TY - JOUR AB - Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation. AU - Felix, Jan AU - Weinhäupl, Katharina AU - Chipot, Christophe AU - Dehez, François AU - Hessel, Audrey AU - Gauto, Diego F. AU - Morlot, Cecile AU - Abian, Olga AU - Gutsche, Irina AU - Velazquez-Campoy, Adrian AU - Schanda, Paul AU - Fraga, Hugo ID - 8406 IS - 9 JF - Science Advances SN - 2375-2548 TI - Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors VL - 5 ER - TY - JOUR AB - NMR relaxation dispersion methods provide a holistic way to observe microsecond time-scale protein backbone motion both in solution and in the solid state. Different nuclei (1H and 15N) and different relaxation dispersion techniques (Bloch–McConnell and near-rotary-resonance) give complementary information about the amplitudes and time scales of the conformational dynamics and provide comprehensive insights into the mechanistic details of the structural rearrangements. In this paper, we exemplify the benefits of the combination of various solution- and solid-state relaxation dispersion methods on a microcrystalline protein (α-spectrin SH3 domain), for which we are able to identify and model the functionally relevant conformational rearrangements around the ligand recognition loop occurring on multiple microsecond time scales. The observed loop motions suggest that the SH3 domain exists in a binding-competent conformation in dynamic equilibrium with a sterically impaired ground-state conformation both in solution and in crystalline form. This inherent plasticity between the interconverting macrostates is compatible with a conformational-preselection model and provides new insights into the recognition mechanisms of SH3 domains. AU - Rovó, Petra AU - Smith, Colin A. AU - Gauto, Diego AU - de Groot, Bert L. AU - Schanda, Paul AU - Linser, Rasmus ID - 8413 IS - 2 JF - Journal of the American Chemical Society KW - Colloid and Surface Chemistry KW - Biochemistry KW - General Chemistry KW - Catalysis SN - 0002-7863 TI - Mechanistic insights into microsecond time-scale motion of solid proteins using complementary 15N and 1H relaxation dispersion techniques VL - 141 ER - TY - JOUR AB - Microsecond to millisecond timescale backbone dynamics of the amyloid core residues in Y145Stop human prion protein (PrP) fibrils were investigated by using 15N rotating frame (R1ρ) relaxation dispersion solid‐state nuclear magnetic resonance spectroscopy over a wide range of spin‐lock fields. Numerical simulations enabled the experimental relaxation dispersion profiles for most of the fibril core residues to be modelled by using a two‐state exchange process with a common exchange rate of 1000 s−1, corresponding to protein backbone motion on the timescale of 1 ms, and an excited‐state population of 2 %. We also found that the relaxation dispersion profiles for several amino acids positioned near the edges of the most structured regions of the amyloid core were better modelled by assuming somewhat higher excited‐state populations (∼5–15 %) and faster exchange rate constants, corresponding to protein backbone motions on the timescale of ∼100–300 μs. The slow backbone dynamics of the core residues were evaluated in the context of the structural model of human Y145Stop PrP amyloid. AU - Shannon, Matthew D. AU - Theint, Theint AU - Mukhopadhyay, Dwaipayan AU - Surewicz, Krystyna AU - Surewicz, Witold K. AU - Marion, Dominique AU - Schanda, Paul AU - Jaroniec, Christopher P. ID - 8412 IS - 2 JF - ChemPhysChem KW - Physical and Theoretical Chemistry KW - Atomic and Molecular Physics KW - and Optics SN - 1439-4235 TI - Conformational dynamics in the core of human Y145Stop prion protein amyloid probed by relaxation dispersion NMR VL - 20 ER - TY - JOUR AB - Studying protein dynamics on microsecond‐to‐millisecond (μs‐ms) time scales can provide important insight into protein function. In magic‐angle‐spinning (MAS) NMR, μs dynamics can be visualized by R1p rotating‐frame relaxation dispersion experiments in different regimes of radio‐frequency field strengths: at low RF field strength, isotropic‐chemical‐shift fluctuation leads to “Bloch‐McConnell‐type” relaxation dispersion, while when the RF field approaches rotary resonance conditions bond angle fluctuations manifest as increased R1p rate constants (“Near‐Rotary‐Resonance Relaxation Dispersion”, NERRD). Here we explore the joint analysis of both regimes to gain comprehensive insight into motion in terms of geometric amplitudes, chemical‐shift changes, populations and exchange kinetics. We use a numerical simulation procedure to illustrate these effects and the potential of extracting exchange parameters, and apply the methodology to the study of a previously described conformational exchange process in microcrystalline ubiquitin. AU - Marion, Dominique AU - Gauto, Diego F. AU - Ayala, Isabel AU - Giandoreggio-Barranco, Karine AU - Schanda, Paul ID - 8411 IS - 2 JF - ChemPhysChem KW - Physical and Theoretical Chemistry KW - Atomic and Molecular Physics KW - and Optics SN - 1439-4235 TI - Microsecond protein dynamics from combined Bloch-McConnell and Near-Rotary-Resonance R1p relaxation-dispersion MAS NMR VL - 20 ER - TY - JOUR AB - We consider billiards obtained by removing three strictly convex obstacles satisfying the non-eclipse condition on the plane. The restriction of the dynamics to the set of non-escaping orbits is conjugated to a subshift on three symbols that provides a natural labeling of all periodic orbits. We study the following inverse problem: does the Marked Length Spectrum (i.e., the set of lengths of periodic orbits together with their labeling), determine the geometry of the billiard table? We show that from the Marked Length Spectrum it is possible to recover the curvature at periodic points of period two, as well as the Lyapunov exponent of each periodic orbit. AU - Bálint, Péter AU - De Simoi, Jacopo AU - Kaloshin, Vadim AU - Leguil, Martin ID - 8415 IS - 3 JF - Communications in Mathematical Physics KW - Mathematical Physics KW - Statistical and Nonlinear Physics SN - 0010-3616 TI - Marked length spectrum, homoclinic orbits and the geometry of open dispersing billiards VL - 374 ER - TY - JOUR AB - The bacterial cell wall is composed of the peptidoglycan (PG), a large polymer that maintains the integrity of the bacterial cell. Due to its multi-gigadalton size, heterogeneity, and dynamics, atomic-resolution studies are inherently complex. Solid-state NMR is an important technique to gain insight into its structure, dynamics and interactions. Here, we explore the possibilities to study the PG with ultra-fast (100 kHz) magic-angle spinning NMR. We demonstrate that highly resolved spectra can be obtained, and show strategies to obtain site-specific resonance assignments and distance information. We also explore the use of proton-proton correlation experiments, thus opening the way for NMR studies of intact cell walls without the need for isotope labeling. AU - Bougault, Catherine AU - Ayala, Isabel AU - Vollmer, Waldemar AU - Simorre, Jean-Pierre AU - Schanda, Paul ID - 8409 IS - 1 JF - Journal of Structural Biology KW - Structural Biology SN - 1047-8477 TI - Studying intact bacterial peptidoglycan by proton-detected NMR spectroscopy at 100 kHz MAS frequency VL - 206 ER - TY - JOUR AU - Schanda, Paul ID - 8407 JF - Journal of Magnetic Resonance KW - Nuclear and High Energy Physics KW - Biophysics KW - Biochemistry KW - Condensed Matter Physics SN - 1090-7807 TI - Relaxing with liquids and solids – A perspective on biomolecular dynamics VL - 306 ER - TY - JOUR AU - Schanda, Paul AU - Chekmenev, Eduard Y. ID - 8410 IS - 2 JF - ChemPhysChem SN - 1439-4235 TI - NMR for Biological Systems VL - 20 ER - TY - CONF AB - This report presents the results of a friendly competition for formal verification of continuous and hybrid systems with linear continuous dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In its third edition, seven tools have been applied to solve six different benchmark problems in the category for linear continuous dynamics (in alphabetical order): CORA, CORA/SX, HyDRA, Hylaa, JuliaReach, SpaceEx, and XSpeed. This report is a snapshot of the current landscape of tools and the types of benchmarks they are particularly suited for. Due to the diversity of problems, we are not ranking tools, yet the presented results provide one of the most complete assessments of tools for the safety verification of continuous and hybrid systems with linear continuous dynamics up to this date. AU - Althoff, Matthias AU - Bak, Stanley AU - Forets, Marcelo AU - Frehse, Goran AU - Kochdumper, Niklas AU - Ray, Rajarshi AU - Schilling, Christian AU - Schupp, Stefan ID - 8570 T2 - EPiC Series in Computing TI - ARCH-COMP19 Category Report: Continuous and hybrid systems with linear continuous dynamics VL - 61 ER - TY - JOUR AB - Inhibiting the histone H3–ASF1 (anti‐silencing function 1) protein–protein interaction (PPI) represents a potential approach for treating numerous cancers. As an α‐helix‐mediated PPI, constraining the key histone H3 helix (residues 118–135) is a strategy through which chemical probes might be elaborated to test this hypothesis. In this work, variant H3118–135 peptides bearing pentenylglycine residues at the i and i+4 positions were constrained by olefin metathesis. Biophysical analyses revealed that promotion of a bioactive helical conformation depends on the position at which the constraint is introduced, but that the potency of binding towards ASF1 is unaffected by the constraint and instead that enthalpy–entropy compensation occurs. AU - Bakail, May M AU - Rodriguez‐Marin, Silvia AU - Hegedüs, Zsófia AU - Perrin, Marie E. AU - Ochsenbein, Françoise AU - Wilson, Andrew J. ID - 9016 IS - 7 JF - ChemBioChem SN - 1439-4227 TI - Recognition of ASF1 by using hydrocarbon‐constrained peptides VL - 20 ER - TY - JOUR AB - Molecular motors are essential to the living, generating fluctuations that boost transport and assist assembly. Active colloids, that consume energy to move, hold similar potential for man-made materials controlled by forces generated from within. Yet, their use as a powerhouse in materials science lacks. Here we show a massive acceleration of the annealing of a monolayer of passive beads by moderate addition of self-propelled microparticles. We rationalize our observations with a model of collisions that drive active fluctuations and activate the annealing. The experiment is quantitatively compared with Brownian dynamic simulations that further unveil a dynamical transition in the mechanism of annealing. Active dopants travel uniformly in the system or co-localize at the grain boundaries as a result of the persistence of their motion. Our findings uncover the potential of internal activity to control materials and lay the groundwork for the rise of materials science beyond equilibrium. AU - Ramananarivo, Sophie AU - Ducrot, Etienne AU - Palacci, Jérémie A ID - 9060 IS - 1 JF - Nature Communications KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Physics and Astronomy KW - General Chemistry SN - 2041-1723 TI - Activity-controlled annealing of colloidal monolayers VL - 10 ER - TY - JOUR AB - Epigenetic reprogramming is required for proper regulation of gene expression in eukaryotic organisms. In Arabidopsis, active DNA demethylation is crucial for seed viability, pollen function, and successful reproduction. The DEMETER (DME) DNA glycosylase initiates localized DNA demethylation in vegetative and central cells, so-called companion cells that are adjacent to sperm and egg gametes, respectively. In rice, the central cell genome displays local DNA hypomethylation, suggesting that active DNA demethylation also occurs in rice; however, the enzyme responsible for this process is unknown. One candidate is the rice REPRESSOR OF SILENCING 1a (ROS1a) gene, which is related to DME and is essential for rice seed viability and pollen function. Here, we report genome-wide analyses of DNA methylation in wild-type and ros1a mutant sperm and vegetative cells. We find that the rice vegetative cell genome is locally hypomethylated compared with sperm by a process that requires ROS1a activity. We show that many ROS1a target sequences in the vegetative cell are hypomethylated in the rice central cell, suggesting that ROS1a also demethylates the central cell genome. Similar to Arabidopsis, we show that sperm non-CG methylation is indirectly promoted by DNA demethylation in the vegetative cell. These results reveal that DNA glycosylase-mediated DNA demethylation processes are conserved in Arabidopsis and rice, plant species that diverged 150 million years ago. Finally, although global non-CG methylation levels of sperm and egg differ, the maternal and paternal embryo genomes show similar non-CG methylation levels, suggesting that rice gamete genomes undergo dynamic DNA methylation reprogramming after cell fusion. AU - Kim, M. Yvonne AU - Ono, Akemi AU - Scholten, Stefan AU - Kinoshita, Tetsu AU - Zilberman, Daniel AU - Okamoto, Takashi AU - Fischer, Robert L. ID - 9460 IS - 19 JF - Proceedings of the National Academy of Sciences KW - Multidisciplinary SN - 0027-8424 TI - DNA demethylation by ROS1a in rice vegetative cells promotes methylation in sperm VL - 116 ER - TY - JOUR AB - A central goal of computational physics and chemistry is to predict material properties by using first-principles methods based on the fundamental laws of quantum mechanics. However, the high computational costs of these methods typically prevent rigorous predictions of macroscopic quantities at finite temperatures, such as heat capacity, density, and chemical potential. Here, we enable such predictions by marrying advanced free-energy methods with data-driven machine-learning interatomic potentials. We show that, for the ubiquitous and technologically essential system of water, a first-principles thermodynamic description not only leads to excellent agreement with experiments, but also reveals the crucial role of nuclear quantum fluctuations in modulating the thermodynamic stabilities of different phases of water. AU - Cheng, Bingqing AU - Engel, Edgar A. AU - Behler, Jörg AU - Dellago, Christoph AU - Ceriotti, Michele ID - 9689 IS - 4 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Ab initio thermodynamics of liquid and solid water VL - 116 ER - TY - JOUR AB - Glyphosate (N-phosphonomethyl glycine) and its commercial herbicide formulations have been shown to exert toxicity via various mechanisms. It has been asserted that glyphosate substitutes for glycine in polypeptide chains leading to protein misfolding and toxicity. However, as no direct evidence exists for glycine to glyphosate substitution in proteins, including in mammalian organisms, we tested this claim by conducting a proteomics analysis of MDA-MB-231 human breast cancer cells grown in the presence of 100 mg/L glyphosate for 6 days. Protein extracts from three treated and three untreated cell cultures were analysed as one TMT-6plex labelled sample, to highlight a specific pattern (+/+/+/−/−/−) of reporter intensities for peptides bearing true glyphosate treatment induced-post translational modifications as well as allowing an investigation of the total proteome. AU - Antoniou, Michael N. AU - Nicolas, Armel AU - Mesnage, Robin AU - Biserni, Martina AU - Rao, Francesco V. AU - Martin, Cristina Vazquez ID - 6819 JF - BMC Research Notes TI - Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells VL - 12 ER - TY - GEN AB - Additional file 1: Table S1. Kinetics of MDA-MB-231 cell growth in either the presence or absence of 100Â mg/L glyphosate. Cell counts are given at day-1 of seeding flasks and following 6-days of continuous culture. Note: no differences in cell numbers were observed between negative control and glyphosate treated cultures. AU - Antoniou, Michael N. AU - Nicolas, Armel AU - Mesnage, Robin AU - Biserni, Martina AU - Rao, Francesco V. AU - Martin, Cristina Vazquez ID - 9784 TI - MOESM1 of Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells ER - TY - GEN AB - More than 100 years after Grigg’s influential analysis of species’ borders, the causes of limits to species’ ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species’ ranges to shift in response to climate change—and yet nearly all of those studies fail to recognise or incorporate evolutionary genetics in a way that relates to theoretical developments. I show that range margins can be understood based on just two measurable parameters: (i) the fitness cost of dispersal—a measure of environmental heterogeneity—and (ii) the strength of genetic drift, which reduces genetic diversity. Together, these two parameters define an ‘expansion threshold’: adaptation fails when genetic drift reduces genetic diversity below that required for adaptation to a heterogeneous environment. When the key parameters drop below this expansion threshold locally, a sharp range margin forms. When they drop below this threshold throughout the species’ range, adaptation collapses everywhere, resulting in either extinction or formation of a fragmented metapopulation. Because the effects of dispersal differ fundamentally with dimension, the second parameter—the strength of genetic drift—is qualitatively different compared to a linear habitat. In two-dimensional habitats, genetic drift becomes effectively independent of selection. It decreases with ‘neighbourhood size’—the number of individuals accessible by dispersal within one generation. Moreover, in contrast to earlier predictions, which neglected evolution of genetic variance and/or stochasticity in two dimensions, dispersal into small marginal populations aids adaptation. This is because the reduction of both genetic and demographic stochasticity has a stronger effect than the cost of dispersal through increased maladaptation. The expansion threshold thus provides a novel, theoretically justified, and testable prediction for formation of the range margin and collapse of the species’ range. AU - Polechova, Jitka ID - 9839 TI - Data from: Is the sky the limit? On the expansion threshold of a species' range ER - TY - JOUR AB - Aromatic residues are located at structurally important sites of many proteins. Probing their interactions and dynamics can provide important functional insight but is challenging in large proteins. Here, we introduce approaches to characterize dynamics of phenylalanine residues using 1H-detected fast magic-angle spinning (MAS) NMR combined with a tailored isotope-labeling scheme. Our approach yields isolated two-spin systems that are ideally suited for artefact-free dynamics measurements, and allows probing motions effectively without molecular-weight limitations. The application to the TET2 enzyme assembly of ~0.5 MDa size, the currently largest protein assigned by MAS NMR, provides insights into motions occurring on a wide range of time scales (ps-ms). We quantitatively probe ring flip motions, and show the temperature dependence by MAS NMR measurements down to 100 K. Interestingly, favorable line widths are observed down to 100 K, with potential implications for DNP NMR. Furthermore, we report the first 13C R1ρ MAS NMR relaxation-dispersion measurements and detect structural excursions occurring on a microsecond time scale in the entry pore to the catalytic chamber and at a trimer interface that was proposed as exit pore. We show that the labeling scheme with deuteration at ca. 50 kHz MAS provides superior resolution compared to 100 kHz MAS experiments with protonated, uniformly 13C-labeled samples. AU - Gauto, Diego F. AU - Macek, Pavel AU - Barducci, Alessandro AU - Fraga, Hugo AU - Hessel, Audrey AU - Terauchi, Tsutomu AU - Gajan, David AU - Miyanoiri, Yohei AU - Boisbouvier, Jerome AU - Lichtenecker, Roman AU - Kainosho, Masatsune AU - Schanda, Paul ID - 8408 IS - 28 JF - Journal of the American Chemical Society KW - Colloid and Surface Chemistry KW - Biochemistry KW - General Chemistry KW - Catalysis SN - 0002-7863 TI - Aromatic ring dynamics, thermal activation, and transient conformations of a 468 kDa enzyme by specific 1H–13C labeling and fast magic-angle spinning NMR VL - 141 ER - TY - JOUR AB - For the Restricted Circular Planar 3 Body Problem, we show that there exists an open set U in phase space of fixed measure, where the set of initial points which lead to collision is O(μ120) dense as μ→0. AU - Guardia, Marcel AU - Kaloshin, Vadim AU - Zhang, Jianlu ID - 8418 IS - 2 JF - Archive for Rational Mechanics and Analysis KW - Mechanical Engineering KW - Mathematics (miscellaneous) KW - Analysis SN - 0003-9527 TI - Asymptotic density of collision orbits in the Restricted Circular Planar 3 Body Problem VL - 233 ER - TY - JOUR AB - In this paper, we show that any smooth one-parameter deformations of a strictly convex integrable billiard table Ω0 preserving the integrability near the boundary have to be tangent to a finite dimensional space passing through Ω0. AU - Huang, Guan AU - Kaloshin, Vadim ID - 8416 IS - 2 JF - Moscow Mathematical Journal SN - 1609-4514 TI - On the finite dimensionality of integrable deformations of strictly convex integrable billiard tables VL - 19 ER - TY - JOUR AB - We review V. I. Arnold’s 1963 celebrated paper [1] Proof of A. N. Kolmogorov’s Theorem on the Conservation of Conditionally Periodic Motions with a Small Variation in the Hamiltonian, and prove that, optimising Arnold’s scheme, one can get “sharp” asymptotic quantitative conditions (as ε → 0, ε being the strength of the perturbation). All constants involved are explicitly computed. AU - Chierchia, Luigi AU - Koudjinan, Edmond ID - 8693 JF - Regular and Chaotic Dynamics TI - V. I. Arnold’s “pointwise” KAM theorem VL - 24 ER - TY - JOUR AB - Anti-silencing function 1 (ASF1) is a conserved H3-H4 histone chaperone involved in histone dynamics during replication, transcription, and DNA repair. Overexpressed in proliferating tissues including many tumors, ASF1 has emerged as a promising therapeutic target. Here, we combine structural, computational, and biochemical approaches to design peptides that inhibit the ASF1-histone interaction. Starting from the structure of the human ASF1-histone complex, we developed a rational design strategy combining epitope tethering and optimization of interface contacts to identify a potent peptide inhibitor with a dissociation constant of 3 nM. When introduced into cultured cells, the inhibitors impair cell proliferation, perturb cell-cycle progression, and reduce cell migration and invasion in a manner commensurate with their affinity for ASF1. Finally, we find that direct injection of the most potent ASF1 peptide inhibitor in mouse allografts reduces tumor growth. Our results open new avenues to use ASF1 inhibitors as promising leads for cancer therapy. AU - Bakail, May M AU - Gaubert, Albane AU - Andreani, Jessica AU - Moal, Gwenaëlle AU - Pinna, Guillaume AU - Boyarchuk, Ekaterina AU - Gaillard, Marie-Cécile AU - Courbeyrette, Regis AU - Mann, Carl AU - Thuret, Jean-Yves AU - Guichard, Bérengère AU - Murciano, Brice AU - Richet, Nicolas AU - Poitou, Adeline AU - Frederic, Claire AU - Le Du, Marie-Hélène AU - Agez, Morgane AU - Roelants, Caroline AU - Gurard-Levin, Zachary A. AU - Almouzni, Geneviève AU - Cherradi, Nadia AU - Guerois, Raphael AU - Ochsenbein, Françoise ID - 9018 IS - 11 JF - Cell Chemical Biology KW - Clinical Biochemistry KW - Molecular Medicine KW - Biochemistry KW - Molecular Biology KW - Pharmacology KW - Drug Discovery SN - 2451-9456 TI - Design on a rational basis of high-affinity peptides inhibiting the histone chaperone ASF1 VL - 26 ER - TY - JOUR AB - Background DNA methylation of active genes, also known as gene body methylation, is found in many animal and plant genomes. Despite this, the transcriptional and developmental role of such methylation remains poorly understood. Here, we explore the dynamic range of DNA methylation in honey bee, a model organism for gene body methylation. Results Our data show that CG methylation in gene bodies globally fluctuates during honey bee development. However, these changes cause no gene expression alterations. Intriguingly, despite the global alterations, tissue-specific CG methylation patterns of complete genes or exons are rare, implying robust maintenance of genic methylation during development. Additionally, we show that CG methylation maintenance fluctuates in somatic cells, while reaching maximum fidelity in sperm cells. Finally, unlike universally present CG methylation, we discovered non-CG methylation specifically in bee heads that resembles such methylation in mammalian brain tissue. Conclusions Based on these results, we propose that gene body CG methylation can oscillate during development if it is kept to a level adequate to preserve function. Additionally, our data suggest that heightened non-CG methylation is a conserved regulator of animal nervous systems. AU - Harris, Keith D. AU - Lloyd, James P. B. AU - Domb, Katherine AU - Zilberman, Daniel AU - Zemach, Assaf ID - 9530 JF - Epigenetics and Chromatin TI - DNA methylation is maintained with high fidelity in the honey bee germline and exhibits global non-functional fluctuations during somatic development VL - 12 ER - TY - JOUR AB - Consider integers 𝑘,ℓ such that 0⩽ℓ⩽(𝑘2) . Given a large graph 𝐺 , what is the fraction of 𝑘 -vertex subsets of 𝐺 which span exactly ℓ edges? When 𝐺 is empty or complete, and ℓ is zero or (𝑘2) , this fraction can be exactly 1. On the other hand, if ℓ is far from these extreme values, one might expect that this fraction is substantially smaller than 1. This was recently proved by Alon, Hefetz, Krivelevich, and Tyomkyn who initiated the systematic study of this question and proposed several natural conjectures. Let ℓ∗=min{ℓ,(𝑘2)−ℓ} . Our main result is that for any 𝑘 and ℓ , the fraction of 𝑘 -vertex subsets that span ℓ edges is at most log𝑂(1)(ℓ∗/𝑘)√ 𝑘/ℓ∗, which is best-possible up to the logarithmic factor. This improves on multiple results of Alon, Hefetz, Krivelevich, and Tyomkyn, and resolves one of their conjectures. In addition, we also make some first steps towards some analogous questions for hypergraphs. Our proofs involve some Ramsey-type arguments, and a number of different probabilistic tools, such as polynomial anticoncentration inequalities, hypercontractivity, and a coupling trick for random variables defined on a ‘slice’ of the Boolean hypercube. AU - Kwan, Matthew Alan AU - Sudakov, Benny AU - Tran, Tuan ID - 9586 IS - 3 JF - Journal of the London Mathematical Society SN - 0024-6107 TI - Anticoncentration for subgraph statistics VL - 99 ER - TY - JOUR AB - An r-cut of a k-uniform hypergraph H is a partition of the vertex set of H into r parts and the size of the cut is the number of edges which have a vertex in each part. A classical result of Edwards says that every m-edge graph has a 2-cut of size m/2+Ω)(m−−√) and this is best possible. That is, there exist cuts which exceed the expected size of a random cut by some multiple of the standard deviation. We study analogues of this and related results in hypergraphs. First, we observe that similarly to graphs, every m-edge k-uniform hypergraph has an r-cut whose size is Ω(m−−√) larger than the expected size of a random r-cut. Moreover, in the case where k = 3 and r = 2 this bound is best possible and is attained by Steiner triple systems. Surprisingly, for all other cases (that is, if k ≥ 4 or r ≥ 3), we show that every m-edge k-uniform hypergraph has an r-cut whose size is Ω(m5/9) larger than the expected size of a random r-cut. This is a significant difference in behaviour, since the amount by which the size of the largest cut exceeds the expected size of a random cut is now considerably larger than the standard deviation. AU - Conlon, David AU - Fox, Jacob AU - Kwan, Matthew Alan AU - Sudakov, Benny ID - 9580 IS - 1 JF - Israel Journal of Mathematics SN - 0021-2172 TI - Hypergraph cuts above the average VL - 233 ER - TY - JOUR AB - An n-vertex graph is called C-Ramsey if it has no clique or independent set of size C log n. All known constructions of Ramsey graphs involve randomness in an essential way, and there is an ongoing line of research towards showing that in fact all Ramsey graphs must obey certain “richness” properties characteristic of random graphs. More than 25 years ago, Erdős, Faudree and Sós conjectured that in any C-Ramsey graph there are Ω(n^5/2) induced subgraphs, no pair of which have the same numbers of vertices and edges. Improving on earlier results of Alon, Balogh, Kostochka and Samotij, in this paper we prove this conjecture. AU - Kwan, Matthew Alan AU - Sudakov, Benny ID - 9585 IS - 8 JF - Transactions of the American Mathematical Society SN - 0002-9947 TI - Proof of a conjecture on induced subgraphs of Ramsey graphs VL - 372 ER - TY - JOUR AB - Progress in the atomic-scale modeling of matter over the past decade has been tremendous. This progress has been brought about by improvements in methods for evaluating interatomic forces that work by either solving the electronic structure problem explicitly, or by computing accurate approximations of the solution and by the development of techniques that use the Born–Oppenheimer (BO) forces to move the atoms on the BO potential energy surface. As a consequence of these developments it is now possible to identify stable or metastable states, to sample configurations consistent with the appropriate thermodynamic ensemble, and to estimate the kinetics of reactions and phase transitions. All too often, however, progress is slowed down by the bottleneck associated with implementing new optimization algorithms and/or sampling techniques into the many existing electronic-structure and empirical-potential codes. To address this problem, we are thus releasing a new version of the i-PI software. This piece of software is an easily extensible framework for implementing advanced atomistic simulation techniques using interatomic potentials and forces calculated by an external driver code. While the original version of the code (Ceriotti et al., 2014) was developed with a focus on path integral molecular dynamics techniques, this second release of i-PI not only includes several new advanced path integral methods, but also offers other classes of algorithms. In other words, i-PI is moving towards becoming a universal force engine that is both modular and tightly coupled to the driver codes that evaluate the potential energy surface and its derivatives. AU - Kapil, Venkat AU - Rossi, Mariana AU - Marsalek, Ondrej AU - Petraglia, Riccardo AU - Litman, Yair AU - Spura, Thomas AU - Cheng, Bingqing AU - Cuzzocrea, Alice AU - Meißner, Robert H. AU - Wilkins, David M. AU - Helfrecht, Benjamin A. AU - Juda, Przemysław AU - Bienvenue, Sébastien P. AU - Fang, Wei AU - Kessler, Jan AU - Poltavsky, Igor AU - Vandenbrande, Steven AU - Wieme, Jelle AU - Corminboeuf, Clemence AU - Kühne, Thomas D. AU - Manolopoulos, David E. AU - Markland, Thomas E. AU - Richardson, Jeremy O. AU - Tkatchenko, Alexandre AU - Tribello, Gareth A. AU - Van Speybroeck, Veronique AU - Ceriotti, Michele ID - 9677 JF - Computer Physics Communications SN - 0010-4655 TI - i-PI 2.0: A universal force engine for advanced molecular simulations VL - 236 ER - TY - JOUR AB - Atomistic modeling of phase transitions, chemical reactions, or other rare events that involve overcoming high free energy barriers usually entails prohibitively long simulation times. Introducing a bias potential as a function of an appropriately chosen set of collective variables can significantly accelerate the exploration of phase space, albeit at the price of distorting the distribution of microstates. Efficient reweighting to recover the unbiased distribution can be nontrivial when employing adaptive sampling techniques such as metadynamics, variationally enhanced sampling, or parallel bias metadynamics, in which the system evolves in a quasi-equilibrium manner under a time-dependent bias. We introduce an iterative unbiasing scheme that makes efficient use of all the trajectory data and that does not require the distribution to be evaluated on a grid. The method can thus be used even when the bias has a high dimensionality. We benchmark this approach against some of the existing schemes on model systems with different complexity and dimensionality. AU - Giberti, F. AU - Cheng, Bingqing AU - Tribello, G. A. AU - Ceriotti, M. ID - 9680 IS - 1 JF - Journal of Chemical Theory and Computation SN - 1549-9618 TI - Iterative unbiasing of quasi-equilibrium sampling VL - 16 ER - TY - JOUR AB - The snow cover dynamics of High Mountain Asia are usually assessed at spatial resolutions of 250 m or greater, but this scale is too coarse to clearly represent the rugged topography common to the region. Higher-resolution measurement of snow-covered area often results in biased sampling due to cloud cover and deep shadows. We therefore develop a Normalized Difference Snow Index-based workflow to delineate snow lines from Landsat Thematic Mapper/Enhanced Thematic Mapper+ imagery and apply it to the upper Langtang Valley in Nepal, processing 194 scenes spanning 1999 to 2013. For each scene, we determine the spatial distribution of snow line altitudes (SLAs) with respect to aspect and across six subcatchments. Our results show that the mean SLA exhibits distinct seasonal behavior based on aspect and subcatchment position. We find that SLA dynamics respond to spatial and seasonal trade-offs in precipitation, temperature, and solar radiation, which act as primary controls. We identify two SLA spatial gradients, which we attribute to the effect of spatially variable precipitation. Our results also reveal that aspect-related SLA differences vary seasonally and are influenced by solar radiation. In terms of seasonal dominant controls, we demonstrate that the snow line is controlled by snow precipitation in winter, melt in premonsoon, a combination of both in postmonsoon, and temperature in monsoon, explaining to a large extent the spatial and seasonal variability of the SLA in the upper Langtang Valley. We conclude that while SLA and snow-covered area are complementary metrics, the SLA has a strong potential for understanding local-scale snow cover dynamics and their controlling mechanisms. AU - Girona‐Mata, Marc AU - Miles, Evan S. AU - Ragettli, Silvan AU - Pellicciotti, Francesca ID - 12600 IS - 8 JF - Water Resources Research KW - Water Science and Technology SN - 0043-1397 TI - High‐resolution snowline delineation from Landsat imagery to infer snow cover controls in a Himalayan catchment VL - 55 ER - TY - JOUR AB - This study aims at developing and applying a spatially-distributed coupled glacier mass balance and ice-flow model to attribute the response of glaciers to natural and anthropogenic climate change. We focus on two glaciers with contrasting surface characteristics: a debris-covered glacier (Langtang Glacier in Nepal) and a clean-ice glacier (Hintereisferner in Austria). The model is applied from the end of the Little Ice Age (1850) to the present-day (2016) and is forced with four bias-corrected General Circulation Models (GCMs) from the historical experiment of the CMIP5 archive. The selected GCMs represent region-specific warm-dry, warm-wet, cold-dry, and cold-wet climate conditions. To isolate the effects of anthropogenic climate change on glacier mass balance and flow runs from these GCMs with and without further anthropogenic forcing after 1970 until 2016 are selected. The outcomes indicate that both glaciers experience the largest reduction in area and volume under warm climate conditions, whereas area and volume reductions are smaller under cold climate conditions. Simultaneously with changes in glacier area and volume, surface velocities generally decrease over time. Without further anthropogenic forcing the results reveal a 3% (9%) smaller decline in glacier area (volume) for the debris-covered glacier and a 18% (39%) smaller decline in glacier area (volume) for the clean-ice glacier. The difference in the magnitude between the two glaciers can mainly be attributed to differences in the response time of the glaciers, where the clean-ice glacier shows a much faster response to climate change. We conclude that the response of the two glaciers can mainly be attributed to anthropogenic climate change and that the impact is larger on the clean-ice glacier. The outcomes show that the model performs well under different climate conditions and that the developed approach can be used for regional-scale glacio-hydrological modeling. AU - Wijngaard, René R. AU - Steiner, Jakob F. AU - Kraaijenbrink, Philip D. A. AU - Klug, Christoph AU - Adhikari, Surendra AU - Banerjee, Argha AU - Pellicciotti, Francesca AU - van Beek, Ludovicus P. H. AU - Bierkens, Marc F. P. AU - Lutz, Arthur F. AU - Immerzeel, Walter W. ID - 12602 JF - Frontiers in Earth Science SN - 2296-6463 TI - Modeling the response of the Langtang Glacier and the Hintereisferner to a changing climate since the Little Ice Age VL - 7 ER - TY - JOUR AB - Ice cliffs and ponds on debris-covered glaciers have received increased attention due to their role in amplifying local melt. However, very few studies have looked at these features on the catchment scale to determine their patterns and changes in space and time. We have compiled a detailed inventory of cliffs and ponds in the Langtang catchment, central Himalaya, from six high-resolution satellite orthoimages and DEMs between 2006 and 2015, and a historic orthophoto from 1974. Cliffs cover between 1.4% (± 0.4%) in the dry and 3.4% (± 0.9%) in the wet seasons and ponds between 0.6% (± 0.1%) and 1.6% (± 0.3%) of the total debris-covered tongues. We find large variations between seasons, as cliffs and ponds tend to grow in the wetter monsoon period, but there is no obvious trend in total area over the study period. The inventory further shows that cliffs are predominately north-facing irrespective of the glacier flow direction. Both cliffs and ponds appear in higher densities several hundred metres from the terminus in areas where tributaries reach the main glacier tongue. On the largest glacier in the catchment ~10% of all cliffs and ponds persisted over nearly a decade. AU - STEINER, JAKOB F. AU - BURI, PASCAL AU - MILES, EVAN S. AU - RAGETTLI, SILVAN AU - Pellicciotti, Francesca ID - 12601 IS - 252 JF - Journal of Glaciology SN - 0022-1430 TI - Supraglacial ice cliffs and ponds on debris-covered glaciers: Spatio-temporal distribution and characteristics VL - 65 ER - TY - JOUR AB - Transposable elements (TEs), the movement of which can damage the genome, are epigenetically silenced in eukaryotes. Intriguingly, TEs are activated in the sperm companion cell – vegetative cell (VC) – of the flowering plant Arabidopsis thaliana. However, the extent and mechanism of this activation are unknown. Here we show that about 100 heterochromatic TEs are activated in VCs, mostly by DEMETER-catalyzed DNA demethylation. We further demonstrate that DEMETER access to some of these TEs is permitted by the natural depletion of linker histone H1 in VCs. Ectopically expressed H1 suppresses TEs in VCs by reducing DNA demethylation and via a methylation-independent mechanism. We demonstrate that H1 is required for heterochromatin condensation in plant cells and show that H1 overexpression creates heterochromatic foci in the VC progenitor cell. Taken together, our results demonstrate that the natural depletion of H1 during male gametogenesis facilitates DEMETER-directed DNA demethylation, heterochromatin relaxation, and TE activation. AU - He, Shengbo AU - Vickers, Martin AU - Zhang, Jingyi AU - Feng, Xiaoqi ID - 12192 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 - Natural depletion of histone H1 in sex cells causes DNA demethylation, heterochromatin decondensation and transposon activation VL - 8 ER - TY - JOUR AB - Meiotic crossover frequency varies within genomes, which influences genetic diversity and adaptation. In turn, genetic variation within populations can act to modify crossover frequency in cis and trans. To identify genetic variation that controls meiotic crossover frequency, we screened Arabidopsis accessions using fluorescent recombination reporters. We mapped a genetic modifier of crossover frequency in Col × Bur populations of Arabidopsis to a premature stop codon within TBP-ASSOCIATED FACTOR 4b (TAF4b), which encodes a subunit of the RNA polymerase II general transcription factor TFIID. The Arabidopsis taf4b mutation is a rare variant found in the British Isles, originating in South-West Ireland. Using genetics, genomics, and immunocytology, we demonstrate a genome-wide decrease in taf4b crossovers, with strongest reduction in the sub-telomeric regions. Using RNA sequencing (RNA-seq) from purified meiocytes, we show that TAF4b expression is meiocyte enriched, whereas its paralog TAF4 is broadly expressed. Consistent with the role of TFIID in promoting gene expression, RNA-seq of wild-type and taf4b meiocytes identified widespread transcriptional changes, including in genes that regulate the meiotic cell cycle and recombination. Therefore, TAF4b duplication is associated with acquisition of meiocyte-specific expression and promotion of germline transcription, which act directly or indirectly to elevate crossovers. This identifies a novel mode of meiotic recombination control via a general transcription factor. AU - Lawrence, Emma J. AU - Gao, Hongbo AU - Tock, Andrew J. AU - Lambing, Christophe AU - Blackwell, Alexander R. AU - Feng, Xiaoqi AU - Henderson, Ian R. ID - 12190 IS - 16 JF - Current Biology KW - General Agricultural and Biological Sciences KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0960-9822 TI - Natural variation in TBP-ASSOCIATED FACTOR 4b controls meiotic crossover and germline transcription in Arabidopsis VL - 29 ER - TY - GEN AB - In this paper, we present the first fully asynchronous distributed key generation (ADKG) algorithm as well as the first distributed key generation algorithm that can create keys with a dual (f,2f+1)−threshold that are necessary for scalable consensus (which so far needs a trusted dealer assumption). In order to create a DKG with a dual (f,2f+1)− threshold we first answer in the affirmative the open question posed by Cachin et al. how to create an AVSS protocol with recovery thresholds f+1