Small molecule induced reactivation of mutant p53 in cancer cells

The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 μM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53

Fairness Testing: Testing Software for Discrimination

This paper defines software fairness and discrimination and develops a testing-based method for measuring if and how much software discriminates, focusing on causality in discriminatory behavior. Evidence of software discrimination has been found in modern software systems that recommend criminal sentences, grant access to financial products, and determine who is allowed to participate in promotions. Our approach, Themis, generates efficient test suites to measure discrimination. Given a schema describing valid system inputs, Themis generates discrimination tests automatically and does not require an oracle. We evaluate Themis on 20 software systems, 12 of which come from prior work with explicit focus on avoiding discrimination. We find that (1) Themis is effective at discovering software discrimination, (2) state-of-the-art techniques for removing discrimination from algorithms fail in many situations, at times discriminating against as much as 98% of an input subdomain, (3) Themis optimizations are effective at producing efficient test suites for measuring discrimination, and (4) Themis is more efficient on systems that exhibit more discrimination. We thus demonstrate that fairness testing is a critical aspect of the software development cycle in domains with possible discrimination and provide initial tools for measuring software discrimination.Comment: Sainyam Galhotra, Yuriy Brun, and Alexandra Meliou. 2017. Fairness Testing: Testing Software for Discrimination. In Proceedings of 2017 11th Joint Meeting of the European Software Engineering Conference and the ACM SIGSOFT Symposium on the Foundations of Software Engineering (ESEC/FSE), Paderborn, Germany, September 4-8, 2017 (ESEC/FSE'17). https://doi.org/10.1145/3106237.3106277, ESEC/FSE, 201

Differential response in downstream processing of CHO cells grown under mild hypothermic conditions.

The manufacture of complex therapeutic proteins using mammalian cells is well established, with several strategies developed to improve productivity. The application of sustained mild hypothermic conditions during culture has been associated with increases in product titer and improved product quality. However, despite associated cell physiological effects, very few studies have investigated the impact on downstream processing (DSP). Characterization of cells grown under mild hypothermic conditions demonstrated that the stationary phase was prolonged by delaying the onset of apoptosis. This enabled cells to maintain viability for extended periods and increase volumetric productivity from 0.74 to 1.02 g L(-1) . However, host cell proteins, measured by ELISA, increased by ∼50%, attributed to the extended time course and higher peak and harvest cell densities. The individual components making up this impurity, as determined by SELDI-TOF MS and 2D-PAGE, were shown to be largely comparable. Under mild hypothermic conditions, cells were less shear sensitive than those maintained at 37°C, enhancing the preliminary primary recovery step. Adaptive changes in membrane fluidity were further investigated by adopting a pronounced temperature shift immediately prior to primary recovery and the improvement observed suggests that such a strategy may be implementable when shear sensitivity is of concern. Early and late apoptotic cells were particularly susceptible to shear, at either temperature, even under the lowest shear rate investigated. These findings demonstrate the importance of considering the impact of cell culture strategies and cell physiology on DSP, by implementing a range of experimental methods for process characterization. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 2013

Earth-Mars transfers through Moon distant retrograde orbits

This paper focuses on trajectory design which is relevant for missions that would follow NASA’s Asteroid Redirect Mission (ARM) to further explore and utilise asteroids and eventually human Mars exploration. Assuming that a refueling gas station is present at a given Lunar Distant Retrograde Orbit (DRO), we analyse ways of departing from the Earth to Mars via that DRO. Thus, the analysis and results presented in this paper add a new cis-lunar departure orbit for Earth-Mars missions. Porkchop plots depicting the required C3 at launch, v1 at arrival, Time of Flight (TOF), and total ∆V for various DRO departure and Mars arrival dates are created and compared with results obtained for low ∆V LEO to Mars trajectories. The results show that low ∆V DRO to Mars transfers generally have lower ∆V and TOF than LEO to Mars maneuvers

The Massive and Distant Clusters of WISE Survey: SZ effect Verification with the Atacama Compact Array -- Localization and Cluster Analysis

The Massive and Distant Clusters of WISE Survey (MaDCoWS) provides a catalog of high-redshift ($0.7\lesssim z\lesssim 1.5$) infrared-selected galaxy clusters. However, the verification of the ionized intracluster medium, indicative of a collapsed and nearly virialized system, is made challenging by the high redshifts of the sample members. The main goal of this work is to test the capabilities of the Atacama Compact Array (ACA; also known as the Morita Array) Band 3 observations, centered at about 97.5 GHz, to provide robust validation of cluster detections via the thermal Sunyaev-Zeldovich (SZ) effect. Using a pilot sample that comprises ten MaDCoWS galaxy clusters, accessible to ACA and representative of the median sample richness, we infer the masses of the selected galaxy clusters and respective detection significance by means of a Bayesian analysis of the interferometric data. Our test of the "Verification with the ACA - Localization and Cluster Analysis" (VACA LoCA) program demonstrates that the ACA can robustly confirm the presence of the virialized intracluster medium in galaxy clusters previously identified in full-sky surveys. In particular, we obtain a significant detection of the SZ effect for seven out of the ten VACA LoCA clusters. We note that this result is independent of the assumed pressure profile. However, the limited angular dynamic range of the ACA in Band 3 alone, short observational integration times, and possible contamination from unresolved sources limit the detailed characterization of the cluster properties and the inference of the cluster masses within scales appropriate for the robust calibration of mass-richness scaling relations.Comment: 19 pages (including appendices), 14 figures, and 4 tables; accepted for publication in A&

Instanton size distribution in O(3)

We present calculations of the size distribution of instantons in the 2d O(3) non-linear sigma-model, and briefly discuss the effects cooling has upon the configurations and the topological objects. (This preprint is also available via anonymous ftp to suna.amtp.liv.ac.uk in /pub/pss/ as instdist.uue.)Comment: 17 pages, LaTeX, needs cite.sty (appended), with appended uuencoded compressed tarfile of PostScript figures, Liverpool preprint LTH-33

Motion of Contact Line of a Crystal Over the Edge of Solid Mask in Epitaxial Lateral Overgrowth

Mathematical model that allows for direct tracking of the homoepitaxial crystal growth out of the window etched in the solid, pre-deposited layer on the substrate is described. The growth is governed by the normal (to the crystal-vapor interface) flux from the vapor phase and by the interface diffusion. The model accounts for possibly inhomogeneous energy of the mask surface and for strong anisotropies of crystal-vapor interfacial energy and kinetic mobility. Results demonstrate that the motion of the crystal-mask contact line slows down abruptly as radius of curvature of the mask edge approaches zero. Numerical procedure is suggested to overcome difficulties associated with ill-posedness of the evolution problem for the interface with strong energy anisotropy. Keywords: Thin films, epitaxy, MOCVD, surface diffusion, interface dynamics, contact lines, rough surfaces, wetting, regularization of ill-posed evolution problems.Comment: 21 pages, 11 figures; to appear in Computational Materials Scienc