Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity

BACKGROUND: Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets. METHODS: We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced tumor adaptation. We use this approach to identify tumor-essential genes as druggable candidates. We apply our method to a set of ER(+) breast tumor samples, collected before (n = 58) and after (n = 60) neoadjuvant treatment with the aromatase inhibitor letrozole, to prioritize genes as targets for combination therapy with letrozole treatment. We validate letrozole-induced tumor adaptation through coexpression and pathway analyses in an independent data set (n = 18). RESULTS: We find pervasive differential coexpression between the untreated and letrozole-treated tumor samples as evidence of letrozole-induced tumor adaptation. Based on patterns of coexpression, we identify ten genes as potential candidates for combination therapy with letrozole including EPCAM, a letrozole-induced essential gene and a target to which drugs have already been developed as cancer therapeutics. Through replication, we validate six letrozole-induced coexpression relationships and confirm the epithelial-to-mesenchymal transition as a process that is upregulated in the residual tumor samples following letrozole treatment. CONCLUSIONS: To derive the greatest benefit from molecularly targeted drugs it is critical to design combination treatment strategies rationally. Incorporating knowledge of the tumor adaptation process into the design provides an opportunity to match targeted drugs to the evolving tumor phenotype and surmount resistance

Contrasting Decollement and Prism Properties over the Sumatra 2004-2005 Earthquake Rupture Boundary

Styles of subduction zone deformation and earthquake rupture dynamics are strongly linked, jointly influencing hazard potential. Seismic reflection profiles across the trench west of Sumatra, Indonesia, show differences across the boundary between the major 2004 and 2005 plate interface earthquakes, which exhibited contrasting earthquake rupture and tsunami generation. In the southern part of the 2004 rupture, we interpret a negative-polarity sedimentary reflector ~500 meters above the subducting oceanic basement as the seaward extension of the plate interface. This predécollement reflector corresponds to unusual prism structure, morphology, and seismogenic behavior that are absent along the 2005 rupture zone. Although margins like the 2004 rupture zone are globally rare, our results suggest that sediment properties influence earthquake rupture, tsunami hazard, and prism development at subducting plate boundaries

A Survey on Continuous Time Computations

We provide an overview of theories of continuous time computation. These theories allow us to understand both the hardness of questions related to continuous time dynamical systems and the computational power of continuous time analog models. We survey the existing models, summarizing results, and point to relevant references in the literature

DNA metabarcoding marker choice skews perception of marine eukaryotic biodiversity

DNA metabarcoding is an increasingly popular technique to investigate biodiversity; however, many methodological unknowns remain, especially concerning the biases resulting from marker choice. Regions of the cytochrome c oxidase subunit I (COI) and 18S rDNA (18S) genes are commonly employed “universal” markers for eukaryotes, but the extent of taxonomic biases introduced by these markers and how such biases may impact metabarcoding performance is not well quantified. Here, focusing on macroeukaryotes, we use standardized sampling from autonomous reef monitoring structures (ARMS) deployed in the world\u27s most biodiverse marine ecosystem, the Coral Triangle, to compare the performance of COI and 18S markers. We then compared metabarcoding data to image-based annotations of ARMS plates. Although both markers provided similar estimates of taxonomic richness and total sequence reads, marker choice skewed estimates of eukaryotic diversity. The COI marker recovered relative abundances of the dominant sessile phyla consistent with image annotations. Both COI and the image annotations provided higher relative abundance estimates of Bryozoa and Porifera and lower estimates of Chordata as compared to 18S, but 18S recovered 25% more phyla than COI. Thus, while COI more reliably reflects the occurrence of dominant sessile phyla, 18S provides a more holistic representation of overall taxonomic diversity. Ideal marker choice is, therefore, contingent on study system and research question, especially in relation to desired taxonomic resolution, and a multimarker approach provides the greatest application across a broad range of research objectives. As metabarcoding becomes an essential tool to monitor biodiversity in our changing world, it is critical to evaluate biases associated with marker choice

Hyperspectral temperature and salt dependencies of absorption by water and heavy water in the 400-750 nm spectral range

The temperature and salt dependencies of absorption by liquid water (H₂O) and heavy water (D₂O) were determined using a hyperspectral absorption and attenuation meter (WET Labs, AC-S). Sodium chloride (NaCl) was used as a proxy for seawater salts. There was no significant temperature (ψₜ) or salt (ψₛ) dependency of absorption at wavelengths 550 nm, ψₜ exhibited peaks at ~604, 662, and 740 nm. A small negative trough in ψₛ occurred at ~590 nm, followed by a small positive peak ~620 nm, a larger negative trough at ~720 nm, and a strong positive peak at ~755 nm. The salt dependency of absorption by heavy water, ψₛᴴ, exhibited a negative power-law shape with very low ψₛᴴ, at wavelengths >550 nm. Our experiments with NaCl, clean open ocean seawater, and artificial seawater support the hypothesis that salts modify the absorption spectra of seawater by modifying the molecular matrix and vibrations of pure water