2,425 research outputs found
Investigating the functionality of an OCT4-short response element in human induced pluripotent stem cells.
Pluripotent stem cells offer great therapeutic promise for personalized treatment platforms for numerous injuries, disorders, and diseases. Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene maintaining pluripotency and self-renewal of mammalian cells. With site-specific integration for gene correction in cellular therapeutics, use of the OCT4 promoter may have advantages when expressing a suicide gene if pluripotency remains. However, the human OCT4 promoter region is 4âkb in size, limiting the capacity of therapeutic genes and other regulatory components for viral vectors, and decreasing the efficiency of homologous recombination. The purpose of this investigation was to characterize the functionality of a novel 967bp OCT4-short response element during pluripotency and to examine the OCT4 titer-dependent response during differentiation to human derivatives not expressing OCT4. Our findings demonstrate that the OCT4-short response element is active in pluripotency and this activity is in high correlation with transgene expression in vitro, and the OCT4-short response element is inactivated when pluripotent cells differentiate. These studies demonstrate that this shortened OCT4 regulatory element is functional and may be useful as part of an optimized safety component in a site-specific gene transferring system that could be used as an efficient and clinically applicable safety platform for gene transfer in cellular therapeutics
Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.
Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy
Racial Differences in Outcomes of an Advance Care Planning Intervention for Dialysis Patients and Their Surrogates
Background: African Americans' beliefs about end-of-life care may differ from those of whites, but racial differences in advance care planning (ACP) outcomes are unknown
Composite Variables: When and How
Use of composite variables is a common practice, but knowledge about what researchers should consider when creating composite variables is lacking
Accurate Hydrogen Spectral Simulations with a Compact Model Atom
Many large scale numerical simulations of astrophysical plasmas must also
reproduce the hydrogen ionization and the resulting emission spectrum, in some
cases quite accurately. We describe a compact model hydrogen atom that can be
readily incorporated into such simulations. It reproduces the recombination
efficiency and line spectrum predicted by much larger calculations for a very
broad range of densities and temperatures. Uncertainties in hydrogen collision
data are the largest source of differences between our compact atom and
predictions of more extensive calculations, and underscore the need for
accurate atomic data.Comment: 18 pages, prepared in MS-Word, Postscript only, 12 Figures, also
available at http://www.pa.uky.edu/~ferguson/bib/bib.html, accepted for
publication in the Astrophysical Journa
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Observation-based modeling of ozone chemistry in the Seoul metropolitan area during the Korea-United States Air Quality Study (KORUS-AQ)
The Seoul Metropolitan Area (SMA) has a population of 24 million and frequently experiences unhealthy levels of ozone (O3). In this work, measurements taken during the Korea-United States Air Quality Study (KORUS-AQ, 2016) are used to explore regional gradients in O3 and its chemical precursors, and an observationally-constrained 0-D photochemical box model is used to quantify key aspects of O3 production including its sensitivity to precursor gases. Box model performance was evaluated by comparing modeled concentrations of select secondary species to airborne measurements. These comparisons indicate that the steady state assumption used in 0-D box models cannot describe select intermediate species, highlighting the importance of having a broad suite of trace gases as model constraints. When fully constrained, aggregated statistics of modeled O3 production rates agreed with observed changes in O3, indicating that the box model was able to represent the majority of O3 chemistry.
Comparison of airborne observations between urban Seoul and a downwind receptor site reveal a positive gradient in O3 coinciding with a negative gradient in NOx, no gradient in CH2O, and a slight positive gradient in modeled rates of O3 production. Together, these observations indicate a radical-limited (VOC-limited) O3 production environment in the SMA. Zero-out simulations identified C7+ aromatics as the dominant VOC contributors to O3 production, with isoprene and anthropogenic alkenes making smaller but appreciable contributions. Simulations of model sensitivity to decreases in NOx produced results that were not spatially uniform, with large increases in O3 production predicted for urban Seoul and decreases in O3 production predicted for far-outlying areas. The policy implications of this work are clear: Effective O3 mitigation strategies in the SMA must focus on reducing local emissions of C7+ aromatics, while reductions in NOx emissions may increase O3 in some areas but generally decrease the regional extent of O3 exposure
Delays in Leniency Application: Is There Really a Race to the Enforcer's Door?
This paper studies cartelsâ strategic behavior in delaying leniency applications, a take-up decision that has been ignored in the previous literature. Using European Commission decisions issued over a 16-year span, we show, contrary to common beliefs and the existing literature, that conspirators
often apply for leniency long after a cartel collapses. We estimate hazard and probit models to study the determinants of leniency-application delays. Statistical tests find that delays are symmetrically affected by antitrust policies and macroeconomic fluctuations. Our results shed light on the design of
enforcement programs against cartels and other forms of conspiracy
Slowing and cooling molecules and neutral atoms by time-varying electric field gradients
A method of slowing, accelerating, cooling, and bunching molecules and
neutral atoms using time-varying electric field gradients is demonstrated with
cesium atoms in a fountain. The effects are measured and found to be in
agreement with calculation. Time-varying electric field gradient slowing and
cooling is applicable to atoms that have large dipole polarizabilities,
including atoms that are not amenable to laser slowing and cooling, to Rydberg
atoms, and to molecules, especially polar molecules with large electric dipole
moments. The possible applications of this method include slowing and cooling
thermal beams of atoms and molecules, launching cold atoms from a trap into a
fountain, and measuring atomic dipole polarizabilities.Comment: 13 pages, 10 figures. Scheduled for publication in Nov. 1 Phys. Rev.
Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors.
Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies
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