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Search Results: 1 - 10 of 148386 matches for " Marcus B. Smolka "
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Chronic DNA Replication Stress Reduces Replicative Lifespan of Cells by TRP53-Dependent, microRNA-Assisted MCM2-7 Downregulation
Gongshi Bai?,Marcus B. Smolka,John C. Schimenti
PLOS Genetics , 2016, DOI: 10.1371/journal.pgen.1005787
Abstract: Circumstances that compromise efficient DNA replication, such as disruptions to replication fork progression, cause a state known as DNA replication stress (RS). Whereas normally proliferating cells experience low levels of RS, excessive RS from intrinsic or extrinsic sources can trigger cell cycle arrest and senescence. Here, we report that a key driver of RS-induced senescence is active downregulation of the Minichromosome Maintenance 2–7 (MCM2-7) factors that are essential for replication origin licensing and which constitute the replicative helicase core. Proliferating cells produce high levels of MCM2-7 that enable formation of dormant origins that can be activated in response to acute, experimentally-induced RS. However, little is known about how physiological RS levels impact MCM2-7 regulation. We found that chronic exposure of primary mouse embryonic fibroblasts (MEFs) to either genetically-encoded or environmentally-induced RS triggered gradual MCM2-7 repression, followed by inhibition of replication and senescence that could be accelerated by MCM hemizygosity. The MCM2-7 reduction in response to RS is TRP53-dependent, and involves a group of Trp53-dependent miRNAs, including the miR-34 family, that repress MCM expression in replication-stressed cells before they undergo terminal cell cycle arrest. miR-34 ablation partially rescued MCM2-7 downregulation and genomic instability in mice with endogenous RS. Together, these data demonstrate that active MCM2-7 repression is a physiologically important mechanism for RS-induced cell cycle arrest and genome maintenance on an organismal level.
Whi5 Regulation by Site Specific CDK-Phosphorylation in Saccharomyces cerevisiae
Michelle V. Wagner, Marcus B. Smolka, Rob A. M. de Bruin, Huilin Zhou, Curt Wittenberg, Steven F. Dowdy
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004300
Abstract: The Whi5 transcriptional repressor is a negative regulator of G1 cell cycle progression in Saccharomyces cerevisiae and is functionally equivalent to the Retinoblastoma (Rb) tumor suppressor protein in mammals. In early G1, Whi5 binds to and inhibits SBF (Swi4/Swi6) transcriptional complexes. At Start, Cln:Cdc28 kinases phosphorylate and inactivate Whi5, causing its dissociation from SBF promoters and nuclear export, allowing activation of SBF transcription and entry into late G1. In an analysis of Whi5 phosphorylation, we found that 10 of the 12 putative CDK phosphorylation sites on Whi5 were occupied in vivo in asynchronously growing cells. In addition, we identified 6 non-CDK Whi5 phosphorylation sites. Whi5 CDK and non-CDK phosphorylation mutants were functional and able to rescue the small cell size of whi5Δ cells. However, the Whi5 CDK mutant with all 12 putative CDK sites changed to alanine causes a dramatic cell cycle phenotype when expressed with a Swi6 CDK phosphorylation mutant. Mutational analysis of Whi5 determined that only four C-terminal CDK sites were necessary and sufficient for Whi5 inactivation when Swi6 CDK sites were also mutated. Although these four Whi5 CDK sites do not wholly determine Whi5 nuclear export, they do impact regulation of cell size. Taken together, these observations begin to dissect the regulatory role of specific phosphorylation sites on Whi5.
Comparative analysis of two-dimensional electrophoresis maps (2-DE) of Helicobacter pylori from Brazilian patients with chronic gastritis and duodenal ulcer: a preliminary report
Pereira, Diego R.B.;Martins, Daniel;Winck, Flavia V.;Smolka, Marcus B.;Nishimura, Nancy F.;Rabelo-Gon?alves, Elizabeth M.A.;Hara, Natalicia H.;Marangoni, Sérgio;Zeitune, José Murilo R.;Novello, José Camillo;
Revista do Instituto de Medicina Tropical de S?o Paulo , 2006, DOI: 10.1590/S0036-46652006000300011
Abstract: helicobacter pylori is a bacterium recognized as the major cause of peptic ulcer and chronic gastritis. recently, a proteome-based approach was developed to investigate pathogenic factors related to h. pylori. in this preliminary study, h. pylori strains were isolated from gastric biopsies of patients with chronic gastritis and duodenal ulcers. a partial proteomic analysis of h. pylori strains was performed by bacterial lyses and proteins were separated by two-dimensional gel electrophoresis (2-de). a comparative analysis was performed to verify a differential protein expression between these two 2-de maps. these data should be useful to clarify the role of different proteins related to bacterial pathogenesis. this study will be completed using a larger number of samples and protein identification of h. pylori by maldi-tof mass spectrometry.
A Massively Parallel Pipeline to Clone DNA Variants and Examine Molecular Phenotypes of Human Disease Mutations
Xiaomu Wei equal contributor,Jishnu Das equal contributor,Robert Fragoza equal contributor,Jin Liang equal contributor,Francisco M. Bastos de Oliveira,Hao Ran Lee,Xiujuan Wang,Matthew Mort,Peter D. Stenson,David N. Cooper,Steven M. Lipkin,Marcus B. Smolka,Haiyuan Yu
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004819
Abstract: Understanding the functional relevance of DNA variants is essential for all exome and genome sequencing projects. However, current mutagenesis cloning protocols require Sanger sequencing, and thus are prohibitively costly and labor-intensive. We describe a massively-parallel site-directed mutagenesis approach, “Clone-seq”, leveraging next-generation sequencing to rapidly and cost-effectively generate a large number of mutant alleles. Using Clone-seq, we further develop a comparative interactome-scanning pipeline integrating high-throughput GFP, yeast two-hybrid (Y2H), and mass spectrometry assays to systematically evaluate the functional impact of mutations on protein stability and interactions. We use this pipeline to show that disease mutations on protein-protein interaction interfaces are significantly more likely than those away from interfaces to disrupt corresponding interactions. We also find that mutation pairs with similar molecular phenotypes in terms of both protein stability and interactions are significantly more likely to cause the same disease than those with different molecular phenotypes, validating the in vivo biological relevance of our high-throughput GFP and Y2H assays, and indicating that both assays can be used to determine candidate disease mutations in the future. The general scheme of our experimental pipeline can be readily expanded to other types of interactome-mapping methods to comprehensively evaluate the functional relevance of all DNA variants, including those in non-coding regions.
The Dung Beetle Dance: An Orientation Behaviour?
Emily Baird,Marcus J. Byrne,Jochen Smolka,Eric J. Warrant,Marie Dacke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030211
Abstract: An interesting feature of dung beetle behaviour is that once they have formed a piece of dung into a ball, they roll it along a straight path away from the dung pile. This straight-line orientation ensures that the beetles depart along the most direct route, guaranteeing that they will not return to the intense competition (from other beetles) that occurs near the dung pile. Before rolling a new ball away from the dung pile, dung beetles perform a characteristic “dance,” in which they climb on top of the ball and rotate about their vertical axis. This dance behaviour can also be observed during the beetles' straight-line departure from the dung pile. The aim of the present study is to investigate the purpose of the dung beetle dance. To do this, we explored the circumstances that elicit dance behaviour in the diurnal ball-rolling dung beetle, Scarabaeus (Kheper) nigroaeneus. Our results reveal that dances are elicited when the beetles lose control of their ball or lose contact with it altogether. We also find that dances can be elicited by both active and passive deviations of course and by changes in visual cues alone. In light of these results, we hypothesise that the dung beetle dance is a visually mediated mechanism that facilitates straight-line orientation in ball-rolling dung beetles by allowing them to 1) establish a roll bearing and 2) return to this chosen bearing after experiencing a disturbance to the roll path.
The Co-Repressor SMRT Delays DNA Damage-Induced Caspase Activation by Repressing Pro-Apoptotic Genes and Modulating the Dynamics of Checkpoint Kinase 2 Activation
Claudio Scafoglio, Marcus Smolka, Huilin Zhou, Valentina Perissi, Michael G. Rosenfeld
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059986
Abstract: Checkpoint kinase 2 (Chk2) is a major regulator of DNA damage response and can induce alternative cellular responses: cell cycle arrest and DNA repair or programmed cell death. Here, we report the identification of a new role of Chk2 in transcriptional regulation that also contributes to modulating the balance between survival and apoptosis following DNA damage. We found that Chk2 interacts with members of the NCoR/SMRT transcriptional co-regulator complexes and serves as a functional component of the repressor complex, being required for recruitment of SMRT on the promoter of pro-apoptotic genes upon DNA damage. Thus, the co-repressor SMRT exerts a critical protective action against genotoxic stress-induced caspase activation, repressing a functionally important cohort of pro-apoptotic genes. Amongst them, SMRT is responsible for basal repression of Wip1, a phosphatase that de-phosphorylates and inactivates Chk2, thus affecting a feedback loop responsible for licensing the correct timing of Chk2 activation and the proper execution of the DNA repair process.
New filtering technique for the impulsive noise reduction in color images
B. Smolka,A. Chydzinski,K. N. Plataniotis,A. N. Venetsanopoulos
Mathematical Problems in Engineering , 2004, DOI: 10.1155/s1024123x04110016
Abstract: We present a novel approach to the problem of impulsive noise reduction for colorimages. The new image-filtering technique is based on the maximization of the similarities between pixels in the filtering window. Themethod is able to remove the noise component, while adapting itself to the local image structure. In this way, the proposed algorithm eliminates impulsive noise while preserving edges and fine image details. Since the algorithm can be considered as a modification of the vector median filter driven by fuzzy membership functions, it is fast, computationally efficient, and easy to implement. Experimental results indicate that the new method is superior, in terms of performance, to algorithms commonly used for impulsive noise reduction.
New filtering technique for the impulsive noise reduction in color images
Smolka B.,Chydzinski A.,Plataniotis K. N.,Venetsanopoulos A. N.
Mathematical Problems in Engineering , 2004,
Abstract: We present a novel approach to the problem of impulsive noise reduction for colorimages. The new image-filtering technique is based on the maximization of the similarities between pixels in the filtering window. Themethod is able to remove the noise component, while adapting itself to the local image structure. In this way, the proposed algorithm eliminates impulsive noise while preserving edges and fine image details. Since the algorithm can be considered as a modification of the vector median filter driven by fuzzy membership functions, it is fast, computationally efficient, and easy to implement. Experimental results indicate that the new method is superior, in terms of performance, to algorithms commonly used for impulsive noise reduction.
Dynamics of Free Surface Perturbations Along an Annular Viscous Film
Linda B. Smolka,Justin North,Bree K. Guerra
Physics , 2007, DOI: 10.1103/PhysRevE.77.036301
Abstract: It is known that an axisymmetric viscous film flowing down the outside of a thin vertical fiber becomes unstable to interfacial perturbations. We present an experimental study using fluids with different densities, surface tensions and viscosities to investigate the growth and dynamics of these interfacial perturbations and to test the assumptions made by previous authors. We find the initial perturbation growth is exponential followed by a slower phase as the amplitude and wavelength saturate in size. Measurements of the perturbation growth for experiments conducted at low and moderate Reynolds numbers are compared to theoretical predictions developed from linear stability theory. Excellent agreement is found between predictions from a long-wave Stokes flow model (Craster & Matar, J. Fluid Mech. 553, 85 (2006)) and data, while fair agreement is found between predictions from a moderate Reynolds number model (Sisoev et al., Chem. Eng. Sci. 61, 7279 (2006)) and data. Furthermore, we find that a known transition in the longer-time perturbation dynamics from unsteady to steady behavior at a critical flow rate, Qc, is correlated to a transition in the rate at which perturbations naturally form along the fiber. For Q < Qc (steady case), the rate of perturbation formation is constant. As a result the position along the fiber where perturbations form is nearly fixed, and the spacing between consecutive perturbations remains constant as they travel 2 m down the fiber. For Q > Qc (unsteady case), the rate of perturbation formation is modulated. As a result the position along the fiber where perturbations form oscillates irregularly, and the initial speed and spacing between perturbations varies resulting in the coalescence of neighboring perturbations further down the fiber.
Beyond the current noise limit in imaging through turbulent medium
A. Popowicz,A. R. Kurek,A. Pollo,B. Smolka
Physics , 2015, DOI: 10.1364/OL.40.002181
Abstract: Shift-and-add is an approach employed to mitigate the phenomenon of resolution degradation in images acquired through a turbulent medium. Using this technique, a large number of consecutive short exposures is registered below the coherence time of the atmosphere or other blurring medium. The acquired images are shifted to the position of the brightest speckle and stacked together to obtain high-resolution and high signal-to-noise frame. In this paper we present a highly efficient method for determination of frames shifts, even if in a single frame the object cannot be distinguished from the background noise. The technique utilizes our custom genetic algorithm, which iteratively evolves a set of image shifts. We used the maximal energy of stacked images as an objective function for shifts estimation and validate the efficiency of the method on simulated and real images of simple and complex sources. Obtained results confirmed, that our proposed method allows for the recovery of spatial distribution of objects even only 2% brighter than their background. The presented approach extends significantly current limits of image reconstruction with the use of shift-and-add method. The applications of our algorithm include both the optical and the infrared imaging. Our method may be also employed as a digital image stabilizer in extremely low light level conditions in professional and consumer applications.
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