, Johan AU - Schaye, Joop AU - Tresse, Laurence AU - Urrutia, Tanya AU - Verhamme, Anne AU - Weilbacher, Peter M. ID - 11501 JF - Astronomy & Astrophysics KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution / galaxies: high-redshift / ISM: lines and bands / ultraviolet: ISM / ultraviolet: galaxies SN - 0004-6361 TI - The MUSE Hubble Ultra Deep Field Survey: XV. The mean rest-UV spectra of Lyα emitters at z > 3 VL - 641 ER - TY - JOUR AB - We report the spectroscopic confirmation of a new protocluster in the COSMOS field at z ∼ 2.2, COSMOS Cluster 2.2 (CC2.2), originally identified as an overdensity of narrowband selected Hα emitting candidates. With only two masks of Keck/MOSFIRE near-IR spectroscopy in both H (∼1.47–1.81 μm) and K (∼1.92–2.40 μm) bands (∼1.5 hr each), we confirm 35 unique protocluster members with at least two emission lines detected with S/N > 3. Combined with 12 extra members from the zCOSMOS-deep spectroscopic survey (47 in total), we estimate a mean redshift and a line-of-sight velocity dispersion of zmean = 2.23224 ± 0.00101 and σlos = 645 ± 69 km s−1 for this protocluster, respectively. Assuming virialization and spherical symmetry for the system, we estimate a total mass of Mvir ∼ (1–2) ×1014M⊙ for the structure. We evaluate a number density enhancement of δg ∼ 7 for this system and we argue that the structure is likely not fully virialized at z ∼ 2.2. However, in a spherical collapse model, δg is expected to grow to a linear matter enhancement of ∼1.9 by z = 0, exceeding the collapse threshold of 1.69, and leading to a fully collapsed and virialized Coma-type structure with a total mass of Mdyn(z = 0) ∼ 9.2 × 1014M⊙ by now. This observationally efficient confirmation suggests that large narrowband emission-line galaxy surveys, when combined with ancillary photometric data, can be used to effectively trace the large-scale structure and protoclusters at a time when they are mostly dominated by star-forming galaxies. AU - Darvish, Behnam AU - Scoville, Nick Z. AU - Martin, Christopher AU - Sobral, David AU - Mobasher, Bahram AU - Rettura, Alessandro AU - Matthee, Jorryt J AU - Capak, Peter AU - Chartab, Nima AU - Hemmati, Shoubaneh AU - Masters, Daniel AU - Nayyeri, Hooshang AU - O’Sullivan, Donal AU - Paulino-Afonso, Ana AU - Sattari, Zahra AU - Shahidi, Abtin AU - Salvato, Mara AU - Lemaux, Brian C. AU - Fèvre, Olivier Le AU - Cucciati, Olga ID - 11513 IS - 1 JF - The Astrophysical Journal KW - Space and Planetary Science KW - Astronomy and Astrophysics SN - 0004-637X TI - Spectroscopic confirmation of a coma cluster progenitor at z ∼ 2.2 VL - 892 ER - TY - JOUR AB - Ly α emission lines are typically found to be redshifted with respect to the systemic redshifts of galaxies, likely due to resonant scattering of Ly α photons. Here, we measure the average velocity offset for a sample of 96 z ≈ 3.3 Ly α emitters (LAEs) with a median Ly α flux (luminosity) of ≈10−17 erg cm−2 s−1 (⁠≈1042 erg s−1⁠) and a median star formation rate (SFR) of ≈1.3 M⊙ yr−1 (not corrected for possible dust extinction), detected by the Multi-Unit Spectroscopic Explorer as part of our MUSEQuBES circumgalactic medium (CGM) survey. By postulating that the stacked CGM absorption profiles of these LAEs, probed by eight background quasars, must be centred on the systemic redshift, we measure an average velocity offset, Voffset = 171\pm 8 km s−1, between the Ly α emission peak and the systemic redshift. The observed Voffset is lower by factors of ≈1.4 and ≈2.6 compared to the velocity offsets measured for narrow-band-selected LAEs and Lyman break galaxies, respectively, which probe galaxies with higher masses and SFRs. Consistent with earlier studies based on direct measurements for individual objects, we find that the Voffset is correlated with the full width at half-maximum of the red peak of the Ly α line, and anticorrelated with the rest-frame equivalent width. Moreover, we find that Voffset is correlated with SFR with a sub-linear scaling relation, Voffset∝SFR0.16±0.03⁠. Adopting the mass scaling for main-sequence galaxies, such a relation suggests that Voffset scales with the circular velocity of the dark matter haloes hosting the LAEs. AU - Muzahid, Sowgat AU - Schaye, Joop AU - Marino, Raffaella Anna AU - Cantalupo, Sebastiano AU - Brinchmann, Jarle AU - Contini, Thierry AU - Wendt, Martin AU - Wisotzki, Lutz AU - Zabl, Johannes AU - Bouché, Nicolas AU - Akhlaghi, Mohammad AU - Chen, Hsiao-Wen AU - Claeyssens, Adélaîde AU - Johnson, Sean AU - Leclercq, Floriane AU - Maseda, Michael AU - Matthee, Jorryt J AU - Richard, Johan AU - Urrutia, Tanya AU - Verhamme, Anne ID - 11528 IS - 2 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: haloes KW - galaxies: high-redshift KW - quasars: absorption lines SN - 0035-8711 TI - MUSEQuBES: Calibrating the redshifts of Lyα emitters using stacked circumgalactic medium absorption profiles VL - 496 ER - TY - JOUR AB - CR7 is among the most luminous Ly α emitters (LAEs) known at z = 6.6 and consists of at least three UV components that are surrounded by Ly α emission. Previous studies have suggested that it may host an extreme ionizing source. Here, we present deep integral field spectroscopy of CR7 with VLT/Multi Unit Spectroscopic Explorer (MUSE). We measure extended emission with a similar halo scale length as typical LAEs at z ≈ 5. CR7’s Ly α halo is clearly elongated along the direction connecting the multiple components, likely tracing the underlying gas distribution. The Ly α emission originates almost exclusively from the brightest UV component, but we also identify a faint kinematically distinct Ly α emitting region nearby a fainter component. Combined with new near-infrared data, the MUSE data show that the rest-frame Ly α equivalent width (EW) is ≈100 Å. This is a factor 4 higher than the EW measured in low-redshift analogues with carefully matched Ly α profiles (and thus arguably H I column density), but this EW can plausibly be explained by star formation. Alternative scenarios requiring active galactic nucleus (AGN) powering are also disfavoured by the narrower and steeper Ly α spectrum and much smaller IR to UV ratio compared to obscured AGN in other Ly α blobs. CR7’s Ly α emission, while extremely luminous, resembles the emission in more common LAEs at lower redshifts very well and is likely powered by a young metal-poor starburst. AU - Matthee, Jorryt J AU - Pezzulli, Gabriele AU - Mackenzie, Ruari AU - Cantalupo, Sebastiano AU - Kusakabe, Haruka AU - Leclercq, Floriane AU - Sobral, David AU - Richard, Johan AU - Wisotzki, Lutz AU - Lilly, Simon AU - Boogaard, Leindert AU - Marino, Raffaella AU - Maseda, Michael AU - Nanayakkara, Themiya ID - 11529 IS - 2 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: high-redshift KW - dark ages KW - reionization KW - first stars KW - cosmology: observations SN - 0035-8711 TI - The nature of CR7 revealed with MUSE: A young starburst powering extended Ly α emission at z = 6.6 VL - 498 ER - TY - JOUR AB - We explore deep rest-frame UV to FIR data in the COSMOS field to measure the individual spectral energy distributions (SED) of the ∼4000 SC4K (Sobral et al.) Lyman α (Ly α) emitters (LAEs) at z ∼ 2–6. We find typical stellar masses of 109.3 ± 0.6 M⊙ and star formation rates (SFR) of SFRSED=4.4+10.5−2.4 M⊙ yr−1 and SFRLyα=5.9+6.3−2.6 M⊙ yr−1, combined with very blue UV slopes of β=−2.1+0.5−0.4⁠, but with significant variations within the population. MUV and β are correlated in a similar way to UV-selected sources, but LAEs are consistently bluer. This suggests that LAEs are the youngest and/or most dust-poor subset of the UV-selected population. We also study the Ly α rest-frame equivalent width (EW0) and find 45 ‘extreme’ LAEs with EW0 > 240 Å (3σ), implying a low number density of (7 ± 1) × 10−7 Mpc−3. Overall, we measure little to no evolution of the Ly α EW0 and scale length parameter (w0), which are consistently high (EW0=140+280−70 Å, w0=129+11−11 Å) from z ∼ 6 to z ∼ 2 and below. However, w0 is anticorrelated with MUV and stellar mass. Our results imply that sources selected as LAEs have a high Ly α escape fraction (fesc,Ly α) irrespective of cosmic time, but fesc,Ly α is still higher for UV-fainter and lower mass LAEs. The least massive LAEs (<109.5 M⊙) are typically located above the star formation ‘main sequence’ (MS), but the offset from the MS decreases towards z ∼ 6 and towards 1010 M⊙. Our results imply a lack of evolution in the properties of LAEs across time and reveals the increasing overlap in properties of LAEs and UV-continuum selected galaxies as typical star-forming galaxies at high redshift effectively become LAEs. AU - Santos, S AU - Sobral, D AU - Matthee, Jorryt J AU - Calhau, J AU - da Cunha, E AU - Ribeiro, B AU - Paulino-Afonso, A AU - Arrabal Haro, P AU - Butterworth, J ID - 11533 IS - 1 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: formation KW - galaxies: high-redshift KW - galaxies: star formation SN - 0035-8711 TI - The evolution of rest-frame UV properties, Ly α EWs, and the SFR–stellar mass relation at z ∼ 2–6 for SC4K LAEs VL - 493 ER - TY - JOUR AB - The observed properties of the Lyman-α (Ly α) emission line are a powerful probe of neutral gas in and around galaxies. We present spatially resolved Ly α spectroscopy with VLT/MUSE targeting VR7, a UV-luminous galaxy at z = 6.532 with moderate Ly α equivalent width (EW0 ≈ 38 Å). These data are combined with deep resolved [CII]158μm spectroscopy obtained with ALMA and UV imaging from HST and we also detect UV continuum with MUSE. Ly α emission is clearly detected with S/N ≈ 40 and FWHM of 374 km s−1. Ly α and [C II] are similarly extended beyond the UV, with effective radius reff = 2.1 ± 0.2 kpc for a single exponential model or reff,Lyα,halo=3.45+1.08−0.87 kpc when measured jointly with the UV continuum. The Ly α profile is broader and redshifted with respect to the [C II] line (by 213 km s−1), but there are spatial variations that are qualitatively similar in both lines and coincide with resolved UV components. This suggests that the emission originates from two components with plausibly different H I column densities. We place VR7 in the context of other galaxies at similar and lower redshift. The Ly α halo scale length is similar at different redshifts and velocity shifts with respect to the systemic are typically smaller. Overall, we find little indications of a more neutral vicinity at higher redshift. This means that the local (∼10 kpc) neutral gas conditions that determine the observed Ly α properties in VR7 resemble the conditions in post-reionization galaxies. AU - Matthee, Jorryt J AU - Sobral, David AU - Gronke, Max AU - Pezzulli, Gabriele AU - Cantalupo, Sebastiano AU - Röttgering, Huub AU - Darvish, Behnam AU - Santos, Sérgio ID - 11534 IS - 2 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: high-redshift KW - dark ages KW - reionization KW - first stars KW - cosmology: observations SN - 0035-8711 TI - Resolved Lyman-α properties of a luminous Lyman-break galaxy in a large ionized bubble at z = 6.53 VL - 492 ER - TY - JOUR AB - While low-luminosity galaxies dominate number counts at all redshifts, their contribution to cosmic reionization is poorly understood due to a lack of knowledge of their physical properties. We isolate a sample of 35 z ≈ 4–5 continuum-faint Lyman-α emitters from deep VLT/MUSE spectroscopy and directly measure their H α emission using stacked Spitzer/IRAC Ch. 1 photometry. Based on Hubble Space Telescope imaging, we determine that the average UV continuum magnitude is fainter than −16 (≈ 0.01 L⋆), implying a median Lyman-α equivalent width of 259 Å. By combining the H α measurement with the UV magnitude, we determine the ionizing photon production efficiency, ξion, a first for such faint galaxies. The measurement of log10 (ξion [Hz erg−1]) = 26.28 (⁠+0.28−0.40⁠) is in excess of literature measurements of both continuum- and emission line-selected samples, implying a more efficient production of ionizing photons in these lower luminosity, Lyman-α-selected systems. We conclude that this elevated efficiency can be explained by stellar populations with metallicities between 4 × 10−4 and 0.008, with light-weighted ages less than 3 Myr. AU - Maseda, Michael V AU - Bacon, Roland AU - Lam, Daniel AU - Matthee, Jorryt J AU - Brinchmann, Jarle AU - Schaye, Joop AU - Labbe, Ivo AU - Schmidt, Kasper B AU - Boogaard, Leindert AU - Bouwens, Rychard AU - Cantalupo, Sebastiano AU - Franx, Marijn AU - Hashimoto, Takuya AU - Inami, Hanae AU - Kusakabe, Haruka AU - Mahler, Guillaume AU - Nanayakkara, Themiya AU - Richard, Johan AU - Wisotzki, Lutz ID - 11531 IS - 4 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - Galaxies: evolution KW - Galaxies: high-redshift KW - Galaxies: ISM SN - 0035-8711 TI - Elevated ionizing photon production efficiency in faint high-equivalent-width Lyman-α emitters VL - 493 ER - TY - JOUR AB - A prediction of the classic active galactic nucleus (AGN) unification model is the presence of ionization cones with different orientations depending on the AGN type. Confirmations of this model exist for present times, but it is less clear in the early Universe. Here, we use the morphology of giant Ly α nebulae around AGNs at redshift z ∼ 3 to probe AGN emission and therefore the validity of the AGN unification model at this redshift. We compare the spatial morphology of 19 nebulae previously found around type I AGNs with a new sample of four Ly α nebulae detected around type II AGNs. Using two independent techniques, we find that nebulae around type II AGNs are more asymmetric than around type I, at least at radial distances r > 30 physical kpc (pkpc) from the ionizing source. We conclude that the type I and type II AGNs in our sample show evidence of different surrounding ionizing geometries. This suggests that the classical AGN unification model is also valid for high-redshift sources. Finally, we discuss how the lack of asymmetry in the inner parts (r ≲ 30 pkpc) and the associated high values of the He II to Ly α ratios in these regions could indicate additional sources of (hard) ionizing radiation originating within or in proximity of the AGN host galaxies. This work demonstrates that the morphologies of giant Ly α nebulae can be used to understand and study the geometry of high-redshift AGNs on circumnuclear scales and it lays the foundation for future studies using much larger statistical samples. AU - den Brok, J S AU - Cantalupo, S AU - Mackenzie, R AU - Marino, R A AU - Pezzulli, G AU - Matthee, Jorryt J AU - Johnson, S D AU - Krumpe, M AU - Urrutia, T AU - Kollatschny, W ID - 11530 IS - 2 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: active KW - galaxies: high-redshift KW - intergalactic medium KW - quasars: emission lines KW - quasars: general SN - 0035-8711 TI - Probing the AGN unification model at redshift z ∼ 3 with MUSE observations of giant Lyα nebulae VL - 495 ER - TY - JOUR AB - Despite recent progress in understanding Ly α emitters (LAEs), relatively little is known regarding their typical black hole activity across cosmic time. Here, we study the X-ray and radio properties of ∼4000 LAEs at 2.2 < z < 6 from the SC4K survey in the COSMOS field. We detect 254 (⁠6.8per cent±0.4per cent⁠) LAEs individually in the X-rays (S/N > 3) with an average luminosity of 1044.31±0.01ergs−1 and average black hole accretion rate (BHAR) of 0.72±0.01 M⊙ yr−1, consistent with moderate to high accreting active galactic neuclei (AGNs). We detect 120 sources in deep radio data (radio AGN fraction of 3.2per cent±0.3per cent⁠). The global AGN fraction (⁠8.6per cent±0.4per cent⁠) rises with Ly α luminosity and declines with increasing redshift. For X-ray-detected LAEs, Ly α luminosities correlate with the BHARs, suggesting that Ly α luminosity becomes a BHAR indicator. Most LAEs (⁠93.1per cent±0.6per cent⁠) at 2 < z < 6 have no detectable X-ray emission (BHARs < 0.017 M⊙ yr−1). The median star formation rate (SFR) of star-forming LAEs from Ly α and radio luminosities is 7.6+6.6−2.8 M⊙ yr−1. The black hole to galaxy growth ratio (BHAR/SFR) for LAEs is <0.0022, consistent with typical star-forming galaxies and the local BHAR/SFR relation. We conclude that LAEs at 2 < z < 6 include two different populations: an AGN population, where Ly α luminosity traces BHAR, and another with low SFRs which remain undetected in even the deepest X-ray stacks but is detected in the radio stacks. AU - Calhau, João AU - Sobral, David AU - Santos, Sérgio AU - Matthee, Jorryt J AU - Paulino-Afonso, Ana AU - Stroe, Andra AU - Simmons, Brooke AU - Barlow-Hall, Cassandra AU - Adams, Benjamin ID - 11539 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: active KW - galaxies: evolution KW - galaxies: high-redshift KW - quasars: supermassive black holes KW - galaxies: star formation KW - cosmology: observations KW - X-rays: galaxies SN - 0035-8711 TI - The X-ray and radio activity of typical and luminous Ly α emitters from z ∼ 2 to z ∼ 6: Evidence for a diverse, evolving population VL - 493 ER -