Luminescence complementation technology for the identification of MYC:TRRAP inhibitors

Mechanism-based targeted therapies have exhibited remarkable success in treating otherwise untreatable or unresectable cancers. Novel targeted therapies that correct dysregulated transcriptional programs in cancer are an unmet medical need. The transcription factor MYC is the most frequently amplified gene in human cancer and is overexpressed because of mutations in an array of oncogenic signaling pathways. The fact that many cancer cells cannot survive without MYC - a phenomenon termed MYC addiction - provides a compelling case for the development of MYC-specific targeted therapies. We propose a new strategy to inhibit MYC function by disrupting its essential interaction with TRRAP using small molecules. To achieve our goal, we developed a platform using luminescence complementation for identifying small molecules as inhibitors of the MYC:TRRAP interaction. Here we present validation of this assay by measuring the disruption of TRRAP binding caused by substitutions to the invariant and essential MYC homology 2 region of MYC

Simultaneous position and mass determination of a nanoscale-thickness cantilever sensor in viscous fluids

We report simultaneous determination of the mass and position of micro-beads attached to a nanoscale-thickness cantilever sensor by analyzing wave propagations along the cantilever while taking into account viscous and inertial loading due to a surrounding fluid. The fluid-structure interaction was identified by measuring the change in the wavenumber under different fluid conditions. The predicted positions and masses agreed with actual measurements. Even at large mass ratios (6%-21%) of the beads to the cantilever, this wave approach enabled accurate determination of the mass and position, demonstrating the potential for highly accurate cantilever sensing of particle-based bio-analytes such as bacteria. © 2015 AIP Publishing LLCopen0

Functional Heterogeneity of Breast Fibroblasts Is Defined by a Prostaglandin Secretory Phenotype that Promotes Expansion of Cancer-Stem Like Cells

Fibroblasts are important in orchestrating various functions necessary for maintaining normal tissue homeostasis as well as promoting malignant tumor growth. Significant evidence indicates that fibroblasts are functionally heterogeneous with respect to their ability to promote tumor growth, but markers that can be used to distinguish growth promoting from growth suppressing fibroblasts remain ill-defined. Here we show that human breast fibroblasts are functionally heterogeneous with respect to tumor-promoting activity regardless of whether they were isolated from normal or cancerous breast tissues. Rather than significant differences in fibroblast marker expression, we show that fibroblasts secreting abundant levels of prostaglandin (PGE2), when isolated from either reduction mammoplasty or carcinoma tissues, were both capable of enhancing tumor growth in vivo and could increase the number of cancer stem-like cells. PGE2 further enhanced the tumor promoting properties of fibroblasts by increasing secretion of IL-6, which was necessary, but not sufficient, for expansion of breast cancer stem-like cells. These findings identify a population of fibroblasts which both produce and respond to PGE2, and that are functionally distinct from other fibroblasts. Identifying markers of these cells could allow for the targeted ablation of tumor-promoting and inflammatory fibroblasts in human breast cancers.United States. Dept. of Defense. Breast Cancer Research Program (Pre-doctoral Traineeship Award)Raymond and Beverly Sackler FoundationBreast Cancer Research FoundationThe Slomo and Cindy Silvian Foundation, Inc.National Cancer Institute (U.S.) (CA125554)National Cancer Institute (U.S.) (CA092644)Raymond and Beverley Sackler Foundatio

1924-25: Abilene Christian College Bible Lectures - Full Text

PREFACE The lectures in this volume were delivered in the auditorium of Abilene Christian College during the last week of February in 1924 and 1925. Not all of the lectures delivered during these two weeks are given here, some of those delivering lectures not having responded with their manuscripts. These are given to the public in the belief that the splendid sermons delivered here ought to be read by thousands of Christians who did not have the opportunity of hearing them. Many of those who heard them will desire to read them. May this contribution to the literature of Christian teaching from the minds of some of our best and most faithful laborers in the Master’s vineyard be a continued blessing to all whose lives they touch. BATSELL BAXTER. __________________ PUBLISHER’S ANNOUNCEMENT This volume of Abilene Christian College Lectures is the fourth and comprises the lectures for February 1924 and 1925. The lectures for 1919 were published in one volume, 1920 and 1921 were combined in one volume, as were also the lectures for 1922 and 1923. By putting the lectures for two years in one volume, the reader is saved the expense of an additional book in order to receive the full benefit of these lectures. That these discourses are of great value is recognized by thousands who have heard them orally or have read them on the printed page. Such carefully prepared addresses really and truly merit a permanent place in the literature of the brotherhood of the churches of Christ. They are filled with expositions and analyses of much benefit to younger brethren who are entering upon lines of public service for the church, and they contain instruction on the word of God that is of much value to those out of the church as well as those in the church. The four books comprising the Abilene Christian College Lectures will make a most valuable addition to all libraries. We are at this time, January, 1926, in position to furnish complete sets or any volume to complete any broken set that any of our readers may have. When our present supply is gone, the books will probably not be reprinted as no plates have been made, and the books will be scarce. The messages of hope and love contained in this volume will find their place into the homes of many thousands, and it is to be ardently hoped that they will be read attentively and that they may contribute much to the extension of the power and kingdom of our Lord and Savior Jesus Christ. G. II. P. SHOWALTER. Austin, Texas, January 1, 1926

Coherent radiation from neutral molecules moving above a grating

We predict and study the quantum-electrodynamical effect of parametric self-induced excitation of a molecule moving above the dielectric or conducting medium with periodic grating. In this case the radiation reaction force modulates the molecular transition frequency which results in a parametric instability of dipole oscillations even from the level of quantum or thermal fluctuations. The present mechanism of instability of electrically neutral molecules is different from that of the well-known Smith-Purcell and transition radiation in which a moving charge and its oscillating image create an oscillating dipole. We show that parametrically excited molecular bunches can produce an easily detectable coherent radiation flux of up to a microwatt.Comment: 4 page

Lysophospholipids Are Associated With Outcomes in Hospitalized Patients With Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) accounts for 70-90% of all TBI cases. Lipid metabolites have important roles in plasma membrane biogenesis, function, and cell signaling. As TBI can compromise plasma membrane integrity and alter brain cell function, we sought to identify circulating phospholipid alterations after mTBI, and determine if these changes were associated with clinical outcomes. Patients with mTBI (Glasgow Coma Score [GCS] ≥13 and loss of consciousness \u3c30 \u3emin) were recruited. A total of 84 mTBI subjects were enrolled after admission to a level I trauma center, with the majority having evidence of traumatic intracranial hemorrhage on brain computed tomography (CT). Plasma samples were collected within 24 h of injury with 32 mTBI subjects returning at 3 months after injury for a second plasma sample to be collected. Thirty-five healthy volunteers were enrolled as controls and had a one-time blood draw. Lipid metabolomics was performed on plasma samples from each subject. Fold change of selected lipid metabolites was determined. Multivariable regression models were created to test associations between lipid metabolites and discharge and 6-month Glasgow Outcomes Scale-Extended (GOSE) outcomes (dichotomized between good [GOSE ≥7] and bad [GOSE ≤6] functional outcomes). Plasma levels of 31 lipid metabolites were significantly associated with discharge GOSE using univariate models; three of these metabolites were significantly increased, while 14 were significantly decreased in subjects with good outcomes compared with subjects with poor outcomes. In multivariable logistic regression models, higher circulating levels of the lysophospholipids (LPL) 1-linoleoyl-glycerophosphocholine (GPC) (18:2), 1-linoleoyl-GPE (18:2), and 1-linolenoyl-GPC (18:3) were associated with both good discharge GOSE (odds ratio [OR] 12.2 [95% CI 3.35, 58.3]

Molecular Valves for Controlling Gas Phase Transport Made from Discrete Angstrom-Sized Pores in Graphene

An ability to precisely regulate the quantity and location of molecular flux is of value in applications such as nanoscale 3D printing, catalysis, and sensor design. Barrier materials containing pores with molecular dimensions have previously been used to manipulate molecular compositions in the gas phase, but have so far been unable to offer controlled gas transport through individual pores. Here, we show that gas flux through discrete angstrom-sized pores in monolayer graphene can be detected and then controlled using nanometer-sized gold clusters, which are formed on the surface of the graphene and can migrate and partially block a pore. In samples without gold clusters, we observe stochastic switching of the magnitude of the gas permeance, which we attribute to molecular rearrangements of the pore. Our molecular valves could be used, for example, to develop unique approaches to molecular synthesis that are based on the controllable switching of a molecular gas flux, reminiscent of ion channels in biological cell membranes and solid state nanopores.Comment: to appear in Nature Nanotechnolog

Luminal Plasma Treatment for Small Diameter Polyvinyl Alcohol Tubular Scaffolds

Plasma-based surface modification is recognized as an effective way to activate biomaterial surfaces, and modulate their interactions with cells, extracellular matrix proteins, and other materials. However, treatment of a luminal surface of a tubular scaffold remains non-trivial to perform in small diameter tubes. Polyvinyl alcohol (PVA) hydrogel, which has been widely used for medical applications, lacks functional groups to mediate cell attachment. This poses an issue for vascular applications, as endothelialization in a vascular graft lumen is crucial to maintain long term graft patency. In this study, a Radio Frequency Glow Discharges (RFGD) treatment in the presence of NH3 was used to modify the luminal surface of 3-mm diameter dehydrated PVA vascular grafts. The grafted nitrogen containing functional groups demonstrated stability, and in vitro endothelialization was successfully maintained for at least 30 days. The plasma-modified PVA displayed a higher percentage of carbonyl groups over the untreated PVA control. Plasma treatment on PVA patterned with microtopographies was also studied, with only the concave microlenses topography demonstrating a significant increase in platelet adhesion. Thus, the study has shown the possibility of modifying a small diameter hydrogel tubular scaffold with the RFGD plasma treatment technique and demonstrated stability in ambient storage conditions for up to 30 days

Spontaneous decay in the presence of dispersing and absorbing bodies: general theory and application to a spherical cavity

A formalism for studying spontaneous decay of an excited two-level atom in the presence of dispersing and absorbing dielectric bodies is developed. An integral equation, which is suitable for numerical solution, is derived for the atomic upper-state-probability amplitude. The emission pattern and the power spectrum of the emitted light are expressed in terms of the Green tensor of the dielectric-matter formation including absorption and dispersion. The theory is applied to the spontaneous decay of an excited atom at the center of a three-layered spherical cavity, with the cavity wall being modeled by a band-gap dielectric of Lorentz type. Both weak coupling and strong coupling are studied, the latter with special emphasis on the cases where the atomic transition is (i) in the normal-dispersion zone near the medium resonance and (ii) in the anomalous-dispersion zone associated with the band gap. In a single-resonance approximation, conditions of the appearance of Rabi oscillations and closed solutions to the evolution of the atomic state population are derived, which are in good agreement with the exact numerical results.Comment: 12 pages, 6 figures, typos fixed, 1 figure adde