TY - GEN AB - Data obtained from the fine-grained simulations used in Figures 2-5, data obtained from the coarse-grained numerical calculations used in Figure 6, and a sample script for the fine-grained simulation as a Jupyter notebook (ZIP) AU - Ucar, Mehmet C AU - Lipowsky, Reinhard ID - 9885 TI - MURL_Dataz ER - TY - JOUR AB - The combined resection of skull-infiltrating tumours and immediate cranioplastic reconstruction predominantly relies on freehand-moulded solutions. Techniques that enable this procedure to be performed easily in routine clinical practice would be useful. A cadaveric study was developed in which a new software tool was used to perform single-stage reconstructions with prefabricated implants after the resection of skull-infiltrating pathologies. A novel 3D visualization and interaction framework was developed to create 10 virtual craniotomies in five cadaveric specimens. Polyether ether ketone (PEEK) implants were manufactured according to the bone defects. The image-guided craniotomy was reconstructed with PEEK and compared to polymethyl methacrylate (PMMA). Navigational accuracy and surgical precision were assessed. The PEEK workflow resulted in up to 10-fold shorter reconstruction times than the standard technique. Surgical precision was reflected by the mean 1.1 ± 0.29 mm distance between the virtual and real craniotomy, with submillimetre precision in 50%. Assessment of the global offset between virtual and actual craniotomy revealed an average shift of 4.5 ± 3.6 mm. The results validated the ‘elective single-stage cranioplasty’ technique as a state-of-the-art virtual planning method and surgical workflow. This patient-tailored workflow could significantly reduce surgical times compared to the traditional, intraoperative acrylic moulding method and may be an option for the reconstruction of bone defects in the craniofacial region. AU - Dodier, Philippe AU - Winter, Fabian AU - Auzinger, Thomas AU - Mistelbauer, Gabriel AU - Frischer, Josa M. AU - Wang, Wei Te AU - Mallouhi, Ammar AU - Marik, Wolfgang AU - Wolfsberger, Stefan AU - Reissig, Lukas AU - Hammadi, Firas AU - Matula, Christian AU - Baumann, Arnulf AU - Bavinzski, Gerhard ID - 7218 IS - 8 JF - International Journal of Oral and Maxillofacial Surgery SN - 0901-5027 TI - Single-stage bone resection and cranioplastic reconstruction: Comparison of a novel software-derived PEEK workflow with the standard reconstructive method VL - 49 ER - TY - JOUR AB - Root system architecture (RSA), governed by the phytohormone auxin, endows plants with an adaptive advantage in particular environments. Using geographically representative arabidopsis (Arabidopsis thaliana) accessions as a resource for GWA mapping, Waidmann et al. and Ogura et al. recently identified two novel components involved in modulating auxin-mediated RSA and conferring plant fitness in particular habitats. AU - Xiao, Guanghui AU - Zhang, Yuzhou ID - 7219 IS - 2 JF - Trends in Plant Science SN - 13601385 TI - Adaptive growth: Shaping auxin-mediated root system architecture VL - 25 ER - TY - JOUR AB - T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin‐related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F‐actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3‐knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon‐like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three‐dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3‐dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities. AU - Obeidy, Peyman AU - Ju, Lining A. AU - Oehlers, Stefan H. AU - Zulkhernain, Nursafwana S. AU - Lee, Quintin AU - Galeano Niño, Jorge L. AU - Kwan, Rain Y.Q. AU - Tikoo, Shweta AU - Cavanagh, Lois L. AU - Mrass, Paulus AU - Cook, Adam J.L. AU - Jackson, Shaun P. AU - Biro, Maté AU - Roediger, Ben AU - Sixt, Michael K AU - Weninger, Wolfgang ID - 7234 IS - 2 JF - Immunology and Cell Biology SN - 08189641 TI - Partial loss of actin nucleator actin-related protein 2/3 activity triggers blebbing in primary T lymphocytes VL - 98 ER - TY - JOUR AB - The cyclin-dependent kinase inhibitor p57KIP2 is encoded by the imprinted Cdkn1c locus, exhibits maternal expression, and is essential for cerebral cortex development. How Cdkn1c regulates corticogenesis is however not clear. To this end we employ Mosaic Analysis with Double Markers (MADM) technology to genetically dissect Cdkn1c gene function in corticogenesis at single cell resolution. We find that the previously described growth-inhibitory Cdkn1c function is a non-cell-autonomous one, acting on the whole organism. In contrast we reveal a growth-promoting cell-autonomous Cdkn1c function which at the mechanistic level mediates radial glial progenitor cell and nascent projection neuron survival. Strikingly, the growth-promoting function of Cdkn1c is highly dosage sensitive but not subject to genomic imprinting. Collectively, our results suggest that the Cdkn1c locus regulates cortical development through distinct cell-autonomous and non-cell-autonomous mechanisms. More generally, our study highlights the importance to probe the relative contributions of cell intrinsic gene function and tissue-wide mechanisms to the overall phenotype. AU - Laukoter, Susanne AU - Beattie, Robert J AU - Pauler, Florian AU - Amberg, Nicole AU - Nakayama, Keiichi I. AU - Hippenmeyer, Simon ID - 7253 JF - Nature Communications SN - 2041-1723 TI - Imprinted Cdkn1c genomic locus cell-autonomously promotes cell survival in cerebral cortex development VL - 11 ER - TY - JOUR AB - Cytoskeletal filaments such as microtubules (MTs) and filamentous actin (F-actin) dynamically support cell structure and functions. In central presynaptic terminals, F-actin is expressed along the release edge and reportedly plays diverse functional roles, but whether axonal MTs extend deep into terminals and play any physiological role remains controversial. At the calyx of Held in rats of either sex, confocal and high-resolution microscopy revealed that MTs enter deep into presynaptic terminal swellings and partially colocalize with a subset of synaptic vesicles (SVs). Electrophysiological analysis demonstrated that depolymerization of MTs specifically prolonged the slow-recovery time component of EPSCs from short-term depression induced by a train of high-frequency stimulation, whereas depolymerization of F-actin specifically prolonged the fast-recovery component. In simultaneous presynaptic and postsynaptic action potential recordings, depolymerization of MTs or F-actin significantly impaired the fidelity of high-frequency neurotransmission. We conclude that MTs and F-actin differentially contribute to slow and fast SV replenishment, thereby maintaining high-frequency neurotransmission. AU - Piriya Ananda Babu, Lashmi AU - Wang, Han Ying AU - Eguchi, Kohgaku AU - Guillaud, Laurent AU - Takahashi, Tomoyuki ID - 7339 IS - 1 JF - Journal of neuroscience TI - Microtubule and actin differentially regulate synaptic vesicle cycling to maintain high-frequency neurotransmission VL - 40 ER - TY - JOUR AB - The ability to sense environmental temperature and to coordinate growth and development accordingly, is critical to the reproductive success of plants. Flowering time is regulated at the level of gene expression by a complex network of factors that integrate environmental and developmental cues. One of the main players, involved in modulating flowering time in response to changes in ambient temperature is FLOWERING LOCUS M (FLM). FLM transcripts can undergo extensive alternative splicing producing multiple variants, of which FLM-β and FLM-δ are the most representative. While FLM-β codes for the flowering repressor FLM protein, translation of FLM-δ has the opposite effect on flowering. Here we show that the cyclin-dependent kinase G2 (CDKG2), together with its cognate cyclin, CYCLYN L1 (CYCL1) affects the alternative splicing of FLM, balancing the levels of FLM-β and FLM-δ across the ambient temperature range. In the absence of the CDKG2/CYCL1 complex, FLM-β expression is reduced while FLM-δ is increased in a temperature dependent manner and these changes are associated with an early flowering phenotype in the cdkg2 mutant lines. In addition, we found that transcript variants retaining the full FLM intron 1 are sequestered in the cell nucleus. Strikingly, FLM intron 1 splicing is also regulated by CDKG2/CYCL1. Our results provide evidence that temperature and CDKs regulate the alternative splicing of FLM, contributing to flowering time definition. AU - Nibau, Candida AU - Gallemi, Marçal AU - Dadarou, Despoina AU - Doonan, John H. AU - Cavallari, Nicola ID - 7350 JF - Frontiers in Plant Science SN - 1664-462X TI - Thermo-sensitive alternative splicing of FLOWERING LOCUS M is modulated by cyclin-dependent kinase G2 VL - 10 ER - TY - JOUR AB - Neuronal responses to complex stimuli and tasks can encompass a wide range of time scales. Understanding these responses requires measures that characterize how the information on these response patterns are represented across multiple temporal resolutions. In this paper we propose a metric – which we call multiscale relevance (MSR) – to capture the dynamical variability of the activity of single neurons across different time scales. The MSR is a non-parametric, fully featureless indicator in that it uses only the time stamps of the firing activity without resorting to any a priori covariate or invoking any specific structure in the tuning curve for neural activity. When applied to neural data from the mEC and from the ADn and PoS regions of freely-behaving rodents, we found that neurons having low MSR tend to have low mutual information and low firing sparsity across the correlates that are believed to be encoded by the region of the brain where the recordings were made. In addition, neurons with high MSR contain significant information on spatial navigation and allow to decode spatial position or head direction as efficiently as those neurons whose firing activity has high mutual information with the covariate to be decoded and significantly better than the set of neurons with high local variations in their interspike intervals. Given these results, we propose that the MSR can be used as a measure to rank and select neurons for their information content without the need to appeal to any a priori covariate. AU - Cubero, Ryan J AU - Marsili, Matteo AU - Roudi, Yasser ID - 7369 JF - Journal of Computational Neuroscience KW - Time series analysis KW - Multiple time scale analysis KW - Spike train data KW - Information theory KW - Bayesian decoding SN - 0929-5313 TI - Multiscale relevance and informative encoding in neuronal spike trains VL - 48 ER - TY - JOUR AB - We present nsCouette, a highly scalable software tool to solve the Navier–Stokes equations for incompressible fluid flow between differentially heated and independently rotating, concentric cylinders. It is based on a pseudospectral spatial discretization and dynamic time-stepping. It is implemented in modern Fortran with a hybrid MPI-OpenMP parallelization scheme and thus designed to compute turbulent flows at high Reynolds and Rayleigh numbers. An additional GPU implementation (C-CUDA) for intermediate problem sizes and a version for pipe flow (nsPipe) are also provided. AU - Lopez Alonso, Jose M AU - Feldmann, Daniel AU - Rampp, Markus AU - Vela-Martín, Alberto AU - Shi, Liang AU - Avila, Marc ID - 7364 JF - SoftwareX TI - nsCouette – A high-performance code for direct numerical simulations of turbulent Taylor–Couette flow VL - 11 ER - TY - JOUR AB - In many real-world systems, information can be transmitted in two qualitatively different ways: by copying or by transformation. Copying occurs when messages are transmitted without modification, e.g. when an offspring receives an unaltered copy of a gene from its parent. Transformation occurs when messages are modified systematically during transmission, e.g. when mutational biases occur during genetic replication. Standard information-theoretic measures do not distinguish these two modes of information transfer, although they may reflect different mechanisms and have different functional consequences. Starting from a few simple axioms, we derive a decomposition of mutual information into the information transmitted by copying versus the information transmitted by transformation. We begin with a decomposition that applies when the source and destination of the channel have the same set of messages and a notion of message identity exists. We then generalize our decomposition to other kinds of channels, which can involve different source and destination sets and broader notions of similarity. In addition, we show that copy information can be interpreted as the minimal work needed by a physical copying process, which is relevant for understanding the physics of replication. We use the proposed decomposition to explore a model of amino acid substitution rates. Our results apply to any system in which the fidelity of copying, rather than simple predictability, is of critical relevance. AU - Kolchinsky, Artemy AU - Corominas-Murtra, Bernat ID - 7431 IS - 162 JF - Journal of the Royal Society Interface TI - Decomposing information into copying versus transformation VL - 17 ER - TY - JOUR AB - Recently Kloeckner described the structure of the isometry group of the quadratic Wasserstein space W_2(R^n). It turned out that the case of the real line is exceptional in the sense that there exists an exotic isometry flow. Following this line of investigation, we compute Isom(W_p(R)), the isometry group of the Wasserstein space W_p(R) for all p \in [1,\infty) \setminus {2}. We show that W_2(R) is also exceptional regarding the parameter p: W_p(R) is isometrically rigid if and only if p is not equal to 2. Regarding the underlying space, we prove that the exceptionality of p = 2 disappears if we replace R by the compact interval [0,1]. Surprisingly, in that case, W_p([0,1]) is isometrically rigid if and only if p is not equal to 1. Moreover, W_1([0,1]) admits isometries that split mass, and Isom(W_1([0,1])) cannot be embedded into Isom(W_1(R)). AU - Geher, Gyorgy Pal AU - Titkos, Tamas AU - Virosztek, Daniel ID - 7389 IS - 8 JF - Transactions of the American Mathematical Society KW - Wasserstein space KW - isometric embeddings KW - isometric rigidity KW - exotic isometry flow SN - 00029947 TI - Isometric study of Wasserstein spaces - the real line VL - 373 ER - TY - JOUR AB - Nanomaterials produced from the bottom-up assembly of nanocrystals may incorporate ∼1020–1021 cm–3 not fully coordinated surface atoms, i.e., ∼1020–1021 cm–3 potential donor or acceptor states that can strongly affect transport properties. Therefore, to exploit the full potential of nanocrystal building blocks to produce functional nanomaterials and thin films, a proper control of their surface chemistry is required. Here, we analyze how the ligand stripping procedure influences the charge and heat transport properties of sintered PbSe nanomaterials produced from the bottom-up assembly of colloidal PbSe nanocrystals. First, we show that the removal of the native organic ligands by thermal decomposition in an inert atmosphere leaves relatively large amounts of carbon at the crystal interfaces. This carbon blocks crystal growth during consolidation and at the same time hampers charge and heat transport through the final nanomaterial. Second, we demonstrate that, by stripping ligands from the nanocrystal surface before consolidation, nanomaterials with larger crystal domains, lower porosity, and higher charge carrier concentrations are obtained, thus resulting in nanomaterials with higher electrical and thermal conductivities. In addition, the ligand displacement leaves the nanocrystal surface unprotected, facilitating oxidation and chalcogen evaporation. The influence of the ligand displacement on the nanomaterial charge transport properties is rationalized here using a two-band model based on the standard Boltzmann transport equation with the relaxation time approximation. Finally, we present an application of the produced functional nanomaterials by modeling, fabricating, and testing a simple PbSe-based thermoelectric device with a ring geometry. AU - Cadavid, Doris AU - Ortega, Silvia AU - Illera, Sergio AU - Liu, Yu AU - Ibáñez, Maria AU - Shavel, Alexey AU - Zhang, Yu AU - Li, Mengyao AU - López, Antonio M. AU - Noriega, Germán AU - Durá, Oscar Juan AU - López De La Torre, M. A. AU - Prades, Joan Daniel AU - Cabot, Andreu ID - 7467 IS - 3 JF - ACS Applied Energy Materials TI - Influence of the ligand stripping on the transport properties of nanoparticle-based PbSe nanomaterials VL - 3 ER - TY - JOUR AB - The flexible development of plants is characterized by a high capacity for post-embryonic organ formation and tissue regeneration, processes, which require tightly regulated intercellular communication and coordinated tissue (re-)polarization. The phytohormone auxin, the main driver for these processes, is able to establish polarized auxin transport channels, which are characterized by the expression and polar, subcellular localization of the PIN1 auxin transport proteins. These channels are demarcating the position of future vascular strands necessary for organ formation and tissue regeneration. Major progress has been made in the last years to understand how PINs can change their polarity in different contexts and thus guide auxin flow through the plant. However, it still remains elusive how auxin mediates the establishment of auxin conducting channels and the formation of vascular tissue and which cellular processes are involved. By the means of sophisticated regeneration experiments combined with local auxin applications in Arabidopsis thaliana inflorescence stems we show that (i) PIN subcellular dynamics, (ii) PIN internalization by clathrin-mediated trafficking and (iii) an intact actin cytoskeleton required for post-endocytic trafficking are indispensable for auxin channel formation, de novo vascular formation and vascular regeneration after wounding. These observations provide novel insights into cellular mechanism of coordinated tissue polarization during auxin canalization. AU - Mazur, Ewa AU - Gallei, Michelle C AU - Adamowski, Maciek AU - Han, Huibin AU - Robert, Hélène S. AU - Friml, Jiří ID - 7465 IS - 4 JF - Plant Science SN - 01689452 TI - Clathrin-mediated trafficking and PIN trafficking are required for auxin canalization and vascular tissue formation in Arabidopsis VL - 293 ER - TY - JOUR AB - Unpaired ligands are secreted signals that act via a GP130-like receptor, domeless, to activate JAK/STAT signalling in Drosophila. Like many mammalian cytokines, unpaireds can be activated by infection and other stresses and can promote insulin resistance in target tissues. However, the importance of this effect in non-inflammatory physiology is unknown. Here, we identify a requirement for unpaired-JAK signalling as a metabolic regulator in healthy adult Drosophila muscle. Adult muscles show basal JAK-STAT signalling activity in the absence of any immune challenge. Plasmatocytes (Drosophila macrophages) are an important source of this tonic signal. Loss of the dome receptor on adult muscles significantly reduces lifespan and causes local and systemic metabolic pathology. These pathologies result from hyperactivation of AKT and consequent deregulation of metabolism. Thus, we identify a cytokine signal that must be received in muscle to control AKT activity and metabolic homeostasis. AU - Kierdorf, Katrin AU - Hersperger, Fabian AU - Sharrock, Jessica AU - Vincent, Crystal M. AU - Ustaoglu, Pinar AU - Dou, Jiawen AU - György, Attila AU - Groß, Olaf AU - Siekhaus, Daria E AU - Dionne, Marc S. ID - 7466 JF - eLife TI - Muscle function and homeostasis require cytokine inhibition of AKT activity in Drosophila VL - 9 ER - TY - JOUR AB - Temporally organized reactivation of experiences during awake immobility periods is thought to underlie cognitive processes like planning and evaluation. While replay of trajectories is well established for the hippocampus, it is unclear whether the medial prefrontal cortex (mPFC) can reactivate sequential behavioral experiences in the awake state to support task execution. We simultaneously recorded from hippocampal and mPFC principal neurons in rats performing a mPFC-dependent rule-switching task on a plus maze. We found that mPFC neuronal activity encoded relative positions between the start and goal. During awake immobility periods, the mPFC replayed temporally organized sequences of these generalized positions, resembling entire spatial trajectories. The occurrence of mPFC trajectory replay positively correlated with rule-switching performance. However, hippocampal and mPFC trajectory replay occurred independently, indicating different functions. These results demonstrate that the mPFC can replay ordered activity patterns representing generalized locations and suggest that mPFC replay might have a role in flexible behavior. AU - Käfer, Karola AU - Nardin, Michele AU - Blahna, Karel AU - Csicsvari, Jozsef L ID - 7472 IS - 1 JF - Neuron SN - 0896-6273 TI - Replay of behavioral sequences in the medial prefrontal cortex during rule switching VL - 106 ER - TY - JOUR AB - We give a Wong-Zakai type characterisation of the solutions of quasilinear heat equations driven by space-time white noise in 1 + 1 dimensions. In order to show that the renormalisation counterterms are local in the solution, a careful arrangement of a few hundred terms is required. The main tool in this computation is a general ‘integration by parts’ formula that provides a number of linear identities for the renormalisation constants. AU - Gerencser, Mate ID - 7388 IS - 3 JF - Annales de l'Institut Henri Poincaré C, Analyse non linéaire SN - 0294-1449 TI - Nondivergence form quasilinear heat equations driven by space-time white noise VL - 37 ER - TY - JOUR AB - Glutaminase (GA) catalyzes the first step in mitochondrial glutaminolysis playing a key role in cancer metabolic reprogramming. Humans express two types of GA isoforms: GLS and GLS2. GLS isozymes have been consistently related to cell proliferation, but the role of GLS2 in cancer remains poorly understood. GLS2 is repressed in many tumor cells and a better understanding of its function in tumorigenesis may further the development of new therapeutic approaches. We analyzed GLS2 expression in HCC, GBM and neuroblastoma cells, as well as in monkey COS-7 cells. We studied GLS2 expression after induction of differentiation with phorbol ester (PMA) and transduction with the full-length cDNA of GLS2. In parallel, we investigated cell cycle progression and levels of p53, p21 and c-Myc proteins. Using the baculovirus system, human GLS2 protein was overexpressed, purified and analyzed for posttranslational modifications employing a proteomics LC-MS/MS platform. We have demonstrated a dual targeting of GLS2 in human cancer cells. Immunocytochemistry and subcellular fractionation gave consistent results demonstrating nuclear and mitochondrial locations, with the latter being predominant. Nuclear targeting was confirmed in cancer cells overexpressing c-Myc- and GFP-tagged GLS2 proteins. We assessed the subnuclear location finding a widespread distribution of GLS2 in the nucleoplasm without clear overlapping with specific nuclear substructures. GLS2 expression and nuclear accrual notably increased by treatment of SH-SY5Y cells with PMA and it correlated with cell cycle arrest at G2/M, upregulation of tumor suppressor p53 and p21 protein. A similar response was obtained by overexpression of GLS2 in T98G glioma cells, including downregulation of oncogene c-Myc. Furthermore, human GLS2 was identified as being hypusinated by MS analysis, a posttranslational modification which may be relevant for its nuclear targeting and/or function. Our studies provide evidence for a tumor suppressor role of GLS2 in certain types of cancer. The data imply that GLS2 can be regarded as a highly mobile and multilocalizing protein translocated to both mitochondria and nuclei. Upregulation of GLS2 in cancer cells induced an antiproliferative response with cell cycle arrest at the G2/M phase. AU - López De La Oliva, Amada R. AU - Campos-Sandoval, José A. AU - Gómez-García, María C. AU - Cardona, Carolina AU - Martín-Rufián, Mercedes AU - Sialana, Fernando J. AU - Castilla, Laura AU - Bae, Narkhyun AU - Lobo, Carolina AU - Peñalver, Ana AU - García-Frutos, Marina AU - Carro, David AU - Enrique, Victoria AU - Paz, José C. AU - Mirmira, Raghavendra G. AU - Gutiérrez, Antonia AU - Alonso, Francisco J. AU - Segura, Juan A. AU - Matés, José M. AU - Lubec, Gert AU - Márquez, Javier ID - 7487 IS - 1 JF - Scientific reports TI - Nuclear translocation of glutaminase GLS2 in human cancer cells associates with proliferation arrest and differentiation VL - 10 ER - TY - JOUR AB - In plants, clathrin mediated endocytosis (CME) represents the major route for cargo internalisation from the cell surface. It has been assumed to operate in an evolutionary conserved manner as in yeast and animals. Here we report characterisation of ultrastructure, dynamics and mechanisms of plant CME as allowed by our advancement in electron microscopy and quantitative live imaging techniques. Arabidopsis CME appears to follow the constant curvature model and the bona fide CME population generates vesicles of a predominantly hexagonal-basket type; larger and with faster kinetics than in other models. Contrary to the existing paradigm, actin is dispensable for CME events at the plasma membrane but plays a unique role in collecting endocytic vesicles, sorting of internalised cargos and directional endosome movement that itself actively promote CME events. Internalized vesicles display a strongly delayed and sequential uncoating. These unique features highlight the independent evolution of the plant CME mechanism during the autonomous rise of multicellularity in eukaryotes. AU - Narasimhan, Madhumitha AU - Johnson, Alexander J AU - Prizak, Roshan AU - Kaufmann, Walter AU - Tan, Shutang AU - Casillas Perez, Barbara E AU - Friml, Jiří ID - 7490 JF - eLife TI - Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants VL - 9 ER - TY - JOUR AB - Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS. AU - Latorre-Pellicer, Ana AU - Ascaso, Ángela AU - Trujillano, Laura AU - Gil-Salvador, Marta AU - Arnedo, Maria AU - Lucia-Campos, Cristina AU - Antoñanzas-Pérez, Rebeca AU - Marcos-Alcalde, Iñigo AU - Parenti, Ilaria AU - Bueno-Lozano, Gloria AU - Musio, Antonio AU - Puisac, Beatriz AU - Kaiser, Frank J. AU - Ramos, Feliciano J. AU - Gómez-Puertas, Paulino AU - Pié, Juan ID - 7488 IS - 3 JF - International Journal of Molecular Sciences SN - 16616596 TI - Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes VL - 21 ER - TY - CONF AB - Neural networks have demonstrated unmatched performance in a range of classification tasks. Despite numerous efforts of the research community, novelty detection remains one of the significant limitations of neural networks. The ability to identify previously unseen inputs as novel is crucial for our understanding of the decisions made by neural networks. At runtime, inputs not falling into any of the categories learned during training cannot be classified correctly by the neural network. Existing approaches treat the neural network as a black box and try to detect novel inputs based on the confidence of the output predictions. However, neural networks are not trained to reduce their confidence for novel inputs, which limits the effectiveness of these approaches. We propose a framework to monitor a neural network by observing the hidden layers. We employ a common abstraction from program analysis - boxes - to identify novel behaviors in the monitored layers, i.e., inputs that cause behaviors outside the box. For each neuron, the boxes range over the values seen in training. The framework is efficient and flexible to achieve a desired trade-off between raising false warnings and detecting novel inputs. We illustrate the performance and the robustness to variability in the unknown classes on popular image-classification benchmarks. AU - Henzinger, Thomas A AU - Lukina, Anna AU - Schilling, Christian ID - 7505 T2 - 24th European Conference on Artificial Intelligence TI - Outside the box: Abstraction-based monitoring of neural networks VL - 325 ER - TY - JOUR AB - In this paper, we introduce a novel method for deriving higher order corrections to the mean-field description of the dynamics of interacting bosons. More precisely, we consider the dynamics of N d-dimensional bosons for large N. The bosons initially form a Bose–Einstein condensate and interact with each other via a pair potential of the form (N−1)−1Ndβv(Nβ·)forβ∈[0,14d). We derive a sequence of N-body functions which approximate the true many-body dynamics in L2(RdN)-norm to arbitrary precision in powers of N−1. The approximating functions are constructed as Duhamel expansions of finite order in terms of the first quantised analogue of a Bogoliubov time evolution. AU - Bossmann, Lea AU - Pavlović, Nataša AU - Pickl, Peter AU - Soffer, Avy ID - 7508 JF - Journal of Statistical Physics SN - 0022-4715 TI - Higher order corrections to the mean-field description of the dynamics of interacting bosons VL - 178 ER - TY - JOUR AB - Cryo electron tomography with subsequent subtomogram averaging is a powerful technique to structurally analyze macromolecular complexes in their native context. Although close to atomic resolution in principle can be obtained, it is not clear how individual experimental parameters contribute to the attainable resolution. Here, we have used immature HIV-1 lattice as a benchmarking sample to optimize the attainable resolution for subtomogram averaging. We systematically tested various experimental parameters such as the order of projections, different angular increments and the use of the Volta phase plate. We find that although any of the prominently used acquisition schemes is sufficient to obtain subnanometer resolution, dose-symmetric acquisition provides considerably better outcome. We discuss our findings in order to provide guidance for data acquisition. Our data is publicly available and might be used to further develop processing routines. AU - Turoňová, Beata AU - Hagen, Wim J.H. AU - Obr, Martin AU - Mosalaganti, Shyamal AU - Beugelink, J. Wouter AU - Zimmerli, Christian E. AU - Kräusslich, Hans Georg AU - Beck, Martin ID - 7511 JF - Nature Communications TI - Benchmarking tomographic acquisition schemes for high-resolution structural biology VL - 11 ER - TY - JOUR AB - Endophytic fungi can be beneficial to plant growth. However, the molecular mechanisms underlying colonization of Acremonium spp. remain unclear. In this study, a novel endophytic Acremonium strain was isolated from the buds of Panax notoginseng and named Acremonium sp. D212. The Acremonium sp. D212 could colonize the roots of P. notoginseng, enhance the resistance of P. notoginseng to root rot disease, and promote root growth and saponin biosynthesis in P. notoginseng. Acremonium sp. D212 could secrete indole‐3‐acetic acid (IAA) and jasmonic acid (JA), and inoculation with the fungus increased the endogenous levels of IAA and JA in P. notoginseng. Colonization of the Acremonium sp. D212 in the roots of the rice line Nipponbare was dependent on the concentration of methyl jasmonate (MeJA) (2 to 15 μM) and 1‐naphthalenacetic acid (NAA) (10 to 20 μM). Moreover, the roots of the JA signalling‐defective coi1‐18 mutant were colonized by Acremonium sp. D212 to a lesser degree than those of the wild‐type Nipponbare and miR393b‐overexpressing lines, and the colonization was rescued by MeJA but not by NAA. It suggests that the cross‐talk between JA signalling and the auxin biosynthetic pathway plays a crucial role in the colonization of Acremonium sp. D212 in host plants. AU - Han, L AU - Zhou, X AU - Zhao, Y AU - Zhu, S AU - Wu, L AU - He, Y AU - Ping, X AU - Lu, X AU - Huang, W AU - Qian, J AU - Zhang, L AU - Jiang, X AU - Zhu, D AU - Luo, C AU - Li, S AU - Dong, Q AU - Fu, Q AU - Deng, K AU - Wang, X AU - Wang, L AU - Peng, S AU - Wu, J AU - Li, W AU - Friml, Jiří AU - Zhu, Y AU - He, X AU - Du, Y ID - 7497 IS - 9 JF - Journal of Integrative Plant Biology SN - 1672-9072 TI - Colonization of endophyte Acremonium sp. D212 in Panax notoginseng and rice mediated by auxin and jasmonic acid VL - 62 ER - TY - JOUR AB - In the past two decades, our understanding of the transition to turbulence in shear flows with linearly stable laminar solutions has greatly improved. Regarding the susceptibility of the laminar flow, two concepts have been particularly useful: the edge states and the minimal seeds. In this nonlinear picture of the transition, the basin boundary of turbulence is set by the edge state's stable manifold and this manifold comes closest in energy to the laminar equilibrium at the minimal seed. We begin this paper by presenting numerical experiments in which three-dimensional perturbations are too energetic to trigger turbulence in pipe flow but they do lead to turbulence when their amplitude is reduced. We show that this seemingly counterintuitive observation is in fact consistent with the fully nonlinear description of the transition mediated by the edge state. In order to understand the physical mechanisms behind this process, we measure the turbulent kinetic energy production and dissipation rates as a function of the radial coordinate. Our main observation is that the transition to turbulence relies on the energy amplification away from the wall, as opposed to the turbulence itself, whose energy is predominantly produced near the wall. This observation is further supported by the similar analyses on the minimal seeds and the edge states. Furthermore, we show that the time evolution of production-over-dissipation curves provides a clear distinction between the different initial amplification stages of the transition to turbulence from the minimal seed. AU - Budanur, Nazmi B AU - Marensi, Elena AU - Willis, Ashley P. AU - Hof, Björn ID - 7534 IS - 2 JF - Physical Review Fluids SN - 2469-990X TI - Upper edge of chaos and the energetics of transition in pipe flow VL - 5 ER - TY - JOUR AB - We consider general self-adjoint polynomials in several independent random matrices whose entries are centered and have the same variance. We show that under certain conditions the local law holds up to the optimal scale, i.e., the eigenvalue density on scales just above the eigenvalue spacing follows the global density of states which is determined by free probability theory. We prove that these conditions hold for general homogeneous polynomials of degree two and for symmetrized products of independent matrices with i.i.d. entries, thus establishing the optimal bulk local law for these classes of ensembles. In particular, we generalize a similar result of Anderson for anticommutator. For more general polynomials our conditions are effectively checkable numerically. AU - Erdös, László AU - Krüger, Torben H AU - Nemish, Yuriy ID - 7512 IS - 12 JF - Journal of Functional Analysis SN - 00221236 TI - Local laws for polynomials of Wigner matrices VL - 278 ER - TY - JOUR AB - In this paper we study the joint convexity/concavity of the trace functions Ψp,q,s(A,B)=Tr(Bq2K∗ApKBq2)s, p,q,s∈R, where A and B are positive definite matrices and K is any fixed invertible matrix. We will give full range of (p,q,s)∈R3 for Ψp,q,s to be jointly convex/concave for all K. As a consequence, we confirm a conjecture of Carlen, Frank and Lieb. In particular, we confirm a weaker conjecture of Audenaert and Datta and obtain the full range of (α,z) for α-z Rényi relative entropies to be monotone under completely positive trace preserving maps. We also give simpler proofs of many known results, including the concavity of Ψp,0,1/p for 02b be integers. We prove that if each k-wise or (k+1)-wise intersection of sets from A has at most b path-connected components, which all are open, then fk+1=0 implies fk≤cfk−1 for some positive constant c depending only on b and k. These results also extend to two-dimensional compact surfaces. AU - Kalai, Gil AU - Patakova, Zuzana ID - 7960 JF - Discrete and Computational Geometry SN - 01795376 TI - Intersection patterns of planar sets VL - 64 ER - TY - JOUR AB - A string graph is the intersection graph of a family of continuous arcs in the plane. The intersection graph of a family of plane convex sets is a string graph, but not all string graphs can be obtained in this way. We prove the following structure theorem conjectured by Janson and Uzzell: The vertex set of almost all string graphs on n vertices can be partitioned into five cliques such that some pair of them is not connected by any edge (n→∞). We also show that every graph with the above property is an intersection graph of plane convex sets. As a corollary, we obtain that almost all string graphs on n vertices are intersection graphs of plane convex sets. AU - Pach, János AU - Reed, Bruce AU - Yuditsky, Yelena ID - 7962 IS - 4 JF - Discrete and Computational Geometry SN - 01795376 TI - Almost all string graphs are intersection graphs of plane convex sets VL - 63 ER - TY - JOUR AB - Binary interaction can cause stellar envelopes to be stripped, which significantly reduces the radius of the star. The orbit of a binary composed of a stripped star and a compact object can therefore be so tight that the gravitational radiation the system produces reaches frequencies accessible to the Laser Interferometer Space Antenna (LISA). Two such stripped stars in tight orbits with white dwarfs are known so far (ZTF J2130+4420 and CD−30°11223), but many more are expected to exist. These binaries provide important constraints for binary evolution models and may be used as LISA verification sources. We develop a Monte Carlo code that uses detailed evolutionary models to simulate the Galactic population of stripped stars in tight orbits with either neutron star or white dwarf companions. We predict 0–100 stripped star + white dwarf binaries and 0–4 stripped star + neutron star binaries with a signal-to-noise ratio >5 after 10 yr of observations with LISA. More than 90% of these binaries are expected to show large radial velocity shifts of ≳200 $\,\mathrm{km}\,{{\rm{s}}}^{-1}$, which are spectroscopically detectable. Photometric variability due to tidal deformation of the stripped star is also expected and has been observed in ZTF J2130+4420 and CD−30°11223. In addition, the stripped star + neutron star binaries are expected to be X-ray bright with LX ≳ 1033–1036 $\,\mathrm{erg}\,{{\rm{s}}}^{-1}$. Our results show that stripped star binaries are promising multimessenger sources for the upcoming electromagnetic and gravitational wave facilities. AU - Götberg, Ylva Louise Linsdotter AU - Korol, V. AU - Lamberts, A. AU - Kupfer, T. AU - Breivik, K. AU - Ludwig, B. AU - Drout, M. R. ID - 13460 IS - 1 JF - The Astrophysical Journal KW - Space and Planetary Science KW - Astronomy and Astrophysics SN - 0004-637X TI - Stars stripped in binaries: The living gravitational-wave sources VL - 904 ER - TY - JOUR AB - Linking epigenetic marks to clinical outcomes improves insight into molecular processes, disease prediction, and therapeutic target identification. Here, a statistical approach is presented to infer the epigenetic architecture of complex disease, determine the variation captured by epigenetic effects, and estimate phenotype-epigenetic probe associations jointly. Implicitly adjusting for probe correlations, data structure (cell-count or relatedness), and single-nucleotide polymorphism (SNP) marker effects, improves association estimates and in 9,448 individuals, 75.7% (95% CI 71.70–79.3) of body mass index (BMI) variation and 45.6% (95% CI 37.3–51.9) of cigarette consumption variation was captured by whole blood methylation array data. Pathway-linked probes of blood cholesterol, lipid transport and sterol metabolism for BMI, and xenobiotic stimuli response for smoking, showed >1.5 times larger associations with >95% posterior inclusion probability. Prediction accuracy improved by 28.7% for BMI and 10.2% for smoking over a LASSO model, with age-, and tissue-specificity, implying associations are a phenotypic consequence rather than causal. AU - Trejo Banos, D AU - McCartney, DL AU - Patxot, M AU - Anchieri, L AU - Battram, T AU - Christiansen, C AU - Costeira, R AU - Walker, RM AU - Morris, SW AU - Campbell, A AU - Zhang, Q AU - Porteous, DJ AU - McRae, AF AU - Wray, NR AU - Visscher, PM AU - Haley, CS AU - Evans, KL AU - Deary, IJ AU - McIntosh, AM AU - Hemani, G AU - Bell, JT AU - Marioni, RE AU - Robinson, Matthew Richard ID - 7999 JF - Nature Communications SN - 2041-1723 TI - Bayesian reassessment of the epigenetic architecture of complex traits VL - 11 ER - TY - JOUR AB - When divergent populations are connected by gene flow, the establishment of complete reproductive isolation usually requires the joint action of multiple barrier effects. One example where multiple barrier effects are coupled consists of a single trait that is under divergent natural selection and also mediates assortative mating. Such multiple‐effect traits can strongly reduce gene flow. However, there are few cases where patterns of assortative mating have been described quantitatively and their impact on gene flow has been determined. Two ecotypes of the coastal marine snail, Littorina saxatilis , occur in North Atlantic rocky‐shore habitats dominated by either crab predation or wave action. There is evidence for divergent natural selection acting on size, and size‐assortative mating has previously been documented. Here, we analyze the mating pattern in L. saxatilis with respect to size in intensively sampled transects across boundaries between the habitats. We show that the mating pattern is mostly conserved between ecotypes and that it generates both assortment and directional sexual selection for small male size. Using simulations, we show that the mating pattern can contribute to reproductive isolation between ecotypes but the barrier to gene flow is likely strengthened more by sexual selection than by assortment. AU - Perini, Samuel AU - Rafajlović, Marina AU - Westram, Anja M AU - Johannesson, Kerstin AU - Butlin, Roger K. ID - 7995 IS - 7 JF - Evolution SN - 00143820 TI - Assortative mating, sexual selection, and their consequences for gene flow in Littorina VL - 74 ER - TY - GEN AB - When divergent populations are connected by gene flow, the establishment of complete reproductive isolation usually requires the joint action of multiple barrier effects. One example where multiple barrier effects are coupled consists of a single trait that is under divergent natural selection and also mediates assortative mating. Such multiple-effect traits can strongly reduce gene flow. However, there are few cases where patterns of assortative mating have been described quantitatively and their impact on gene flow has been determined. Two ecotypes of the coastal marine snail, Littorina saxatilis, occur in North Atlantic rocky-shore habitats dominated by either crab predation or wave action. There is evidence for divergent natural selection acting on size, and size-assortative mating has previously been documented. Here, we analyze the mating pattern in L. saxatilis with respect to size in intensively-sampled transects across boundaries between the habitats. We show that the mating pattern is mostly conserved between ecotypes and that it generates both assortment and directional sexual selection for small male size. Using simulations, we show that the mating pattern can contribute to reproductive isolation between ecotypes but the barrier to gene flow is likely strengthened more by sexual selection than by assortment. AU - Perini, Samuel AU - Rafajlovic, Marina AU - Westram, Anja M AU - Johannesson, Kerstin AU - Butlin, Roger ID - 8809 TI - Data from: Assortative mating, sexual selection and their consequences for gene flow in Littorina ER - TY - JOUR AB - Post-tetanic potentiation (PTP) is an attractive candidate mechanism for hippocampus-dependent short-term memory. Although PTP has a uniquely large magnitude at hippocampal mossy fiber-CA3 pyramidal neuron synapses, it is unclear whether it can be induced by natural activity and whether its lifetime is sufficient to support short-term memory. We combined in vivo recordings from granule cells (GCs), in vitro paired recordings from mossy fiber terminals and postsynaptic CA3 neurons, and “flash and freeze” electron microscopy. PTP was induced at single synapses and showed a low induction threshold adapted to sparse GC activity in vivo. PTP was mainly generated by enlargement of the readily releasable pool of synaptic vesicles, allowing multiplicative interaction with other plasticity forms. PTP was associated with an increase in the docked vesicle pool, suggesting formation of structural “pool engrams.” Absence of presynaptic activity extended the lifetime of the potentiation, enabling prolonged information storage in the hippocampal network. AU - Vandael, David H AU - Borges Merjane, Carolina AU - Zhang, Xiaomin AU - Jonas, Peter M ID - 8001 IS - 3 JF - Neuron SN - 0896-6273 TI - Short-term plasticity at hippocampal mossy fiber synapses is induced by natural activity patterns and associated with vesicle pool engram formation VL - 107 ER - TY - JOUR AB - The interaction of strong near-infrared (NIR) laser pulses with wide-bandgap dielectrics produces high harmonics in the extreme ultraviolet (XUV) wavelength range. These observations have opened up the possibility of attosecond metrology in solids, which would benefit from a precise measurement of the emission times of individual harmonics with respect to the NIR laser field. Here we show that, when high-harmonics are detected from the input surface of a magnesium oxide crystal, a bichromatic probing of the XUV emission shows a clear synchronization largely consistent with a semiclassical model of electron–hole recollisions in bulk solids. On the other hand, the bichromatic spectrogram of harmonics originating from the exit surface of the 200 μm-thick crystal is strongly modified, indicating the influence of laser field distortions during propagation. Our tracking of sub-cycle electron and hole re-collisions at XUV energies is relevant to the development of solid-state sources of attosecond pulses. AU - Vampa, Giulio AU - Lu, Jian AU - You, Yong Sing AU - Baykusheva, Denitsa Rangelova AU - Wu, Mengxi AU - Liu, Hanzhe AU - Schafer, Kenneth J AU - Gaarde, Mette B AU - Reis, David A AU - Ghimire, Shambhu ID - 13998 IS - 14 JF - Journal of Physics B: Atomic, Molecular and Optical Physics KW - Condensed Matter Physics KW - Atomic and Molecular Physics KW - and Optics SN - 0953-4075 TI - Attosecond synchronization of extreme ultraviolet high harmonics from crystals VL - 53 ER - TY - JOUR AB - Attosecond chronoscopy has revealed small but measurable delays in photoionization, characterized by the ejection of an electron on absorption of a single photon. Ionization-delay measurements in atomic targets provide a wealth of information about the timing of the photoelectric effect, resonances, electron correlations and transport. However, extending this approach to molecules presents challenges, such as identifying the correct ionization channels and the effect of the anisotropic molecular landscape on the measured delays. Here, we measure ionization delays from ethyl iodide around a giant dipole resonance. By using the theoretical value for the iodine atom as a reference, we disentangle the contribution from the functional ethyl group, which is responsible for the characteristic chemical reactivity of a molecule. We find a substantial additional delay caused by the presence of a functional group, which encodes the effect of the molecular potential on the departing electron. Such information is inaccessible to the conventional approach of measuring photoionization cross-sections. The results establish ionization-delay measurements as a valuable tool in investigating the electronic properties of molecules. AU - Biswas, Shubhadeep AU - Förg, Benjamin AU - Ortmann, Lisa AU - Schötz, Johannes AU - Schweinberger, Wolfgang AU - Zimmermann, Tomáš AU - Pi, Liangwen AU - Baykusheva, Denitsa Rangelova AU - Masood, Hafiz A. AU - Liontos, Ioannis AU - Kamal, Amgad M. AU - Kling, Nora G. AU - Alharbi, Abdullah F. AU - Alharbi, Meshaal AU - Azzeer, Abdallah M. AU - Hartmann, Gregor AU - Wörner, Hans J. AU - Landsman, Alexandra S. AU - Kling, Matthias F. ID - 13999 IS - 7 JF - Nature Physics KW - General Physics and Astronomy SN - 1745-2473 TI - Probing molecular environment through photoemission delays VL - 16 ER - TY - JOUR AB - Microelectromechanical systems and integrated photonics provide the basis for many reliable and compact circuit elements in modern communication systems. Electro-opto-mechanical devices are currently one of the leading approaches to realize ultra-sensitive, low-loss transducers for an emerging quantum information technology. Here we present an on-chip microwave frequency converter based on a planar aluminum on silicon nitride platform that is compatible with slot-mode coupled photonic crystal cavities. We show efficient frequency conversion between two propagating microwave modes mediated by the radiation pressure interaction with a metalized dielectric nanobeam oscillator. We achieve bidirectional coherent conversion with a total device efficiency of up to ~60%, a dynamic range of 2 × 10^9 photons/s and an instantaneous bandwidth of up to 1.7 kHz. A high fidelity quantum state transfer would be possible if the drive dependent output noise of currently ~14 photons s^−1 Hz^−1 is further reduced. Such a silicon nitride based transducer is in situ reconfigurable and could be used for on-chip classical and quantum signal routing and filtering, both for microwave and hybrid microwave-optical applications. AU - Fink, Johannes M AU - Kalaee, M. AU - Norte, R. AU - Pitanti, A. AU - Painter, O. ID - 8038 IS - 3 JF - Quantum Science and Technology TI - Efficient microwave frequency conversion mediated by a photonics compatible silicon nitride nanobeam oscillator VL - 5 ER - TY - JOUR AB - Genetic perturbations that affect bacterial resistance to antibiotics have been characterized genome-wide, but how do such perturbations interact with subsequent evolutionary adaptation to the drug? Here, we show that strong epistasis between resistance mutations and systematically identified genes can be exploited to control spontaneous resistance evolution. We evolved hundreds of Escherichia coli K-12 mutant populations in parallel, using a robotic platform that tightly controls population size and selection pressure. We find a global diminishing-returns epistasis pattern: strains that are initially more sensitive generally undergo larger resistance gains. However, some gene deletion strains deviate from this general trend and curtail the evolvability of resistance, including deletions of genes for membrane transport, LPS biosynthesis, and chaperones. Deletions of efflux pump genes force evolution on inferior mutational paths, not explored in the wild type, and some of these essentially block resistance evolution. This effect is due to strong negative epistasis with resistance mutations. The identified genes and cellular functions provide potential targets for development of adjuvants that may block spontaneous resistance evolution when combined with antibiotics. AU - Lukacisinova, Marta AU - Fernando, Booshini AU - Bollenbach, Mark Tobias ID - 8037 JF - Nature Communications TI - Highly parallel lab evolution reveals that epistasis can curb the evolution of antibiotic resistance VL - 11 ER - TY - JOUR AB - The mitochondrial respiratory chain, formed by five protein complexes, utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains, however, fragmentary due to bottlenecks in understanding redox-driven conformational transitions and their interplay with the hydrated proton pathways. Complex I from Thermus thermophilus encases 16 subunits with nine iron–sulfur clusters, reduced by electrons from NADH. Here, employing the latest crystal structure of T. thermophilus complex I, we have used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron–sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which allosterically couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol form—a design essential for menaquinol release. Remarkably, the barriers to diffusive menaquinone dynamics are lesser than that of the more ubiquitous ubiquinone, and the naphthoquinone headgroup of the former furnishes stronger binding interactions with the pocket, favoring menaquinone for charge transport in T. thermophilus. Our computations are consistent with experimentally validated mutations and hierarchize the key residues into three functional classes, identifying new mutation targets. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the transmembrane subunits are found to be responsible for proton pumping. Put together, the simulations reveal the molecular design principles linking redox reactions to quinone turnover to proton translocation in complex I. AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun Kit AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M. R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 8040 IS - 20 JF - Journal of the American Chemical Society SN - 00027863 TI - Charge transfer and chemo-mechanical coupling in respiratory complex I VL - 142 ER - TY - JOUR AB - When tiny soft ferromagnetic particles are placed along a liquid interface and exposed to a vertical magnetic field, the balance between capillary attraction and magnetic repulsion leads to self-organization into well-defined patterns. Here, we demonstrate experimentally that precessing magnetic fields induce metachronal waves on the periphery of these assemblies, similar to the ones observed in ciliates and some arthropods. The outermost layer of particles behaves like an array of cilia or legs whose sequential movement causes a net and controllable locomotion. This bioinspired many-particle swimming strategy is effective even at low Reynolds number, using only spatially uniform fields to generate the waves. AU - Collard, Ylona AU - Grosjean, Galien M AU - Vandewalle, Nicolas ID - 8036 JF - Communications Physics TI - Magnetically powered metachronal waves induce locomotion in self-assemblies VL - 3 ER - TY - JOUR AB - With decreasing Reynolds number, Re, turbulence in channel flow becomes spatio-temporally intermittent and self-organises into solitary stripes oblique to the mean flow direction. We report here the existence of localised nonlinear travelling wave solutions of the Navier–Stokes equations possessing this obliqueness property. Such solutions are identified numerically using edge tracking coupled with arclength continuation. All solutions emerge in saddle-node bifurcations at values of Re lower than the non-localised solutions. Relative periodic orbit solutions bifurcating from branches of travelling waves have also been computed. A complete parametric study is performed, including their stability, the investigation of their large-scale flow, and the robustness to changes of the numerical domain. AU - Paranjape, Chaitanya S AU - Duguet, Yohann AU - Hof, Björn ID - 8043 JF - Journal of Fluid Mechanics SN - 00221120 TI - Oblique stripe solutions of channel flow VL - 897 ER - TY - GEN AB - The mitochondrial respiratory chain, formed by five protein complexes, utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains, however, fragmentary due to bottlenecks in understanding redox-driven conformational transitions and their interplay with the hydrated proton pathways. Complex I from Thermus thermophilus encases 16 subunits with nine iron–sulfur clusters, reduced by electrons from NADH. Here, employing the latest crystal structure of T. thermophilus complex I, we have used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron–sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which allosterically couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol forma design essential for menaquinol release. Remarkably, the barriers to diffusive menaquinone dynamics are lesser than that of the more ubiquitous ubiquinone, and the naphthoquinone headgroup of the former furnishes stronger binding interactions with the pocket, favoring menaquinone for charge transport in T. thermophilus. Our computations are consistent with experimentally validated mutations and hierarchize the key residues into three functional classes, identifying new mutation targets. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the transmembrane subunits are found to be responsible for proton pumping. Put together, the simulations reveal the molecular design principles linking redox reactions to quinone turnover to proton translocation in complex I. AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M. R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 9326 TI - Charge transfer and chemo-mechanical coupling in respiratory complex I ER - TY - JOUR AB - We consider systems of N bosons in a box of volume one, interacting through a repulsive two-body potential of the form κN3β−1V(Nβx). For all 0<β<1, and for sufficiently small coupling constant κ>0, we establish the validity of Bogolyubov theory, identifying the ground state energy and the low-lying excitation spectrum up to errors that vanish in the limit of large N. AU - Boccato, Chiara AU - Brennecke, Christian AU - Cenatiempo, Serena AU - Schlein, Benjamin ID - 8042 IS - 7 JF - Journal of the European Mathematical Society SN - 14359855 TI - The excitation spectrum of Bose gases interacting through singular potentials VL - 22 ER - TY - GEN AB - Additional analyses of the trajectories AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun Kit AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M.R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 9713 TI - Supporting information ER - TY - GEN AU - Gupta, Chitrak AU - Khaniya, Umesh AU - Chan, Chun Kit AU - Dehez, Francois AU - Shekhar, Mrinal AU - Gunner, M.R. AU - Sazanov, Leonid A AU - Chipot, Christophe AU - Singharoy, Abhishek ID - 9878 TI - Movies ER - TY - JOUR AB - Background: The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment. Methods: The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo. Results: Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system. Conclusion: We propose that the chemokine axis CCL20–CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy. AU - Hippe, Andreas AU - Braun, Stephan Alexander AU - Oláh, Péter AU - Gerber, Peter Arne AU - Schorr, Anne AU - Seeliger, Stephan AU - Holtz, Stephanie AU - Jannasch, Katharina AU - Pivarcsi, Andor AU - Buhren, Bettina AU - Schrumpf, Holger AU - Kislat, Andreas AU - Bünemann, Erich AU - Steinhoff, Martin AU - Fischer, Jens AU - Lira, Sérgio A. AU - Boukamp, Petra AU - Hevezi, Peter AU - Stoecklein, Nikolas Hendrik AU - Hoffmann, Thomas AU - Alves, Frauke AU - Sleeman, Jonathan AU - Bauer, Thomas AU - Klufa, Jörg AU - Amberg, Nicole AU - Sibilia, Maria AU - Zlotnik, Albert AU - Müller-Homey, Anja AU - Homey, Bernhard ID - 8093 JF - British Journal of Cancer SN - 0007-0920 TI - EGFR/Ras-induced CCL20 production modulates the tumour microenvironment VL - 123 ER - TY - JOUR AB - In the setting of the fractional quantum Hall effect we study the effects of strong, repulsive two-body interaction potentials of short range. We prove that Haldane’s pseudo-potential operators, including their pre-factors, emerge as mathematically rigorous limits of such interactions when the range of the potential tends to zero while its strength tends to infinity. In a common approach the interaction potential is expanded in angular momentum eigenstates in the lowest Landau level, which amounts to taking the pre-factors to be the moments of the potential. Such a procedure is not appropriate for very strong interactions, however, in particular not in the case of hard spheres. We derive the formulas valid in the short-range case, which involve the scattering lengths of the interaction potential in different angular momentum channels rather than its moments. Our results hold for bosons and fermions alike and generalize previous results in [6], which apply to bosons in the lowest angular momentum channel. Our main theorem asserts the convergence in a norm-resolvent sense of the Hamiltonian on the whole Hilbert space, after appropriate energy scalings, to Hamiltonians with contact interactions in the lowest Landau level. AU - Seiringer, Robert AU - Yngvason, Jakob ID - 8091 JF - Journal of Statistical Physics SN - 00224715 TI - Emergence of Haldane pseudo-potentials in systems with short-range interactions VL - 181 ER -