1,759 research outputs found
Moments of spectral functions: Monte Carlo evaluation and verification
The subject of the present study is the Monte Carlo path-integral evaluation
of the moments of spectral functions. Such moments can be computed by formal
differentiation of certain estimating functionals that are
infinitely-differentiable against time whenever the potential function is
arbitrarily smooth. Here, I demonstrate that the numerical differentiation of
the estimating functionals can be more successfully implemented by means of
pseudospectral methods (e.g., exact differentiation of a Chebyshev polynomial
interpolant), which utilize information from the entire interval . The algorithmic detail that leads to robust numerical
approximations is the fact that the path integral action and not the actual
estimating functional are interpolated. Although the resulting approximation to
the estimating functional is non-linear, the derivatives can be computed from
it in a fast and stable way by contour integration in the complex plane, with
the help of the Cauchy integral formula (e.g., by Lyness' method). An
interesting aspect of the present development is that Hamburger's conditions
for a finite sequence of numbers to be a moment sequence provide the necessary
and sufficient criteria for the computed data to be compatible with the
existence of an inversion algorithm. Finally, the issue of appearance of the
sign problem in the computation of moments, albeit in a milder form than for
other quantities, is addressed.Comment: 13 pages, 2 figure
Production of trans-Neptunian binaries through chaos-assisted capture
The recent discovery of binary objects in the Kuiper-belt opens an invaluable
window into past and present conditions in the trans-Neptunian part of the
Solar System. For example, knowledge of how these objects formed can be used to
impose constraints on planetary formation theories. We have recently proposed a
binary-object formation model based on the notion of chaos-assisted capture.
Here we present a more detailed analysis with calculations performed in the
spatial (three-dimensional) three- and four-body Hill approximations. It is
assumed that the potential binary partners are initially following heliocentric
Keplerian orbits and that their relative motion becomes perturbed as these
objects undergo close encounters. First, the mass, velocity, and orbital
element distribu- tions which favour binary formation are identified in the
circular and elliptical Hill limits. We then consider intruder scattering in
the circular Hill four-body problem and find that the chaos-assisted capture
mechanism is consistent with observed, apparently randomly distributed, binary
mutual orbit inclinations. It also predicts asymmetric distributions of
retrograde versus prograde orbits. The time-delay induced by chaos on particle
transport through the Hill sphere is analogous to the formation of a resonance
in a chemical reaction. Implications for binary formation rates are considered
and the 'fine-tuning' problem recently identified by Noll et al. (2007) is also
addressed.Comment: submitted to MNRA
Design considerations for engineering 3D models to study vascular pathologies in vitro
Many cardiovascular diseases (CVD) are driven by pathological remodelling of blood vessels, which can lead to aneurysms, myocardial infarction, ischaemia and strokes. Aberrant remodelling is driven by changes in vascular cell behaviours combined with degradation, modification, or abnormal deposition of extracellular matrix (ECM) proteins. The underlying mechanisms that drive the pathological remodelling of blood vessels are multifaceted and disease specific; however, unravelling them may be key to developing therapies. Reductionist models of blood vessels created in vitro that combine cells with biomaterial scaffolds may serve as useful analogues to study vascular disease progression in a controlled environment. This review presents the main considerations for developing such in vitro models. We discuss how the design of blood vessel models impacts experimental readouts, with a particular focus on the maintenance of normal cellular phenotypes, strategies that mimic normal cell-ECM interactions, and approaches that foster intercellular communication between vascular cell types. We also highlight how choice of biomaterials, cellular arrangements and the inclusion of mechanical stimulation using fluidic devices together impact the ability of blood vessel models to mimic in vivo conditions. In the future, by combining advances in materials science, cell biology, fluidics and modelling, it may be possible to create blood vessel models that are patient-specific and can be used to develop and test therapies
A Hydrogel-Integrated Culture Device to Interrogate T Cell Activation with Physicochemical Cues
The recent rise of adoptive T cell therapy (ATCT) as a promising cancer immunotherapy has triggered increased interest in therapeutic T cell bioprocessing. T cell activation is a critical processing step and is known to be modulated by physical parameters, such as substrate stiffness. Nevertheless, relatively little is known about how biophysical factors regulate immune cells, such as T cells. Understanding how T cell activation is modulated by physical and biochemical cues may offer novel methods to control cell behavior for therapeutic cell processing. Inspired by T cell mechanosensitivity, we developed a multiwell, reusable, customizable, two-dimensional (2D) polyacrylamide (PA) hydrogel-integrated culture device to study the physicochemical stimulation of Jurkat T cells. Substrate stiffness and ligand density were tuned by concentrations of the hydrogel cross-linker and antibody in the coating solution, respectively. We cultured Jurkat T cells on 2D hydrogels of different stiffnesses that presented surface-immobilized stimulatory antibodies against CD3 and CD28 and demonstrated that Jurkat T cells stimulated by stiff hydrogels (50.6 ± 15.1 kPa) exhibited significantly higher interleukin-2 (IL-2) secretion, but lower proliferation, than those stimulated by softer hydrogels (7.1 ± 0.4 kPa). In addition, we found that increasing anti-CD3 concentration from 10 to 30 μg/mL led to a significant increase in IL-2 secretion from cells stimulated on 7.1 ± 0.4 and 9.3 ± 2.4 kPa gels. Simultaneous tuning of substrate stiffness and stimulatory ligand density showed that the two parameters synergize (two-way ANOVA interaction effect: p < 0.001) to enhance IL-2 secretion. Our results demonstrate the importance of physical parameters in immune cell stimulation and highlight the potential of designing future immunostimulatory biomaterials that are mechanically tailored to balance stimulatory strength and downstream proliferative capacity of therapeutic T cells
Modelling background intensity in Affymetrix Genechips
DNA microarrays are devices that are able, in principle, to detect and
quantify the presence of specific nucleic acid sequences in complex biological
mixtures. The measurement consists in detecting fluorescence signals from
several spots on the microarray surface onto which different probe sequences
are grafted. One of the problems of the data analysis is that the signal
contains a noisy background component due to non-specific binding. This paper
presents a physical model for background estimation in Affymetrix Genechips. It
combines two different approaches. The first is based on the sequence
composition, specifically its sequence dependent hybridization affinity. The
second is based on the strong correlation of intensities from locations which
are the physical neighbors of a specific spot on the chip. Both effects are
incorporated in a background functional which contains 24 free parameters,
fixed by minimization on a training data set. In all data analyzed the sequence
specific parameters, obtained by minimization, are found to strongly correlate
with empirically determined stacking free energies for RNA/DNA hybridization in
solution. Moreover, there is an overall agreement with experimental background
data and we show that the physics-based model proposed in this paper performs
on average better than purely statistical approaches for background
calculations. The model thus provides an interesting alternative method for
background subtraction schemes in Affymetrix Genechips.Comment: 8 pages, 4 figure
Faster disease progression in Parkinson's disease with type 2 diabetes is not associated with increased α-synuclein, tau, amyloid-β or vascular pathology
AIMS: Growing evidence suggests a shared pathogenesis between Parkinson's disease and diabetes although the underlying mechanisms remain unknown. The aim of this study is to evaluate the effect of type 2 diabetes on Parkinson's disease progression and to correlate neuropathological findings to elucidate pathogenic mechanisms. METHODS: In this cohort study, medical records were retrospectively reviewed of cases with pathologically-confirmed Parkinson's disease with and without pre-existing type 2 diabetes. Time to disability milestones (recurrent falls, wheelchair dependence, dementia, and care home placement) and survival were compared to assess disease progression and their risk estimated using Cox hazard regression models. Correlation with pathological data was performed, including quantification of α-synuclein in key brain regions and staging of vascular, Lewy and Alzheimer's pathologies. RESULTS: Patients with PD and diabetes (male 76%; age at death 78.6 ± 6.2 years) developed earlier falls (P < 0.001), wheelchair dependence (P = 0.004), dementia (P < 0.001), care home admission (P < 0.001) and had reduced survival (P < 0.001). Predating diabetes was independently associated with a two to three-fold increase in the risk of disability and death. Neuropathological assessment did not show any differences in global or regional vascular pathology, α-synuclein load in key brain areas, staging of Lewy pathology or Alzheimer's disease pathology. CONCLUSIONS: Pre-existing type 2 diabetes contributes to faster disease progression and reduced survival in Parkinson's disease which is not driven by increased vascular, Lewy or Alzheimer's pathologies. Additional non-specific neurodegeneration related to chronic brain insulin resistance may be involved
Properties of continuous Fourier extension of the discrete cosine transform and its multidimensional generalization
A versatile method is described for the practical computation of the discrete
Fourier transforms (DFT) of a continuous function given by its values
at the points of a uniform grid generated by conjugacy classes
of elements of finite adjoint order in the fundamental region of
compact semisimple Lie groups. The present implementation of the method is for
the groups SU(2), when is reduced to a one-dimensional segment, and for
in multidimensional cases. This simplest case
turns out to result in a transform known as discrete cosine transform (DCT),
which is often considered to be simply a specific type of the standard DFT.
Here we show that the DCT is very different from the standard DFT when the
properties of the continuous extensions of these two discrete transforms from
the discrete grid points to all points are
considered. (A) Unlike the continuous extension of the DFT, the continuous
extension of (the inverse) DCT, called CEDCT, closely approximates
between the grid points . (B) For increasing , the derivative of CEDCT
converges to the derivative of . And (C), for CEDCT the principle of
locality is valid. Finally, we use the continuous extension of 2-dimensional
DCT to illustrate its potential for interpolation, as well as for the data
compression of 2D images.Comment: submitted to JMP on April 3, 2003; still waiting for the referee's
Repor
Differential regulation of human bone marrow mesenchymal stromal cell chondrogenesis by hypoxia inducible factor-1α hydroxylase inhibitors
The transcriptional profile induced by hypoxia plays important roles in the chondrogenic differentiation of marrow stromal/stem cells (MSC) and is mediated by the Hypoxia Inducible Factor complex. However, various compounds can also stabilise HIF's oxygen-responsive element, HIF-1α, at normoxia and mimic many hypoxia-induced cellular responses. Such compounds may prove efficacious in cartilage tissue engineering, where microenvironmental cues may mediate functional tissue formation. Here, we investigated three HIF stabilising compounds, which each have distinct mechanisms of action, to understand how they differentially influenced the chondrogenesis of human bone marrow-derived MSC (hBM-MSC) in vitro. hBM-MSCs were chondrogenically-induced in TGF-β3 -containing media in the presence of HIF-stabilising compounds. HIF-1α stabilisation was assessed by HIF-1α immunofluorescence staining, expression of HIF target and articular chondrocyte specific genes by qPCR, and cartilage-like extracellular matrix (ECM) production by immunofluorescence and histochemical staining. We demonstrate that all three compounds induced similar levels of HIF-1α nuclear localisation. However, whilst the 2-oxoglutarate analogue Dimethyloxalylglycine (DMOG) promoted upregulation of a selection of HIF target genes, Desferrioxamine (DFX) and Cobalt Chloride (CoCl2 ), compounds that chelate or compete with Fe2+ , respectively, did not. Moreover, DMOG induced a more chondrogenic transcriptional profile, which was abolished by Acriflavine, an inhibitor of HIF-1α-HIF-β binding, whilst the chondrogenic effects of DFX and CoCl2 were more limited. Together, these data suggest that HIF-1α function during hBM-MSC chondrogenesis may be regulated by mechanisms with a greater dependence on 2-oxoglutarate than Fe2+ availability. These results may have important implications for understanding cartilage disease and developing targeted therapies for cartilage repair. This article is protected by copyright. All rights reserved
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