Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies

Predicted modulated differential rates for direct WIMP searches at low energy transfers

The differential event rate for direct detection of dark matter, both the time averaged and the modulated one due to the motion of the Earth, are discussed. The calculations focus on relatively light cold dark matter candidates (WIMP) and low energy transfers. It is shown that for sufficiently light WIMPs the extraction of relatively large nucleon cross sections is possible. Furthermore for some WIMP masses the modulation amplitude may change sign, meaning that, in such a case, the maximum rate may occur six months later than naively expected. This effect can be exploited to yield information about the mass of the dark matter candidate, if and when the observation of the modulation of the event rate is established.Comment: 16 pages, 22 figures; references adde

Fitting the Gamma-Ray Spectrum from Dark Matter with DMFIT: GLAST and the Galactic Center Region

We study the potential of GLAST to unveil particle dark matter properties with gamma-ray observations of the Galactic center region. We present full GLAST simulations including all gamma-ray sources known to date in a region of 4 degrees around the Galactic center, in addition to the diffuse gamma-ray background and to the dark matter signal. We introduce DMFIT, a tool that allows one to fit gamma-ray emission from pair-annihilation of generic particle dark matter models and to extract information on the mass, normalization and annihilation branching ratios into Standard Model final states. We assess the impact and systematic effects of background modeling and theoretical priors on the reconstruction of dark matter particle properties. Our detailed simulations demonstrate that for some well motivated supersymmetric dark matter setups with one year of GLAST data it will be possible not only to significantly detect a dark matter signal over background, but also to estimate the dark matter mass and its dominant pair-annihilation mode.Comment: 37 pages, 16 figures, submitted to JCA

Direct versus indirect detection in mSUGRA with self-consistent halo models

We perform a detailed analysis of the detection prospects of neutralino dark matter in the mSUGRA framework. We focus on models with a thermal relic density, estimated with high accuracy using the DarkSUSY package, in the range favored by current precision cosmological measurements. Direct and indirect detection rates are computed implementing two models for the dark matter halo, tracing opposite regimes for the phase of baryon infall, with fully consistent density profiles and velocity distribution functions. This has allowed, for the first time, a fully consistent comparison between direct and indirect detection prospects. We discuss all relevant regimes in the mSUGRA parameter space, underlining relevant effects, and providing the basis for extending the discussion to alternative frameworks. In general, we find that direct detection and searches for antideuterons in the cosmic rays seems to be the most promising ways to search for neutralinos in these scenarios.Comment: 26 pages, 9 figure

Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies

Inelastic Dark Matter, Non-Standard Halos and the DAMA/LIBRA Results

The DAMA collaboration have claimed to detect particle dark matter (DM) via an annual modulation in their observed recoil event rate. This appears to be in strong disagreement with the null results of other experiments if interpreted in terms of elastic DM scattering, while agreement for a small region of parameter space is possible for inelastic DM (iDM) due to the altered kinematics of the collision. To date most analyses assume a simple galactic halo DM velocity distribution, the Standard Halo Model, but direct experimental support for the SHM is severely lacking and theoretical studies indicate possible significant differences. We investigate the dependence of DAMA and the other direct detection experiments on the local DM velocity distribution, utilizing the results of the Via Lactea and Dark Disc numerical simulations. We also investigate effects of varying the solar circular velocity, the DM escape velocity, and the DAMA quenching factor within experimental limits. Our data set includes the latest ZEPLIN-III results, as well as full publicly available data sets. Due to the more sensitive dependence of the inelastic cross section on the velocity distribution, we find that with Via Lactea the DAMA results can be consistent with all other experiments over an enlarged region of iDM parameter space, with higher mass particles being preferred, while Dark Disc does not lead to an improvement. A definitive test of DAMA for iDM requires heavy element detectors.Comment: 22 pages, 10 figures, PDFLaTex Additional analysis of Via Lactea simulation include

Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation

INTRODUCTION: The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss. RESULTS: RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3'-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets' steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression. DISCUSSION: Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells

Can annihilating Dark Matter be lighter than a few GeVs?

We estimate the gamma ray fluxes from the residual annihilations of Dark Matter particles having a mass mdm \in [MeV, O(GeV)] and compare them to observations. We find that particles lighter than O(100 MeV) are excluded unless their cross section is S-wave suppressed.Comment: 4 pages. No figure. Values corrected (last column Table.1). Text clarified. Conclusions unchange

Using metadynamics to explore complex free-energy landscapes

Metadynamics is an atomistic simulation technique that allows, within the same framework, acceleration of rare events and estimation of the free energy of complex molecular systems. It is based on iteratively \u2018filling\u2019 the potential energy of the system by a sum of Gaussians centred along the trajectory followed by a suitably chosen set of collective variables (CVs), thereby forcing the system to migrate from one minimum to the next. The power of metadynamics is demonstrated by the large number of extensions and variants that have been developed. The first scope of this Technical Review is to present a critical comparison of these variants, discussing their advantages and disadvantages. The effectiveness of metadynamics, and that of the numerous alternative methods, is strongly influenced by the choice of the CVs. If an important variable is neglected, the resulting estimate of the free energy is unreliable, and predicted transition mechanisms may be qualitatively wrong. The second scope of this Technical Review is to discuss how the CVs should be selected, how to verify whether the chosen CVs are sufficient or redundant, and how to iteratively improve the CVs using machine learning approaches