Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies

BACKGROUND: While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease.

RESULTS: We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations.

Memory Cost Analysis for OpenFlow Multiple Table Lookup

Multiple Table Lookup architectures in Software Defined Networking (SDN) open the door for exciting new network applications. The development of the OpenFlow protocol supported the SDN paradigm. However, the first version of the OpenFlow protocol specified a single table lookup model with the associated constraints in flow entry numbers and search capabilities. With the introduction of multiple table lookup in OpenFlow v1.1, flexible and efficient search to support SDN application innovation became possible. However, implementation of multiple table lookup in hardware to meet high performance requirements is non-trivial. One possible approach involves the use of multi-dimensional lookup algorithms. A high lookup performance can be achieved by using embedded memory for flow entry storage. A detailed study of OpenFlow flow filters for multi-dimensional lookup is presented in this paper. Based on a proposed multiple table lookup architecture, the memory consumption and update performance using parallel single field searches are evaluated. The results demonstrate an efficient multi-table lookup implementation with minimum memory usage.

An evidential fusion approach for gender profiling

CCTV (Closed-Circuit TeleVision) systems are broadly deployed in the present world. To ensure in-time reaction for intelligent surveillance, it is a fundamental task for real-world applications to determine the gender of people of interest. However, normal video algorithms for gender profiling (usually face profiling) have three drawbacks. First, the profiling result is always uncertain. Second, the profiling result is not stable. The degree of certainty usually varies over time, sometimes even to the extent that a male is classified as a female, and vice versa. Third, for a robust profiling result in cases that a person’s face is not visible, other features, such as body shape, are required. These algorithms may provide different recognition results - at the very least, they will provide different degrees of certainties. To overcome these problems, in this paper, we introduce an Dempster-Shafer (DS) evidential approach that makes use of profiling results from multiple algorithms over a period of time, in particular, Denoeux’s cautious rule is applied for fusing mass functions through time lines. Experiments show that this approach does provide better results than single profiling results and classic fusion results. Furthermore, it is found that if severe mis-classification has occurred at the beginning of the time line, the combination can yield undesirable results. To remedy this weakness, we further propose three extensions to the evidential approach proposed above incorporating notions of time-window, time-attenuation, and time-discounting, respectively. These extensions also applies Denoeux’s rule along with time lines and take the DS approach as a special case. Experiments show that these three extensions do provide better results than their predecessor when mis-classifications occur.

Challenging conventional risk assessment with respect to human exposure to multiple food contaminants in food: A case study using maize

Mycotoxins and heavy metals are ubiquitous in the environment and contaminate many foods. The widespread use of pesticides in crop production to control disease contributes further to the chemical contamination of foods. Thus multiple chemical contaminants threaten the safety of many food commodities; hence the present study used maize as a model crop to identify the severity in terms of human exposure when multiple contaminants are present. High Content Analysis (HCA) measuring multiple endpoints was used to determine cytotoxicity of complex mixtures of mycotoxins, heavy metals and pesticides. Endpoints included nuclear intensity (NI), nuclear area (NA), plasma membrane permeability (PMP), mitochondrial membrane potential (MMP) and mitochondrial mass (MM). At concentrations representing legal limits of each individual contaminant in maize (3. ng/ml ochratoxin A (OTA), 1. μg/ml fumonisin B1 (FB1), 2. ng/ml aflatoxin B1 (AFB1), 100. ng/ml cadmium (Cd), 150. ng/ml arsenic (As), 50. ng/ml chlorpyrifos (CP) and 5. μg/ml pirimiphos methyl (PM), the mixtures (tertiary mycotoxins plus Cd/As) and (tertiary mycotoxins plus Cd/As/CP/PM) were cytotoxic for NA and MM endpoints with a difference of up to 13.6% (. p≤. 0.0001) and 12% (. p≤. 0.0001) respectively from control values. The most cytotoxic mixture was (tertiary mycotoxins plus Cd/As/CP/PM) across all 4 endpoints (NA, NI, MM and MMP) with increases up to 61.3%, 23.0%, 61.4% and 36.3% (. p≤. 0.0001) respectively. Synergy was evident for two endpoints (NI and MM) at concentrations contaminating maize above legal limits, with differences between expected and measured values of (6.2-12.4% (. p≤. 0.05-. p≤. 0.001) and 4.5-12.3% (. p≤. 0.05-. p≤. 0.001) for NI and MM, respectively. The study introduces for the first time, a holistic approach to identify the impact in terms of toxicity to humans when multiple chemical contaminants are present in foodstuffs. Governmental regulatory bodies must begin to contemplate how to safeguard the population when such mixtures of contaminants are found in foods and this study starts to address this critical issue.

A Tractable Approach to Uplink Spectral Efficiency of Two-Tier Massive MIMO Cellular HetNets

This letter investigates the uplink spectral efficiency (SE) of a two-tier cellular network, where massive multiple-input multiple-output macro base stations are overlaid with dense small cells. Macro user equipments (MUEs) and small cells with single user equipment uniformly scattered are modeled as two independent homogeneous Poisson point processes. By applying stochastic geometry, we analyze the SE of the multiuser uplink at a macro base station that employs a zero-forcing detector and we obtain a novel lower bound as well as its approximation. According to the simple and near-exact analytical expression, we observe that the ideal way to improve the SE is by increasing the MUE density and the base station antennas synchronously rather than increasing them individually. Furthermore, a large value of path loss exponent has a positive effect on the SE due to the reduced aggregated interference.

Parallel Time Series Analysis and Income Inequality: A New Approach to Comparative Case Studies

This case study deals with the role of time series analysis in sociology, and its relationship with the wider literature and methodology of comparative case study research. Time series analysis is now well-represented in top-ranked sociology journals, often in the form of ‘pooled time series’ research designs. These studies typically pool multiple countries together into a pooled time series cross-section panel, in order to provide a larger sample for more robust and comprehensive analysis. This approach is well suited to exploring trans-national phenomena, and for elaborating useful macro-level theories specific to social structures, national policies, and long-term historical processes. It is less suited however, to understanding how these global social processes work in different countries. As such, the complexities of individual countries - which often display very different or contradictory dynamics than those suggested in pooled studies – are subsumed. Meanwhile, a robust literature on comparative case-based methods exists in the social sciences, where researchers focus on differences between cases, and the complex ways in which they co-evolve or diverge over time. A good example of this is the inequality literature, where although panel studies suggest a general trend of rising inequality driven by the weakening power of labour, marketisation of welfare, and the rising power of capital, some countries have still managed to remain resilient. This case study takes a closer look at what can be learned by applying the insights of case-based comparative research to the method of time series analysis. Taking international income inequality as its point of departure, it argues that we have much to learn about the viability of different combinations of policy options by examining how they work in different countries over time. By taking representative cases from different welfare systems (liberal, social democratic, corporatist, or antipodean), we can better sharpen our theories of how policies can be more specifically engineered to offset rising inequality. This involves a fundamental realignment of the strategy of time series analysis, grounding it instead in a qualitative appreciation of the historical context of cases, as a basis for comparing effects between different countries.

Measuring the macrosystem in post-accord Northern Ireland: A social-ecological approach

The macrosystem refers to the overarching patterns that influence behavior at each level of the social ecology (Bronfenbrenner, 1977), making it a necessary component for assessing human development in contexts of political violence. This article proposes a method for systematically measuring the macrosystem in Northern Ireland that allows for a subnational analysis, multiple time units, and indicators of both low-level violence and positive relations. Articles were randomly chosen for each weekday in 2006-2011 from two prominent Northern Irish newspapers and coded according to their reflection of positive relations and political tensions between Catholics and Protestants. The newspaper data were then compared to existing macro-level measurements in Northern Ireland. We found that the newspaper data provided a more nuanced understanding of fluctuations in intergroup relations than the corresponding measures. This has practical implications for peacebuilding and advances our methods for assessing the impact of macro-level processes on individual development.

Real-Time Multiple Event Detection and Classification Using Moving Window PCA

This paper proposes a method for the detection and classification of multiple events in an electrical power system in real-time, namely; islanding, high frequency events (loss of load) and low frequency events (loss of generation). This method is based on principal component analysis of frequency measurements and employs a moving window approach to combat the time-varying nature of power systems, thereby increasing overall situational awareness of the power system. Numerical case studies using both real data, collected from the UK power system, and simulated case studies, constructed using DigSilent PowerFactory, for islanding events, as well as both loss of load and generation dip events, are used to demonstrate the reliability of the proposed method.

Incomplete DJH rearrangements as a novel tumor target for minimal residual disease quantitation in multiple myeloma using real-time PCR.

The hypervariable regions of immunoglobulin heavy-chain (IgH) rearrangements provide a specific tumor marker in multiple myeloma (MM). Recently, real-time PCR assays have been developed in order to quantify the number of tumor cells after treatment. However, these strategies are hampered by the presence of somatic hypermutation (SH) in VDJH rearrangements from multiple myeloma (MM) patients, which causes mismatches between primers and/or probes and the target, leading to a nonaccurate quantification of tumor cells. Our group has recently described a 60% incidence of incomplete DJH rearrangements in MM patients, with no or very low rates of SH. In this study, we compare the efficiency of a real-time PCR approach for the analysis of both complete and incomplete IgH rearrangements in eight MM patients using only three JH consensus probes. We were able to design an allele-specific oligonucleotide for both the complete and incomplete rearrangement in all patients. DJH rearrangements fulfilled the criteria of effectiveness for real-time PCR in all samples (ie no unspecific amplification, detection of less than 10 tumor cells within 10(5) polyclonal background and correlation coefficients of standard curves higher than 0.98). By contrast, only three out of eight VDJH rearrangements fulfilled these criteria. Further analyses showed that the remaining five VDJH rearrangements carried three or more somatic mutations in the probe and primer sites, leading to a dramatic decrease in the melting temperature. These results support the use of incomplete DJH rearrangements instead of complete somatically mutated VDJH rearrangements for investigation of minimal residual disease in multiple myeloma.

Secure 5G Wireless Communications: A Joint Relay Selection and Wireless Power Transfer Approach

In this paper, we investigate the secrecy performance of an energy harvesting relay system, where a legitimate source communicates with a legitimate destination via the assistance of multiple trusted relays. In the considered system, the source and relays deploy the time-switching-based radio frequency energy harvesting technique to harvest energy from a multi-antenna beacon. Different antenna selection and relay selection schemes are applied to enhance the security of the system. Specifically, two relay selection schemes based on the partial and full knowledge of channel state information, i.e., optimal relay selection and partial relay selection, and two antenna selection schemes for harvesting energy at source and relays, i.e., maximizing energy harvesting channel for the source and maximizing energy harvesting channel for the selected relay, are proposed. The exact and asymptotic expressions of secrecy outage probability in these schemes are derived. We demonstrate that applying relay selection approaches in the considered energy harvesting system can enhance the security performance. In particular, optimal relay selection scheme outperforms partial relay selection scheme and achieves full secrecy diversity order, regardless of energy harvesting scenarios.

A Two-Stage Online Approach for Collaborative Multi-Agent Planning under Uncertainty

In a team of multiple agents, the pursuance of a common goal is a defining characteristic. Since agents may have different capabilities, and effects of actions may be uncertain, a common goal can generally only be achieved through a careful cooperation between the different agents. In this work, we propose a novel two-stage planner that combines online planning at both team level and individual level through a subgoal delegation scheme. The proposal brings the advantages of online planning approaches to the multi-agent setting. A number of modifications are made to a classical UCT approximate algorithm to (i) adapt it to the application domains considered, (ii) reduce the branching factor in the underlying search process, and (iii) effectively manage uncertain information of action effects by using information fusion mechanisms. The proposed online multi-agent planner reduces the cost of planning and decreases the temporal cost of reaching a goal, while significantly increasing the chance of success of achieving the common goal. 

Joint Analysis of Multiple Algorithms and Performance Measures

There has been an increasing interest in the development of new methods using Pareto optimality to deal with multi-objective criteria (for example, accuracy and time complexity). Once one has developed an approach to a problem of interest, the problem is then how to compare it with the state of art. In machine learning, algorithms are typically evaluated by comparing their performance on different data sets by means of statistical tests. Standard tests used for this purpose are able to consider jointly neither performance measures nor multiple competitors at once. The aim of this paper is to resolve these issues by developing statistical procedures that are able to account for multiple competing measures at the same time and to compare multiple algorithms altogether. In particular, we develop two tests: a frequentist procedure based on the generalized likelihood-ratio test and a Bayesian procedure based on a multinomial-Dirichlet conjugate model. We further extend them by discovering conditional independences among measures to reduce the number of parameters of such models, as usually the number of studied cases is very reduced in such comparisons. Data from a comparison among general purpose classifiers is used to show a practical application of our tests.

Complexity of risk: Mixed methods approach to understanding youth risk and insecurity in post-conflict settings

In settings of intergroup conflict, identifying contextually-relevant risk factors for youth development in an important task. In Vukovar, Croatia, a city devastated during the war in former Yugoslavia, ethno-political tensions remain. The current study utilized a mixed method approach to identify two salient community-level risk factors (ethnic tension and general antisocial behavior) and related emotional insecurity responses (ethnic and non-ethnic insecurity) among youth in Vukovar. In Study 1, focus group discussions (N=66) with mother, fathers, and adolescents 11 to 15-years-old were analyzed using the Constant Comparative Method, revealing two types of risk and insecurity responses. In Study 2, youth (N=227, 58% male, M=15.88 SD=1.12 years old) responded to quantitative scales developed from the focus groups; discriminate validity was demonstrated and path analyses established predictive validity between each type of risk and insecurity. First, community ethnic tension (i.e., threats related to war/ethnic identity) significantly predicted ethnic insecurity for all youth (β=.41, p<.001). Second, experience with community antisocial behavior (i.e., general crime found in any context) predicted non-ethnic community insecurity for girls (β=.32, p<.05), but not for boys. These findings are the first to show multiple forms of emotional insecurity at the community level; implications for future research are discussed.