291 research outputs found
Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis
Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder
that ultimately causes gradual narrowing of the left ventricular outflow orifice with
ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation
is the hallmark pathology defining this process; however, fibrotic extracellular matrix
(ECM) remodeling that leads to extensive deposition of fibrous connective tissue
and distortion of the valvular microarchitecture similarly has major biomechanical and
functional consequences for heart valve function. Significant advances have been made
to unravel the complex mechanisms that govern these active, cell-mediated processes,
yet the interplay between fibrosis and calcification and the individual contribution to
progressive extracellular matrix stiffening require further clarification. Specifically, we
discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns
in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3)
imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5)
molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse
remodeling. This review explores our current understanding of the cellular and molecular
drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD
Elastogenesis Correlates With Pigment Production in Murine Aortic Valve Leaflets
Objective: Aortic valve (AV) leaflets rely on a precise extracellular matrix (ECM)
microarchitecture for appropriate biomechanical performance. The ECM structure is
maintained by valvular interstitial cells (VICs), which reside within the leaflets. The
presence of pigment produced by a melanocytic population of VICs in mice with dark
coats has been generally regarded as a nuisance, as it interferes with histological analysis
of the AV leaflets. However, our previous studies have shown that the presence of
pigment correlates with increased mechanical stiffness within the leaflets as measured
by nanoindentation analyses. In the current study, we seek to better characterize the
phenotype of understudied melanocytic VICs, explore the role of these VICs in ECM
patterning, and assess the presence of these VICs in human aortic valve tissues.
Approach and Results: Immunofluorescence and immunohistochemistry revealed that
melanocytes within murine AV leaflets express phenotypic markers of either neuronal or
glial cells. These VIC subpopulations exhibited regional patterns that corresponded to
the distribution of elastin and glycosaminoglycan ECM proteins, respectively. VICs with
neuronal and glial phenotypes were also found in human AV leaflets and showed ECM
associations similar to those observed in murine leaflets. A subset of VICs within human
AV leaflets also expressed dopachrome tautomerase, a common melanocyte marker. A
spontaneous mouse mutant with no aortic valve pigmentation lacked elastic fibers and
had reduced elastin gene expression within AV leaflets. A hyperpigmented transgenic
mouse exhibited increased AV leaflet elastic fibers and elastin gene expression.
Conclusions: Melanocytic VIC subpopulations appear critical for appropriate
elastogenesis in mouse AVs, providing new insight into the regulation of AV ECM
homeostasis. The identification of a similar VIC population in human AVs suggests
conservation across species
Ultrafast Laser-Induced Melting of Long-Range Magnetic Order in Multiferroic TbMnO3
We performed ultrafast time-resolved near-infrared pump, resonant soft X-ray
diffraction probe measurements to investigate the coupling between the
photoexcited electronic system and the spin cycloid magnetic order in
multiferroic TbMnO3 at low temperatures. We observe melting of the long range
antiferromagnetic order at low excitation fluences with a decay time constant
of 22.3 +- 1.1 ps, which is much slower than the ~1 ps melting times previously
observed in other systems. To explain the data we propose a simple model of the
melting process where the pump laser pulse directly excites the electronic
system, which then leads to an increase in the effective temperature of the
spin system via a slower relaxation mechanism. Despite this apparent increase
in the effective spin temperature, we do not observe changes in the wavevector
q of the antiferromagnetic spin order that would typically correlate with an
increase in temperature under equilibrium conditions. We suggest that this
behavior results from the extremely low magnon group velocity that hinders a
change in the spin-spiral wavevector on these time scales.Comment: 9 pages, 4 figure
An assessment of the resolution limitation due to radiation-damage in x-ray diffraction microscopy
X-ray diffraction microscopy (XDM) is a new form of x-ray imaging that is
being practiced at several third-generation synchrotron-radiation x-ray
facilities. Although only five years have elapsed since the technique was first
introduced, it has made rapid progress in demonstrating high-resolution
threedimensional imaging and promises few-nm resolution with much larger
samples than can be imaged in the transmission electron microscope. Both life-
and materials-science applications of XDM are intended, and it is expected that
the principal limitation to resolution will be radiation damage for life
science and the coherent power of available x-ray sources for material science.
In this paper we address the question of the role of radiation damage. We use a
statistical analysis based on the so-called "dose fractionation theorem" of
Hegerl and Hoppe to calculate the dose needed to make an image of a lifescience
sample by XDM with a given resolution. We conclude that the needed dose scales
with the inverse fourth power of the resolution and present experimental
evidence to support this finding. To determine the maximum tolerable dose we
have assembled a number of data taken from the literature plus some
measurements of our own which cover ranges of resolution that are not well
covered by reports in the literature. The tentative conclusion of this study is
that XDM should be able to image frozen-hydrated protein samples at a
resolution of about 10 nm with "Rose-criterion" image quality.Comment: 9 pages, 4 figure
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