Publications by authors named "Gary B Fogel"

42 Publications

Emerging Patterns in HIV-1 gp120 Variable Domains in Anatomical Tissues in the Absence of a Plasma Viral Load.

AIDS Res Hum Retroviruses 2019 06 10;35(6):588-596. Epub 2019 Apr 10.

6 Departments of Laboratory Medicine, Pathology and Medicine, The University of California at San Francisco, San Francisco, California.

The HIV envelope protein contains five hypervariable domains (V1-V5) that are fundamental for cell entry. We contrasted modifications in the variable domains derived from a panel of 24 tissues from 7 subjects with no measurable plasma viral load (NPVL) to variable domains from 76 tissues from 15 subjects who had a detectable plasma viral load (PVL) at death. NPVL subject's V1 and V2 domains were usually highly length variable, whereas length variation in PVL sequences was more conserved. Longer V1s contained more charged residues, whereas longer V2s were more glycosylated. Structural analysis demonstrated V1/V2 charge, and N-site additions/subtractions were localized to the CD4 binding pocket. Diversified envelopes in tissues during therapy may represent a mechanism for HIV persistence in tissues, as binding pocket complexity is associated with HIV that may escape neutralization, whereas shorter envelopes are associated with increased infectivity. Further analysis of tissue-derived envelope sequences may enable better understanding of potential immunological approaches targeting the persistent HIV reservoir.
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http://dx.doi.org/10.1089/AID.2018.0267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588100PMC
June 2019

Brain-specific HIV Nef identified in multiple patients with neurological disease.

J Neurovirol 2018 02 23;24(1):1-15. Epub 2017 Oct 23.

The University of California, San Francisco, CA, USA.

HIV-1 Nef is a flexible, multifunctional protein with several cellular targets that is required for pathogenicity of the virus. This protein maintains a high degree of genetic variation among intra- and inter-host isolates. HIV Nef is relevant to HIV-associated neurological diseases (HAND) in patients treated with combined antiretroviral therapy because of the protein's role in promoting survival and migration of infected brain macrophages. In this study, we analyzed 2020 HIV Nef sequences derived from 22 different tissues and 31 subjects using a novel computational approach. This approach combines statistical regression and evolved neural networks (ENNs) to classify brain sequences based on the physical and chemical characteristics of functional Nef domains. Based on training, testing, and validation data, the method successfully classified brain Nef sequences at 84.5% and provided informative features for further examination. These included physicochemical features associated with the Src-homology-3 binding domain, the Nef loop (including the AP-2 Binding region), and a cytokine-binding domain. Non-brain sequences from patients with HIV-associated neurological disease were frequently classified as brain, suggesting that the approach could indicate neurological risk using blood-derived virus or for the development of biomarkers for use in assay systems aimed at drug efficacy studies for the treatment of HIV-associated neurological diseases.
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http://dx.doi.org/10.1007/s13365-017-0586-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792318PMC
February 2018

Structure-based analysis of Bacilli and plasmid dihydrofolate reductase evolution.

J Mol Graph Model 2017 01 22;71:135-153. Epub 2016 Nov 22.

Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, USA; Department of Chemistry, Southwestern College, 900 Otay Lakes Rd., Chula Vista, CA 91910, USA. Electronic address:

Dihydrofolate reductase (DHFR), a key enzyme in tetrahydrofolate-mediated biosynthetic pathways, has a structural motif known to be highly conserved over a wide range of organisms. Given its critical role in purine and amino acid synthesis, DHFR is a well established therapeutic target for treating a wide range of prokaryotic and eukaryotic infections as well as certain types of cancer. Here we present a structural-based computer analysis of bacterial (Bacilli) and plasmid DHFR evolution. We generated a structure-based sequence alignment using 7 wild-type DHFR x-ray crystal structures obtained from the RCSB Protein Data Bank and 350 chromosomal and plasmid homology models we generated from sequences obtained from the NCBI Protein Database. We used these alignments to compare active site and non-active site conservation in terms of amino acid residues, secondary structure and amino acid residue class. With respect to amino acid sequences and residue classes, active-site positions in both plasmid and chromosomal DHFR are significantly more conserved than non-active site positions. Secondary structure conservation was similar for active site and non-active site positions. Plasmid-encoded DHFR proteins have greater degree of sequence and residue class conservation, particularly in sequence positions associated with a network of concerted protein motions, than chromosomal-encoded DHFR proteins. These structure-based were used to build DHFR specific phylogenetic trees from which evidence for horizontal gene transfer was identified.
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http://dx.doi.org/10.1016/j.jmgm.2016.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203806PMC
January 2017

HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi's Sarcoma during AIDS.

Sarcoma 2016 29;2016:4510483. Epub 2016 Aug 29.

The AIDS and Cancer Specimen Resource, University of California at San Francisco and the Department of Laboratory Medicine, Pathology, and Medicine, University of California at San Francisco, 1001 Poterero Ave, Bldg 3, Rm 207, UCSF Box 1317, San Francisco, CA 94110, USA.

Kaposi's sarcoma (KS) in HIV-infected individuals can have a wide range of clinical outcomes, from indolent skin tumors to a life-threatening visceral cancer. KS tumors contain endothelial-related cells and inflammatory cells that may be HIV-infected. In this study we tested if HIV evolutionary patterns distinguish KS tumor relatedness and progression. Multisite autopsies from participants who died from HIV-AIDS with KS prior to the availability of antiretroviral therapy were identified at the AIDS and Cancer Specimen Resource (ACSR). Two patients (KS1 and KS2) died predominantly from non-KS-associated disease and KS3 died due to aggressive and metastatic KS within one month of diagnosis. Skin and visceral tumor and nontumor autopsy tissues were obtained (n = 12). Single genome sequencing was used to amplify HIV RNA and DNA, which was present in all tumors. Independent HIV tumor clades in phylogenies differentiated KS1 and KS2 from KS3, whose sequences were interrelated by both phylogeny and selection. HIV compartmentalization was confirmed in KS1 and KS2 tumors; however, in KS3, no compartmentalization was observed among sampled tissues. While the sample size is small, the HIV evolutionary patterns observed in all patients suggest an interplay between tumor cells and HIV-infected cells which provides a selective advantage and could promote KS progression.
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http://dx.doi.org/10.1155/2016/4510483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019946PMC
September 2016

2015 Information Processing in Cells and Tissues (IPCAT 2015).

Biosystems 2016 Aug;146:1-2

Intelligent Systems Group, University of York, York YO10 5DD, England, UK.

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http://dx.doi.org/10.1016/j.biosystems.2016.07.001DOI Listing
August 2016

HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads.

J Virol 2016 10 29;90(20):8968-83. Epub 2016 Sep 29.

National Neurological AIDS Bank, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA David Geffen School of Medicine and Olive View-UCLA Medical Center, Department of Neurology, Los Angeles, California, USA.

Unlabelled: HIV infection treatment strategies have historically defined effectiveness through measuring patient plasma HIV RNA. While combined antiretroviral therapy (cART) can reduce plasma viral load (pVL) to undetectable levels, the degree that HIV is eliminated from other anatomical sites remains unclear. We investigated the HIV DNA levels in 229 varied autopsy tissues from 20 HIV-positive (HIV(+)) cART-treated study participants with low or undetectable plasma VL and cerebrospinal fluid (CSF) VL prior to death who were enrolled in the National Neurological AIDS Bank (NNAB) longitudinal study and autopsy cohort. Extensive medical histories were obtained for each participant. Autopsy specimens, including at least six brain and nonbrain tissues per participant, were reviewed by study pathologists. HIV DNA, measured in tissues by quantitative and droplet digital PCR, was identified in 48/87 brain tissues and 82/142 nonbrain tissues at levels >200 HIV copies/million cell equivalents. No participant was found to be completely free of tissue HIV. Parallel sequencing studies from some tissues recovered intact HIV DNA and RNA. Abnormal histological findings were identified in all participants, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. All brain tissues demonstrated some degree of pathology. Ninety-five percent of participants had some degree of atherosclerosis, and 75% of participants died with cancer. This study assists in characterizing the anatomical locations of HIV, in particular, macrophage-rich tissues, such as the central nervous system (CNS) and testis. Additional studies are needed to determine if the HIV recovered from tissues promotes the pathogenesis of inflammatory diseases, such as HIV-associated neurocognitive disorders, cancer, and atherosclerosis.

Importance: It is well-known that combined antiretroviral therapy (cART) can reduce plasma HIV to undetectable levels; however, cART cannot completely clear HIV infection. An ongoing question is, "Where is HIV hiding?" A well-studied HIV reservoir is "resting" T cells, which can be isolated from blood products and succumb to cART once activated. Less-studied reservoirs are anatomical tissue samples, which have unknown cART penetration, contain a comparably diverse spectrum of potentially HIV-infected immune cells, and are important since <2% of body lymphocytes actually reside in blood. We examined 229 varied autopsy specimens from 20 HIV(+) participants who died while on cART and identified that >50% of tissues were HIV infected. Additionally, we identified considerable pathology in participants' tissues, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. This study substantiates that tissue-associated HIV is present despite cART and can inform future studies into HIV persistence.
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http://dx.doi.org/10.1128/JVI.00674-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5044815PMC
October 2016

On the Physicochemical and Structural Modifications Associated with HIV-1 Subtype B Tropism Transition.

AIDS Res Hum Retroviruses 2016 08 1;32(8):829-40. Epub 2016 Jun 1.

4 Department of Laboratory Medicine, Pathology, and Medicine, and the AIDS and Cancer Specimen Resource, University of California , San Francisco, California.

HIV-1 enters immune cells via binding the viral envelope to a host cell CD4 receptor, and then a secondary co-receptor, usually CCR5 (R5) or CXCR4 (X4), and some HIV can utilize both co-receptors (R5X4). Although a small set of amino-acid properties such as charge and sequence length applied to HIV-1 envelope V3 loop sequence data can be used to predict co-receptor usage, we sought to expand the fundamental understanding of the physiochemical basis of tropism by analyzing many, perhaps less obvious, amino-acid properties over a diverse array of HIV sequences. We examined 74 amino-acid physicochemical scales over 1,559 V3 loop sequences with biologically tested tropisms downloaded from the Los Alamos HIV sequence database. Linear regressions were then calculated for each feature relative to three tropism transitions (R5→X4; R5→R5X4; R5X4→X4). Independent correlations were rank ordered to determine informative features. A structural analysis of the V3 loop was performed to better interpret these findings relative to HIV tropism states. Similar structural changes are required for R5 and R5X4 to transition to X4, thus suggesting that R5 and R5X4 types are more similar than either phenotype is to X4. Overall, the analysis suggests a continuum of viral tropism that is only partially related to charge; in fact, the analysis suggests that charge modification may be primarily attributed to decreased R5 usage, and further structural changes, particularly those associated with β-sheet structure, are likely required for full X4 usage.
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http://dx.doi.org/10.1089/AID.2015.0373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971420PMC
August 2016

Identification of dual-tropic HIV-1 using evolved neural networks.

Biosystems 2015 Nov 28;137:12-9. Epub 2015 Sep 28.

University of California at San Francisco, Department of Laboratory Medicine and The AIDS and Cancer Specimen Resource, San Francisco, CA 94143, United States.

Blocking the binding of the envelope HIV-1 protein to immune cells is a popular concept for development of anti-HIV therapeutics. R5 HIV-1 binds CCR5, X4 HIV-1 binds CXCR4, and dual-tropic HIV-1 can bind either coreceptor for cellular entry. R5 viruses are associated with early infection and over time can evolve to X4 viruses that are associated with immune failure. Dual-tropic HIV-1 is less studied; however, it represents functional antigenic intermediates during the transition of R5 to X4 viruses. Viral tropism is linked partly to the HIV-1 envelope V3 domain, where the amino acid sequence helps dictate the receptor a particular virus will target; however, using V3 sequence information to identify dual-tropic HIV-1 isolates has remained difficult. Our goal in this study was to elucidate features of dual-tropic HIV-1 isolates that assist in the biological understanding of dual-tropism and develop an approach for their detection. Over 1559 HIV-1 subtype B sequences with known tropisms were analyzed. Each sequence was represented by 73 structural, biochemical and regional features. These features were provided to an evolved neural network classifier and evaluated using balanced and unbalanced data sets. The study resolved R5X4 viruses from R5 with an accuracy of 81.8% and from X4 with an accuracy of 78.8%. The approach also identified a set of V3 features (hydrophobicity, structural and polarity) that are associated with tropism transitions. The ability to distinguish R5X4 isolates will improve computational tropism decisions for R5 vs. X4 and assist in HIV-1 research and drug development efforts.
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http://dx.doi.org/10.1016/j.biosystems.2015.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921197PMC
November 2015

MicroRNA dynamics during human embryonic stem cell differentiation to pancreatic endoderm.

Gene 2015 Dec 20;574(2):359-70. Epub 2015 Aug 20.

Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92121 USA. Electronic address:

MicroRNAs (miRNAs) are small non-coding RNAs that have emerged as critical regulators of human embryonic stem cell (hESC) pluripotency and differentiation. Despite the wealth of information about the role individual that miRNAs play in these two processes, there has yet to be a large-scale temporal analysis of the dynamics of miRNA expression as hESCs move from pluripotency into defined lineages. In this report, we used Next Generation Sequencing (NGS) to map temporal expression of miRNAs over ten 24-hour intervals as pluripotent cells were differentiated into pancreatic endoderm. Of the 2042 known human miRNAs, 694 had non-zero expression on all 11 days. Of these 694 miRNAs, 494 showed statistically significant changes in expression during differentiation. Clusters of miRNAs were identified, each displaying unique expression profiles distributed over multiple days. Selected miRNAs associated with pluripotency/differentiation (miR-302/367 and miR-371/372/373) and development/growth (miR-21, miR-25, miR-103, miR-9, and miR-92a) were found to have distinct expression profiles correlated with changes in media used to drive the differentiation process. Taken together, the clustering of miRNAs to identify expression dynamics that occur over longer periods of time (days vs. hours) provides unique insight into specific stages of differentiation. Major shifts in defined stages of hESC differentiation appear to be heavily dependent upon changes in external environmental factors, rather than intrinsic conditions in the cells.
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http://dx.doi.org/10.1016/j.gene.2015.08.027DOI Listing
December 2015

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques.

J Virol 2015 Aug 3;89(16):8484-96. Epub 2015 Jun 3.

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA

Unlabelled: While a clear understanding of the events leading to successful establishment of host-specific viral populations and productive infection in the central nervous system (CNS) has not yet been reached, the simian immunodeficiency virus (SIV)-infected rhesus macaque provides a powerful model for the study of human immunodeficiency virus (HIV) intrahost evolution and neuropathogenesis. The evolution of the gp120 and nef genes, which encode two key proteins required for the establishment and maintenance of infection, was assessed in macaques that were intravenously inoculated with the same viral swarm and allowed to naturally progress to simian AIDS and potential SIV-associated encephalitis (SIVE). Longitudinal plasma samples and immune markers were monitored until terminal illness. Single-genome sequencing was employed to amplify full-length env through nef transcripts from plasma over time and from brain tissues at necropsy. nef sequences diverged from the founder virus faster than gp120 diverged. Host-specific sequence populations were detected in nef (~92 days) before they were detected in gp120 (~182 days). At necropsy, similar brain nef sequences were found in different macaques, indicating convergent evolution, while gp120 brain sequences remained largely host specific. Molecular clock and selection analyses showed weaker clock-like behavior and stronger selection pressure in nef than in gp120, with the strongest nef selection in the macaque with SIVE. Rapid nef diversification, occurring prior to gp120 diversification, indicates that early adaptation of nef in the new host is essential for successful infection. Moreover, the convergent evolution of nef sequences in the CNS suggests a significant role for nef in establishing neurotropic strains.

Importance: The SIV-infected rhesus macaque model closely resembles HIV-1 immunopathogenesis, neuropathogenesis, and disease progression in humans. Macaques were intravenously infected with identical viral swarms to investigate evolutionary patterns in the gp120 and nef genes leading to the emergence of host-specific viral populations and potentially linked to disease progression. Although each macaque exhibited unique immune profiles, macaque-specific nef sequences evolving under selection were consistently detected in plasma samples at 3 months postinfection, significantly earlier than in gp120 macaque-specific sequences. On the other hand, nef sequences in brain tissues, collected at necropsy of two animals with detectable infection in the central nervous system (CNS), revealed convergent evolution. The results not only indicate that early adaptation of nef in the new host may be essential for successful infection, but also suggest that specific nef variants may be required for SIV to efficiently invade CNS macrophages and/or enhance macrophage migration, resulting in HIV neuropathology.
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http://dx.doi.org/10.1128/JVI.01010-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524235PMC
August 2015

Factors related to HIV-associated neurocognitive impairment differ with age.

J Neurovirol 2015 Feb 18;21(1):56-65. Epub 2014 Nov 18.

Natural Selection, Inc., San Diego, CA, 92121, USA.

Over 50% of HIV-infected (HIV+) persons are expected to be over age 50 by 2015. The pathogenic effects of HIV, particularly in cases of long-term infection, may intersect with those of age-related illnesses and prolonged exposure to combined antiretroviral therapy (cART). One potential outcome is an increased prevalence of neurocognitive impairment in older HIV+ individuals, as well as an altered presentation of HIV-associated neurocognitive disorders (HANDs). In this study, we employed stepwise regression to examine 24 features sometimes associated with HAND in 40 older (55-73 years of age) and 30 younger (32-50 years of age) HIV+, cART-treated participants without significant central nervous system confounds. The features most effective in generating a true assessment of the likelihood of HAND diagnosis differed between older and younger cohorts, with the younger cohort containing features associated with drug abuse that were correlated to HAND and the older cohort containing features that were associated with lipid disorders mildly associated with HAND. As the HIV-infected population grows and the demographics of the epidemic change, it is increasingly important to re-evaluate features associated with neurocognitive impairment. Here, we have identified features, routinely collected in primary care settings, that provide more accurate diagnostic value than a neurocognitive screening measure among younger and older HIV individuals.
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http://dx.doi.org/10.1007/s13365-014-0296-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320020PMC
February 2015

sRNA-seq analysis of human embryonic stem cells and definitive endoderm reveals differentially expressed microRNAs and novel IsomiRs with distinct targets.

Stem Cells 2014 Sep;32(9):2360-72

Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, California, USA.

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.
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http://dx.doi.org/10.1002/stem.1739DOI Listing
September 2014

HIV-associated neuropathogenesis: a systems biology perspective for modeling and therapy.

Biosystems 2014 May 13;119:53-61. Epub 2014 Apr 13.

University of Florida, 2055 Mowry Road, Department of Pathology and Laboratory Medicine, Gainesville, FL 32610, USA. Electronic address:

Despite the development of powerful antiretroviral drugs, HIV-1 associated neurological disorders (HAND) will affect approximately half of those infected with HIV-1. Combined anti-retroviral therapy (cART) targets viral replication and increases T-cell counts, but it does not always control macrophage polarization, brain infection or inflammation. Moreover, it remains difficult to identify those at risk for HAND. New therapies that focus on modulating host immune response by making use of biological pathways could prove to be more effective than cART for the treatment of neuroAIDS. Additionally, while numerous HAND biomarkers have been suggested, they are of little use without methods for appropriate data integration and a systems-level interpretation. Machine learning, could be used to develop multifactorial computational models that provide clinicians and researchers with the ability to identify which factors (in what combination and relative importance) are considered important to outcome.
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http://dx.doi.org/10.1016/j.biosystems.2014.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112533PMC
May 2014

Dynamical and topological robustness of the mammalian cell cycle network: a reverse engineering approach.

Biosystems 2014 Jan 6;115:23-32. Epub 2013 Nov 6.

Natural Selection, Inc., 5910 Pacific Center Boulevard, Suite 315, San Diego, CA 92121, USA.

A common gene regulatory network model is the threshold Boolean network, used for example to model the Arabidopsis thaliana floral morphogenesis network or the fission yeast cell cycle network. In this paper, we analyze a logical model of the mammalian cell cycle network and its threshold Boolean network equivalent. Firstly, the robustness of the network was explored with respect to update perturbations, in particular, what happened to the attractors for all the deterministic updating schemes. Results on the number of different limit cycles, limit cycle lengths, basin of attraction size, for all the deterministic updating schemes were obtained through mathematical and computational tools. Secondly, we analyzed the topology robustness of the network, by reconstructing synthetic networks that contained exactly the same attractors as the original model by means of a swarm intelligence approach. Our results indicate that networks may not be very robust given the great variety of limit cycles that a network can obtain depending on the updating scheme. In addition, we identified an omnipresent network with interactions that match with the original model as well as the discovery of new interactions. The techniques presented in this paper are general, and can be used to analyze other logical or threshold Boolean network models of gene regulatory networks.
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http://dx.doi.org/10.1016/j.biosystems.2013.10.007DOI Listing
January 2014

Longitudinal analysis of intra-host simian immunodeficiency virus recombination in varied tissues of the rhesus macaque model for neuroAIDS.

J Gen Virol 2013 Nov 20;94(Pt 11):2469-2479. Epub 2013 Aug 20.

Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.

Human immunodeficiency virus intra-host recombination has never been studied in vivo both during early infection and throughout disease progression. The CD8-depleted rhesus macaque model of neuroAIDS was used to investigate the impact of recombination from early infection up to the onset of neuropathology in animals inoculated with a simian immunodeficiency virus (SIV) swarm. Several lymphoid and non-lymphoid tissues were collected longitudinally at 21 days post-infection (p.i.), 61 days p.i. and necropsy (75-118 days p.i.) from four macaques that developed SIV-encephalitis or meningitis, as well as from two animals euthanized at 21 days p.i. The number of recombinant sequences and breakpoints in different tissues and over time from each primate were compared. Breakpoint locations were mapped onto predicted RNA and protein secondary structures. Recombinants were found at each time point and in each primate as early as 21 days p.i. No association was found between recombination rates and specific tissue of origin. Several identical breakpoints were identified in sequences derived from different tissues in the same primate and among different primates. Breakpoints predominantly mapped to unpaired nucleotides or pseudoknots in RNA secondary structures, and proximal to glycosylation sites and cysteine residues in protein sequences, suggesting selective advantage in the emergence of specific recombinant sequences. Results indicate that recombinant sequences can become fixed very early after infection with a heterogeneous viral swarm. Features of RNA and protein secondary structure appear to play a role in driving the production of recombinants and their selection in the rapid disease model of neuroAIDS.
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http://dx.doi.org/10.1099/vir.0.055335-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809109PMC
November 2013

HIV-1 Nef in macrophage-mediated disease pathogenesis.

Int Rev Immunol 2012 Dec;31(6):432-50

BioInfoExperts, Thibodaux, LA, USA.

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 Nef-macrophage interaction and how this relationship contributes to disease pathogenesis.
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http://dx.doi.org/10.3109/08830185.2012.737073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544535PMC
December 2012

Modeling the evolution of drug resistance in malaria.

J Comput Aided Mol Des 2012 Dec 21;26(12):1343-53. Epub 2012 Nov 21.

Southwestern College, Chula Vista, CA 91910, USA.

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.
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http://dx.doi.org/10.1007/s10822-012-9618-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535480PMC
December 2012

From pluripotency to islets: miRNAs as critical regulators of human cellular differentiation.

Adv Genet 2012 ;79:1-34

Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA.

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.
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http://dx.doi.org/10.1016/B978-0-12-394395-8.00001-3DOI Listing
December 2012

Lynn Margulis (1938-2011).

Biosystems 2012 Feb 20;107(2):65. Epub 2011 Dec 20.

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http://dx.doi.org/10.1016/j.biosystems.2011.12.003DOI Listing
February 2012

Features associated with survival in metastatic melanoma patients treated with patient-specific dendritic cell vaccines.

Cancer Biother Radiopharm 2011 Aug 3;26(4):407-15. Epub 2011 Aug 3.

Hoag Cancer Institute; One Hoag Drive, Newport Beach, CA 92658, USA.

Previously, a 54% 5-year survival was reported for metastatic melanoma patients treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from autologous proliferating tumor cells. This study attempted to determine which clinical and laboratory factors best explained long-term survival in this group of patients. Univariate analyses were used to identify factors associated with continuous survival after initiating vaccine therapy. Multivariate logistic regression was used to identify independent factors to classify survival at 3.5 years. Survivors were followed a minimum of 3.7 years (median: 5.7). Univariate analyses identified eight features associated with improved survival: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, no measurable disease at study entry, receiving 8 vaccinations, age <50 years, normal baseline lactate dehydrogenase, no history of visceral metastases, anergy to standard skin tests, and failure of interferon-gamma (IFN-γ) to induce apoptosis in autologous tumor cells. After examining 54 variables for which complete information was available over all patients, the best multivariate regression for survival at 3.5 years utilized six features: prior radiation therapy, younger age, male gender, ECOG PS 0, higher numbers of cells administered during the first 3 injections, and lower numbers of viable cells administered during the first 3 injections. This model correctly classified survival for 28 of 32 patients (87%) and death for 20 of 22 (91%). When features with incomplete information were included in the analysis, addition of IFN-γ-induced apoptosis (n=49) improved predictive accuracy to 27 of 29 (93%) for survival and 19 of 20 (95%) for death. Dependencies between variables were common, but these multivariate linear models yielded high classification accuracy for survival at 3.5 years and identified two features of the vaccine itself as being of independent significance.
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http://dx.doi.org/10.1089/cbr.2011.0973DOI Listing
August 2011

Structural-based analysis of dihydrofolate reductase evolution.

Mol Phylogenet Evol 2011 Oct 17;61(1):212-30. Epub 2011 Jun 17.

Southwestern College, 900 Otay Lakes Rd., Chula Vista, CA 91910, USA.

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.
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http://dx.doi.org/10.1016/j.ympev.2011.06.005DOI Listing
October 2011

Simulating natural selection as a culling mechanism on finite populations with the hawk-dove game.

Biosystems 2011 Apr 8;104(1):57-62. Epub 2011 Jan 8.

Natural Selection Inc., 9330 Scranton Rd., San Diego, CA 92121, USA.

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.
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http://dx.doi.org/10.1016/j.biosystems.2011.01.002DOI Listing
April 2011

HIV-1 nef protein visits B-cells via macrophage nanotubes: a mechanism for AIDS-related lymphoma pathogenesis?

Curr HIV Res 2010 Dec;8(8):638-40

Polytechnic Institute of New York University, Brooklyn, NY, USA.

This letter refers to the recent demonstration that HIV-1 infected macrophages form specialized conduits that connect to B-cells (1). The conduit selectively transports the HIV-1 nef protein, providing nef with numerous means to interfere with cellular processes. Currently, no consideration of the connection between the conduit and the development of AIDS-related lymphoma (ARL) has been offered. ARL is one of the primary causes of death in the HIV-infected population and is related to B-cell proliferation and activation. In this letter we discuss several studies that link HIV-infected macrophages and specific forms of the nef protein to the development of ARL. The conduits discovered by Xu et al. may lead to a better understanding of how HIV infection results in lymphomagenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471533PMC
http://dx.doi.org/10.2174/157016210794088209DOI Listing
December 2010

HIV-miR-H1 evolvability during HIV pathogenesis.

Biosystems 2010 Aug 31;101(2):88-96. Epub 2010 May 31.

BioInfoExperts, Thibodaux, LA 70302, USA.

The discovery of microRNAs (miRNAs) in viruses has generated considerable attention into their functional relevance in processes such as cell death, viral proliferation, and oncogenesis. Two early studies found no detectable miRNAs expressed within HIV; however, several studies have verified the existence and function of three HIV miRNAs, most notably HIV-miR-TAR, thus making the earlier results controversial. Although miRNAs are highly conserved within most species, HIV is known to have a high mutation rate, which could contribute to the opposing experimental findings and raises questions about whether all HIV miRNAs are robust enough to maintain their integrity, especially in viral regions prone to insertions and deletions. In addition, could the evolvability of HIV miRNAs contribute to the diversity in HIV disease pathogenesis? To address this question, we examined mutations in 1293 sequences in a suspect HIV miRNA, called miR-H1, derived from a large variety of tissues from seven patients. We found considerable diversity within the structures, including a patient-specific deletion and the potential for the development of new miRNAs as a result of deletions. We also note a potential disease association between a less stable miR-H1 and the development of AIDS-related lymphoma (ARL).
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http://dx.doi.org/10.1016/j.biosystems.2010.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478900PMC
August 2010

An approach for classification of highly imbalanced data using weighting and undersampling.

Amino Acids 2010 Nov 22;39(5):1385-91. Epub 2010 Apr 22.

School of Electrical and Electronic Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore, 639798, Singapore.

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.
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http://dx.doi.org/10.1007/s00726-010-0595-2DOI Listing
November 2010

Di-codon usage for classification of genes.

Biosystems 2009 Oct 3;98(1):1-6. Epub 2009 Jul 3.

BioInfomatics Institute, Singapore.

Genes are often classified into biologically related groups so that inferences on their functions can be made. This paper demonstrates that the di-codon usage is a useful feature for gene classification and gives better classification accuracy than the codon usage. Our experiments with different classifiers show that support vector machines performs better than other classifiers in classifying genes by using di-codon usage as features. The method is illustrated on 1841 HLA sequences which are classified into two major classes, HLA-I and HLA-II, and further classified into the subclasses of major classes. By using both codon and di-codon features, we show near perfect accuracies in the classification of HLA molecules into major classes and their sub-classes.
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http://dx.doi.org/10.1016/j.biosystems.2009.06.005DOI Listing
October 2009

A novel in silico approach to drug discovery via computational intelligence.

J Chem Inf Model 2009 Apr;49(4):1105-21

Southwestern College, 900 Otay Lakes Road, Chula Vista, California 91910, USA.

A computational intelligence drug discovery platform is introduced as an innovative technology designed to accelerate high-throughput drug screening for generalized protein-targeted drug discovery. This technology results in collections of novel small molecule compounds that bind to protein targets as well as details on predicted binding modes and molecular interactions. The approach was tested on dihydrofolate reductase (DHFR) for novel antimalarial drug discovery; however, the methods developed can be applied broadly in early stage drug discovery and development. For this purpose, an initial fragment library was defined, and an automated fragment assembly algorithm was generated. These were combined with a computational intelligence screening tool for prescreening of compounds relative to DHFR inhibition. The entire method was assayed relative to spaces of known DHFR inhibitors and with chemical feasibility in mind, leading to experimental validation in future studies.
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http://dx.doi.org/10.1021/ci9000647DOI Listing
April 2009

Extensive HIV-1 intra-host recombination is common in tissues with abnormal histopathology.

PLoS One 2009 31;4(3):e5065. Epub 2009 Mar 31.

BioInfoExperts, Thibodaux, LA, USA.

There is evidence that immune-activated macrophages infected with the Human Immunodeficiency Virus (HIV) are associated with tissue damage and serve as a long-lived viral reservoir during therapy. In this study, we analyzed 780 HIV genetic sequences generated from 53 tissues displaying normal and abnormal histopathology. We found up to 50% of the sequences from abnormal lymphoid and macrophage rich non-lymphoid tissues were intra-host viral recombinants. The presence of extensive recombination, especially in non-lymphoid tissues, implies that HIV-1 infected macrophages may significantly contribute to the generation of elusive viral genotypes in vivo. Because recombination has been implicated in immune evasion, the acquisition of drug-resistance mutations, and alterations of viral co-receptor usage, any attempt towards the successful eradication of HIV-1 requires therapeutic approaches targeting tissue macrophages.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659430PMC
May 2009

A transition to a new Editor-in-Chief.

Authors:
Gary B Fogel

Biosystems 2009 Feb;95(2):89

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http://dx.doi.org/10.1016/j.biosystems.2008.12.005DOI Listing
February 2009

Evolutionary computation for discovery of composite transcription factor binding sites.

Nucleic Acids Res 2008 Dec 15;36(21):e142. Epub 2008 Oct 15.

Natural Selection, Inc, San Diego, CA 92121, USA.

Previous research demonstrated the use of evolutionary computation for the discovery of transcription factor binding sites (TFBS) in promoter regions upstream of coexpressed genes. However, it remained unclear whether or not composite TFBS elements, commonly found in higher organisms where two or more TFBSs form functional complexes, could also be identified by using this approach. Here, we present an important refinement of our previous algorithm and test the identification of composite elements using NFAT/AP-1 as an example. We demonstrate that by using appropriate existing parameters such as window size, novel-scoring methods such as central bonusing and methods of self-adaptation to automatically adjust the variation operators during the evolutionary search, TFBSs of different sizes and complexity can be identified as top solutions. Some of these solutions have known experimental relationships with NFAT/AP-1. We also indicate that even after properly tuning the model parameters, the choice of the appropriate window size has a significant effect on algorithm performance. We believe that this improved algorithm will greatly augment TFBS discovery.
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http://dx.doi.org/10.1093/nar/gkn738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588514PMC
December 2008