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Lamers S.L.,BioInfoExperts | Fogel G.B.,Natural Selection Inc. | Singer E.J.,University of California at Los Angeles | Salemi M.,University of Florida | And 4 more authors.
International Reviews of Immunology | Year: 2012

Combined anti-retroviral therapy (cART) has significantly reduced the number of AIDS-associated illnesses and changed the course of HIV-1 disease in developed countries. Despite the ability of cART to maintain high CD4 T-cell counts, a number of macrophage-mediated diseases can still occur in HIV-infected subjects. These diseases include lymphoma, metabolic diseases, and HIV-associated neurological disorders. Within macrophages, the HIV-1 regulatory protein "Nef" can modulate surface receptors, interact with signaling pathways, and promote specific environments that contribute to each of these pathologies. Moreover, genetic variation in Nef may also guide the macrophage response. Herein, we review findings relating to the Nefmacrophage interaction and how this relationship contributes to disease pathogenesis. © 2012 Informa Healthcare USA, Inc.


Hecht D.,Southwestern College at Winfield | Fogel G.B.,Natural Selection Inc.
Journal of Computer-Aided Molecular Design | Year: 2012

Plasmodium falciparum, the causal agent of malaria, continues to evolve resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine. Here we study the amino acid replacements in dihydrofolate reductase (DHFR) that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH. The chain of amino acid replacements that has led to resistance can be inferred in a computer, leading to a broader understanding of the coevolution between the drug and target. This in silico approach suggests that only a small set of specific active site replacements in the proper order could have led to the resistant strains in the wild today. A similar approach can be used on any target of interest to anticipate likely pathways of future resistance for more effective drug development. © 2012 Springer Science+Business Media Dordrecht.


Hinton A.,University of California at San Diego | Hunter S.,University of California at San Diego | Reyes G.,University of California at San Diego | Fogel G.B.,Natural Selection Inc. | King C.C.,University of California at San Diego
Advances in Genetics | Year: 2012

MicroRNAs (miRNAs) actively regulate differentiation as pluripotent cells become cells of pancreatic endocrine lineage, including insulin-producing β cells. The process is dynamic; some miRNAs help maintain pluripotency, while others drive cell fate decisions. Here, we survey the current literature and describe the biological role of selected miRNAs in maintenance of both mouse and human embryonic stem cell (ESC) pluripotency. Subsequently, we review the increasing evidence that miRNAs act at selected points in differentiation to regulate decisions about early cell fate (definitive endoderm and mesoderm), formation of pancreatic precursor cells, endocrine cell function, as well as epithelial to mesenchymal transition. © 2012 Elsevier Inc.


Anand A.,Nanyang Technological University | Pugalenthi G.,Nanyang Technological University | Fogel G.B.,Natural Selection Inc | Suganthan P.N.,Nanyang Technological University
Amino Acids | Year: 2010

Real-world datasets commonly have issues with data imbalance. There are several approaches such as weighting, sub-sampling, and data modeling for handling these data. Learning in the presence of data imbalances presents a great challenge to machine learning. Techniques such as support-vector machines have excellent performance for balanced data, but may fail when applied to imbalanced datasets. In this paper, we propose a new undersampling technique for selecting instances from the majority class. The performance of this approach was evaluated in the context of several real biological imbalanced data. The ratios of negative to positive samples vary from ~9:1 to ~100:1. Useful classifiers have high sensitivity and specificity. Our results demonstrate that the proposed selection technique improves the sensitivity compared to weighted support-vector machine and available results in the literature for the same datasets. © 2010 Springer-Verlag.


Hecht D.,Southwestern College at Winfield | Fogel G.B.,Natural Selection Inc.
2012 IEEE Symposium on Computational Intelligence and Computational Biology, CIBCB 2012 | Year: 2012

The evolution of drug resistance in malaria continues to be a widespread concern. Many of these drugs target key proteins such as dihydrofolate reductase (DHFR). However in malaria, the structural plasticity of DHFR allows it to maintain its active site and catalytic activity, while resisting drug binding. One way to better understand this process is through the appreciation of DHFR structural evolution in general, and then use in silico evolution to model both the drug docking and the likely amino acid changes in DHFR that will occur as a result. Using a comprehensive phylogenetic analysis of DHFR, we have generated a method that generates variant DHFR proteins and sequentially scores the docking of the natural cofactor NADPH and the known anti-malarial drug pyrimethamine in order to determine fitness. Iteration of this process allows the opportunity to model the coevolutionary processes involved with drug resistance and to predict responses to pharmaceuticals in advance of their use in the field. © 2012 IEEE.


Hinton A.,University of California at San Diego | Hunter S.E.,University of California at San Diego | Afrikanova I.,University of California at San Diego | Jones G.A.,University of California at San Diego | And 4 more authors.
Stem Cells | Year: 2014

MicroRNAs (miRNAs) are noncoding, regulatory RNAs expressed dynamically during differentiation of human embryonic stem cells (hESCs) into defined lineages. Mapping developmental expression of miRNAs during transition from pluripotency to definitive endoderm (DE) should help to elucidate the mechanisms underlying lineage specification and ultimately enhance differentiation protocols. In this report, next generation sequencing was used to build upon our previous analysis of miRNA expression in human hESCs and DE. From millions of sequencing reads, 747 and 734 annotated miRNAs were identified in pluripotent and DE cells, respectively, including 77 differentially expressed miRNAs. Among these, four of the top five upregulated miRNAs were previously undetected in DE. Furthermore, the stem-loop for miR-302a, an important miRNA for both hESCs self-renewal and endoderm specification, produced several highly expressed miRNA species (isomiRs). Overall, isomiRs represented >10% of sequencing reads in >40% of all detected stem-loop arms, suggesting that the impact of these abundant miRNA species may have been overlooked in previous studies. Because of their relative abundance, the role of differential isomiR targeting was studied using the miR-302 cluster as a model system. A miRNA mimetic for miR-302a-5p, but not miR-302a-5p(+3), decreased expression of orthodenticle homeobox 2 (OTX2). Conversely, isomiR 302a-5p(+3) selectively decreased expression of tuberous sclerosis protein 1, but not OTX2, indicating nonoverlapping specificity of miRNA processing variants. Taken together, our characterization of miRNA expression, which includes novel miRNAs and isomiRs, helps establish a foundation for understanding the role of miRNAs in DE formation and selective targeting by isomiRs. Stem Cells 2014;32:2360-2372 © 2014 AlphaMed Press.


Fogel G.B.,Natural Selection Inc.
IEEE Computational Intelligence Magazine | Year: 2010

The IEEE 2010 World Congress on Computational Intelligence (WCCI) to be held in July in Barcelona, Spain, is organized by IEEE CIS during even years. IEEE CIS accepts complete responsibility for the technical, financial, publicity and administrative aspects of the conference. Such conferences must include the IEEE logo and name in the conference title and all conference publications and announcements. A second approach to involvement with IEEE CIS is called 'Co-Sponsorship.' Co-Sponsored conferences indicate shared involvement among several entities, one of which is the IEEE CIS. A third approach to involvement is 'Technical Co-Sponsorship.' Technical Co-Sponsorship indicates direct and substantial involvement by the IEEE CIS solely in the organization of the technical program. The IEEE name may not be used in the conference title, but the IEEE logo may be used in conference publications and promotional materials.


Fogel G.B.,Natural Selection Inc. | Fogel D.B.,Natural Selection Inc.
BioSystems | Year: 2011

The behaviors of individuals and species are often explained in terms of evolutionary stable strategies (ESSs). The analysis of ESSs determines which, if any, combinations of behaviors cannot be invaded by alternative strategies. Two assumptions required to generate an ESS (i.e., an infinite population and payoffs described only on the average) do not hold under natural conditions. Previous experiments indicated that under more realistic conditions of finite populations and stochastic payoffs, populations may evolve in trajectories that are unrelated to an ESS, even in very simple games. The simulations offered here extend earlier research by employing truncation selection with random parental selection in a hawk-dove game. Payoffs are determined in pairwise contests using either the expected outcome, or the result of a random variable. In each case, however, the mean fraction of hawks over many generations and across many independent trials does not conform to the expected ESS. Implications of these results and philosophical underpinnings of ESS theory are offered. © 2011 Elsevier Ireland Ltd.


Fogel G.B.,Natural Selection Inc.
IEEE Computational Intelligence Magazine | Year: 2013

The first IEEE Life Sciences Grand Challenges Conference (IEEE LSGCC) was held at the National Academy of Sciences in Washington, D.C. on October 4-5, 2012. The meeting was largely focused on medical applications, including improved devices, use of robots as medical assistants, even visualization methods for modeling of biological systems such as blood flow in the heart so that new types of replacement valves could be tested in a realistic simulation environment where the researcher can interact with the simulation in three dimensional projections. Nobel Prize winner Phillip Sharp lectured on the convergence of the life sciences, physical sciences, and engineering.


Hecht D.,Southwestern College at Winfield | Tran J.,Brown University | Fogel G.B.,Natural Selection Inc.
Molecular Phylogenetics and Evolution | Year: 2011

The evolution of dihydrofolate reductase (DHFR) was studied through a comprehensive structural-based analysis. An amino acid sequence alignment was generated from a superposition of experimentally determined X-ray crystal structures of wild-type (wt) DHFR from the Protein Data Bank (PDB). Using this structure-based alignment of DHFR, a metric was generated for the degree of conservation at each alignment site - not only in terms of amino acid residue, but also secondary structure, and residue class. A phylogenetic tree was generated using the alignment that compared favorably with the canonical phylogeny. This structure-based alignment was used to confirm that the degree of conservation of active-site residues in terms of both sequence as well as structure was significantly greater than non-active site residues. These results can be used in helping to understand the likely future evolution of DHFR in response to novel therapies. © 2011 Elsevier Inc.

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