1,584 research outputs found
Quantitative Stability of Linear Infinite Inequality Systems under Block Perturbations with Applications to Convex Systems
The original motivation for this paper was to provide an efficient
quantitative analysis of convex infinite (or semi-infinite) inequality systems
whose decision variables run over general infinite-dimensional (resp.
finite-dimensional) Banach spaces and that are indexed by an arbitrary fixed
set . Parameter perturbations on the right-hand side of the inequalities are
required to be merely bounded, and thus the natural parameter space is
. Our basic strategy consists of linearizing the parameterized
convex system via splitting convex inequalities into linear ones by using the
Fenchel-Legendre conjugate. This approach yields that arbitrary bounded
right-hand side perturbations of the convex system turn on constant-by-blocks
perturbations in the linearized system. Based on advanced variational analysis,
we derive a precise formula for computing the exact Lipschitzian bound of the
feasible solution map of block-perturbed linear systems, which involves only
the system's data, and then show that this exact bound agrees with the
coderivative norm of the aforementioned mapping. In this way we extend to the
convex setting the results of [3] developed for arbitrary perturbations with no
block structure in the linear framework under the boundedness assumption on the
system's coefficients. The latter boundedness assumption is removed in this
paper when the decision space is reflexive. The last section provides the aimed
application to the convex case
The Age of the Galactic Disk
I review different methods devised to derive the age of the Galactic Disk,
namely the Radio-active Decay (RD), the Cool White Dwarf Luminosity Function
(CWDLF), old opne clusters (OOC) and the Color Magnitude Diagram (CMD) of the
stars in the solar vicinity. I argue that the disk is likely to be 8-10 Gyr
old. Since the bulk of globulars has an age around 13 Gyr, the possibility
emerges that the Galaxy experienced a minimum of Star Formation at the end of
the halo/bulge formation. This minimum might reflect the time at which the
Galaxy started to acquire material to form the disk inside-out.Comment: 10 pages, 4 figure, invited review, in "The chemical evolution of the
Milky Way : Stars vs Clusters, Vulcano (Italy), 20-24 September 199
CFTR with a partially deleted R domain corrects the cystic fibrosis chloride transport defect in human airway epithelia in vitro and in mouse nasal mucosa in vivo
On the probability of cost-effectiveness using data from randomized clinical trials
BACKGROUND: Acceptability curves have been proposed for quantifying the probability that a treatment under investigation in a clinical trial is cost-effective. Various definitions and estimation methods have been proposed. Loosely speaking, all the definitions, Bayesian or otherwise, relate to the probability that the treatment under consideration is cost-effective as a function of the value placed on a unit of effectiveness. These definitions are, in fact, expressions of the certainty with which the current evidence would lead us to believe that the treatment under consideration is cost-effective, and are dependent on the amount of evidence (i.e. sample size). METHODS: An alternative for quantifying the probability that the treatment under consideration is cost-effective, which is independent of sample size, is proposed. RESULTS: Non-parametric methods are given for point and interval estimation. In addition, these methods provide a non-parametric estimator and confidence interval for the incremental cost-effectiveness ratio. An example is provided. CONCLUSIONS: The proposed parameter for quantifying the probability that a new therapy is cost-effective is superior to the acceptability curve because it is not sample size dependent and because it can be interpreted as the proportion of patients who would benefit if given the new therapy. Non-parametric methods are used to estimate the parameter and its variance, providing the appropriate confidence intervals and test of hypothesis
The gray matter volume of the amygdala is correlated with the perception of melodic intervals: a voxel-based morphometry study
Music is not simply a series of organized pitches, rhythms, and timbres, it is capable of evoking emotions. In the present study, voxel-based morphometry (VBM) was employed to explore the neural basis that may link music to emotion. To do this, we identified the neuroanatomical correlates of the ability to extract pitch interval size in a music segment (i.e., interval perception) in a large population of healthy young adults (N = 264). Behaviorally, we found that interval perception was correlated with daily emotional experiences, indicating the intrinsic link between music and emotion. Neurally, and as expected, we found that interval perception was positively correlated with the gray matter volume (GMV) of the bilateral temporal cortex. More important, a larger GMV of the bilateral amygdala was associated with better interval perception, suggesting that the amygdala, which is the neural substrate of emotional processing, is also involved in music processing. In sum, our study provides one of first neuroanatomical evidence on the association between the amygdala and music, which contributes to our understanding of exactly how music evokes emotional responses
Curved Tails in Polymerization-Based Bacterial Motility
The curved actin ``comet-tail'' of the bacterium Listeria monocytogenes is a
visually striking signature of actin polymerization-based motility. Similar
actin tails are associated with Shigella flexneri, spotted-fever Rickettsiae,
the Vaccinia virus, and vesicles and microspheres in related in vitro systems.
We show that the torque required to produce the curvature in the tail can arise
from randomly placed actin filaments pushing the bacterium or particle. We find
that the curvature magnitude determines the number of actively pushing
filaments, independent of viscosity and of the molecular details of force
generation. The variation of the curvature with time can be used to infer the
dynamics of actin filaments at the bacterial surface.Comment: 8 pages, 2 figures, Latex2
Effect of parasympathetic stimulation on brain activity during appraisal of fearful expressions
Autonomic nervous system activity is an important component of human emotion. Mental processes influence bodily physiology, which in turn feeds back to influence thoughts and feelings. Afferent cardiovascular signals from arterial baroreceptors in the carotid sinuses are processed within the brain and contribute to this two-way communication with the body. These carotid baroreceptors can be stimulated non-invasively by externally applying focal negative pressure bilaterally to the neck. In an experiment combining functional neuroimaging (fMRI) with carotid stimulation in healthy participants, we tested the hypothesis that manipulating afferent cardiovascular signals alters the central processing of emotional information (fearful and neutral facial expressions). Carotid stimulation, compared with sham stimulation, broadly attenuated activity across cortical and brainstem regions. Modulation of emotional processing was apparent as a significant expression-by-stimulation interaction within left amygdala, where responses during appraisal of fearful faces were selectively reduced by carotid stimulation. Moreover, activity reductions within insula, amygdala, and hippocampus correlated with the degree of stimulation-evoked change in the explicit emotional ratings of fearful faces. Across participants, individual differences in autonomic state (heart rate variability, a proxy measure of autonomic balance toward parasympathetic activity) predicted the extent to which carotid stimulation influenced neural (amygdala) responses during appraisal and subjective rating of fearful faces. Together our results provide mechanistic insight into the visceral component of emotion by identifying the neural substrates mediating cardiovascular influences on the processing of fear signals, potentially implicating central baroreflex mechanisms for anxiolytic treatment targets
Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition
Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy
An Experimental and Computational Study of the Effect of ActA Polarity on the Speed of Listeria monocytogenes Actin-based Motility
Listeria monocytogenes is a pathogenic bacterium that moves within infected cells and spreads directly between cells by harnessing the cell's dendritic actin machinery. This motility is dependent on expression of a single bacterial surface protein, ActA, a constitutively active Arp2,3 activator, and has been widely studied as a biochemical and biophysical model system for actin-based motility. Dendritic actin network dynamics are important for cell processes including eukaryotic cell motility, cytokinesis, and endocytosis. Here we experimentally altered the degree of ActA polarity on a population of bacteria and made use of an ActA-RFP fusion to determine the relationship between ActA distribution and speed of bacterial motion. We found a positive linear relationship for both ActA intensity and polarity with speed. We explored the underlying mechanisms of this dependence with two distinctly different quantitative models: a detailed agent-based model in which each actin filament and branched network is explicitly simulated, and a three-state continuum model that describes a simplified relationship between bacterial speed and barbed-end actin populations. In silico bacterial motility required a cooperative restraining mechanism to reconstitute our observed speed-polarity relationship, suggesting that kinetic friction between actin filaments and the bacterial surface, a restraining force previously neglected in motility models, is important in determining the effect of ActA polarity on bacterial motility. The continuum model was less restrictive, requiring only a filament number-dependent restraining mechanism to reproduce our experimental observations. However, seemingly rational assumptions in the continuum model, e.g. an average propulsive force per filament, were invalidated by further analysis with the agent-based model. We found that the average contribution to motility from side-interacting filaments was actually a function of the ActA distribution. This ActA-dependence would be difficult to intuit but emerges naturally from the nanoscale interactions in the agent-based representation
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