2,059 research outputs found
Intranuclear strain measured by iterative warping in cells under mechanical and osmotic stress
The nucleus is a membrane bound organelle and regulation center for gene expression in the cell. Mechanical forces transfer to the nucleus directly and indirectly through specific cellular cytoskeletal structures and pathways. There is increasing evidence that the transferred forces to the nucleus orchestrate gene expression activity. Methods to characterize nuclear mechanics typically study isolated cells or cells embedded in 3D gel matrices. Often report only aspect ratio and volume changes, measures that oversimplify the inherent complexity of internal strain patterns. This presents technical challenges to simultaneously observe small scale nuclear mechanics and gene expression levels inside the nuclei of cells embedded in their native extracellular environment. Therefore, a hybrid imaging and model based image registration technique has been developed to enabled us to explore links between biomechanical and biochemical signaling within individual cells. The hybrid technique uses an iterative warping deformable image registration to measure intranuclear strain fields that are correlated to nuclear structures. Three cell mechanics methods were developed to examine the mechanical response of the nucleus under different mechanical conditions. 1) Strain transfer from tissue to nuclei in a cartilage tissue deformation model paired with nascent RNA expression, 2) strain transfer to the nucleus with different cell types on a stretchable membrane, and 3) force traction microscopy of cells during osmotic stress. Intranuclear strain fields provide spatial details of the nucleus that when paired with single cell biochemical assays will provide insight into how mechanical forces transferred to the nucleus influence gene expression
Topographic Constraints on Magma Accumulations Below the Actively Uuplifting Uturuncu and Lazufre Volcanic Centers in the Central Andes
Geodetic surveys of Volcán Uturuncu and the Lazufre volcanic complex in the Central Andes of South America reveal sustained surface uplift from magmatic intrusion at depth. However, the decadal timescales of geodetic surveys are short relative to the timescales of magma chamber growth. Thus, from geodesy alone, it is difficult to infer the deformation and hence magma accumulation history of these volcanoes. Here we combine data from InSAR, long-wavelength topography, GPS and high-resolution topographic surveys of lake shorelines and rivers, and lava flow morphology to constrain the spatial and temporal evolution of magmatism at Uturuncu and Lazufre. Near Uturuncu, dated lake shorelines show no evidence of tilting since ca. 16 ka, and we find no evidence of deformation in the long-wavelength topography. A lack of net surface displacement suggests that uplift related to a rising diapir must be less than a century old, or, more likely, magmatic inflation at Uturuncu is transient over millennial timescales and is therefore not recorded in the topography. At Lazufre, we also find no evidence for sustained uplift recorded in Late Pleistocene lake shorelines. However, the orientations of multiple dated lava flows suggest that the long-wavelength dome at the center of Lazufre’s uplift has persisted since at least 400 ka. Additionally, we find that the radial distribution of volcanic vents at Lazufre, coupled with the presence of an apical graben, is consistent with experimental and theoretical predictions of magmatic doming. The dome’s longevity indicates significant magma storage at depth, and therefore Lazufre is likely a highly evolved pre-caldera magmatic system. These two case studies demonstrate that combining geomorphic and geophysical data sets to extend the geodetic record back in time can help determine the style and magnitude of magma transport in volcanic systems
Mining Public Domain Data to Develop Selective DYRK1A Inhibitors
Kinases represent one of the most intensively pursued groups of targets in modern-day drug discovery. Often it is desirable to achieve selective inhibition of the kinase of interest over the remaining ∼500 kinases in the human kinome. This is especially true when inhibitors are intended to be used to study the biology of the target of interest. We present a pipeline of open-source software that analyzes public domain data to repurpose compounds that have been used in previous kinase inhibitor development projects. We define the dual-specificity tyrosine-regulated kinase 1A (DYRK1A) as the kinase of interest, and by addition of a single methyl group to the chosen starting point we remove glycogen synthase kinase β (GSK3β) and cyclin-dependent kinase (CDK) inhibition. Thus, in an efficient manner we repurpose a GSK3β/CDK chemotype to deliver 8b, a highly selective DYRK1A inhibitor
Mechanical design and development of TES bolometer detector arrays for the Advanced ACTPol experiment
The next generation Advanced ACTPol (AdvACT) experiment is currently underway
and will consist of four Transition Edge Sensor (TES) bolometer arrays, with
three operating together, totaling ~5800 detectors on the sky. Building on
experience gained with the ACTPol detector arrays, AdvACT will utilize various
new technologies, including 150mm detector wafers equipped with multichroic
pixels, allowing for a more densely packed focal plane. Each set of detectors
includes a feedhorn array of stacked silicon wafers which form a spline profile
leading to each pixel. This is then followed by a waveguide interface plate,
detector wafer, back short cavity plate, and backshort cap. Each array is
housed in a custom designed structure manufactured from high purity copper and
then gold plated. In addition to the detector array assembly, the array package
also encloses cryogenic readout electronics. We present the full mechanical
design of the AdvACT high frequency (HF) detector array package along with a
detailed look at the detector array stack assemblies. This experiment will also
make use of extensive hardware and software previously developed for ACT, which
will be modified to incorporate the new AdvACT instruments. Therefore, we
discuss the integration of all AdvACT arrays with pre-existing ACTPol
infrastructure.Comment: 9 pages, 5 figures, SPIE Astronomical Telescopes and Instrumentation
conference proceeding
Precision Epoch of Reionization studies with next-generation CMB experiments
Future arcminute resolution polarization data from ground-based Cosmic
Microwave Background (CMB) observations can be used to estimate the
contribution to the temperature power spectrum from the primary anisotropies
and to uncover the signature of reionization near in the small
angular-scale temperature measurements. Our projections are based on combining
expected small-scale E-mode polarization measurements from Advanced ACTPol in
the range with simulated temperature data from the full Planck
mission in the low and intermediate region, . We show that
the six basic cosmological parameters determined from this combination of data
will predict the underlying primordial temperature spectrum at high multipoles
to better than accuracy. Assuming an efficient cleaning from
multi-frequency channels of most foregrounds in the temperature data, we
investigate the sensitivity to the only residual secondary component, the
kinematic Sunyaev-Zel'dovich (kSZ) term. The CMB polarization is used to break
degeneracies between primordial and secondary terms present in temperature and,
in effect, to remove from the temperature data all but the residual kSZ term.
We estimate a detection of the diffuse homogeneous kSZ signal from
expected AdvACT temperature data at , leading to a measurement of
the amplitude of matter density fluctuations, , at precision.
Alternatively, by exploring the reionization signal encoded in the patchy kSZ
measurements, we bound the time and duration of the reionization with
and . We find that
these constraints degrade rapidly with large beam sizes, which highlights the
importance of arcminute-scale resolution for future CMB surveys.Comment: 10 pages, 10 figure
Optical modeling and polarization calibration for CMB measurements with ACTPol and Advanced ACTPol
The Atacama Cosmology Telescope Polarimeter (ACTPol) is a polarization
sensitive upgrade to the Atacama Cosmology Telescope. Located at an elevation
of 5190 m, ACTPol measures the Cosmic Microwave Background (CMB) temperature
and polarization with arcminute-scale angular resolution. Calibration of the
detector angles is a critical step in producing maps of the CMB polarization.
Polarization angle offsets in the detector calibration can cause leakage in
polarization from E to B modes and induce a spurious signal in the EB and TB
cross correlations, which eliminates our ability to measure potential
cosmological sources of EB and TB signals, such as cosmic birefringence. We
present our optical modeling and measurements associated with calibrating the
detector angles in ACTPol.Comment: 12 pages, 8 figures, conference proceedings submitted to Proceedings
of SPIE; added reference in section 2 and merged repeated referenc
Application of Fluorescence-Guided Surgery to Subsurface Cancers Requiring Wide Local Excision: Literature Review and Novel Developments Toward Indirect Visualization.
The excision of tumors by wide local excision is challenging because the mass must be removed entirely without ever viewing it directly. Positive margin rates in sarcoma resection remain in the range of 20% to 35% and are associated with increased recurrence and decreased survival. Fluorescence-guided surgery (FGS) may improve surgical accuracy and has been utilized in other surgical specialties. ABY-029, an anti-epidermal growth factor receptor Affibody molecule covalently bound to the near-infrared fluorophore IRDye 800CW, is an excellent candidate for future FGS applications in sarcoma resection; however, conventional methods with direct surface tumor visualization are not immediately applicable. A novel technique involving imaging through a margin of normal tissue is needed. We review the past and present applications of FGS and present a novel concept of indirect FGS for visualizing tumor through a margin of normal tissue and aiding in excising the entire lesion as a single, complete mass with tumor-free margins
Critical perspectives on ‘consumer involvement’ in health research: epistemological dissonance and the know-do gap
Researchers in the area of health and social care (both in Australia and internationally) are encouraged to involve consumers throughout the research process, often on ethical, political and methodological grounds, or simply as ‘good practice’. This paper presents findings from a qualitative study in the UK of researchers’ experiences and views of consumer involvement in health research.
Two main themes are presented in the paper. Firstly, we explore the ‘know-do gap’ which relates to the tensions between researchers’ perceptions of the potential benefits of, and their actual practices in relation to, consumer involvement. Secondly, we focus on one of the reasons for this ‘know-do gap’, namely epistemological dissonance. Findings are linked to issues around consumerism in research, lay/professional knowledges, the (re)production of professional and consumer identities and the maintenance of boundaries between consumers and researchers
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