TY - JOUR AB - Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation. AU - Torrini, Consuelo AU - Cubero, Ryan J AU - Dirkx, Ellen AU - Braga, Luca AU - Ali, Hashim AU - Prosdocimo, Giulia AU - Gutierrez, Maria Ines AU - Collesi, Chiara AU - Licastro, Danilo AU - Zentilin, Lorena AU - Mano, Miguel AU - Zacchigna, Serena AU - Vendruscolo, Michele AU - Marsili, Matteo AU - Samal, Areejit AU - Giacca, Mauro ID - 7128 IS - 9 JF - Cell Reports KW - cardiomyocyte KW - cell cycle KW - Cofilin2 KW - cytoskeleton KW - Hippo KW - microRNA KW - regeneration KW - YAP SN - 2211-1247 TI - Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation VL - 27 ER - TY - JOUR AB - We show that statistical criticality, i.e. the occurrence of power law frequency distributions, arises in samples that are maximally informative about the underlying generating process. In order to reach this conclusion, we first identify the frequency with which different outcomes occur in a sample, as the variable carrying useful information on the generative process. The entropy of the frequency, that we call relevance, provides an upper bound to the number of informative bits. This differs from the entropy of the data, that we take as a measure of resolution. Samples that maximise relevance at a given resolution—that we call maximally informative samples—exhibit statistical criticality. In particular, Zipf's law arises at the optimal trade-off between resolution (i.e. compression) and relevance. As a byproduct, we derive a bound of the maximal number of parameters that can be estimated from a dataset, in the absence of prior knowledge on the generative model. Furthermore, we relate criticality to the statistical properties of the representation of the data generating process. We show that, as a consequence of the concentration property of the asymptotic equipartition property, representations that are maximally informative about the data generating process are characterised by an exponential distribution of energy levels. This arises from a principle of minimal entropy, that is conjugate of the maximum entropy principle in statistical mechanics. This explains why statistical criticality requires no parameter fine tuning in maximally informative samples. AU - Cubero, Ryan J AU - Jo, Junghyo AU - Marsili, Matteo AU - Roudi, Yasser AU - Song, Juyong ID - 7130 IS - 6 JF - Journal of Statistical Mechanics: Theory and Experiment KW - optimization under uncertainty KW - source coding KW - large deviation SN - 1742-5468 TI - Statistical criticality arises in most informative representations VL - 2019 ER - TY - JOUR AB - In this work, we use algebraic methods for studying distance computation and subgraph detection tasks in the congested clique model. Specifically, we adapt parallel matrix multiplication implementations to the congested clique, obtaining an O(n1−2/ω) round matrix multiplication algorithm, where ω<2.3728639 is the exponent of matrix multiplication. In conjunction with known techniques from centralised algorithmics, this gives significant improvements over previous best upper bounds in the congested clique model. The highlight results include: 1. triangle and 4-cycle counting in O(n0.158) rounds, improving upon the O(n1/3) algorithm of Dolev et al. [DISC 2012], 2. a (1+o(1))-approximation of all-pairs shortest paths in O(n0.158) rounds, improving upon the O~(n1/2)-round (2+o(1))-approximation algorithm given by Nanongkai [STOC 2014], and 3. computing the girth in O(n0.158) rounds, which is the first non-trivial solution in this model. In addition, we present a novel constant-round combinatorial algorithm for detecting 4-cycles. AU - Censor-Hillel, Keren AU - Kaski, Petteri AU - Korhonen, Janne AU - Lenzen, Christoph AU - Paz, Ami AU - Suomela, Jukka ID - 7150 IS - 6 JF - Distributed Computing SN - 0178-2770 TI - Algebraic methods in the congested clique VL - 32 ER - TY - BOOK AB - Wissen Sie, was sich hinter künstlicher Intelligenz und maschinellem Lernen verbirgt? Dieses Sachbuch erklärt Ihnen leicht verständlich und ohne komplizierte Formeln die grundlegenden Methoden und Vorgehensweisen des maschinellen Lernens. Mathematisches Vorwissen ist dafür nicht nötig. Kurzweilig und informativ illustriert Lisa, die Protagonistin des Buches, diese anhand von Alltagssituationen. Ein Buch für alle, die in Diskussionen über Chancen und Risiken der aktuellen Entwicklung der künstlichen Intelligenz und des maschinellen Lernens mit Faktenwissen punkten möchten. Auch für Schülerinnen und Schüler geeignet! ED - Kersting, Kristian ED - Lampert, Christoph ED - Rothkopf, Constantin ID - 7171 SN - 978-3-658-26762-9 TI - Wie Maschinen Lernen: Künstliche Intelligenz Verständlich Erklärt ER - TY - JOUR AB - Aprotic alkali metal–oxygen batteries require reversible formation of metal superoxide or peroxide on cycling. Severe parasitic reactions cause poor rechargeability, efficiency, and cycle life and have been shown to be caused by singlet oxygen (1O2) that forms at all stages of cycling. However, its formation mechanism remains unclear. We show that disproportionation of superoxide, the product or intermediate on discharge and charge, to peroxide and oxygen is responsible for 1O2 formation. While the overall reaction is driven by the stability of peroxide and thus favored by stronger Lewis acidic cations such as Li+, the 1O2 fraction is enhanced by weak Lewis acids such as organic cations. Concurrently, the metal peroxide yield drops with increasing 1O2. The results explain a major parasitic pathway during cell cycling and the growing severity in K–, Na–, and Li–O2 cells based on the growing propensity for disproportionation. High capacities and rates with peroxides are now realized to require solution processes, which form peroxide or release O2via disproportionation. The results therefore establish the central dilemma that disproportionation is required for high capacity but also responsible for irreversible reactions. Highly reversible cell operation requires hence finding reaction routes that avoid disproportionation. AU - Mourad, Eléonore AU - Petit, Yann K. AU - Spezia, Riccardo AU - Samojlov, Aleksej AU - Summa, Francesco F. AU - Prehal, Christian AU - Leypold, Christian AU - Mahne, Nika AU - Slugovc, Christian AU - Fontaine, Olivier AU - Brutti, Sergio AU - Freunberger, Stefan Alexander ID - 7275 IS - 8 JF - Energy & Environmental Science SN - 1754-5692 TI - Singlet oxygen from cation driven superoxide disproportionation and consequences for aprotic metal–O2 batteries VL - 12 ER - TY - JOUR AB - Non-aqueous lithium-oxygen batteries cycle by forming lithium peroxide during discharge and oxidizing it during recharge. The significant problem of oxidizing the solid insulating lithium peroxide can greatly be facilitated by incorporating redox mediators that shuttle electron-holes between the porous substrate and lithium peroxide. Redox mediator stability is thus key for energy efficiency, reversibility, and cycle life. However, the gradual deactivation of redox mediators during repeated cycling has not conclusively been explained. Here, we show that organic redox mediators are predominantly decomposed by singlet oxygen that forms during cycling. Their reaction with superoxide, previously assumed to mainly trigger their degradation, peroxide, and dioxygen, is orders of magnitude slower in comparison. The reduced form of the mediator is markedly more reactive towards singlet oxygen than the oxidized form, from which we derive reaction mechanisms supported by density functional theory calculations. Redox mediators must thus be designed for stability against singlet oxygen. AU - Kwak, Won-Jin AU - Kim, Hun AU - Petit, Yann K. AU - Leypold, Christian AU - Nguyen, Trung Thien AU - Mahne, Nika AU - Redfern, Paul AU - Curtiss, Larry A. AU - Jung, Hun-Gi AU - Borisov, Sergey M. AU - Freunberger, Stefan Alexander AU - Sun, Yang-Kook ID - 7280 JF - Nature Communications SN - 2041-1723 TI - Deactivation of redox mediators in lithium-oxygen batteries by singlet oxygen VL - 10 ER - TY - JOUR AB - Singlet oxygen (1O2) causes a major fraction of the parasitic chemistry during the cycling of non‐aqueous alkali metal‐O2 batteries and also contributes to interfacial reactivity of transition‐metal oxide intercalation compounds. We introduce DABCOnium, the mono alkylated form of 1,4‐diazabicyclo[2.2.2]octane (DABCO), as an efficient 1O2 quencher with an unusually high oxidative stability of ca. 4.2 V vs. Li/Li+. Previous quenchers are strongly Lewis basic amines with too low oxidative stability. DABCOnium is an ionic liquid, non‐volatile, highly soluble in the electrolyte, stable against superoxide and peroxide, and compatible with lithium metal. The electrochemical stability covers the required range for metal–O2 batteries and greatly reduces 1O2 related parasitic chemistry as demonstrated for the Li–O2 cell. AU - Petit, Yann K. AU - Leypold, Christian AU - Mahne, Nika AU - Mourad, Eléonore AU - Schafzahl, Lukas AU - Slugovc, Christian AU - Borisov, Sergey M. AU - Freunberger, Stefan Alexander ID - 7276 IS - 20 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - DABCOnium: An efficient and high-voltage stable singlet oxygen quencher for metal-O2 cells VL - 58 ER - TY - JOUR AB - Li–O2 batteries are plagued by side reactions that cause poor rechargeability and efficiency. These reactions were recently revealed to be predominantly caused by singlet oxygen, which can be neutralized by chemical traps or physical quenchers. However, traps are irreversibly consumed and thus only active for a limited time, and so far identified quenchers lack oxidative stability to be suitable for typically required recharge potentials. Thus, reducing the charge potential within the stability limit of the quencher and/or finding more stable quenchers is required. Here, we show that dimethylphenazine as a redox mediator decreases the charge potential well within the stability limit of the quencher 1,4-diazabicyclo[2.2.2]octane. The quencher can thus mitigate the parasitic reactions without being oxidatively decomposed. At the same time the quencher protects the redox mediator from singlet oxygen attack. The mutual conservation of the redox mediator and the quencher is rational for stable and effective Li–O2 batteries. AU - Kwak, Won-Jin AU - Freunberger, Stefan Alexander AU - Kim, Hun AU - Park, Jiwon AU - Nguyen, Trung Thien AU - Jung, Hun-Gi AU - Byon, Hye Ryung AU - Sun, Yang-Kook ID - 7281 IS - 11 JF - ACS Catalysis SN - 2155-5435 TI - Mutual conservation of redox mediator and singlet oxygen quencher in Lithium–Oxygen batteries VL - 9 ER - TY - JOUR AB - Interphases that form on the anode surface of lithium-ion batteries are critical for performance and lifetime, but are poorly understood. Now, a decade-old misconception regarding a main component of the interphase has been revealed, which could potentially lead to improved devices. AU - Freunberger, Stefan Alexander ID - 7282 IS - 9 JF - Nature Chemistry SN - 1755-4330 TI - Interphase identity crisis VL - 11 ER - TY - JOUR AB - Potassium–air batteries, which suffer from oxygen cathode and potassium metal anode degradation, can be cycled thousands of times when an organic anode replaces the metal. AU - Petit, Yann K. AU - Freunberger, Stefan Alexander ID - 7283 IS - 4 JF - Nature Materials SN - 1476-1122 TI - Thousands of cycles VL - 18 ER - TY - JOUR AB - In this issue of Joule, Dongmin Im and coworkers from Samsung in South Korea describe a prototype lithium-O2 battery that reaches ∼700 Wh kg–1 and ∼600 Wh L–1 on the cell level. They cut all components to the minimum to reach this value. Difficulties filling the pores with discharge product and inhomogeneous cell utilization turn out to limit the achievable energy. Their work underlines the importance of reporting performance with respect to full cell weight and volume. AU - Prehal, Christian AU - Freunberger, Stefan Alexander ID - 7284 IS - 2 JF - Joule SN - 2542-4351 TI - Li-O2 cell-scale energy densities VL - 3 ER - TY - GEN AB - Telencephalic organoids generated from human pluripotent stem cells (hPSCs) are emerging as an effective system to study the distinct features of the developing human brain and the underlying causes of many neurological disorders. While progress in organoid technology has been steadily advancing, many challenges remain including rampant batch-to-batch and cell line-to-cell line variability and irreproducibility. Here, we demonstrate that a major contributor to successful cortical organoid production is the manner in which hPSCs are maintained prior to differentiation. Optimal results were achieved using fibroblast-feeder-supported hPSCs compared to feeder-independent cells, related to differences in their transcriptomic states. Feeder-supported hPSCs display elevated activation of diverse TGFβ superfamily signaling pathways and increased expression of genes associated with naïve pluripotency. We further identify combinations of TGFβ-related growth factors that are necessary and together sufficient to impart broad telencephalic organoid competency to feeder-free hPSCs and enable reproducible formation of brain structures suitable for disease modeling. AU - Watanabe, Momoko AU - Haney, Jillian R. AU - Vishlaghi, Neda AU - Turcios, Felix AU - Buth, Jessie E. AU - Gu, Wen AU - Collier, Amanda J. AU - Miranda, Osvaldo AU - Chen, Di AU - Sabri, Shan AU - Clark, Amander T. AU - Plath, Kathrin AU - Christofk, Heather R. AU - Gandal, Michael J. AU - Novitch, Bennett G. ID - 7358 T2 - bioRxiv TI - TGFβ superfamily signaling regulates the state of human stem cell pluripotency and competency to create telencephalic organoids ER - TY - CONF AB - The genus g(G) of a graph G is the minimum g such that G has an embedding on the orientable surface M_g of genus g. A drawing of a graph on a surface is independently even if every pair of nonadjacent edges in the drawing crosses an even number of times. The Z_2-genus of a graph G, denoted by g_0(G), is the minimum g such that G has an independently even drawing on M_g. By a result of Battle, Harary, Kodama and Youngs from 1962, the graph genus is additive over 2-connected blocks. In 2013, Schaefer and Stefankovic proved that the Z_2-genus of a graph is additive over 2-connected blocks as well, and asked whether this result can be extended to so-called 2-amalgamations, as an analogue of results by Decker, Glover, Huneke, and Stahl for the genus. We give the following partial answer. If G=G_1 cup G_2, G_1 and G_2 intersect in two vertices u and v, and G-u-v has k connected components (among which we count the edge uv if present), then |g_0(G)-(g_0(G_1)+g_0(G_2))|<=k+1. For complete bipartite graphs K_{m,n}, with n >= m >= 3, we prove that g_0(K_{m,n})/g(K_{m,n})=1-O(1/n). Similar results are proved also for the Euler Z_2-genus. We express the Z_2-genus of a graph using the minimum rank of partial symmetric matrices over Z_2; a problem that might be of independent interest. AU - Fulek, Radoslav AU - Kyncl, Jan ID - 7401 SN - 1868-8969 T2 - 35th International Symposium on Computational Geometry (SoCG 2019) TI - Z_2-Genus of graphs and minimum rank of partial symmetric matrices VL - 129 ER - TY - CHAP AB - We illustrate the ingredients of the state-of-the-art of model-based approach for the formal design and verification of cyber-physical systems. To capture the interaction between a discrete controller and its continuously evolving environment, we use the formal models of timed and hybrid automata. We explain the steps of modeling and verification in the tools Uppaal and SpaceEx using a case study based on a dual-chamber implantable pacemaker monitoring a human heart. We show how to design a model as a composition of components, how to construct models at varying levels of detail, how to establish that one model is an abstraction of another, how to specify correctness requirements using temporal logic, and how to verify that a model satisfies a logical requirement. AU - Alur, Rajeev AU - Giacobbe, Mirco AU - Henzinger, Thomas A AU - Larsen, Kim G. AU - Mikučionis, Marius ED - Steffen, Bernhard ED - Woeginger, Gerhard ID - 7453 SN - 1611-3349 T2 - Computing and Software Science TI - Continuous-time models for system design and analysis VL - 10000 ER - TY - JOUR AB - We report the fabrication of BaTiO3-Ni magnetoelectric nanocomposites comprising of BaTiO3 nanotubes surrounded by Ni matrix. BaTiO3 nanotubes obtained from the hydrothermal transformation of TiO2 have both inner and outer surfaces, which facilitates greater magnetoelectric coupling with the surrounding Ni matrix. The magnetoelectric coupling was studied by measuring the piezoelectric behavior in the presence of an in-plane direct magnetic field. A higher magnetoelectric voltage coefficient of 110 mV/cm·Oe was obtained, because of better coupling between Ni and BaTiO3 through the walls of the nanotubes. Such nanocomposite developed directly on Ti substrate may lead to efficient fabrication of magnetoelectric devices. AU - Vadla, Samba Siva AU - Costanzo, Tommaso AU - John, Subish AU - Caruntu, Gabriel AU - Roy, Somnath C. ID - 7459 JF - Scripta Materialia SN - 1359-6462 TI - Local probing of magnetoelectric coupling in BaTiO3-Ni 1–3 composites VL - 159 ER - TY - JOUR AB - The sebaceous gland (SG) is an essential component of the skin, and SG dysfunction is debilitating1,2. Yet, the cellular bases for its origin, development and subsequent maintenance remain poorly understood. Here, we apply large-scale quantitative fate mapping to define the patterns of cell fate behaviour during SG development and maintenance. We show that the SG develops from a defined number of lineage-restricted progenitors that undergo a programme of independent and stochastic cell fate decisions. Following an expansion phase, equipotent progenitors transition into a phase of homeostatic turnover, which is correlated with changes in the mechanical properties of the stroma and spatial restrictions on gland size. Expression of the oncogene KrasG12D results in a release from these constraints and unbridled gland expansion. Quantitative clonal fate analysis reveals that, during this phase, the primary effect of the Kras oncogene is to drive a constant fate bias with little effect on cell division rates. These findings provide insight into the developmental programme of the SG, as well as the mechanisms that drive tumour progression and gland dysfunction. AU - Andersen, Marianne Stemann AU - Hannezo, Edouard B AU - Ulyanchenko, Svetlana AU - Estrach, Soline AU - Antoku, Yasuko AU - Pisano, Sabrina AU - Boonekamp, Kim E. AU - Sendrup, Sarah AU - Maimets, Martti AU - Pedersen, Marianne Terndrup AU - Johansen, Jens V. AU - Clement, Ditte L. AU - Feral, Chloe C. AU - Simons, Benjamin D. AU - Jensen, Kim B. ID - 7476 IS - 8 JF - Nature Cell Biology SN - 1465-7392 TI - Tracing the cellular dynamics of sebaceous gland development in normal and perturbed states VL - 21 ER - TY - JOUR AB - Although the aggregation of the amyloid-β peptide (Aβ) into amyloid fibrils is a well-established hallmark of Alzheimer’s disease, the complex mechanisms linking this process to neurodegeneration are still incompletely understood. The nematode worm C. elegans is a valuable model organism through which to study these mechanisms because of its simple nervous system and its relatively short lifespan. Standard Aβ-based C. elegans models of Alzheimer’s disease are designed to study the toxic effects of the overexpression of Aβ in the muscle or nervous systems. However, the wide variety of effects associated with the tissue-level overexpression of Aβ makes it difficult to single out and study specific cellular mechanisms related to the onset of Alzheimer’s disease. Here, to better understand how to investigate the early events affecting neuronal signalling, we created a C. elegans model expressing Aβ42, the 42-residue form of Aβ, from a single-copy gene insertion in just one pair of glutamatergic sensory neurons, the BAG neurons. In behavioural assays, we found that the Aβ42-expressing animals displayed a subtle modulation of the response to CO2, compared to controls. Ca2+ imaging revealed that the BAG neurons in young Aβ42-expressing nematodes were activated more strongly than in control animals, and that neuronal activation remained intact until old age. Taken together, our results suggest that Aβ42-expression in this very subtle model of AD is sufficient to modulate the behavioural response but not strong enough to generate significant neurotoxicity, suggesting that slightly more aggressive perturbations will enable effectively studies of the links between the modulation of a physiological response and its associated neurotoxicity. AU - Sinnige, Tessa AU - Ciryam, Prashanth AU - Casford, Samuel AU - Dobson, Christopher M. AU - de Bono, Mario AU - Vendruscolo, Michele ID - 7548 IS - 5 JF - PLOS ONE SN - 1932-6203 TI - Expression of the amyloid-β peptide in a single pair of C. elegans sensory neurons modulates the associated behavioural response VL - 14 ER - TY - JOUR AB - The BH3-only family of proteins is key for initiating apoptosis in a variety of contexts, and may also contribute to non-apoptotic cellular processes. Historically, the nematode Caenorhabditis elegans has provided a powerful system for studying and identifying conserved regulators of BH3-only proteins. In C. elegans, the BH3-only protein egl-1 is expressed during development to cell-autonomously trigger most developmental cell deaths. Here we provide evidence that egl-1 is also transcribed after development in the sensory neuron pair URX without inducing apoptosis. We used genetic screening and epistasis analysis to determine that its transcription is regulated in URX by neuronal activity and/or in parallel by orthologs of Protein Kinase G and the Salt-Inducible Kinase family. Because several BH3-only family proteins are also expressed in the adult nervous system of mammals, we suggest that studying egl-1 expression in URX may shed light on mechanisms that regulate conserved family members in higher organisms. AU - Cohn, Jesse AU - Dwivedi, Vivek AU - Valperga, Giulio AU - Zarate, Nicole AU - de Bono, Mario AU - Horvitz, H. Robert AU - Pierce, Jonathan T. ID - 7547 IS - 11 JF - G3: Genes, Genomes, Genetics SN - 2160-1836 TI - Activity-dependent regulation of the proapoptotic BH3-only gene egl-1 in a living neuron pair in Caenorhabditis elegans VL - 9 ER - TY - JOUR AB - We consider an optimal control problem for an abstract nonlinear dissipative evolution equation. The differential constraint is penalized by augmenting the target functional by a nonnegative global-in-time functional which is null-minimized in the evolution equation is satisfied. Different variational settings are presented, leading to the convergence of the penalization method for gradient flows, noncyclic and semimonotone flows, doubly nonlinear evolutions, and GENERIC systems. AU - Portinale, Lorenzo AU - Stefanelli, Ulisse ID - 7550 IS - 2 JF - Advances in Mathematical Sciences and Applications SN - 1343-4373 TI - Penalization via global functionals of optimal-control problems for dissipative evolution VL - 28 ER - TY - GEN AB - There is increasing evidence that protein binding to specific sites along DNA can activate the reading out of genetic information without coming into direct physical contact with the gene. There also is evidence that these distant but interacting sites are embedded in a liquid droplet of proteins which condenses out of the surrounding solution. We argue that droplet-mediated interactions can account for crucial features of gene regulation only if the droplet is poised at a non-generic point in its phase diagram. We explore a minimal model that embodies this idea, show that this model has a natural mechanism for self-tuning, and suggest direct experimental tests. AU - Bialek, William AU - Gregor, Thomas AU - Tkačik, Gašper ID - 7552 T2 - arXiv:1912.08579 TI - Action at a distance in transcriptional regulation ER -