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Article ; Online: What can the ideal gas say about global pandemics? Reinterpreting the basic reproduction number

Dickson, Bradley M

medRxiv

Abstract: Through analysis of the ideal gas, we construct a random walk that on average matches the standard susceptible-infective-removed (SIR) model. We show that the most widely referenced parameter, the 9basic reproduction number9 (R ... 0 ... ), is ... ...

Abstract	Through analysis of the ideal gas, we construct a random walk that on average matches the standard susceptible-infective-removed (SIR) model. We show that the most widely referenced parameter, the 9basic reproduction number9 (R<sub>0</sub>), is fundamentally connected to the relative odds of increasing or decreasing the infectives population. As a consequence, for R<sub>0</sub> > 1 the probability that no outbreak occurs is 1/R<sub>0</sub>. In stark contrast to a deterministic SIR, when R<sub>0</sub> = 1.5 the random walk has a 67% chance of avoiding outbreak. Thus, an alternative, probabilistic, interpretation of R<sub>0</sub> arises, which provides a novel estimate of the critical population density γ/r without fitting SIR models. We demonstrate that SARS-CoV2 in the United States is consistent with our model and attempt an estimate of γ/r. In doing so, we uncover a significant source of bias in public data reporting. Data are aggregated on political boundaries, which bear no concern for dispersion of population density. We show that this introduces bias in fits and parameter estimates, a concern for understanding fundamental virus parameters and for policy making. Anonymized data at the resolution required for contact tracing would afford access to γ/r without fitting. The random walk SIR developed here highlights the intuition that any epidemic is stochastic and recovers all the key parameter values noted by Kermack and McKendrick in 1927.
Keywords	covid19
Language	English
Publishing date	2020-07-11
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.07.09.20150128
Database	COVID19

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Article ; Online: Erroneous Rates and False Statistical Confirmations from Infrequent Metadynamics and Other Equivalent Violations of the Hyperdynamics Paradigm.

Dickson, Bradley M

Journal of chemical theory and computation

2018 Volume 15, Issue 1, Page(s) 78–83

Abstract: Recent combinations of hyperdynamics and adaptive biasing potentials or free-energy-based bias potentials introduce an implicit assumption: the bias potential needs only be zero on the prominent free-energy barriers of interest. Herein we demonstrate ... ...

Abstract	Recent combinations of hyperdynamics and adaptive biasing potentials or free-energy-based bias potentials introduce an implicit assumption: the bias potential needs only be zero on the prominent free-energy barriers of interest. Herein we demonstrate that this implicit assumption is flawed. Thus, hyperdynamics in collective variables is likely to fail unless there are no hidden barriers within the initial state. Moreoever, the one-sample Kolmogorov-Smirnov test used to declare "trust" in hyperdynamics is shown to be unable to classify this failure. In fact, nonzero bias potential on hidden barriers emerges as a contradiction of the hypothesis that a Poisson distributed set of hyperdynamics escape times is a correctly distributed set of escape times. We demonstrate failure in the alanine dipeptide benchmark, and we present an apparent failure for a protein conformation change. The standards for "trustworthy" hyperdynamics in collective variables must be raised.
MeSH term(s)	Molecular Dynamics Simulation ; Thermodynamics
Language	English
Publishing date	2018-12-06
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.8b00848
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Analysis of histone antibody specificity directly in sequencing data using siQ-ChIP.

Kupai, Ariana / Vaughan, Robert M / Rothbart, Scott B / Dickson, Bradley M

bioRxiv : the preprint server for biology

2023

Abstract: We previously developed sans spike-in quantitative chromatin immunoprecipitation sequencing (siQ-ChIP), a technique that introduces an absolute quantitative scale to ChIP-seq data without reliance on spike-in normalization approaches. The physical model ... ...

Abstract	We previously developed sans spike-in quantitative chromatin immunoprecipitation sequencing (siQ-ChIP), a technique that introduces an absolute quantitative scale to ChIP-seq data without reliance on spike-in normalization approaches. The physical model of siQ-ChIP predicted that the IP step of ChIP would produce a classical binding isotherm when antibody or epitope was titrated. Here, we define experimental conditions in which this titration is observable for antibodies that recognize modified states of histone proteins. We show that minimally sequenced points along an isotherm can reveal differential binding specificities that are associated with on- and off-target epitope interactions. This work demonstrates that the interpretation of histone post-translational modification distribution from ChIP-seq data has a dependence on antibody concentration. Collectively, these studies introduce a simplified and reproducible experimental method to generate quantitative ChIP-seq data without spike-in normalization and demonstrate that histone antibody specificity can be analyzed directly in ChIP-seq experiments.
Language	English
Publishing date	2023-03-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.08.531745
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Article ; Online: Streamlined quantitative analysis of histone modification abundance at nucleosome-scale resolution with siQ-ChIP version 2.0.

Dickson, Bradley M / Kupai, Ariana / Vaughan, Robert M / Rothbart, Scott B

Scientific reports

2023 Volume 13, Issue 1, Page(s) 7508

Abstract: We recently introduced an absolute and physical quantitative scale for chromatin immunoprecipitation followed by sequencing (ChIP-seq). The scale itself was determined directly from measurements routinely made on sequencing samples without additional ... ...

Abstract	We recently introduced an absolute and physical quantitative scale for chromatin immunoprecipitation followed by sequencing (ChIP-seq). The scale itself was determined directly from measurements routinely made on sequencing samples without additional reagents or spike-ins. We called this approach sans spike-in quantitative ChIP, or siQ-ChIP. Herein, we extend those results in several ways. First, we simplified the calculations defining the quantitative scale, reducing practitioner burden. Second, we reveal a normalization constraint implied by the quantitative scale and introduce a new scheme for generating 'tracks'. The constraint requires that tracks are probability distributions so that quantified ChIP-seq is analogous to a mass distribution. Third, we introduce some whole-genome analyses that allow us, for example, to project the IP mass (immunoprecipitated mass) onto the genome to evaluate how much of any genomic interval was captured in the IP. We applied siQ-ChIP to p300/CBP inhibition and compare our results to those of others. We detail how the same data-level observations are misinterpreted in the literature when tracks are not understood as probability densities and are compared without correct quantitative scaling, and we offer new interpretations of p300/CBP inhibition outcomes.
MeSH term(s)	Nucleosomes/genetics ; Histone Code ; Chromatin Immunoprecipitation ; Chromatin Immunoprecipitation Sequencing ; Genomics
Chemical Substances	Nucleosomes
Language	English
Publishing date	2023-05-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-34430-2
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Article ; Online: Overfill Protection and Hyperdynamics in Adaptively Biased Simulations.

Dickson, Bradley M

Journal of chemical theory and computation

2017

Abstract: Two problems associated with adaptively biased simulations are considered: overfilling and time scale estimation. First, a simple and computationally efficient procedure for limiting the bias fill-depth of any adaptive biasing potential is introduced. ... ...

Abstract	Two problems associated with adaptively biased simulations are considered: overfilling and time scale estimation. First, a simple and computationally efficient procedure for limiting the bias fill-depth of any adaptive biasing potential is introduced. The resulting bias potential floods only up to a specified level and avoids bias accumulation in higher regions of free energy. Second, hyperdynamics can be invoked in combination with this depth-limited bias potential to estimate time scales. We argue that allowing the bias to equilibrate to a set depth is one crux in efficient hyperdynamics application. In both simple (alanine dipeptide) and complex (ligand residence) test cases, the useable boost factors are 6-8 times larger when the bias fill depth is directly controlled, as opposed to controlling the update frequency. Update frequency has emerged as a proxy for controlling the fill height of adaptive biases, with infrequent metadynamics being an example. The Kolmogorov-Smirnov test is shown to be insufficient for determining the trustworthiness of a hyperdynamics simulation, and a more robust strategy is described. Overfill limiting and hyperdynamics have been added to the fABMACS project.
Language	English
Publishing date	2017-11-20
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.7b00821
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Article ; Online: Survey of adaptive biasing potentials: comparisons and outlook.

Dickson, Bradley M

Current opinion in structural biology

2017 Volume 43, Page(s) 63–67

Abstract: Adaptive biasing potentials are becoming a standard tool of the trade for problems in chemistry, material science, biology, and drug discovery. These methods are easy to use, easy to distribute, reliable, and make otherwise impossible simulations ... ...

Abstract	Adaptive biasing potentials are becoming a standard tool of the trade for problems in chemistry, material science, biology, and drug discovery. These methods are easy to use, easy to distribute, reliable, and make otherwise impossible simulations possible. In this review we survey a number of adaptive bias potentials, and take a critical look at how they work. The biases fall into two basic classes, each having distinct attributes and levels of complexity. The vantage point from which the biases are discussed has only emerged in the last couple of years, and allows for a unified treatment of all the biases. We conclude with remarks about computational efficiency of the biases, which is largely overlooked in the current literature.
Language	English
Publishing date	2017-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2016.11.007
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Article ; Online: μ-tempered metadynamics: Artifact independent convergence times for wide hills.

Dickson, Bradley M

The Journal of chemical physics

2015 Volume 143, Issue 23, Page(s) 234109

Abstract: Recent analysis of well-tempered metadynamics (WTmetaD) showed that it converges without mollification artifacts in the bias potential. Here, we explore how metadynamics heals mollification artifacts, how healing impacts convergence time, and whether ... ...

Abstract	Recent analysis of well-tempered metadynamics (WTmetaD) showed that it converges without mollification artifacts in the bias potential. Here, we explore how metadynamics heals mollification artifacts, how healing impacts convergence time, and whether alternative temperings may be used to improve efficiency. We introduce "μ-tempered" metadynamics as a simple tempering scheme, inspired by a related mollified adaptive biasing potential, that results in artifact independent convergence of the free energy estimate. We use a toy model to examine the role of artifacts in WTmetaD and solvated alanine dipeptide to compare the well-tempered and μ-tempered frameworks demonstrating fast convergence for hill widths as large as 60(∘) for μTmetaD.
Language	English
Publishing date	2015-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	3113-6
ISSN	1089-7690 ; 0021-9606
ISSN (online)	1089-7690
ISSN	0021-9606
DOI	10.1063/1.4937939
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Article: Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.

Vaughan, Robert M / Dickson, Bradley M / Martin, Katie R / MacKeigan, Jeffrey P

bioRxiv : the preprint server for biology

2023

Abstract: Kinase domains are highly conserved within protein kinases in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain ... ...

Abstract	Kinase domains are highly conserved within protein kinases in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. The serine/threonine kinases ULK1 and ULK2 are highly conserved with N- and C-terminal domains, phosphate-binding P-loops, αC-helix, regulatory and catalytic spines, and activation loop DFG and APE motifs. Here, we performed molecular dynamics (MD) simulations to understand better the potency and selectivity of the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the αC-helix. Large movements in the P-loop are also associated with ULK-101 inhibitor binding and exit from ULK2. Our data further suggests that ULK-101 could induce a folded P-loop conformation and hydrophobic pocket reflected in its nanomolar potency and kinome selectivity.
Language	English
Publishing date	2023-12-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.01.569261
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Article ; Online: How fluxional reactants limit the accuracy/efficiency of infrequent metadynamics.

Khan, Salman A / Dickson, Bradley M / Peters, Baron

The Journal of chemical physics

2020 Volume 153, Issue 5, Page(s) 54125

Abstract: In an infrequent metadynamics (iMetaD) simulation, a well-tempered metadynamics bias accumulates in the reactant basin, accelerating escapes to the product state. Like the earlier hyperdynamics strategy, iMetaD enables estimates of the unbiased escape ... ...

Abstract	In an infrequent metadynamics (iMetaD) simulation, a well-tempered metadynamics bias accumulates in the reactant basin, accelerating escapes to the product state. Like the earlier hyperdynamics strategy, iMetaD enables estimates of the unbiased escape rates. However, iMetaD applies the bias to visited locations in a collective variable (CV) space, not to the more specific visited locations in a full configuration space as done in hyperdynamics. This difference makes rate estimates from iMetaD sensitive to the choice of CVs, to parameters that control the bias deposition rate, and to the preparation of the initial state within the reactant basin. This paper uses an extremely simple discrete state model to illustrate complications that can arise in systems that exhibit fluxional transitions between sub-basins of the reactant state. Specifically, we show how the reactant-to-product escape time and relaxation times within the reactant basin(s) impose bounds on the admissible parameter choices for an iMetaD calculation. Predictions from the discrete state model are validated by iMetaD simulations on a corresponding two-dimensional potential energy surface.
Language	English
Publishing date	2020-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	3113-6
ISSN	1089-7690 ; 0021-9606
ISSN (online)	1089-7690
ISSN	0021-9606
DOI	10.1063/5.0006980
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Article ; Online: DNA strand asymmetry generated by CpG hemimethylation has opposing effects on CTCF binding.

Thomas, Stacey L / Xu, Ting-Hai / Carpenter, Brittany L / Pierce, Steven E / Dickson, Bradley M / Liu, Minmin / Liang, Gangning / Jones, Peter A

Nucleic acids research

2023 Volume 51, Issue 12, Page(s) 5997–6005

Abstract: CpG methylation generally occurs on both DNA strands and is essential for mammalian development and differentiation. Until recently, hemimethylation, in which only one strand is methylated, was considered to be simply a transitory state generated during ... ...

Abstract	CpG methylation generally occurs on both DNA strands and is essential for mammalian development and differentiation. Until recently, hemimethylation, in which only one strand is methylated, was considered to be simply a transitory state generated during DNA synthesis. The discovery that a subset of CCCTC-binding factor (CTCF) binding sites is heritably hemimethylated suggests that hemimethylation might have an unknown biological function. Here we show that the binding of CTCF is profoundly altered by which DNA strand is methylated and by the specific CTCF binding motif. CpG methylation on the motif strand can inhibit CTCF binding by up to 7-fold, whereas methylation on the opposite strand can stimulate binding by up to 4-fold. Thus, hemimethylation can alter binding by up to 28-fold in a strand-specific manner. The mechanism for sensing methylation on the opposite strand requires two critical residues, V454 and S364, within CTCF zinc fingers 7 and 4. Similar to methylation, CpG hydroxymethylation on the motif strand can inhibit CTCF binding by up to 4-fold. However, hydroxymethylation on the opposite strand removes the stimulatory effect. Strand-specific methylation states may therefore provide a mechanism to explain the transient and dynamic nature of CTCF-mediated chromatin interactions.
MeSH term(s)	Animals ; Binding Sites ; CCCTC-Binding Factor/metabolism ; Chromatin ; CpG Islands ; DNA/metabolism ; DNA Methylation ; Mammals/genetics ; Repressor Proteins/metabolism
Chemical Substances	CCCTC-Binding Factor ; Chromatin ; DNA (9007-49-2) ; Repressor Proteins
Language	English
Publishing date	2023-04-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad293
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