326 research outputs found
Jamming in Systems Composed of Frictionless Ellipse-Shaped Particles
We study the structural and mechanical properties of jammed ellipse packings,
and find that the nature of the jamming transition in these systems is
fundamentally different from that for spherical particles. Ellipse packings are
generically hypostatic with more degrees of freedom than constraints. The
spectra of low energy excitations possess two gaps and three distinct branches
over a range of aspect ratios. In the zero compression limit, the energy of the
modes in the lowest branch increases {\it quartically} with deformation
amplitude, and the density of states possesses a -function at zero
frequency. We identify scaling relations that collapse the low-frequency part
of the spectra for different aspect ratios. Finally, we find that the degree of
hypostaticity is determined by the number of quartic modes of the packing.Comment: 4 pages, 4 figure
Origin of Corrections to Mean-field at the Onset of Unjamming
We present a detailed analysis of the unjamming transition in 2D frictionless
disk packings using a static correlation function that has been widely used to
study disordered systems. We show that this point-to-set (PTS) correlation
function exhibits a dominant length scale that diverges as the unjamming
transition is approached through decompression. In addition, we identify
deviations from meanfield predictions, and present detailed analysis of the
origin of non-meanfield behavior. A mean-field bulk-surface argument is
reviewed. Corrections to this argument are identified, which lead to a change
in the functional form of the critical PTS boundary size. An entropic
description of the origin of the correlations is presented, and simple rigidity
assumptions are shown to predict the functional form of the critical PTS
boundary size as a function of the pressure
Constraints and vibrations in static packings of ellipsoidal particles
We numerically investigate the mechanical properties of static packings of
ellipsoidal particles in 2D and 3D over a range of aspect ratio and compression
. While amorphous packings of spherical particles at jamming onset
() are isostatic and possess the minimum contact number required for them to be collectively jammed, amorphous packings of
ellipsoidal particles generally possess fewer contacts than expected for
collective jamming () from naive counting arguments, which
assume that all contacts give rise to linearly independent constraints on
interparticle separations. To understand this behavior, we decompose the
dynamical matrix for static packings of ellipsoidal particles into two
important components: the stiffness and stress matrices. We find that
the stiffness matrix possesses eigenmodes
with zero eigenvalues even at finite compression, where is the number of
particles. In addition, these modes are nearly eigenvectors of the
dynamical matrix with eigenvalues that scale as , and thus finite
compression stabilizes packings of ellipsoidal particles. At jamming onset, the
harmonic response of static packings of ellipsoidal particles vanishes, and the
total potential energy scales as for perturbations by amplitude
along these `quartic' modes, . These findings illustrate
the significant differences between static packings of spherical and
ellipsoidal particles.Comment: 18 pages, 21 figure
CYTOCHROME P450 DIFFERENCE SPECTRA Effect of Chemical Structure on Type II Spectra in Mouse Hepatic M icrosomes
Quantifying single nucleotide variant detection sensitivity in exome sequencing
BACKGROUND: The targeted capture and sequencing of genomic regions has rapidly demonstrated its utility in genetic studies. Inherent in this technology is considerable heterogeneity of target coverage and this is expected to systematically impact our sensitivity to detect genuine polymorphisms. To fully interpret the polymorphisms identified in a genetic study it is often essential to both detect polymorphisms and to understand where and with what probability real polymorphisms may have been missed. RESULTS: Using down-sampling of 30 deeply sequenced exomes and a set of gold-standard single nucleotide variant (SNV) genotype calls for each sample, we developed an empirical model relating the read depth at a polymorphic site to the probability of calling the correct genotype at that site. We find that measured sensitivity in SNV detection is substantially worse than that predicted from the naive expectation of sampling from a binomial. This calibrated model allows us to produce single nucleotide resolution SNV sensitivity estimates which can be merged to give summary sensitivity measures for any arbitrary partition of the target sequences (nucleotide, exon, gene, pathway, exome). These metrics are directly comparable between platforms and can be combined between samples to give âpower estimatesâ for an entire study. We estimate a local read depth of 13X is required to detect the alleles and genotype of a heterozygous SNV 95% of the time, but only 3X for a homozygous SNV. At a mean on-target read depth of 20X, commonly used for rare disease exome sequencing studies, we predict 5â15% of heterozygous and 1â4% of homozygous SNVs in the targeted regions will be missed. CONCLUSIONS: Non-reference alleles in the heterozygote state have a high chance of being missed when commonly applied read coverage thresholds are used despite the widely held assumption that there is good polymorphism detection at these coverage levels. Such alleles are likely to be of functional importance in population based studies of rare diseases, somatic mutations in cancer and explaining the âmissing heritabilityâ of quantitative traits
Task specific influences of Parkinsonâs disease on the striato-thalamo-cortical and cerebello-thalamo-cortical motor circuitries
The motor deficits in Parkinsonâs disease (PD) have been primarily associated with internally guided (IG), but not externally guided (EG), tasks. This study investigated the functional mechanisms underlying this phenomenon using genetically-matched twins. Functional magnetic resonance images were obtained from a monozygotic twin pair discordant for clinical PD. Single-photon emission computed tomography neuroimaging using [123I](â)-2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane confirmed their disease-discordant status by demonstrating a severe loss of transporter binding in the PD-twin, whereas the non-PD-twin was normal. Six runs of fMRI data were acquired from each twin performing EG and IG right-hand finger sequential tasks. The percentage of voxels activated in each of several regions of interest (ROI) was calculated. Multiple analysis of variance was used to compare each twinâs activity in ROIs constituting the striato-thalamo-cortical motor circuits [basal ganglia (BG)-cortical circuitry, but including the globus pallidus/putamen, thalamus, supplementary motor area, and primary motor cortex] and cerebello-thalamo-cortical circuits (referred to as the cerebellarâcortical circuitry, including the cerebellum, thalamus, somatosensory cortex, and lateral premotor cortex). During the EG task, there were no significant differences between the twins in bilateral BG-cortical pathways, either basally or after levodopa, whereas the PD-twin had relatively increased activity in the cerebellar-cortical pathways basally that was normalized by levodopa. During the IG task, the PD-twin had less activation than the non-PD-twin in ROIs of the bilateral BG-cortical and cerebellar-cortical pathways. Levodopa normalized the hypoactivation in the contralateral BG-cortical pathway, but âover-correctedâ the activation in the ipsilateral BG-cortical and bilateral cerebellar-cortical pathways. In this first fMRI study of twins discordant for PD, the data support the hypothesis that BG-cortical and cerebellar-cortical pathways are task-specifically influenced by PD. The levodopa-induced âover-activationâ of BG-cortical and cerebellar-cortical pathways, and its relevance to both compensatory changes in PD and the long-term effects of levodopa in PD, merit further exploration
Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors
Recently, we demonstrated that D1 agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D1 receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D1 receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D1 receptor after internalization in response to these two compounds with that of dopamine. We found that dopamine caused the receptor to be rapidly recycled to the cell surface within 1 h of removal. Conversely, A-77636 caused the receptor to be retained intracellularly up to 48 h after agonist removal. Most surprisingly, the D1 receptor recovered to the cell surface 48 h after removal of dinapsoline. Taken together, these data indicate that these agonists target the D1 receptor to different intracellular trafficking pathways, demonstrating that the phenomenon of functional selectivity at the D1 receptor is operative for cellular events that are temporally downstream of immediate receptor activation. We hypothesize that these differential effects result from interactions of the synthetic ligands with aspects of the D1 receptor that are distal from the ligand binding domain
Routes for breaching and protecting genetic privacy
We are entering the era of ubiquitous genetic information for research,
clinical care, and personal curiosity. Sharing these datasets is vital for
rapid progress in understanding the genetic basis of human diseases. However,
one growing concern is the ability to protect the genetic privacy of the data
originators. Here, we technically map threats to genetic privacy and discuss
potential mitigation strategies for privacy-preserving dissemination of genetic
data.Comment: Draft for comment
- âŚ