Adipose‐Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA‐31

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135340/1/sct3201654440.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135340/2/Supplemental_Information.pd

A novel HLA-B18 restricted CD8+ T cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen

NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8<sup>+</sup>T cell epitope, NY-ESO-1<sub>88–96</sub> (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1<sub>157–165</sub> epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1<sub>88–96</sub> is much more efficiently cross-presented from the soluble form, than NY-ESO-1<sub>157–165</sub>. On the other hand, NY-ESO-1<sub>157–165</sub> is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A<sub>26–35</sub>; whereas NY-ESO-1<sub>88–96</sub> was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1<sub>88–96</sub> is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18+ melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1<sub>88–96</sub> from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8<sup>+</sup>T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed

Thermodynamics of nanodomain formation and breakdown in Scanning Probe Microscopy: Landau-Ginzburg-Devonshire approach

Thermodynamics of tip-induced nanodomain formation in scanning probe microscopy of ferroelectric films and crystals is studied using the Landau-Ginzburg-Devonshire phenomenological approach. The local redistribution of polarization induced by the biased probe apex is analyzed including the effects of polarization gradients, field dependence of dielectric properties, intrinsic domain wall width, and film thickness. The polarization distribution inside subcritical nucleus of the domain preceding the nucleation event is very smooth and localized below the probe, and the electrostatic field distribution is dominated by the tip. In contrast, polarization distribution inside the stable domain is rectangular-like, and the associated electrostatic fields clearly illustrate the presence of tip-induced and depolarization field components. The calculated coercive biases of domain formation are in a good agreement with available experimental results for typical ferroelectric materials. The microscopic origin of the observed domain tip elongation in the region where the probe electric field is much smaller than the intrinsic coercive field is the positive depolarization field in front of the moving counter domain wall. For infinitely thin domain walls local domain breakdown through the sample depth appears. The results obtained here are complementary to the Landauer-Molotskii energetic approach.Comment: 35 pages, 8 figures, suplementary attached, to be submitted to Phys. Rev.

Translational Symmetry Breaking in the Superconducting State of the Cuprates: Analysis of the Quasiparticle Density of States

Motivated by the recent STM experiments of J.E. Hoffman et.al. and C. Howald et.al., we study the effects of weak translational symmetry breaking on the quasiparticle spectrum of a d-wave superconductor. We develop a general formalism to discuss periodic charge order, as well as quasiparticle scattering off localized defects. We argue that the STM experiments in $Bi_2Sr_2CaCu_2O_{8+\delta}$ cannot be explained using a simple charge density wave order parameter, but are consistent with the presence of a periodic modulation in the electron hopping or pairing amplitude. We review the effects of randomness and pinning of the charge order and compare it to the impurity scattering of quasiparticles. We also discuss implications of weak translational symmetry breaking for ARPES experiments.Comment: 12 pages, 9 figs; (v2) minor corrections to formalism, discussions of dispersion, structure factors and sum rules added; (v3) discussion of space-dependent normalization added. To be published in PR

Effect of Peierls transition in armchair carbon nanotube on dynamical behaviour of encapsulated fullerene

The changes of dynamical behaviour of a single fullerene molecule inside an armchair carbon nanotube caused by the structural Peierls transition in the nanotube are considered. The structures of the smallest C20 and Fe@C20 fullerenes are computed using the spin-polarized density functional theory. Significant changes of the barriers for motion along the nanotube axis and rotation of these fullerenes inside the (8,8) nanotube are found at the Peierls transition. It is shown that the coefficients of translational and rotational diffusions of these fullerenes inside the nanotube change by several orders of magnitude. The possibility of inverse orientational melting, i.e. with a decrease of temperature, for the systems under consideration is predicted.Comment: 9 pages, 6 figures, 1 tabl

Effect of nonstationarities on detrended fluctuation analysis

Detrended fluctuation analysis (DFA) is a scaling analysis method used to quantify long-range power-law correlations in signals. Many physical and biological signals are ``noisy'', heterogeneous and exhibit different types of nonstationarities, which can affect the correlation properties of these signals. We systematically study the effects of three types of nonstationarities often encountered in real data. Specifically, we consider nonstationary sequences formed in three ways: (i) stitching together segments of data obtained from discontinuous experimental recordings, or removing some noisy and unreliable parts from continuous recordings and stitching together the remaining parts -- a ``cutting'' procedure commonly used in preparing data prior to signal analysis; (ii) adding to a signal with known correlations a tunable concentration of random outliers or spikes with different amplitude, and (iii) generating a signal comprised of segments with different properties -- e.g. different standard deviations or different correlation exponents. We compare the difference between the scaling results obtained for stationary correlated signals and correlated signals with these three types of nonstationarities.Comment: 17 pages, 10 figures, corrected some typos, added one referenc

Characterization of Sleep Stages by Correlations of Heartbeat Increments

We study correlation properties of the magnitude and the sign of the increments in the time intervals between successive heartbeats during light sleep, deep sleep, and REM sleep using the detrended fluctuation analysis method. We find short-range anticorrelations in the sign time series, which are strong during deep sleep, weaker during light sleep and even weaker during REM sleep. In contrast, we find long-range positive correlations in the magnitude time series, which are strong during REM sleep and weaker during light sleep. We observe uncorrelated behavior for the magnitude during deep sleep. Since the magnitude series relates to the nonlinear properties of the original time series, while the signs series relates to the linear properties, our findings suggest that the nonlinear properties of the heartbeat dynamics are more pronounced during REM sleep. Thus, the sign and the magnitude series provide information which is useful in distinguishing between the sleep stages.Comment: 7 pages, 4 figures, revte

Combination Therapies Targeting Alk-Aberrant Neuroblastoma in Preclinical Models.

BACKGROUND: ALK activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1-2% of cases. Lorlatinib, a third generation ALK inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. AIMS: To study the preclinical activity of ALK inhibitors alone and combined with chemotherapy or idasanutlin. METHODS: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSION: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma

Visualization and quantitation of the expression of microRNAs and their target genes in neuroblastoma single cells using imaging cytometry

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are regulatory molecules that play an important role in many physiological processes, including cell growth, differentiation, and apoptosis. In addition to modulating normal cellular functions, it has also been reported that miRNAs are involved in the development of many pathologies, including cardiovascular diseases, cancer, inflammation, and neurodegeneration. Methods for the sensitive detection and measurement of specific miRNAs and their cellular targets are essential for both basic research endeavours, as well as diagnostic efforts aimed at understanding the role of miRNAs in disease processes.</p> <p>Findings</p> <p>In this study, we describe a novel, imaging cytometry-based protocol that allows for simultaneous visualisation and quantification of miRNAs and their putative targets. We validated this methodology in a neuronal cell line by examining the relationship of the miRNA miR-124 and its known target, cyclin dependent kinase 6 (CDK6). We found that ectopic overexpression of miR-124 resulted in the downregulation of CDK6, decreased cellular proliferation, and induced cellular morphological changes.</p> <p>Conclusions</p> <p>This method is suitable for analysing the expression and cellular localisation of miRNAs and target proteins in small cell subsets within a heterogeneous cell suspension. We believe that our cytometry-based methodology will be easily adaptable to miRNA studies in many areas of biomedical research including neuroscience, stem cell biology, immunology, and oncology.</p

Fractionalization patterns in strongly correlated electron systems: Spin-charge separation and beyond

We discuss possible patterns of electron fractionalization in strongly interacting electron systems. A popular possibility is one in which the charge of the electron has been liberated from its Fermi statistics. Such a fractionalized phase contains in it the seed of superconductivity. Another possibility occurs when the spin of the electron, rather than its charge, is liberated from its Fermi statistics. Such a phase contains in it the seed of magnetism, rather than superconductivity. We consider models in which both of these phases occur and study possible phase transitions between them. We describe other fractionalized phases, distinct from these, in which fractions of the electron themselves fractionalize, and discuss the topological characterization of such phases. These ideas are illustrated with specific models of p-wave superconductors, Kondo lattices, and coexistence between d-wave superconductivity and antiferromagnetism.Comment: 28 pages, 11 fig