3,257 research outputs found
Concerted activities of Mcm4, Sld3 and Dbf4 in control of origin activation and DNA replication fork progression
Eukaryotic chromosomes initiate DNA synthesis from multiple replication origins in a temporally specific manner during S phase. The replicative helicase Mcm2-7 functions in both initiation and fork progression and thus is an important target of regulation. Mcm4, a helicase subunit, possesses an unstructured regulatory domain that mediates control from multiple kinase signaling pathways, including the Dbf4-dependent Cdc7 kinase (DDK). Following replication stress in S phase, Dbf4 and Sld3, an initiation factor and essential target of Cyclin-Dependent Kinase (CDK), are targets of the checkpoint kinase Rad53 for inhibition of initiation from origins that have yet to be activated, so-called late origins. Here, whole genome DNA replication profile analysis is employed to access under various conditions the effect of mutations that alter the Mcm4 helicase regulatory domain and the Rad53 targets, Sld3 and Dbf4. Late origin firing occurs under genotoxic stress when the controls on Mcm4, Sld3 and Dbf4 are simultaneously eliminated. The regulatory domain of Mcm4 plays an important role in the timing of late origin firing, both in an unperturbed S phase and dNTP limitation. Furthermore, checkpoint control of Sld3 impacts fork progression under replication stress. This effect is parallel to the role of the Mcm4 regulatory domain in monitoring fork progression. Hypomorph mutations in sld3 are suppressed by a mcm4 regulatory domain mutation. Thus, in response cellular conditions, the functions executed by Sld3, Dbf4 and the regulatory domain of Mcm4 intersect to control origin firing and replication fork progression, thereby ensuring genome stability
Reply to Murrell et al.: Noise matters
The concept of statistical “equitability” plays a central role in the 2011 paper by Reshef et al. (1). Formalizing equitability first requires formalizing the notion of a “noisy functional relationship,” that is, a relationship between two real variables, X and Y, having the form Y=f(X)+η, where f is a function and η is a noise term. Whether a dependence measure satisfies equitability strongly depends on what mathematical properties the noise term η is allowed to have: the narrower one’s definition of noise, the weaker the equitability criterion becomes
Modeling multi-particle complexes in stochastic chemical systems
Large complexes of classical particles play central roles in biology, in polymer physics, and in other disciplines. However, physics currently lacks mathematical methods for describing such complexes in terms of component particles, interaction energies, and assembly rules. Here we describe a Fock space structure that addresses this need, as well as diagrammatic methods that facilitate the use of this formalism. These methods can dramatically simplify the equations governing both equilibrium and non-equilibrium stochastic chemical systems. A mathematical relationship between the set of all complexes and a list of rules for complex assembly is also identified
Inducer dynamics full-flow, full-admission hydraulic turbine drive Interim report for tasks 1, 2, and 3
Hydrodynamical and mechanical design layout for two-speed hydraulic turbine inducer, computer simulation of pumping system and test facility performance, and study of demonstration uni
Slow roll in simple non-canonical inflation
We consider inflation using a class of non-canonical Lagrangians for which
the modification to the kinetic term depends on the field, but not its
derivatives. We generalize the standard Hubble slow roll expansion to the
non-canonical case and derive expressions for observables in terms of the
generalized slow roll parameters. We apply the general results to the
illustrative case of ``Slinky'' inflation, which has a simple, exactly
solvable, non-canonical representation. However, when transformed into a
canonical basis, Slinky inflation consists of a field oscillating on a
multi-valued potential. We calculate the power spectrum of curvature
perturbations for Slinky inflation directly in the non-canonical basis, and
show that the spectrum is approximately a power law on large scales, with a
``blue'' power spectrum. On small scales, the power spectrum exhibits strong
oscillatory behavior. This is an example of a model in which the widely used
solution of Garriga and Mukhanov gives the wrong answer for the power spectrum.Comment: 9 pages, LaTeX, four figures. (V2: minor changes to text. Version
submitted to JCAP.
Domain within the helicase subunit Mcm4 integrates multiple kinase signals to control DNA replication initiation and fork progression
Eukaryotic DNA synthesis initiates from multiple replication origins and progresses through bidirectional replication forks to ensure efficient duplication of the genome. Temporal control of initiation from origins and regulation of replication fork functions are important aspects for maintaining genome stability. Multiple kinase-signaling pathways are involved in these processes. The Dbf4-dependent Cdc7 kinase (DDK), cyclin-dependent kinase (CDK), and Mec1, the yeast Ataxia telangiectasia mutated/Ataxia telangiectasia mutated Rad3-related checkpoint regulator, all target the structurally disordered N-terminal serine/threonine-rich domain (NSD) of mini-chromosome maintenance subunit 4 (Mcm4), a subunit of the mini-chromosome maintenance (MCM) replicative helicase complex. Using whole-genome replication profile analysis and single-molecule DNA fiber analysis, we show that under replication stress the temporal pattern of origin activation and DNA replication fork progression are altered in cells with mutations within two separate segments of the Mcm4 NSD. The proximal segment of the NSD residing next to the DDK-docking domain mediates repression of late-origin firing by checkpoint signals because in its absence late origins become active despite an elevated DNA damage-checkpoint response. In contrast, the distal segment of the NSD at the N terminus plays no role in the temporal pattern of origin firing but has a strong influence on replication fork progression and on checkpoint signaling. Both fork progression and checkpoint response are regulated by the phosphorylation of the canonical CDK sites at the distal NSD. Together, our data suggest that the eukaryotic MCM helicase contains an intrinsic regulatory domain that integrates multiple signals to coordinate origin activation and replication fork progression under stress conditions
The Emergence of the Modern Universe: Tracing the Cosmic Web
This is the report of the Ultraviolet-Optical Working Group (UVOWG)
commissioned by NASA to study the scientific rationale for new missions in
ultraviolet/optical space astronomy approximately ten years from now, when the
Hubble Space Telescope (HST) is de-orbited. The UVOWG focused on a scientific
theme, The Emergence of the Modern Universe, the period from redshifts z = 3 to
0, occupying over 80% of cosmic time and beginning after the first galaxies,
quasars, and stars emerged into their present form. We considered
high-throughput UV spectroscopy (10-50x throughput of HST/COS) and wide-field
optical imaging (at least 10 arcmin square). The exciting science to be
addressed in the post-HST era includes studies of dark matter and baryons, the
origin and evolution of the elements, and the major construction phase of
galaxies and quasars. Key unanswered questions include: Where is the rest of
the unseen universe? What is the interplay of the dark and luminous universe?
How did the IGM collapse to form the galaxies and clusters? When were galaxies,
clusters, and stellar populations assembled into their current form? What is
the history of star formation and chemical evolution? Are massive black holes a
natural part of most galaxies? A large-aperture UV/O telescope in space
(ST-2010) will provide a major facility in the 21st century for solving these
scientific problems. The UVOWG recommends that the first mission be a 4m
aperture, SIRTF-class mission that focuses on UV spectroscopy and wide-field
imaging. In the coming decade, NASA should investigate the feasibility of an 8m
telescope, by 2010, with deployable optics similar to NGST. No high-throughput
UV/Optical mission will be possible without significant NASA investments in
technology, including UV detectors, gratings, mirrors, and imagers.Comment: Report of UV/O Working Group to NASA, 72 pages, 13 figures, Full
document with postscript figures available at
http://casa.colorado.edu/~uvconf/UVOWG.htm
New Solutions of the Inflationary Flow Equations
The inflationary flow equations are a frequently used method of surveying the
space of inflationary models. In these applications the infinite hierarchy of
differential equations is truncated in a way which has been shown to be
equivalent to restricting the set of models considered to those characterized
by polynomial inflaton potentials. This paper explores a different method of
solving the flow equations, which does not truncate the hierarchy and in
consequence covers a much wider class of models while retaining the practical
usability of the standard approach.Comment: References added, and a couple of comment
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