TY - JOUR AB - The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms. AU - Michael, Alicia Kathleen AU - Harvey, Stacy L. AU - Sammons, Patrick J. AU - Anderson, Amanda P. AU - Kopalle, Hema M. AU - Banham, Alison H. AU - Partch, Carrie L. ID - 15160 IS - 5 JF - Molecular Cell KW - Cell Biology KW - Molecular Biology SN - 1097-2765 TI - Cancer/Testis antigen PASD1 silences the circadian clock VL - 58 ER - TY - JOUR AB - It is widely recognized that BMAL1 is an essential subunit of the primary transcription factor that drives rhythmic circadian transcription in the nucleus. In a surprising turn, Lipton et al. now show that BMAL1 rhythmically interacts with translational machinery in the cytosol to stimulate protein synthesis in response to mTOR signaling. AU - Michael, Alicia Kathleen AU - Asimgil, Hande AU - Partch, Carrie L. ID - 15159 IS - 9 JF - Trends in Biochemical Sciences KW - Molecular Biology KW - Biochemistry SN - 0968-0004 TI - Cytosolic BMAL1 moonlights as a translation factor VL - 40 ER - TY - JOUR AB - The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the “morbidostat”, a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations—an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution. AU - Chevereau, Guillaume AU - Dravecka, Marta AU - Batur, Tugce AU - Guvenek, Aysegul AU - Ayhan, Dilay AU - Toprak, Erdal AU - Bollenbach, Mark Tobias ID - 1619 IS - 11 JF - PLoS Biology TI - Quantifying the determinants of evolutionary dynamics leading to drug resistance VL - 13 ER - TY - JOUR AB - Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical one-step nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet–rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory. AU - Šarić, Anđela AU - Chebaro, Yassmine C. AU - Knowles, Tuomas P. J. AU - Frenkel, Daan ID - 10382 IS - 50 JF - Proceedings of the National Academy of Sciences KW - multidisciplinary SN - 0027-8424 TI - Crucial role of nonspecific interactions in amyloid nucleation VL - 111 ER - TY - JOUR AB - We use numerical simulations to compute the equation of state of a suspension of spherical self-propelled nanoparticles in two and three dimensions. We study in detail the effect of excluded volume interactions and confinement as a function of the system's temperature, concentration, and strength of the propulsion. We find a striking nonmonotonic dependence of the pressure on the temperature and provide simple scaling arguments to predict and explain the occurrence of such anomalous behavior. We explicitly show how our results have important implications for the effective forces on passive components suspended in a bath of active particles. AU - Mallory, S. A. AU - Šarić, Anđela AU - Valeriani, C. AU - Cacciuto, A. ID - 10383 IS - 5 JF - Physical Review E SN - 1539-3755 TI - Anomalous thermomechanical properties of a self-propelled colloidal fluid VL - 89 ER - TY - JOUR AB - Diffraction-unlimited far-field super-resolution fluorescence (nanoscopy) methods typically rely on transiently transferring fluorophores between two states, whereby this transfer is usually laid out as a switch. However, depending on whether this is induced in a spatially controlled manner using a pattern of light (coordinate-targeted) or stochastically on a single-molecule basis, specific requirements on the fluorophores are imposed. Therefore, the fluorophores are usually utilized just for one class of methods only. In this study we demonstrate that the reversibly switchable fluorescent protein Dreiklang enables live-cell recordings in both spatially controlled and stochastic modes. We show that the Dreiklang chromophore entails three different light-induced switching mechanisms, namely a reversible photochemical one, off-switching by stimulated emission, and a reversible transfer to a long-lived dark state from the S1 state, all of which can be utilized to overcome the diffraction barrier. We also find that for the single-molecule- based stochastic GSDIM approach (ground-state depletion followed by individual molecule return), Dreiklang provides a larger number of on-off localization events as compared to its progenitor Citrine. Altogether, Dreiklang is a versatile probe for essentially all popular forms of live-cell fluorescence nanoscopy. AU - Jensen, Nickels AU - Danzl, Johann G AU - Willig, Katrin AU - Lavoie Cardinal, Flavie AU - Brakemann, Tanja AU - Hell, Stefan AU - Jakobs, Stefan ID - 1058 IS - 4 JF - ChemPhysChem TI - Coordinate-targeted and coordinate-stochastic super-resolution microscopy with the reversibly switchable fluorescent protein dreiklang VL - 15 ER - TY - JOUR AB - In the last several decades, developmental biology has clarified the molecular mechanisms of embryogenesis and organogenesis. In particular, it has demonstrated that the “tool-kit genes” essential for regulating developmental processes are not only highly conserved among species, but are also used as systems at various times and places in an organism to control distinct developmental events. Therefore, mutations in many of these tool-kit genes may cause congenital diseases involving morphological abnormalities. This link between genes and abnormal morphological phenotypes underscores the importance of understanding how cells behave and contribute to morphogenesis as a result of gene function. Recent improvements in live imaging and in quantitative analyses of cellular dynamics will advance our understanding of the cellular pathogenesis of congenital diseases associated with aberrant morphologies. In these studies, it is critical to select an appropriate model organism for the particular phenomenon of interest. AU - Hashimoto, Masakazu AU - Morita, Hitoshi AU - Ueno, Naoto ID - 10815 IS - 1 JF - Congenital Anomalies KW - Developmental Biology KW - Embryology KW - General Medicine KW - Pediatrics KW - Perinatology KW - and Child Health SN - 0914-3505 TI - Molecular and cellular mechanisms of development underlying congenital diseases VL - 54 ER - TY - BOOK AB - Auxin is an important signaling compound in plants and vital for plant development and growth. The present book, Auxin and its Role in Plant Development, provides the reader with detailed and comprehensive insight into the functioning of the molecule on the whole and specifically in plant development. In the first part, the functioning, metabolism and signaling pathways of auxin in plants are explained, the second part depicts the specific role of auxin in plant development and the third part describes the interaction and functioning of the signaling compound upon stimuli of the environment. Each chapter is written by international experts in the respective field and designed for scientists and researchers in plant biology, plant development and cell biology to summarize the recent progress in understanding the role of auxin and suggest future perspectives for auxin research. ED - Zažímalová, Eva ED - Petrášek, Jan ED - Benková, Eva ID - 10811 SN - 9783709115251 TI - Auxin and Its Role in Plant Development ER - TY - CONF AB - We revisit the parameterized model checking problem for token-passing systems and specifications in indexed CTL  ∗ \X. Emerson and Namjoshi (1995, 2003) have shown that parameterized model checking of indexed CTL  ∗ \X in uni-directional token rings can be reduced to checking rings up to some cutoff size. Clarke et al. (2004) have shown a similar result for general topologies and indexed LTL \X, provided processes cannot choose the directions for sending or receiving the token. We unify and substantially extend these results by systematically exploring fragments of indexed CTL  ∗ \X with respect to general topologies. For each fragment we establish whether a cutoff exists, and for some concrete topologies, such as rings, cliques and stars, we infer small cutoffs. Finally, we show that the problem becomes undecidable, and thus no cutoffs exist, if processes are allowed to choose the directions in which they send or from which they receive the token. AU - Aminof, Benjamin AU - Jacobs, Swen AU - Khalimov, Ayrat AU - Rubin, Sasha ID - 10884 SN - 0302-9743 T2 - Verification, Model Checking, and Abstract Interpretation TI - Parameterized model checking of token-passing systems VL - 8318 ER - TY - CHAP AB - Saddle periodic orbits are an essential and stable part of the topological skeleton of a 3D vector field. Nevertheless, there is currently no efficient algorithm to robustly extract these features. In this chapter, we present a novel technique to extract saddle periodic orbits. Exploiting the analytic properties of such an orbit, we propose a scalar measure based on the finite-time Lyapunov exponent (FTLE) that indicates its presence. Using persistent homology, we can then extract the robust cycles of this field. These cycles thereby represent the saddle periodic orbits of the given vector field. We discuss the different existing FTLE approximation schemes regarding their applicability to this specific problem and propose an adapted version of FTLE called Normalized Velocity Separation. Finally, we evaluate our method using simple analytic vector field data. AU - Kasten, Jens AU - Reininghaus, Jan AU - Reich, Wieland AU - Scheuermann, Gerik ED - Bremer, Peer-Timo ED - Hotz, Ingrid ED - Pascucci, Valerio ED - Peikert, Ronald ID - 10893 SN - 1612-3786 T2 - Topological Methods in Data Analysis and Visualization III TI - Toward the extraction of saddle periodic orbits VL - 1 ER -