TY - CONF AB - The study of fluxoid states and fluxoid dynamics in mesoscopic iron-based superconducting rings is valuable for characterizing the basic properties of the superconductor, and may also provide important insight into the superconducting paring symmetry. We report the fabrications of micron-sized rings and disks from thin films of Fe(Se, Te) grown by molecular beam epitaxy. In order to study fluxoid states in rings we developed a custom-tailored version of magnetic force microscopy (MFM). This technique has a number of qualitative advantages for working with mesoscopic superconducting samples in comparison to the conventional MFM and other imaging techniques. We observed metastable fluxoid states in rings of different sizes. Thermally activated fluxoid dynamics of these states was studied and modeled. In addition, we found different regimes of interaction between Fe(Se, Te) ring and MFM tip which are explained. Possibilities of the existence of exotic vortex states and proposals for experiments to test the symmetry of the superconducting order parameter in iron based superconductors are analyzed. AU - Polshyn, Hryhoriy AU - Zhang, Can AU - Naibert, Tyler AU - Eckstein, James AU - Budakian, Raffi ID - 10748 IS - 1 SN - 0003-0503 T2 - APS March Meeting 2015 TI - Study of Fe (Se, Te) micron-sized rings by magnetic force microscopy VL - 60 ER - TY - JOUR AB - Mathematical models are of fundamental importance in the understanding of complex population dynamics. For instance, they can be used to predict the population evolution starting from different initial conditions or to test how a system responds to external perturbations. For this analysis to be meaningful in real applications, however, it is of paramount importance to choose an appropriate model structure and to infer the model parameters from measured data. While many parameter inference methods are available for models based on deterministic ordinary differential equations, the same does not hold for more detailed individual-based models. Here we consider, in particular, stochastic models in which the time evolution of the species abundances is described by a continuous-time Markov chain. These models are governed by a master equation that is typically difficult to solve. Consequently, traditional inference methods that rely on iterative evaluation of parameter likelihoods are computationally intractable. The aim of this paper is to present recent advances in parameter inference for continuous-time Markov chain models, based on a moment closure approximation of the parameter likelihood, and to investigate how these results can help in understanding, and ultimately controlling, complex systems in ecology. Specifically, we illustrate through an agricultural pest case study how parameters of a stochastic individual-based model can be identified from measured data and how the resulting model can be used to solve an optimal control problem in a stochastic setting. In particular, we show how the matter of determining the optimal combination of two different pest control methods can be formulated as a chance constrained optimization problem where the control action is modeled as a state reset, leading to a hybrid system formulation. AU - Parise, Francesca AU - Lygeros, John AU - Ruess, Jakob ID - 10794 JF - Frontiers in Environmental Science KW - General Environmental Science SN - 2296-665X TI - Bayesian inference for stochastic individual-based models of ecological systems: a pest control simulation study VL - 3 ER - TY - CONF AB - We consider concurrent mean-payoff games, a very well-studied class of two-player (player 1 vs player 2) zero-sum games on finite-state graphs where every transition is assigned a reward between 0 and 1, and the payoff function is the long-run average of the rewards. The value is the maximal expected payoff that player 1 can guarantee against all strategies of player 2. We consider the computation of the set of states with value 1 under finite-memory strategies for player 1, and our main results for the problem are as follows: (1) we present a polynomial-time algorithm; (2) we show that whenever there is a finite-memory strategy, there is a stationary strategy that does not need memory at all; and (3) we present an optimal bound (which is double exponential) on the patience of stationary strategies (where patience of a distribution is the inverse of the smallest positive probability and represents a complexity measure of a stationary strategy). AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus ID - 10796 IS - 1 SN - 978-161197374-7 T2 - Proceedings of the Twenty-Sixth Annual ACM-SIAM Symposium on Discrete Algorithms TI - The value 1 problem under finite-memory strategies for concurrent mean-payoff games VL - 2015 ER - TY - JOUR AB - Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect. AU - Isrie, Mala AU - Breuss, Martin AU - Tian, Guoling AU - Hansen, Andi H AU - Cristofoli, Francesca AU - Morandell, Jasmin AU - Kupchinsky, Zachari A AU - Sifrim, Alejandro AU - Rodriguez Rodriguez, Celia AU - Dapena, Elena P AU - Doonanco, Kurston AU - Leonard, Norma AU - Tinsa, Faten AU - Moortgat, Stéphanie AU - Ulucan, Hakan AU - Koparir, Erkan AU - Karaca, Ender AU - Katsanis, Nicholas AU - Marton, Valeria AU - Vermeesch, Joris R AU - Davis, Erica E AU - Cowan, Nicholas J AU - Keays, David AU - Van Esch, Hilde ID - 1106 IS - 6 JF - The American Journal of Human Genetics TI - Mutations in either TUBB or MAPRE2 cause circumferential skin creases Kunze type VL - 97 ER - TY - JOUR AB - Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging. AU - Mertens, Jerome AU - Paquola, Apuã C.M. AU - Ku, Manching AU - Hatch, Emily AU - Böhnke, Lena AU - Ladjevardi, Shauheen AU - McGrath, Sean AU - Campbell, Benjamin AU - Lee, Hyungjun AU - Herdy, Joseph R. AU - Gonçalves, J. Tiago AU - Toda, Tomohisa AU - Kim, Yongsung AU - Winkler, Jürgen AU - Yao, Jun AU - HETZER, Martin W AU - Gage, Fred H. ID - 11079 IS - 6 JF - Cell Stem Cell KW - Cell Biology KW - Genetics KW - Molecular Medicine SN - 1934-5909 TI - Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects VL - 17 ER - TY - JOUR AB - Nucleoporins (Nups) are a family of proteins best known as the constituent building blocks of nuclear pore complexes (NPCs), membrane-embedded channels that mediate nuclear transport across the nuclear envelope. Recent evidence suggests that several Nups have additional roles in controlling the activation and silencing of developmental genes; however, the mechanistic details of these functions remain poorly understood. Here, we show that depletion of Nup153 in mouse embryonic stem cells (mESCs) causes the derepression of developmental genes and induction of early differentiation. This loss of stem cell identity is not associated with defects in the nuclear import of key pluripotency factors. Rather, Nup153 binds around the transcriptional start site (TSS) of developmental genes and mediates the recruitment of the polycomb-repressive complex 1 (PRC1) to a subset of its target loci. Our results demonstrate a chromatin-associated role of Nup153 in maintaining stem cell pluripotency by functioning in mammalian epigenetic gene silencing. AU - Jacinto, Filipe V. AU - Benner, Chris AU - HETZER, Martin W ID - 11077 IS - 12 JF - Genes & Development KW - Developmental Biology KW - Genetics SN - 0890-9369 TI - The nucleoporin Nup153 regulates embryonic stem cell pluripotency through gene silencing VL - 29 ER - TY - JOUR AB - Aging is associated with the decline of protein, cell, and organ function. Here, we use an integrated approach to characterize gene expression, bulk translation, and cell biology in the brains and livers of young and old rats. We identify 468 differences in protein abundance between young and old animals. The majority are a consequence of altered translation output, that is, the combined effect of changes in transcript abundance and translation efficiency. In addition, we identify 130 proteins whose overall abundance remains unchanged but whose sub-cellular localization, phosphorylation state, or splice-form varies. While some protein-level differences appear to be a generic property of the rats’ chronological age, the majority are specific to one organ. These may be a consequence of the organ’s physiology or the chronological age of the cells within the tissue. Taken together, our study provides an initial view of the proteome at the molecular, sub-cellular, and organ level in young and old rats. AU - Ori, Alessandro AU - Toyama, Brandon H. AU - Harris, Michael S. AU - Bock, Thomas AU - Iskar, Murat AU - Bork, Peer AU - Ingolia, Nicholas T. AU - HETZER, Martin W AU - Beck, Martin ID - 11078 IS - 3 JF - Cell Systems KW - Cell Biology KW - Histology KW - Pathology and Forensic Medicine SN - 2405-4712 TI - Integrated transcriptome and proteome analyses reveal organ-specific proteome deterioration in old rats VL - 1 ER - TY - JOUR AB - Previously, we identified the nucleoporin gp210/Nup210 as a critical regulator of muscle and neuronal differentiation, but how this nucleoporin exerts its function and whether it modulates nuclear pore complex (NPC) activity remain unknown. Here, we show that gp210/Nup210 mediates muscle cell differentiation in vitro via its conserved N-terminal domain that extends into the perinuclear space. Removal of the C-terminal domain, which partially mislocalizes gp210/Nup210 away from NPCs, efficiently rescues the differentiation defect caused by the knockdown of endogenous gp210/Nup210. Unexpectedly, a gp210/Nup210 mutant lacking the NPC-targeting transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. We demonstrate that the endoplasmic reticulum (ER) stress-specific caspase cascade is exacerbated during Nup210 depletion and that blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells. Our results suggest that the role of gp210/Nup210 in cell differentiation is mediated by its large luminal domain, which can act independently of NPC association and appears to play a pivotal role in the maintenance of nuclear envelope/ER homeostasis. AU - Gomez-Cavazos, J. Sebastian AU - HETZER, Martin W ID - 11075 IS - 6 JF - Journal of Cell Biology KW - Cell Biology SN - 0021-9525 TI - The nucleoporin gp210/Nup210 controls muscle differentiation by regulating nuclear envelope/ER homeostasis VL - 208 ER - TY - JOUR AB - Nuclear pore complexes (NPCs) are composed of several copies of ∼30 different proteins called nucleoporins (Nups). NPCs penetrate the nuclear envelope (NE) and regulate the nucleocytoplasmic trafficking of macromolecules. Beyond this vital role, NPC components influence genome functions in a transport-independent manner. Nups play an evolutionarily conserved role in gene expression regulation that, in metazoans, extends into the nuclear interior. Additionally, in proliferative cells, Nups play a crucial role in genome integrity maintenance and mitotic progression. Here we discuss genome-related functions of Nups and their impact on essential DNA metabolism processes such as transcription, chromosome duplication, and segregation. AU - Ibarra, Arkaitz AU - HETZER, Martin W ID - 11076 IS - 4 JF - Genes & Development KW - Developmental Biology KW - Genetics SN - 0890-9369 TI - Nuclear pore proteins and the control of genome functions VL - 29 ER - TY - JOUR AB - Human cancer cells bear complex chromosome rearrangements that can be potential drivers of cancer development. However, the molecular mechanisms underlying these rearrangements have been unclear. Zhang et al. use a new technique combining live-cell imaging and single-cell sequencing to demonstrate that chromosomes mis-segregated to micronuclei frequently undergo chromothripsis-like rearrangements in the subsequent cell cycle. AU - Hatch, Emily M. AU - HETZER, Martin W ID - 11073 IS - 7 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - Linking micronuclei to chromosome fragmentation VL - 161 ER -