DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity.

An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity poses challenges for cancer treatment, motivating the need for combination therapies. Single-cell technologies are now available to guide effective drug combinations by accounting for intratumoral heterogeneity through the analysis of the signaling perturbations of an individual tumor sample screened by a drug panel. In particular, Mass Cytometry Time-of-Flight (CyTOF) is a high-throughput single-cell technology that enables the simultaneous measurements of multiple ([Formula: see text]40) intracellular and surface markers at the level of single cells for hundreds of thousands of cells in a sample. We developed a computational framework, entitled Drug Nested Effects Models (DRUG-NEM), to analyze CyTOF single-drug perturbation data for the purpose of individualizing drug combinations. DRUG-NEM optimizes drug combinations by choosing the minimum number of drugs that produce the maximal desired intracellular effects based on nested effects modeling. We demonstrate the performance of DRUG-NEM using single-cell drug perturbation data from tumor cell lines and primary leukemia samples

The vicious cycle: fundraising and perceived visibility in US presidential primaries

Scholars of presidential primaries have long posited a dynamic positive feedback loop between fundraising and electoral success. Yet existing work on both directions of this feedback remains inconclusive and is often explicitly cross-sectional, ignoring the dynamic aspect of the hypothesis. Pairing high-frequency FEC data on contributions and expenditures with Iowa Electronic Markets data on perceived probability of victory, we examine the bidirectional feedback between contributions and viability. We find robust, significant positive feedback in both directions. This might suggest multiple equilibria: a candidate initially anointed as the front-runner able to sustain such status solely by the fundraising advantage conferred despite possessing no advantage in quality. However, simulations suggest the feedback loop cannot, by itself, sustain advantage. Given the observed durability of front-runners, it would thus seem there is either some other feedback at work and/or the process by which the initial front-runner is identified is informative of candidate quality

High-speed civil transport flight- and propulsion-control technological issues

Technology advances required in the flight and propulsion control system disciplines to develop a high speed civil transport (HSCT) are identified. The mission and requirements of the transport and major flight and propulsion control technology issues are discussed. Each issue is ranked and, for each issue, a plan for technology readiness is given. Certain features are unique and dominate control system design. These features include the high temperature environment, large flexible aircraft, control-configured empennage, minimizing control margins, and high availability and excellent maintainability. The failure to resolve most high-priority issues can prevent the transport from achieving its goals. The flow-time for hardware may require stimulus, since market forces may be insufficient to ensure timely production. Flight and propulsion control technology will contribute to takeoff gross weight reduction. Similar technology advances are necessary also to ensure flight safety for the transport. The certification basis of the HSCT must be negotiated between airplane manufacturers and government regulators. Efficient, quality design of the transport will require an integrated set of design tools that support the entire engineering design team

Sustainable Development Indicator Frameworks and Initiatives

Agricultural and Food Policy, Environmental Economics and Policy, Farm Management, Production Economics,

Non-Invasive Ambient Intelligence in Real Life: Dealing with Noisy Patterns to Help Older People

This paper aims to contribute to the field of ambient intelligence from the perspective of real environments, where noise levels in datasets are significant, by showing how machine learning techniques can contribute to the knowledge creation, by promoting software sensors. The created knowledge can be actionable to develop features helping to deal with problems related to minimally labelled datasets. A case study is presented and analysed, looking to infer high-level rules, which can help to anticipate abnormal activities, and potential benefits of the integration of these technologies are discussed in this context. The contribution also aims to analyse the usage of the models for the transfer of knowledge when different sensors with different settings contribute to the noise levels. Finally, based on the authors’ experience, a framework proposal for creating valuable and aggregated knowledge is depicted.This research was partially funded by Fundación Tecnalia Research & Innovation, and J.O.-M. also wants to recognise the support obtained from the EU RFCS program through project number 793505 ‘4.0 Lean system integrating workers and processes (WISEST)’ and from the grant PRX18/00036 given by the Spanish Secretaría de Estado de Universidades, Investigación, Desarrollo e Innovación del Ministerio de Ciencia, Innovación y Universidades

On green routing and scheduling problem

The vehicle routing and scheduling problem has been studied with much interest within the last four decades. In this paper, some of the existing literature dealing with routing and scheduling problems with environmental issues is reviewed, and a description is provided of the problems that have been investigated and how they are treated using combinatorial optimization tools

QuaDMutEx: quadratic driver mutation explorer

Background Somatic mutations accumulate in human cells throughout life. Some may have no adverse consequences, but some of them may lead to cancer. A cancer genome is typically unstable, and thus more mutations can accumulate in the DNA of cancer cells. An ongoing problem is to figure out which mutations are drivers - play a role in oncogenesis, and which are passengers - do not play a role. One way of addressing this question is through inspection of somatic mutations in DNA of cancer samples from a cohort of patients and detection of patterns that differentiate driver from passenger mutations. Results We propose QuaDMutEx, a method that incorporates three novel elements: a new gene set penalty that includes non-linear penalization of multiple mutations in putative sets of driver genes, an ability to adjust the method to handle slow- and fast-evolving tumors, and a computationally efficient method for finding gene sets that minimize the penalty, through a combination of heuristic Monte Carlo optimization and exact binary quadratic programming. Compared to existing methods, the proposed algorithm finds sets of putative driver genes that show higher coverage and lower excess coverage in eight sets of cancer samples coming from brain, ovarian, lung, and breast tumors. Conclusions Superior ability to improve on both coverage and excess coverage on different types of cancer shows that QuaDMutEx is a tool that should be part of a state-of-the-art toolbox in the driver gene discovery pipeline. It can detect genes harboring rare driver mutations that may be missed by existing methods. QuaDMutEx is available for download from https://github.com/bokhariy/QuaDMutEx under the GNU GPLv3 license