1,224 research outputs found
DNA nanotweezers studied with a coarse-grained model of DNA
We introduce a coarse-grained rigid nucleotide model of DNA that reproduces
the basic thermodynamics of short strands: duplex hybridization,
single-stranded stacking and hairpin formation, and also captures the essential
structural properties of DNA: the helical pitch, persistence length and
torsional stiffness of double-stranded molecules, as well as the comparative
flexibility of unstacked single strands. We apply the model to calculate the
detailed free-energy landscape of one full cycle of DNA 'tweezers', a simple
machine driven by hybridization and strand displacement.Comment: 4 pages, 5 figure
Quantitative Proteomic Approach Identifies Vpr Binding Protein as Novel Host Factor Supporting Influenza A Virus Infections in Human Cells
Influenza A virus infections are a major cause for respiratory disease in humans, which affects all age groups and contributes substantially to global morbidity and mortality. IAV have a large natural host reservoir in avian species. However, many avian IAV strains lack adaptation to other hosts and hardly propagate in humans. While seasonal or pandemic influenza A virus (IAV) strains replicate efficiently in permissive human cells, many avian IAV cause abortive non-productive infections in these hosts despite successful cell entry. However, the precise reasons for these differential outcomes are poorly defined. We hypothesized that the distinct course of an IAV infection with a given virus strain is determined by the differential interplay between specific host and viral factors. By using Spike-in SILAC mass spectrometry-based quantitative proteomics we characterized sets of cellular factors whose abundance is specifically up- or down-regulated in the course of permissive vs. non-permissive IAV infection, respectively. This approach allowed for the definition and quantitative comparison of about 3500 proteins in human lung epithelial cells in response to seasonal or low-pathogenic avian H3N2 IAV. Many identified proteins were similarly regulated by both virus strains, but also 16 candidates with distinct changes in permissive vs. non-permissive infection were found. RNAi-mediated knockdown of these differentially regulated host factors identified Vpr binding protein (VprBP) as pro-viral host factor since its down-regulation inhibited efficient propagation of seasonal IAV while over-expression increased viral replication of both seasonal and avian IAV. These results not only show that there are similar differences in the overall changes during permissive and non-permissive imfluenza virus infections, but also provide a basis to evaluate VprBP as novel anti-IAV drug target
Chromatin: a tunable spring at work inside chromosomes
This paper focuses on mechanical aspects of chromatin biological functioning.
Within a basic geometric modeling of the chromatin assembly, we give for the
first time the complete set of elastic constants (twist and bend persistence
lengths, stretch modulus and twist-stretch coupling constant) of the so-called
30-nm chromatin fiber, in terms of DNA elastic properties and geometric
properties of the fiber assembly. The computation naturally embeds the fiber
within a current analytical model known as the ``extensible worm-like rope'',
allowing a straightforward prediction of the force-extension curves. We show
that these elastic constants are strongly sensitive to the linker length, up to
1 bp, or equivalently to its twist, and might locally reach very low values,
yielding a highly flexible and extensible domain in the fiber. In particular,
the twist-stretch coupling constant, reflecting the chirality of the chromatin
fiber, exhibits steep variations and sign changes when the linker length is
varied.
We argue that this tunable elasticity might be a key feature for chromatin
function, for instance in the initiation and regulation of transcription.Comment: 38 pages 15 figure
Effects of finite curvature on soliton dynamics in a chain of nonlinear oscillators
We consider a curved chain of nonlinear oscillators and show that the
interplay of curvature and nonlinearity leads to a number of qualitative
effects. In particular, the energy of nonlinear localized excitations centered
on the bending decreases when curvature increases, i.e. bending manifests
itself as a trap for excitations. Moreover, the potential of this trap is
double-well, thus leading to a symmetry breaking phenomenon: a symmetric
stationary state may become unstable and transform into an energetically
favorable asymmetric stationary state. The essentials of symmetry breaking are
examined analytically for a simplified model. We also demonstrate a threshold
character of the scattering process, i.e. transmission, trapping, or reflection
of the moving nonlinear excitation passing through the bending.Comment: 13 pages (LaTeX) with 10 figures (EPS
Attraction between DNA molecules mediated by multivalent ions
The effective force between two parallel DNA molecules is calculated as a
function of their mutual separation for different valencies of counter- and
salt ions and different salt concentrations. Computer simulations of the
primitive model are used and the shape of the DNA molecules is accurately
modelled using different geometrical shapes. We find that multivalent ions
induce a significant attraction between the DNA molecules whose strength can be
tuned by the averaged valency of the ions. The physical origin of the
attraction is traced back either to electrostatics or to entropic
contributions. For multivalent counter- and monovalent salt ions, we find a
salt-induced stabilization effect: the force is first attractive but gets
repulsive for increasing salt concentration. Furthermore, we show that the
multivalent-ion-induced attraction does not necessarily correlate with DNA
overcharging.Comment: 51 pages and 13 figure
Transgenic Expression of the Anti-parasitic Factor TEP1 in the Malaria Mosquito Anopheles gambiae
Mosquitoes genetically engineered to be resistant to Plasmodium parasites represent a promising novel approach in the fight against malaria. The insect immune system itself is a source of anti-parasitic genes potentially exploitable for transgenic designs. The Anopheles gambiae thioester containing protein 1 (TEP1) is a potent anti-parasitic protein. TEP1 is secreted and circulates in the mosquito hemolymph, where its activated cleaved form binds and eliminates malaria parasites. Here we investigated whether TEP1 can be used to create malaria resistant mosquitoes. Using a GFP reporter transgene, we determined that the fat body is the main site of TEP1 expression. We generated transgenic mosquitoes that express TEP1r, a potent refractory allele of TEP1, in the fat body and examined the activity of the transgenic protein in wild-type or TEP1 mutant genetic backgrounds. Transgenic TEP1r rescued loss-of-function mutations, but did not increase parasite resistance in the presence of a wild-type susceptible allele. Consistent with previous reports, TEP1 protein expressed from the transgene in the fat body was taken up by hemocytes upon a challenge with injected bacteria. Furthermore, although maturation of transgenic TEP1 into the cleaved form was impaired in one of the TEP1 mutant lines, it was still sufficient to reduce parasite numbers and induce parasite melanization. We also report here the first use of Transcription Activator Like Effectors (TALEs) in Anopheles gambiae to stimulate expression of endogenous TEP1. We found that artificial elevation of TEP1 expression remains moderate in vivo and that enhancement of endogenous TEP1 expression did not result in increased resistance to Plasmodium. Taken together, our results reveal the difficulty of artificially influencing TEP1-mediated Plasmodium resistance, and contribute to further our understanding of the molecular mechanisms underlying mosquito resistance to Plasmodium parasites
Finite difference calculations of permeability in large domains in a wide porosity range.
Determining effective hydraulic, thermal, mechanical and electrical properties of porous materials by means of classical physical experiments is often time-consuming and expensive. Thus, accurate numerical calculations of material properties are of increasing interest in geophysical, manufacturing, bio-mechanical and environmental applications, among other fields. Characteristic material properties (e.g. intrinsic permeability, thermal conductivity and elastic moduli) depend on morphological details on the porescale such as shape and size of pores and pore throats or cracks. To obtain reliable predictions of these properties it is necessary to perform numerical analyses of sufficiently large unit cells. Such representative volume elements require optimized numerical simulation techniques. Current state-of-the-art simulation tools to calculate effective permeabilities of porous materials are based on various methods, e.g. lattice Boltzmann, finite volumes or explicit jump Stokes methods. All approaches still have limitations in the maximum size of the simulation domain. In response to these deficits of the well-established methods we propose an efficient and reliable numerical method which allows to calculate intrinsic permeabilities directly from voxel-based data obtained from 3D imaging techniques like X-ray microtomography. We present a modelling framework based on a parallel finite differences solver, allowing the calculation of large domains with relative low computing requirements (i.e. desktop computers). The presented method is validated in a diverse selection of materials, obtaining accurate results for a large range of porosities, wider than the ranges previously reported. Ongoing work includes the estimation of other effective properties of porous media
Numerical Calculations of the B1g Raman Spectrum of the Two-Dimensional Heisenberg Model
The B1g Raman spectrum of the two-dimensional S=1/2 Heisenberg model is
discussed within Loudon-Fleury theory at both zero and finite temperature. The
exact T=0 spectrum for lattices with up to 6*6 sites is computed using Lanczos
exact diagonalization. A quantum Monte Carlo (QMC) method is used to calculate
the corresponding imaginary-time correlation function and its first two
derivatives for lattices with up to 16*16 spins. The imaginary-time data is
continued to real frequency using the maximum-entropy method, as well as a fit
based on spinwave theory. The numerical results are compared with spinwave
calculations for finite lattices. There is a surprisingly large change in the
exact spectrum going from 4*4 to 6*6 sites. In the former case there is a
single dominant two-magnon peak at frequency w/J appr. 3.0, whereas in the
latter case there are two approximately equal-sized peaks at w/J appr. 2.7 and
3.9. This is in good qualitative agreement with the spinwave calculations
including two-magnon processes on the same lattices. Both the Lanczos and the
QMC results indicate that the actual infinite-size two-magnon profile is
broader than the narrow peak obtained in spinwave theory, but the positions of
the maxima agree to within a few percent. The higher-order contributions
present in the numerical results are merged with the two-magnon profile and
extend up to frequencies w/J appr. 7. The first three frequency cumulants of
the spectrum are in excellent agreement with results previously obtained from a
series expansion around the Ising limit. Typical experimental B1g$ spectra for
La2CuO4 are only slightly broader than what we obtain here. The exchange
constant extracted from the peak position is J appr. 1400K, in good agreement
with values obtained from neutron scattering and NMR experiments.Comment: 15 pages, Revtex, 13 PostScript figure
Bending and Base-Stacking Interactions in Double-Stranded Semiflexible Polymer
Simple expressions for the bending and the base-stacking energy of
double-stranded semiflexible biopolymers (such as DNA and actin) are derived.
The distribution of the folding angle between the two strands is obtained by
solving a Schr\"{o}dinger equation variationally. Theoretical results based on
this model on the extension versus force and extension versus degree of
supercoiling relations of DNA chain are in good agreement with the experimental
observations of Cluzel {\it et al.} [Science {\bf 271}, 792 (1996)], Smith {\it
et al.} [{\it ibid.} {\bf 271}, 795 (1996)], and Strick {\it et al.} [{\it
ibid.} {\bf 271}, 1835 (1996)].Comment: 8 pages in Revtex format, with 4 EPS figure
Uncovering the underlying mechanisms and whole-brain dynamics of deep brain stimulation for Parkinson's disease
Deep brain stimulation (DBS) for Parkinson's disease is a highly effective treatment in controlling otherwise debilitating symptoms. Yet the underlying brain mechanisms are currently not well understood. Whole-brain computational modeling was used to disclose the effects of DBS during resting-state functional Magnetic Resonance Imaging in ten patients with Parkinson's disease. Specifically, we explored the local and global impact that DBS has in creating asynchronous, stable or critical oscillatory conditions using a supercritical bifurcation model. We found that DBS shifts global brain dynamics of patients towards a Healthy regime. This effect was more pronounced in very specific brain areas such as the thalamus, globus pallidus and orbitofrontal regions of the right hemisphere (with the left hemisphere not analyzed given artifacts arising from the electrode lead). Global aspects of integration and synchronization were also rebalanced. Empirically, we found higher communicability and coherence brain measures during DBS-ON compared to DBS-OFF. Finally, using our model as a framework, artificial in silico DBS was applied to find potential alternative target areas for stimulation and whole-brain rebalancing. These results offer important insights into the underlying large-scale effects of DBS as well as in finding novel stimulation targets, which may offer a route to more efficacious treatmentsIn this work, Gustavo Deco is supported by the ERC Advanced Grant: DYSTRUCTURE (n. 295129), by the Spanish Research Project PSI2016-75688-P and by the the European Union's Horizon 2020 research and innovation programme under grant agreement n. 720270 (HBP SGA1). Morten Kringelbach is supported by the ERC Consolidator Grant CAREGIVING (n. 615539) and the Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117). Victor M Saenger is supported by the Research Personnel Training program PSI2013-42091-P funded by the Spanish Ministry of Economy and Competitiveness.info:eu-repo/semantics/publishedVersio
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