A 4-D dataset for validation of crystal growth in a complex three-phase material, ice cream

Four dimensional (4D, or 3D plus time) X-ray tomographic imaging of phase changes in materials is quickly becoming an accepted tool for quantifying the development of microstructures to both inform and validate models. However, most of the systems studied have been relatively simple binary compositions with only two phases. In this study we present a quantitative dataset of the phase evolution in a complex three-phase material, ice cream. The microstructure of ice cream is an important parameter in terms of sensorial perception, and therefore quantification and modelling of the evolution of the microstructure with time and temperature is key to understanding its fabrication and storage. The microstructure consists of three phases, air cells, ice crystals, and unfrozen matrix. We perform in situ synchrotron X-ray imaging of ice cream samples using in-line phase contrast tomography, housed within a purpose built cold-stage (-40 to +20oC) with finely controlled variation in specimen temperature. The size and distribution of ice crystals and air cells during programmed temperature cycling are determined using 3D quantification. The microstructural evolution of three-phase materials has many other important applications ranging from biological to structural and functional material, hence this dataset can act as a validation case for numerical investigations on faceted and non-faceted crystal growth in a range of materials

Phase Separation of Rigid-Rod Suspensions in Shear Flow

We analyze the behavior of a suspension of rigid rod-like particles in shear flow using a modified version of the Doi model, and construct diagrams for phase coexistence under conditions of constant imposed stress and constant imposed strain rate, among paranematic, flow-aligning nematic, and log-rolling nematic states. We calculate the effective constitutive relations that would be measured through the regime of phase separation into shear bands. We calculate phase coexistence by examining the stability of interfacial steady states and find a wide range of possible ``phase'' behaviors.Comment: 23 pages 19 figures, revised version to be published in Physical Review

Effects of iron-rich intermetallics and grain structure on semisolid tensile properties of Al-Cu 206 cast alloys near solidus temperature

The effects of iron-rich intermetallics and grain size on the semisolid tensile properties of Al-Cu 206 cast alloys near the solidus were evaluated in relation to the mush microstructure. Analyses of the stress–displacement curves showed that the damage expanded faster in the mush structure dominated by plate-like β-Fe compared to the mush structure dominated by Chinese script-like α-Fe. While there was no evidence of void formation on the β-Fe intermetallics, they blocked the interdendritic liquid channels and thus hindered liquid flow and feeding during semisolid deformation. In contrast, the interdendritic liquid flows more freely within the mush structure containing α-Fe. The tensile properties of the alloy containing α-Fe are generally higher than those containing β-Fe over the crucial liquid fraction range of ~0.6 to 2.8 pct, indicating that the latter alloy may be more susceptible to stress-related casting defects such as hot tearing. A comparison of the semisolid tensile properties of the alloy containing α-Fe with different grain sizes showed that the maximum stress and elongation of the alloy with finer grains were moderately higher for the liquid fractions of ~2.2 to 3.6 pct. The application of semisolid tensile properties for the evaluation of the hot tearing susceptibility of experimental alloys is discussed

Synchrotron radiography studies of shear-induced dilation in semi-solid Al alloys and steels

An improved understanding of the response of solidifying microstructures to load is required to further minimize casting defects and optimize casting processes. This article overviews synchrotron radiography studies that directly measure the micromechanics of semisolid alloy deformation in a thin sample direct-shear cell. It is shown that shear-induced dilation (also known as Reynolds’ dilatancy) occurs in semisolid alloys with morphologies ranging from equiaxed-dendritic to globular, at solid fractions from the dendrite coherency point to ~90% solid, and it occurs in both Al alloys and carbon steels. Discrete-element method simulations that treat solidifying microstructures as granular materials are then used to explore the origins of dilatancy in semisolid alloys

On the Deformation of Dendrites During Directional Solidification of a Nickel-Based Superalloy

Abstract: Synchrotron X-ray imaging has been used to examine in situ the deformation of dendrites that takes place during the solidification of a nickel-based superalloy. By combining absorption and diffraction contrast imaging, deformation events could be classified by their localization and permanence. In particular, a deformation mechanism arising from thermal contraction in a temperature gradient was elucidated through digital image correlation. It was concluded that this mechanism may explain the small misorientations typically observed in single crystal castings

The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors

Abstract Background Anti-cancer drugs access solid tumors via blood vessels, and must penetrate tumor tissue to reach all cancer cells. Previous studies have demonstrated steep gradients of decreasing doxorubicin fluorescence with increasing distance from blood vessels, such that many tumor cells are not exposed to drug. Studies using multilayered cell cultures show that increased P-glycoprotein (PgP) is associated with better penetration of doxorubicin, while PgP inhibitors decrease drug penetration in tumor tissue. Here we evaluate the effect of PgP expression on doxorubicin distribution in vivo. Methods Mice bearing tumor sublines with either high or low expression of PgP were treated with doxorubicin, with or without pre-treatment with the PgP inhibitors verapamil or PSC 833. The distribution of doxorubicin in relation to tumor blood vessels was quantified using immunofluorescence. Results Our results indicate greater uptake of doxorubicin by cells near blood vessels in wild type as compared to PgP-overexpressing tumors, and pre-treatment with verapamil or PSC 833 increased uptake in PgP-overexpressing tumors. However, there were steeper gradients of decreasing doxorubicin fluorescence in wild-type tumors compared to PgP overexpressing tumors, and treatment of PgP overexpressing tumors with PgP inhibitors led to steeper gradients and greater heterogeneity in the distribution of doxorubicin. Conclusion PgP inhibitors increase uptake of doxorubicin in cells close to blood vessels, have little effect on drug uptake into cells at intermediate distances, and might have a paradoxical effect to decrease doxorubicin uptake into distal cells. This effect probably contributes to the limited success of PgP inhibitors in clinical trials

Understanding missed opportunities for more timely diagnosis of cancer in symptomatic patients after presentation.

The diagnosis of cancer is a complex, multi-step process. In this paper, we highlight factors involved in missed opportunities to diagnose cancer more promptly in symptomatic patients and discuss responsible mechanisms and potential strategies to shorten intervals from presentation to diagnosis. Missed opportunities are instances in which post-hoc judgement indicates that alternative decisions or actions could have led to more timely diagnosis. They can occur in any of the three phases of the diagnostic process (initial diagnostic assessment; diagnostic test performance and interpretation; and diagnostic follow-up and coordination) and can involve patient, doctor/care team, and health-care system factors, often in combination. In this perspective article, we consider epidemiological 'signals' suggestive of missed opportunities and draw on evidence from retrospective case reviews of cancer patient cohorts to summarise factors that contribute to missed opportunities. Multi-disciplinary research targeting such factors is important to shorten diagnostic intervals post presentation. Insights from the fields of organisational and cognitive psychology, human factors science and informatics can be extremely valuable in this emerging research agenda. We provide a conceptual foundation for the development of future interventions to minimise the occurrence of missed opportunities in cancer diagnosis, enriching current approaches that chiefly focus on clinical decision support or on widening access to investigations.We acknowledge the helpful and incisive comments by Dr Rikke Sand Andersen (Aarhus University, Denmark) in conceptualising this piece and in drafts of the manuscript. The work is independent research supported by different funding schemes. GL was supported by a Post-Doctoral Fellowship by the National Institute for Health Research (PDF-2011-04-047) until the end of 2014 and by a Cancer Research UK Clinician Scientist Fellowship award (A18180) from 2015. HS is supported by the VA Health Services Research and Development Service (CRE 12-033; Presidential Early Career Award for Scientists and Engineers USA 14-274), the VA National Center for Patient Safety, the Agency for Health Care Research and Quality (R01HS022087) and in part by the Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (CIN 13–413). PV was supported by CaP, funded by The Danish Cancer Society and the Novo Nordisk Foundation.This is the final version of the article. It first appeared at http://dx.doi.org/10.1038/bjc.2015.4

A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity

Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation

Quantifying the Proteolytic Release of Extracellular Matrix-Sequestered VEGF with a Computational Model

BACKGROUND: VEGF proteolysis by plasmin or matrix metalloproteinases (MMPs) is believed to play an important role in regulating vascular patterning in vivo by releasing VEGF from the extracellular matrix (ECM). However, a quantitative understanding of the kinetics of VEGF cleavage and the efficiency of cell-mediated VEGF release is currently lacking. To address these uncertainties, we develop a molecular-detailed quantitative model of VEGF proteolysis, used here in the context of an endothelial sprout. METHODOLOGY AND FINDINGS: To study a cell's ability to cleave VEGF, the model captures MMP secretion, VEGF-ECM binding, VEGF proteolysis from VEGF165 to VEGF114 (the expected MMP cleavage product of VEGF165) and VEGF receptor-mediated recapture. Using experimental data, we estimated the effective bimolecular rate constant of VEGF165 cleavage by plasmin to be 328 M(-1) s(-1) at 25 degrees C, which is relatively slow compared to typical MMP-ECM proteolysis reactions. While previous studies have implicated cellular proteolysis in growth factor processing, we show that single cells do not individually have the capacity to cleave VEGF to any appreciable extent (less than 0.1% conversion). In addition, we find that a tip cell's receptor system will not efficiently recapture the cleaved VEGF due to an inability of cleaved VEGF to associate with Neuropilin-1. CONCLUSIONS: Overall, VEGF165 cleavage in vivo is likely to be mediated by the combined effect of numerous cells, instead of behaving in a single-cell-directed, autocrine manner. We show that heparan sulfate proteoglycans (HSPGs) potentiate VEGF cleavage by increasing the VEGF clearance time in tissues. In addition, we find that the VEGF-HSPG complex is more sensitive to proteases than is soluble VEGF, which may imply its potential relevance in receptor signaling. Finally, according to our calculations, experimentally measured soluble protease levels are approximately two orders of magnitude lower than that needed to reconcile levels of VEGF cleavage seen in pathological situations