Overlapping functionality of the Pht proteins in zinc homeostasis of streptococcus pneumoniae

Streptococcus pneumoniae is a globally significant pathogen that causes a range of diseases, including pneumonia, sepsis, meningitis, and otitis media. Its ability to cause disease depends upon the acquisition of nutrients from its environment, including transition metal ions such as zinc. The pneumococcus employs a number of surface proteins to achieve this, among which are four highly similar polyhistidine triad (Pht) proteins. It has previously been established that these proteins collectively aid in the delivery of zinc to the ABC transporter substrate-binding protein AdcAII. Here we have investigated the contribution of each individual Pht protein to pneumococcal zinc homeostasis by analyzing mutant strains expressing only one of the four pht genes. Under conditions of low zinc availability, each of these mutants showed superior growth and zinc accumulation profiles relative to a mutant strain lacking all four genes, indicating that any of the four Pht proteins are able to facilitate delivery of zinc to AdcAII. However, optimal growth and zinc accumulation in vitro and pneumococcal survival and proliferation in vivo required production of all four Pht proteins, indicating that, despite their overlapping functionality, the proteins are not dispensable without incurring a fitness cost. We also show that surface-attached forms of the Pht proteins are required for zinc recruitment and that they do not contribute to defense against extracellular zinc stress

An efficient genetic algorithm for large-scale transmit power control of dense and robust wireless networks in harsh industrial environments

The industrial wireless local area network (IWLAN) is increasingly dense, due to not only the penetration of wireless applications to shop floors and warehouses, but also the rising need of redundancy for robust wireless coverage. Instead of simply powering on all access points (APs), there is an unavoidable need to dynamically control the transmit power of APs on a large scale, in order to minimize interference and adapt the coverage to the latest shadowing effects of dominant obstacles in an industrial indoor environment. To fulfill this need, this paper formulates a transmit power control (TPC) model that enables both powering on/off APs and transmit power calibration of each AP that is powered on. This TPC model uses an empirical one-slope path loss model considering three-dimensional obstacle shadowing effects, to enable accurate yet simple coverage prediction. An efficient genetic algorithm (GA), named GATPC, is designed to solve this TPC model even on a large scale. To this end, it leverages repair mechanism-based population initialization, crossover and mutation, parallelism as well as dedicated speedup measures. The GATPC was experimentally validated in a small-scale IWLAN that is deployed a real industrial indoor environment. It was further numerically demonstrated and benchmarked on both small- and large-scales, regarding the effectiveness and the scalability of TPC. Moreover, sensitivity analysis was performed to reveal the produced interference and the qualification rate of GATPC in function of varying target coverage percentage as well as number and placement direction of dominant obstacles. (C) 2018 Elsevier B.V. All rights reserved

Multigene signatures of responses to chemotherapy derived by biochemically-inspired machine learning.

Pharmacogenomic responses to chemotherapy drugs can be modeled by supervised machine learning of expression and copy number of relevant gene combinations. Such biochemical evidence can form the basis of derived gene signatures using cell line data, which can subsequently be examined in patients that have been treated with the same drugs. These gene signatures typically contain elements of multiple biochemical pathways which together comprise multiple origins of drug resistance or sensitivity. The signatures can capture variation in these responses to the same drug among different patients

Topological Analysis of Metabolic Networks Integrating Co-Segregating Transcriptomes and Metabolomes in Type 2 Diabetic Rat Congenic Series

Background: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus is caused by complex organ-specific cellular mechanisms contributing to impaired insulin secretion and insulin resistance. Methods: We used systematic metabotyping by 1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualise shortest paths between metabolites and genes significantly associated with each genomic block. Results: Despite strong genomic similarities (95-99%) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific metabotypes (mQTL) and genome-wide expression traits (eQTL). Variation in key metabolites like glucose, succinate, lactate or 3-hydroxybutyrate, and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing shortest path length drove prioritization of biological validations by gene silencing. Conclusions: These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulations and to characterize novel functional roles for genes determining tissue-specific metabolism

A Graph-Theoretical Approach to the Selection of the Minimum Tiling Path from a Physical Map

The problem of computing the minimum tiling path (MTP) from a set of clones arranged in a physical map is a cornerstone of hierarchical (clone-by-clone) genome sequencing projects. We formulate this problem in a graph theoretical framework, and then solve by a combination of minimum hitting set and minimum spanning tree algorithms. The tool implementing this strategy, called FMTP, shows improved performance compared to the widely used software FPC. When we execute FMTP and FPC on the same physical map, the MTP produced by FMTP covers a higher portion of the genome, and uses a smaller number of clones. For instance, on the rice genome the MTP produced by our tool would reduce by about 11 percent the cost of a clone-by-clone sequencing project. Source code, benchmark data sets, and documentation of FMTP are freely available at \u3ehttp://code.google.com/p/fingerprint-based-minimal-tiling-path/ under MIT license

Improving Statistical Learning within Functional Genomic Experiments by means of Feature Selection

A Statistical learning approach concerns with understanding and modelling complex datasets. Based on a given training data, its main aim is to build a model that maps the relationship between a set of input features and a considered response in a predictive way. Classification is the foremost task of such a learning process. It has applications encompassing many important fields in modern biology, including microarray data as well as other functional genomic experiments. Microarray technology allow measuring tens of thousands of genes (features) simultaneously. However, the expressions of these genes are usually observed in a small number, tens to few hundreds, of tissue samples (observations). This common characteristic of high dimensionality has a great impact on the learning processes, since most of genes are noisy, redundant or non-relevant to the considered learning task. Both the prediction accuracy and interpretability of a constructed model are believed to be enhanced by performing the learning process based only on selected informative features. Motivated by this notion, a novel statistical method, named Proportional Overlapping Scores (POS), is proposed for selecting features based on overlapping analysis of gene expression data across different classes of a considered classification task. This method results in a measure, called POS score, of a feature’s relevance to the learning task. POS is further extended to minimize the redundancy among the selected features. The proposed approaches are validated on several publicly available gene expression datasets using widely used classifiers to observe effects on their prediction accuracy. Selection stability is also examined to address the captured biological knowledge in the obtained results. The experimental results of classification error rates computed using the Random Forest, k NearestNeighbor and Support VectorMachine classifiers show that the proposals achieve a better performance than widely used gene selection methods

Optimization as a design strategy. Considerations based on building simulation-assisted experiments about problem decomposition

In this article the most fundamental decomposition-based optimization method - block coordinate search, based on the sequential decomposition of problems in subproblems - and building performance simulation programs are used to reason about a building design process at micro-urban scale and strategies are defined to make the search more efficient. Cyclic overlapping block coordinate search is here considered in its double nature of optimization method and surrogate model (and metaphore) of a sequential design process. Heuristic indicators apt to support the design of search structures suited to that method are developed from building-simulation-assisted computational experiments, aimed to choose the form and position of a small building in a plot. Those indicators link the sharing of structure between subspaces ("commonality") to recursive recombination, measured as freshness of the search wake and novelty of the search moves. The aim of these indicators is to measure the relative effectiveness of decomposition-based design moves and create efficient block searches. Implications of a possible use of these indicators in genetic algorithms are also highlighted.Comment: 48 pages. 12 figures, 3 table

Refining interaction search through signed iterative Random Forests

Advances in supervised learning have enabled accurate prediction in biological systems governed by complex interactions among biomolecules. However, state-of-the-art predictive algorithms are typically black-boxes, learning statistical interactions that are difficult to translate into testable hypotheses. The iterative Random Forest algorithm took a step towards bridging this gap by providing a computationally tractable procedure to identify the stable, high-order feature interactions that drive the predictive accuracy of Random Forests (RF). Here we refine the interactions identified by iRF to explicitly map responses as a function of interacting features. Our method, signed iRF, describes subsets of rules that frequently occur on RF decision paths. We refer to these rule subsets as signed interactions. Signed interactions share not only the same set of interacting features but also exhibit similar thresholding behavior, and thus describe a consistent functional relationship between interacting features and responses. We describe stable and predictive importance metrics to rank signed interactions. For each SPIM, we define null importance metrics that characterize its expected behavior under known structure. We evaluate our proposed approach in biologically inspired simulations and two case studies: predicting enhancer activity and spatial gene expression patterns. In the case of enhancer activity, s-iRF recovers one of the few experimentally validated high-order interactions and suggests novel enhancer elements where this interaction may be active. In the case of spatial gene expression patterns, s-iRF recovers all 11 reported links in the gap gene network. By refining the process of interaction recovery, our approach has the potential to guide mechanistic inquiry into systems whose scale and complexity is beyond human comprehension