Typing tumors using pathways selected by somatic evolution.

Many recent efforts to analyze cancer genomes involve aggregation of mutations within reference maps of molecular pathways and protein networks. Here, we find these pathway studies are impeded by molecular interactions that are functionally irrelevant to cancer or the patient's tumor type, as these interactions diminish the contrast of driver pathways relative to individual frequently mutated genes. This problem can be addressed by creating stringent tumor-specific networks of biophysical protein interactions, identified by signatures of epistatic selection during tumor evolution. Using such an evolutionarily selected pathway (ESP) map, we analyze the major cancer genome atlases to derive a hierarchical classification of tumor subtypes linked to characteristic mutated pathways. These pathways are clinically prognostic and predictive, including the TP53-AXIN-ARHGEF17 combination in liver and CYLC2-STK11-STK11IP in lung cancer, which we validate in independent cohorts. This ESP framework substantially improves the definition of cancer pathways and subtypes from tumor genome data

Cortical Columns Computing Systems: Microarchitecture Model, Functional Building Blocks, and Design Tools

Reverse-engineering the human brain has been a grand challenge for researchers in machine learning, experimental neuroscience, and computer architecture. Current deep neural networks (DNNs), motivated by the same challenge, have achieved remarkable results in Machine Learning applications. However, despite their original inspiration from the brain, DNNs have largely moved away from biological plausibility, resorting to intensive statistical processing on huge amounts of data. This has led to exponentially increasing demand on hardware compute resources that is quickly becoming economically and technologically unsustainable. Recent neuroscience research has led to a new theory on human intelligence, that suggests Cortical Columns (CCs) as the fundamental processing units in the neocortex that encapsulate intelligence. Each CC has the potential to learn models of complete objects through continuous predict-sense-update loops. This leads to the overarching question: Can we build Cortical Columns Computing Systems (C3S) that possess brain-like capabilities as well as brain-like efficiency? This chapter presents ongoing research in the Neuromorphic Computer Architecture Lab (NCAL) at Carnegie Mellon University (CMU) focusing on addressing this question. Our initial findings indicate that designing truly intelligent and extremely energy-efficient C3S-based sensory processing units, using off-the-shelf digital CMOS technology and tools, is quite feasible and very promising, and certainly warrants further research exploration

Transcriptional profiling and consensus molecular subtype (CMS) assignment to understand response and resistance to anti-EGFR therapy in colorectal cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1057/thumbnail.jp

Safer Chemicals Design Diagrams

The NRF2-ARE antioxidant pathway is an important biological sensing and regulating system that responds to chemical insults. At minute level, it protects a living species to go through hard environmental conditions. However, when the external disruption exceeds the inherent resilience, cellular damage can occur, eventually leading to cytotoxicity. Therefore, studying the likelihood of a chemical activating the NRF2-ARE pathway is interesting to discovering therapeutic agents and designing safer chemicals. In this research, we engaged a combination of computational chemistry, statistical learning and mechanistic toxicology to estimate the likelihood of a chemical to perturb this critical toxicological pathway and derive a scheme to guide chemical design with safer potency

Surface-Based Morphometric Analysis of Hippocampal Subfields in Mild Cognitive Impairment and Alzheimer's Disease

The hippocampus is widely studied with neuroimaging techniques given its importance in learning and memory and its potential as a biomarker for Alzheimer's disease (AD). Its complex folding anatomy often presents analytical challenges. In particular, the critical subfield information is typically not addressed by the existing hippocampal shape studies. To bridge this gap, we present a computational framework for surface-based morphometric analysis of hippocampal subfields. The major strengths of this framework are as follows: (a) it performs detailed hippocampal shape analysis, (b) it embraces, rather than ignores, the important hippocampal subfield information, and (c) it analyzes regular magnetic resonance imaging scans and is applicable to large scale studies. We demonstrate its effectiveness by applying it to the identification of regional hippocampal subfield atrophy patterns associated with mild cognitive impairment and AD

Interface engineering of mesoporous triphasic cobalt-copper phosphides as active electrocatalysts for overall water splitting

Efficient electrocatalysts for water splitting are essential for viable generation of highly purified hydrogen. Hence there is a need to develop robust catalysts to eliminate barriers associated with sluggish kinetics associated with both anodic oxygen and cathodic hydrogen evolution reactions. Herein, we report a two-step nanocasting-solid phase phosphorization approach to generate ordered mesoporous triphasic phosphides CoP@Cu2P-Cu3P. We show that it is a highly efficient bifunctional electrocatalyst useful for overall water splitting. The mesoporous triphasic CoP@Cu2P-Cu3P only requires a low overpotential of 255 mV and 188 mV to achieve 10 mA cm(-2) for oxygen and hydrogen evolution reactions, respectively. The combination of mesoporous pores (similar to 5.6 nm) with very thin walls (similar to 3.7 nm) and conductive networks in triphasic CoP@Cu2P-Cu3P enable rapid rate of electron transfer and mass transfer. In addition, when CoP@Cu2P-Cu3P is used to fabricate symmetric electrodes, the high surface area mesoporous structure and synergetic effects between phases together contribute to a low cell voltage of 1.54 V to drive a current density 10 mA cm(-2). This performance is superior to noble-metal-based Pt/C-IrO2/C. This work provides a new approach for the facile design and application of multiphase phosphides as highly active bifunctional and stable electrocatalysts for water-alkali electrolyzers

Now You See It, Now You Don't: The Disappearing Central Engine of the Quasar J1011+5442

We report the discovery of a new "changing-look" quasar, SDSS J101152.98+544206.4, through repeat spectroscopy from the Time Domain Spectroscopic Survey. This is an addition to a small but growing set of quasars whose blue continua and broad optical emission lines have been observed to decline by a large factor on a time scale of approximately a decade. The 5100 Angstrom monochromatic continuum luminosity of this quasar drops by a factor of > 9.8 in a rest-frame time interval of < 9.7 years, while the broad H-alpha luminosity drops by a factor of 55 in the same amount of time. The width of the broad H-alpha line increases in the dim state such that the black hole mass derived from the appropriate single-epoch scaling relation agrees between the two epochs within a factor of 3. The fluxes of the narrow emission lines do not appear to change between epochs. The light curve obtained by the Catalina Sky Survey suggests that the transition occurs within a rest-frame time interval of approximately 500 days. We examine three possible mechanisms for this transition suggested in the recent literature. An abrupt change in the reddening towards the central engine is disfavored by the substantial difference between the timescale to obscure the central engine and the observed timescale of the transition. A decaying tidal disruption flare is consistent with the decay rate of the light curve but not with the prolonged bright state preceding the decay, nor can this scenario provide the power required by the luminosities of the emission lines. An abrupt drop in the accretion rate onto the supermassive black hole appears to be the most plausible explanation for the rapid dimming.Comment: Submitted to MNRA