255 results on '"Kennedy RC"'
Search Results
2. Highly evolvable malaria vectors: The genomes of 16 Anopheles mosquitoes
- Author
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Neafsey, DE, Waterhouse, RM, Abai, MR, Aganezov, SS, Alekseyev, MA, Allen, JE, Amon, J, Arcà, B, Arensburger, P, Artemov, G, Assour, LA, Basseri, H, Berlin, A, Birren, BW, Blandin, SA, Brockman, AI, Burkot, TR, Burt, A, Chan, CS, Chauve, C, Chiu, JC, Christensen, M, Costantini, C, Davidson, VLM, Deligianni, E, Dottorini, T, Dritsou, V, Gabriel, SB, Guelbeogo, WM, Hall, AB, Han, MV, Hlaing, T, Hughes, DST, Jenkins, AM, Jiang, X, Jungreis, I, Kakani, EG, Kamali, M, Kemppainen, P, Kennedy, RC, Kirmitzoglou, IK, Koekemoer, LL, Laban, N, Langridge, N, Lawniczak, MKN, Lirakis, M, Lobo, NF, Lowy, E, MacCallum, RM, Mao, C, Maslen, G, Mbogo, C, McCarthy, J, Michel, K, Mitchell, SN, Moore, W, Murphy, KA, Naumenko, AN, Nolan, T, Novoa, EM, O'Loughlin, S, Oringanje, C, Oshaghi, MA, Pakpour, N, Papathanos, PA, Peery, AN, Povelones, M, Prakash, A, Price, DP, Rajaraman, A, Reimer, LJ, Rinker, DC, Rokas, A, Russell, TL, Sagnon, N, Sharakhova, MV, Shea, T, Simão, FA, Simard, F, Slotman, MA, Somboon, P, Stegniy, V, Struchiner, CJ, and Thomas, GWC
- Abstract
© 2015, american association for the advancement of science. All rigths reserved. Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ∼100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.
- Published
- 2015
3. Genomic analysis of two phlebotomine sand fly vectors of Leishmania from the New and Old World.
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Labbé F, Abdeladhim M, Abrudan J, Araki AS, Araujo RN, Arensburger P, Benoit JB, Brazil RP, Bruno RV, Bueno da Silva Rivas G, Carvalho de Abreu V, Charamis J, Coutinho-Abreu IV, da Costa-Latgé SG, Darby A, Dillon VM, Emrich SJ, Fernandez-Medina D, Figueiredo Gontijo N, Flanley CM, Gatherer D, Genta FA, Gesing S, Giraldo-Calderón GI, Gomes B, Aguiar ERGR, Hamilton JGC, Hamarsheh O, Hawksworth M, Hendershot JM, Hickner PV, Imler JL, Ioannidis P, Jennings EC, Kamhawi S, Karageorgiou C, Kennedy RC, Krueger A, Latorre-Estivalis JM, Ligoxygakis P, Meireles-Filho ACA, Minx P, Miranda JC, Montague MJ, Nowling RJ, Oliveira F, Ortigão-Farias J, Pavan MG, Horacio Pereira M, Nobrega Pitaluga A, Proveti Olmo R, Ramalho-Ortigao M, Ribeiro JMC, Rosendale AJ, Sant'Anna MRV, Scherer SE, Secundino NFC, Shoue DA, da Silva Moraes C, Gesto JSM, Souza NA, Syed Z, Tadros S, Teles-de-Freitas R, Telleria EL, Tomlinson C, Traub-Csekö YM, Marques JT, Tu Z, Unger MF, Valenzuela J, Ferreira FV, de Oliveira KPV, Vigoder FM, Vontas J, Wang L, Weedall GD, Zhioua E, Richards S, Warren WC, Waterhouse RM, Dillon RJ, and McDowell MA
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- Animals, Humans, Genomics, Phlebotomus parasitology, Psychodidae parasitology, Leishmania genetics, Leishmaniasis, Cutaneous
- Abstract
Phlebotomine sand flies are of global significance as important vectors of human disease, transmitting bacterial, viral, and protozoan pathogens, including the kinetoplastid parasites of the genus Leishmania, the causative agents of devastating diseases collectively termed leishmaniasis. More than 40 pathogenic Leishmania species are transmitted to humans by approximately 35 sand fly species in 98 countries with hundreds of millions of people at risk around the world. No approved efficacious vaccine exists for leishmaniasis and available therapeutic drugs are either toxic and/or expensive, or the parasites are becoming resistant to the more recently developed drugs. Therefore, sand fly and/or reservoir control are currently the most effective strategies to break transmission. To better understand the biology of sand flies, including the mechanisms involved in their vectorial capacity, insecticide resistance, and population structures we sequenced the genomes of two geographically widespread and important sand fly vector species: Phlebotomus papatasi, a vector of Leishmania parasites that cause cutaneous leishmaniasis, (distributed in Europe, the Middle East and North Africa) and Lutzomyia longipalpis, a vector of Leishmania parasites that cause visceral leishmaniasis (distributed across Central and South America). We categorized and curated genes involved in processes important to their roles as disease vectors, including chemosensation, blood feeding, circadian rhythm, immunity, and detoxification, as well as mobile genetic elements. We also defined gene orthology and observed micro-synteny among the genomes. Finally, we present the genetic diversity and population structure of these species in their respective geographical areas. These genomes will be a foundation on which to base future efforts to prevent vector-borne transmission of Leishmania parasites., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
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- 2023
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4. Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-to-in vivo predictions of hepatic clearance.
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Krishnan P, Smith AK, Ropella GEP, Dutta L, Kennedy RC, and Hunt CA
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- Humans, Kinetics, Metabolic Clearance Rate, Models, Biological, Hepatocytes metabolism, Liver metabolism
- Abstract
Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms. The virtual culture is a software analog of hepatocytes in vitro, and the virtual human maps to hepatocytes within a liver within an idealized model human. Mobile objects (virtual compounds) map to amounts of xenobiotics. Earlier versions of the two systems achieved quantitative validation targets for intrinsic clearance (virtual culture) and hepatic clearance (virtual human). The major difference between the two systems is the spatial organization of the virtual hepatocytes. For each pair of experiments (virtual culture, virtual human), hepatocytes are configured the same. Probabilistic rules govern virtual compound movements and interactions with other objects. We focus on highly permeable virtual compounds and fix their extracellular unbound fraction at one of seven values (0.05-1.0). Hepatocytes contain objects that can bind and remove compounds, analogous to metabolism. We require that, for a subset of compound properties, per-hepatocyte compound exposure and removal rates during culture experiments directly predict corresponding measures made during virtual human experiments. That requirement serves as a cross-system validation target; we identify compound properties that enable achieving it. We then change compound properties, ceteris paribus, and provide model mechanism-based explanations for when and why measures made during culture experiments under- (or over-) predict corresponding measures made during virtual human experiments. The results show that, from the perspective of compound removal, the organization of hepatocytes within virtual livers is more efficient than within cultures, and the greater the efficiency difference, the larger the underprediction. That relationship is noteworthy because most in vitro-to-in vivo extrapolation methods abstract away the structural organization of hepatocytes within a liver. More work is needed on multiple fronts, including the study of an expanded variety of virtual compound properties. Nevertheless, the results support the feasibility of the approach and plan., Competing Interests: The authors declare no competing interests. GEPR’s affiliation with Tempus Dictum Inc. does not alter our adherence to PLOS ONE policies on sharing data and materials.
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- 2022
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5. Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.
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Smith AK, Ropella GEP, McGill MR, Krishnan P, Dutta L, Kennedy RC, Jaeschke H, and Hunt CA
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- Acetaminophen toxicity, Animals, Chemical and Drug Induced Liver Injury, Computational Biology, Computer Simulation, Hepatocytes enzymology, Liver drug effects, Liver enzymology, Mice, Monte Carlo Method, Software, Alanine Transaminase blood, Biomarkers blood, Hepatocytes drug effects, Necrosis
- Abstract
Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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6. Dichotomous Role of Plasmin in Regulation of Macrophage Function after Acetaminophen Overdose.
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Roth K, Strickland J, Joshi N, Deng M, Kennedy RC, Rockwell CE, Luyendyk JP, Billiar TR, and Copple BL
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- Animals, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury metabolism, Drug Overdose, Inflammation Mediators metabolism, Kupffer Cells drug effects, Kupffer Cells metabolism, Macrophages drug effects, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Necrosis, Acetaminophen toxicity, Analgesics, Non-Narcotic toxicity, Chemical and Drug Induced Liver Injury pathology, Fibrinolysin metabolism, Kupffer Cells pathology, Macrophages pathology
- Abstract
Kupffer cells and monocyte-derived macrophages are critical for liver repair after acetaminophen (APAP) overdose. These cells produce promitogenic cytokines and growth factors, and they phagocytose dead cell debris, a process that is critical for resolution of inflammation. The factors that regulate these dynamic functions of macrophages after APAP overdose, however, are not fully understood. We tested the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function after APAP-induced liver injury. In these studies, inhibition of plasmin in mice with tranexamic acid delayed up-regulation of proinflammatory cytokines after APAP overdose. In culture, plasmin directly, and in synergy with high-mobility group B1, stimulated Kupffer cells and bone marrow-derived macrophages to produce cytokines by a mechanism that required NF-κB. Inhibition of plasmin in vivo also prevented trafficking of monocyte-derived macrophages into necrotic lesions after APAP overdose. This prevented phagocytic removal of dead cells, prevented maturation of monocyte-derived macrophages into F4/80-expressing macrophages, and prevented termination of proinflammatory cytokine production. Our studies reveal further that phagocytosis is an important stimulus for cessation of proinflammatory cytokine production as treatment of proinflammatory, monocyte-derived macrophages, isolated from APAP-treated mice, with necrotic hepatocytes decreased expression of proinflammatory cytokines. Collectively, these studies demonstrate that plasmin is an important regulator of macrophage function after APAP overdose., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2019
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7. Correction to: Management of industrial high-pressure fluid injection injuries (IHPFII): the Water Jetting Association (WJA) experience with water driven injuries.
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Rodríguez-Villar S, Kennedy RC, Dall'Antonia M, and Menichetti CP
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The original article can be found online.
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- 2019
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8. Management of industrial high-pressure fluid injection injuries (IHPFII): the Water Jetting Association (WJA) experience with water driven injuries.
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Rodríguez-Villar S, Kennedy RC, Dall'Antonia M, and Menichetti CP
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- Acute Kidney Injury etiology, Acute Kidney Injury therapy, Amputation, Surgical, Brain Injuries, Traumatic etiology, Brain Injuries, Traumatic mortality, Compartment Syndromes etiology, Compartment Syndromes therapy, Edema etiology, Exsanguination etiology, Exsanguination mortality, Humans, Occupational Injuries etiology, Occupational Injuries mortality, Rhabdomyolysis etiology, Rhabdomyolysis therapy, Soft Tissue Injuries etiology, Subcutaneous Emphysema diagnostic imaging, Subcutaneous Emphysema etiology, Wound Infection etiology, Brain Injuries, Traumatic therapy, Exsanguination therapy, Hydrostatic Pressure adverse effects, Occupational Injuries therapy, Soft Tissue Injuries therapy, Wound Infection therapy
- Abstract
Background: Industrial high-pressure fluid injection injuries (IHPFII) are largely occupational in nature, where these injuries are most often sustained by male manual workers. Such traumatic injuries are largely sustained with water, grease, paint, gasoline or paint thinner. IHPFII are extremely serious injuries with life and limb-threatening potential carrying the risk of life-long disability., Methods: We reviewed the Water Jetting Association© adverse incident database of advisory alerts detailing cases from around the world that have been brought to the association's attention and the English-language literature on high-pressure hydrostatic injuries from 1937 to 2018., Results: Accidents involving high-pressure water jets in the industry are uncommon. The clinical impact in all of the cases reviewed and the effects of water jet impacts range from instant fatalities at scene to loss of limb function and amputation. The majority of observed fatalities are due to major hemorrhage (exsanguination) secondary to the direct dissection of great vessels or high-energy blunt soft tissue injury and traumatic brain injury., Conclusions: As with any other trauma, IHPWJI commonly result in amputation or death. Nonetheless, a lack of comprehension of the potential severity of injuries and range of infective complications appears to be largely due to the apparent benignity of the initial presentation of the wound. This in turn leads to delays (both avoidable and unavoidable) in the transfer to appropriate medical facilities and definitive care. There is an identifiable need for education (including for health care providers across multiple levels), training and the availability of personal trauma kits for the timely and effective management of IHPWJI from the initial jet impact on the scene, as well as a need for an established referral system.
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- 2019
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9. Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.
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Kennedy RC, Smith AK, Ropella GEP, McGill MR, Jaeschke H, and Hunt CA
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- Acetaminophen metabolism, Activation, Metabolic, Analgesics, Non-Narcotic metabolism, Animals, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Computer Simulation, Glutathione metabolism, Hepatocytes metabolism, Hepatocytes pathology, Male, Mice, Inbred C57BL, Necrosis, Signal Transduction, Time Factors, Acetaminophen toxicity, Analgesics, Non-Narcotic toxicity, Cell Communication drug effects, Chemical and Drug Induced Liver Injury etiology, Hepatocytes drug effects, Models, Biological, Systems Biology
- Abstract
Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology.)
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- 2019
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10. Chronic low-level cadmium exposure in rats affects cytokine production by activated T cells.
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Turley AE, Zagorski JW, Kennedy RC, Freeborn RA, Bursley JK, Edwards JR, and Rockwell CE
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Cadmium is a toxic metal and common environmental contaminant. Chronic cadmium exposure results in kidney, bone, reproductive, and immune toxicity as well as cancer. Cadmium induces splenomegaly and affects the adaptive immune system, but specific effects vary depending on the dose, model, and endpoint. This study investigates the effects of subchronic, oral, and low-dose cadmium exposure (32 ppm cadmium chloride in drinking water for 10 weeks) on the rat immune system, focusing on T cell function. Cadmium-exposed animals demonstrated slight increases in the spleen-to-body weight ratios, and decreases in overall splenic cell numbers and markers of oxidative stress. The relative ratios of splenic cell populations remained similar, except for modest increases in regulatory T cells in the cadmium-exposed animals. Cadmium exposure also significantly increased the production of IFNγ, a pro-inflammatory cytokine, and IL-10, a cytokine produced by multiple T cell subsets that typically inhibits IFNγ expression, by activated T cells. The increase in IFNγ and IL-10 suggests that cadmium exposure may affect multiple T cell subsets. Collectively, this study suggests that subchronic, low-dose cadmium exposure impacts both immune cell function and cellularity, and may enhance inflammatory responses.
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- 2019
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11. The Nrf2 activator tBHQ inhibits the activation of primary murine natural killer cells.
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Boss AP, Freeborn RA, Duriancik DM, Kennedy RC, Gardner EM, and Rockwell CE
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- Animals, Antioxidants pharmacology, Cells, Cultured, Female, Gene Expression Regulation drug effects, Granzymes genetics, Granzymes metabolism, Ionomycin pharmacology, Killer Cells, Natural physiology, Mice, Mice, Inbred C57BL, NF-E2-Related Factor 2 genetics, Perforin genetics, Perforin metabolism, Spleen cytology, Spleen drug effects, Hydroquinones pharmacology, Killer Cells, Natural drug effects, Lymphocyte Activation drug effects, NF-E2-Related Factor 2 metabolism
- Abstract
Tert-butylhydroquinone (tBHQ) is a commonly used food preservative with known immunomodulatory activity; however, there is little information regarding its role on natural killer (NK) cell activation and function. tBHQ is a known activator of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which results in induction of cytoprotective genes. Activation of Nrf2 has been shown to modulate immune responses in a number of different models. In addition, studies in our laboratory have shown that tBHQ inhibits numerous early events following T cell activation. In the current study, we investigated whether activated NK cells are impacted by tBHQ, since many signaling cascades that control NK cell effector function also contribute to T cell function. Splenocytes were isolated from female, wild-type C57Bl/6J mice and treated with 1 μM or 5 μM tBHQ. NK cell function was assessed after activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin for 24 h. Activation of NK cells in the presence of tBHQ decreased total NK cell percentage, production of intracellular interferon gamma (IFNɣ), granzyme B, and perforin, and induction of the cell surface proteins CD25 and CD69, which are markers of NK cell activation. In addition to NK cell effector function, NK cell maturation was also altered in response to tBHQ. Notably, this is the first study to demonstrate that the Nrf2 activator, tBHQ, negatively impacts effector function and maturation of NK cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
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- 2018
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12. Temporal dynamics of gut microbiota in triclocarban-exposed weaned rats.
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Kennedy RC, Fling RR, Robeson MS, Saxton AM, Schneider LG, Darcy JL, Bemis DA, Zhao L, and Chen J
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- Animals, Feces microbiology, Female, Lactation, Rats, Rats, Sprague-Dawley, Weaning, Anti-Infective Agents toxicity, Carbanilides toxicity, Gastrointestinal Microbiome drug effects, Water Pollutants, Chemical toxicity
- Abstract
Widely used as an antimicrobial in antibacterial bar soaps, triclocarban (3,4,4'-trichlorocarbanilide; TCC) is effective against Gram-positive bacteria but shows little efficacy against Gram-negative strains, potentially altering the composition of indigenous microflora within and on the human body. To date, the consequence of continuous or previous nonprescription antimicrobial exposure from compounds in personal care products on commensal microflora is still elusive. Previous research has shown that TCC exposure during gestation and lactation induced dysbiosis of gut microbial communities among exposed dams and neonates. However, the impact of antimicrobial exposure specifically after discontinuation of the use of TCC on the gut microbiota has not been investigated. In this study, weaned Sprague Dawley rats (postnatal day, PND 22) were provided ad lib access to TCC-supplemented diet (0.2% w/w or 0.5% w/w) for 4 weeks (phase I) followed by a 4-week washout period (phase II) to determine gut microflora changes both during continuous exposure to TCC and to determine the potential rebound following TCC withdrawal. Fecal samples were collected at baseline (PND 22) prior to TCC exposure and throughout phase I and phase II. The V4 region of 16S rDNA was sequenced from extracted total fecal DNA with the MiSeq platform. Exposure to both 0.2% w/w and 0.5% w/w TCC was sufficient to alter diversity of microbiota during phase I of treatment. This effect was further prolonged into phase II, even when TCC exposure was discontinued. Collectively, these data highlight the impact of both continuous and prior TCC exposure on gut microbial ecology and shed light onto the potential long-term health risk of daily nonprescription antimicrobial personal care product use.
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- 2018
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13. Simulation enabled search for explanatory mechanisms of the fracture healing process.
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Kennedy RC, Marmor M, Marcucio R, and Hunt CA
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- Animals, Biomechanical Phenomena, Computer Simulation, Humans, Mice, Models, Biological, Monte Carlo Method, Software, Tibia pathology, Biomimetics, Bony Callus pathology, Fracture Healing, Fractures, Bone pathology
- Abstract
A significant portion of bone fractures fail to heal properly, increasing healthcare costs. Advances in fracture management have slowed because translation barriers have limited generation of mechanism-based explanations for the healing process. When uncertainties are numerous, analogical modeling can be an effective strategy for developing plausible explanations of complex phenomena. We demonstrate the feasibility of engineering analogical models in software to facilitate discovery of biomimetic explanations for how fracture healing may progress. Concrete analogical models-Callus Analogs-were created using the MASON simulation toolkit. We designated a Target Region initial state within a characteristic tissue section of mouse tibia fracture at day-7 and posited a corresponding day-10 Target Region final state. The goal was to discover a coarse-grain analog mechanism that would enable the discretized initial state to transform itself into the corresponding Target Region final state, thereby providing an alternative way to study the healing process. One of nine quasi-autonomous Tissue Unit types is assigned to each grid space, which maps to an 80×80 μm region of the tissue section. All Tissue Units have an opportunity each time step to act based on individualized logic, probabilities, and information about adjacent neighbors. Action causes transition from one Tissue Unit type to another, and simulation through several thousand time steps generates a coarse-grain analog-a theory-of the healing process. We prespecified a minimum measure of success: simulated and actual Target Region states achieve ≥ 70% Similarity. We used an iterative refinement protocol to explore many combinations of Tissue Unit logic and action constraints. Workflows progressed through four stages of analog mechanisms. Similarities of 73-90% were achieved for Mechanisms 2-4. The range of Upper-Level similarities increased to 83-94% when we allowed for uncertainty about two Tissue Unit designations. We have demonstrated how Callus Analog experiments provide domain experts with a fresh medium and tools for thinking about and understanding the fracture healing process.
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- 2018
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14. Inhibition of early T cell cytokine production by arsenic trioxide occurs independently of Nrf2.
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VanDenBerg KR, Freeborn RA, Liu S, Kennedy RC, Zagorski JW, and Rockwell CE
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- Animals, Antigens, CD metabolism, Arsenic Trioxide, Arsenicals, Mice, Mice, Inbred C57BL, Spleen cytology, Spleen metabolism, T-Lymphocytes metabolism, Cytokines biosynthesis, NF-E2-Related Factor 2 metabolism, Oxides toxicity, T-Lymphocytes drug effects
- Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a stress-activated transcription factor that induces a variety of cytoprotective genes. Nrf2 also mediates immunosuppressive effects in multiple inflammatory models. Upon activation, Nrf2 dissociates from its repressor protein, Keap1, and translocates to the nucleus where it induces Nrf2 target genes. The Nrf2-Keap1 interaction is disrupted by the environmental toxicant and chemotherapeutic agent arsenic trioxide (ATO). The purpose of the present study was to determine the effects of ATO on early events of T cell activation and the role of Nrf2 in those effects. The Nrf2 target genes Hmox-1, Nqo-1, and Gclc were all upregulated by ATO (1-2 μM) in splenocytes derived from wild-type, but not Nrf2-null, mice, suggesting that Nrf2 is activated by ATO in splenocytes. ATO also inhibited IFNγ, IL-2, and GM-CSF mRNA and protein production in wild-type splenocytes activated with the T cell activator, anti-CD3/anti-CD28. However, ATO also decreased production of these cytokines in activated splenocytes from Nrf2-null mice, suggesting the inhibition is independent of Nrf2. Interestingly, ATO inhibited TNFα protein secretion, but not mRNA expression, in activated splenocytes suggesting the inhibition is due to post-transcriptional modification. In addition, c-Fos DNA binding was significantly diminished by ATO in wild-type and Nrf2-null splenocytes activated with anti-CD3/anti-CD28, consistent with the observed inhibition of cytokine production by ATO. Collectively, this study suggests that although ATO activates Nrf2 in splenocytes, inhibition of early T cell cytokine production by ATO occurs independently of Nrf2 and may instead be due to impaired AP-1 DNA binding.
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- 2017
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15. Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments.
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Smith AK, Petersen BK, Ropella GE, Kennedy RC, Kaplowitz N, Ookhtens M, and Hunt CA
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- Animals, Computational Biology, Computer Simulation, Mice, Acetaminophen toxicity, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Chemical and Drug Induced Liver Injury physiopathology, Liver drug effects, Liver metabolism, Liver pathology, Liver physiopathology, Models, Biological
- Abstract
Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1) influential variables cannot be controlled, and 2) it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1) a glutathione depletion threshold diminishes in the CV direction; and 2) ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose., Competing Interests: The authors have declared that no competing interests exist.
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- 2016
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16. Triclocarban and Health: the Jury Is Still Out.
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Kennedy RC, Terry PD, and Chen J
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- 2016
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17. Differential effects on adiposity and serum marker of bone formation by post-weaning exposure to methylparaben and butylparaben.
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Hu P, Kennedy RC, Chen X, Zhang J, Shen CL, Chen J, and Zhao L
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- Animals, Biomarkers blood, Body Weight drug effects, Bone Remodeling, Feeding Behavior, Female, Male, Mice, Mice, Inbred C57BL, Osteogenesis, Preservatives, Pharmaceutical toxicity, Random Allocation, Weaning, Adiposity drug effects, Collagen Type I blood, Parabens toxicity, Peptide Fragments blood, Peptides blood, Procollagen blood
- Abstract
Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We and others have reported that parabens promote adipogenesis in vitro. Here, we investigated the effects of post-weaning exposure to parabens (methylparaben and butylparaben) on body weight, white adipose tissue mass, and obesity associated metabolic biomarkers in female obesity-prone C57BL/6J mice fed with a chow diet or a high fat diet. Methylparaben exposure by daily oral gavage (100 mg/kg/day) increased adiposity and serum leptin levels compared to the controls when fed the chow diet, but not the high fat diet. In contrast, butylparaben exposure did not induce such effects. Exposure to either paraben induced changes in gene expression related to adipocyte differentiation and lipogenesis in the white adipose tissue (WAT) and the liver, regardless of diet. Moreover, exposure to both parabens under the chow diet significantly decreased serum procollagen type 1 N-terminal propeptide (P1NP) but had no effects on C-terminal telopeptide of type I collagen (CTX-I) levels, suggesting that post-weaning exposure to paraben may negatively affect bone formation, but not bone resorption. Taken together, our results demonstrate that post-weaning exposure to paraben, methylparaben in particular, promotes adipogenesis but suppresses serum marker of bone formation in vivo. Our results add to the growing body of literature indicating potential negative health outcomes associated with paraben exposure. Further study of early life exposure to paraben on the development of fat and bone is warranted.
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- 2016
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18. Temporal Development of Gut Microbiota in Triclocarban Exposed Pregnant and Neonatal Rats.
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Kennedy RC, Fling RR, Robeson MS, Saxton AM, Donnell RL, Darcy JL, Bemis DA, Liu J, Zhao L, and Chen J
- Subjects
- Animals, Animals, Newborn, Biodiversity, Feces microbiology, Female, Gestational Age, Lactation, Pregnancy, Rats, Anti-Infective Agents, Local pharmacology, Carbanilides pharmacology, Gastrointestinal Microbiome, Maternal Exposure, Prenatal Exposure Delayed Effects
- Abstract
Alteration of gut microbial colonization process may influence susceptibility of the newborn/infant to infectious and chronic disease. Infectious disease risk leads to widespread use of non-prescription antimicrobials in household products such as Triclocarban (TCC), an antimicrobial compound in personal care products. TCC concentrates in and is transferred through the milk to suckling offspring. TCC exposure during gestation and lactation significantly reduced phylogenetic diversity (PD) among exposed dams and neonates. Among dams using weighted UniFrac distances, TCC induced significant dysbiosis of gut microbiota by gestational day (GD) 18, a trend that continued after delivery. Similarly, an overall restructuring of gut microbiota occurred in neonates. By postnatal day (PND) 12, communities separated based on exposure status and became significantly different at PND 16. The ability of TCC to drive microbial dysbiosis warrants future investigation to evaluate the safety of non-prescription antimicrobial use, including TCC, during critical exposure windows.
- Published
- 2016
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19. Genomic insights into the Ixodes scapularis tick vector of Lyme disease.
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Gulia-Nuss M, Nuss AB, Meyer JM, Sonenshine DE, Roe RM, Waterhouse RM, Sattelle DB, de la Fuente J, Ribeiro JM, Megy K, Thimmapuram J, Miller JR, Walenz BP, Koren S, Hostetler JB, Thiagarajan M, Joardar VS, Hannick LI, Bidwell S, Hammond MP, Young S, Zeng Q, Abrudan JL, Almeida FC, Ayllón N, Bhide K, Bissinger BW, Bonzon-Kulichenko E, Buckingham SD, Caffrey DR, Caimano MJ, Croset V, Driscoll T, Gilbert D, Gillespie JJ, Giraldo-Calderón GI, Grabowski JM, Jiang D, Khalil SMS, Kim D, Kocan KM, Koči J, Kuhn RJ, Kurtti TJ, Lees K, Lang EG, Kennedy RC, Kwon H, Perera R, Qi Y, Radolf JD, Sakamoto JM, Sánchez-Gracia A, Severo MS, Silverman N, Šimo L, Tojo M, Tornador C, Van Zee JP, Vázquez J, Vieira FG, Villar M, Wespiser AR, Yang Y, Zhu J, Arensburger P, Pietrantonio PV, Barker SC, Shao R, Zdobnov EM, Hauser F, Grimmelikhuijzen CJP, Park Y, Rozas J, Benton R, Pedra JHF, Nelson DR, Unger MF, Tubio JMC, Tu Z, Robertson HM, Shumway M, Sutton G, Wortman JR, Lawson D, Wikel SK, Nene VM, Fraser CM, Collins FH, Birren B, Nelson KE, Caler E, and Hill CA
- Subjects
- Animals, Gene Expression Profiling, Genomics, Lyme Disease transmission, Oocytes, Xenopus laevis, Anaplasma phagocytophilum, Arachnid Vectors genetics, Genome genetics, Ixodes genetics, Ligand-Gated Ion Channels genetics
- Abstract
Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.
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- 2016
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20. A cell-centered, agent-based framework that enables flexible environment granularities.
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Kennedy RC, Ropella GE, and Hunt CA
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- Cell Nucleus metabolism, Computational Biology methods, Computer Graphics, Epithelial Cells metabolism, Humans, Software, Biomimetics methods, Computer Simulation, Models, Biological
- Abstract
Background: Mechanistic explanations of cell-level phenomena typically adopt an observer perspective. Explanations developed from a cell's perspective may offer new insights. Agent-based models lend themselves to model from an individual perspective, and existing agent-based models generally utilize a regular lattice-based environment. A framework which utilizes a cell's perspective in an off-lattice environment could improve the overall understanding of biological phenomena., Results: We present an agent-based, discrete event framework, with a demonstrative focus on biomimetic agents. The framework was first developed in 2-dimensions and then extended, with a subset of behaviors, to 3-dimensions. The framework is expected to facilitate studies of more complex biological phenomena through exploitation of a dynamic Delaunay and Voronoi off-lattice environment. We used the framework to model biological cells and to specifically demonstrate basic biological cell behaviors in two- and three-dimensional space. Potential use cases are highlighted, suggesting the utility of the framework in various scenarios., Conclusions: The framework presented in this manuscript expands on existing cell- and agent-centered methods by offering a new perspective in an off-lattice environment. As the demand for biomimetic models grows, the demand for new methods, such as the presented Delaunay and Voronoi framework, is expected to increase.
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- 2016
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21. Transplacental passage of antimicrobial paraben preservatives.
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Towers CV, Terry PD, Lewis D, Howard B, Chambers W, Armistead C, Weitz B, Porter S, Borman CJ, Kennedy RC, and Chen J
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- Black or African American statistics & numerical data, Female, Humans, Maternal-Fetal Exchange drug effects, Parabens analysis, Pregnancy blood, Preservatives, Pharmaceutical analysis, White People statistics & numerical data, Fetal Blood chemistry, Parabens pharmacokinetics, Placenta metabolism, Preservatives, Pharmaceutical pharmacokinetics
- Abstract
Parabens are widely used preservatives suspected of being endocrine disruptors, with implications for human growth and development. The most common paraben found in consumer products is methylparaben. To date, no study has examined whether these substances cross the human placenta. A total of 100 study subjects (50 mother-child pairs) were enrolled at two medical institutions, serving primarily African-American and Caucasian women, respectively. A maternal blood sample was drawn on admission and a paired cord blood sample was obtained at delivery. Of the 50 mothers, 47 (94%) showed methylparaben in their blood (mean level 20.41 ng/l), and 47 in cords bloods (mean level 36.54 ng/l). There were 45 mother-child pairs where methylparaben was found in both samples. Of these, the fetal level was higher than the maternal level in 23 (51%). For butylparaben, only 4 mothers (8%) showed detectable levels (mean 40.54 ng/l), whereas 8 cord blood samples (16%) were positive (mean 32.5 ng/l). African-American mothers and infants showed higher prevalence of detectable levels (P=0.017). Methylparaben and butylparaben demonstrate transplacental passage. Additional studies are needed to examine potential differences in exposure by geography and demographics, what products are used by pregnant women that contain these preservatives, as well as any potential long-term effects in the growth and development of exposed children.
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- 2015
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22. Extraction of 3,4,4'-Trichlorocarbanilide from Rat Fecal Samples for Determination by High Pressure Liquid Chromatography-Tandem Mass Spectrometry.
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Kennedy RC, Fling RR, Terry PD, Menn FM, Chen J, and Borman CJ
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- Animals, Male, Rats, Rats, Sprague-Dawley, Carbanilides isolation & purification, Chromatography, High Pressure Liquid methods, Feces chemistry, Tandem Mass Spectrometry methods, Water Pollutants, Chemical isolation & purification
- Abstract
Triclocarban (3,4,4'-Trichlorocarbanilide; TCC) in the environment has been well documented. Methods have been developed to monitor TCC levels from various matrices including water, sediment, biosolids, plants, blood and urine; however, no method has been developed to document the concentration of TCC in fecal content after oral exposure in animal studies. In the present study, we developed and validated a method that uses liquid extraction coupled with HPLC-MS/MS determination to measure TCC in feces. The limit of detection and limit of quantitation in control rats without TCC exposure was 69.0 ng/g and 92.9 ng/g of feces, respectively. The base levels of TCC in feces were lower than LOD. At 12 days of treatment, the fecal TCC concentration increased to 2220 µg/g among 0.2% w/w exposed animals. The concentration in fecal samples decreased over the washout period in 0.2% w/w treated animals to 0.399 µ/g feces after exposure was removed for 28 days. This method required a small amount of sample (0.1 g) with simple sample preparation. Given its sensitivity and efficiency, this method may be useful for monitoring TCC exposure in toxicological studies of animals.
- Published
- 2015
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23. Mosquito genomics. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes.
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Neafsey DE, Waterhouse RM, Abai MR, Aganezov SS, Alekseyev MA, Allen JE, Amon J, Arcà B, Arensburger P, Artemov G, Assour LA, Basseri H, Berlin A, Birren BW, Blandin SA, Brockman AI, Burkot TR, Burt A, Chan CS, Chauve C, Chiu JC, Christensen M, Costantini C, Davidson VL, Deligianni E, Dottorini T, Dritsou V, Gabriel SB, Guelbeogo WM, Hall AB, Han MV, Hlaing T, Hughes DS, Jenkins AM, Jiang X, Jungreis I, Kakani EG, Kamali M, Kemppainen P, Kennedy RC, Kirmitzoglou IK, Koekemoer LL, Laban N, Langridge N, Lawniczak MK, Lirakis M, Lobo NF, Lowy E, MacCallum RM, Mao C, Maslen G, Mbogo C, McCarthy J, Michel K, Mitchell SN, Moore W, Murphy KA, Naumenko AN, Nolan T, Novoa EM, O'Loughlin S, Oringanje C, Oshaghi MA, Pakpour N, Papathanos PA, Peery AN, Povelones M, Prakash A, Price DP, Rajaraman A, Reimer LJ, Rinker DC, Rokas A, Russell TL, Sagnon N, Sharakhova MV, Shea T, Simão FA, Simard F, Slotman MA, Somboon P, Stegniy V, Struchiner CJ, Thomas GW, Tojo M, Topalis P, Tubio JM, Unger MF, Vontas J, Walton C, Wilding CS, Willis JH, Wu YC, Yan G, Zdobnov EM, Zhou X, Catteruccia F, Christophides GK, Collins FH, Cornman RS, Crisanti A, Donnelly MJ, Emrich SJ, Fontaine MC, Gelbart W, Hahn MW, Hansen IA, Howell PI, Kafatos FC, Kellis M, Lawson D, Louis C, Luckhart S, Muskavitch MA, Ribeiro JM, Riehle MA, Sharakhov IV, Tu Z, Zwiebel LJ, and Besansky NJ
- Subjects
- Animals, Anopheles classification, Base Sequence, Chromosomes, Insect genetics, Drosophila genetics, Humans, Insect Vectors classification, Molecular Sequence Data, Phylogeny, Sequence Alignment, Anopheles genetics, Evolution, Molecular, Genome, Insect, Insect Vectors genetics, Malaria transmission
- Abstract
Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts., (Copyright © 2015, American Association for the Advancement of Science.)
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- 2015
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24. Early life triclocarban exposure during lactation affects neonate rat survival.
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Kennedy RC, Menn FM, Healy L, Fecteau KA, Hu P, Bae J, Gee NA, Lasley BL, Zhao L, and Chen J
- Subjects
- Age Factors, Animals, Animals, Newborn, Anti-Infective Agents blood, Carbanilides blood, Endocrine Disruptors metabolism, Female, Gestational Age, Mammary Glands, Animal drug effects, Mammary Glands, Animal metabolism, Mammary Glands, Animal pathology, Milk metabolism, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Sprague-Dawley, Risk Assessment, Anti-Infective Agents toxicity, Carbanilides toxicity, Endocrine Disruptors toxicity, Lactation, Maternal Exposure
- Abstract
Triclocarban (3,4,4'-trichlorocarbanilide; TCC), an antimicrobial used in bar soaps, affects endocrine function in vitro and in vivo. This study investigates whether TCC exposure during early life affects the trajectory of fetal and/or neonatal development. Sprague Dawley rats were provided control, 0.2% weight/weight (w/w), or 0.5% w/w TCC-supplemented chow through a series of 3 experiments that limited exposure to critical growth periods: gestation, gestation and lactation, or lactation only (cross-fostering) to determine the susceptible windows of exposure for developmental consequences. Reduced offspring survival occurred when offspring were exposed to TCC at concentrations of 0.2% w/w and 0.5% w/w during lactation, in which only 13% of offspring raised by 0.2% w/w TCC dams survived beyond weaning and no offspring raised by 0.5% w/w TCC dams survived to this period. In utero exposure status had no effect on survival, as all pups nursed by control dams survived regardless of their in utero exposure status. Microscopic evaluation of dam mammary tissue revealed involution to be a secondary outcome of TCC exposure rather than a primary effect of compound administration. The average concentration of TCC in the milk was almost 4 times that of the corresponding maternal serum levels. The results demonstrate that gestational TCC exposure does not affect the ability of dams to carry offspring to term but TCC exposure during lactation has adverse consequences on the survival of offspring although the mechanism of reduced survival is currently unknown. This information highlights the importance of evaluating the safety of TCC application in personal care products and the impacts during early life exposure., (© The Author(s) 2014.)
- Published
- 2015
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25. Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi.
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Jiang X, Peery A, Hall AB, Sharma A, Chen XG, Waterhouse RM, Komissarov A, Riehle MM, Shouche Y, Sharakhova MV, Lawson D, Pakpour N, Arensburger P, Davidson VL, Eiglmeier K, Emrich S, George P, Kennedy RC, Mane SP, Maslen G, Oringanje C, Qi Y, Settlage R, Tojo M, Tubio JM, Unger MF, Wang B, Vernick KD, Ribeiro JM, James AA, Michel K, Riehle MA, Luckhart S, Sharakhov IV, and Tu Z
- Subjects
- Animals, Anopheles metabolism, Chromosome Mapping, Chromosomes, Insect genetics, Cluster Analysis, Evolution, Molecular, Genome, Insect, Humans, Insect Proteins genetics, Insect Proteins metabolism, Malaria transmission, Phylogeny, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Synteny, Transcriptome, Urban Population, Anopheles genetics, Insect Vectors genetics
- Abstract
Background: Anopheles stephensi is the key vector of malaria throughout the Indian subcontinent and Middle East and an emerging model for molecular and genetic studies of mosquito-parasite interactions. The type form of the species is responsible for the majority of urban malaria transmission across its range., Results: Here, we report the genome sequence and annotation of the Indian strain of the type form of An. stephensi. The 221 Mb genome assembly represents more than 92% of the entire genome and was produced using a combination of 454, Illumina, and PacBio sequencing. Physical mapping assigned 62% of the genome onto chromosomes, enabling chromosome-based analysis. Comparisons between An. stephensi and An. gambiae reveal that the rate of gene order reshuffling on the X chromosome was three times higher than that on the autosomes. An. stephensi has more heterochromatin in pericentric regions but less repetitive DNA in chromosome arms than An. gambiae. We also identify a number of Y-chromosome contigs and BACs. Interspersed repeats constitute 7.1% of the assembled genome while LTR retrotransposons alone comprise more than 49% of the Y contigs. RNA-seq analyses provide new insights into mosquito innate immunity, development, and sexual dimorphism., Conclusions: The genome analysis described in this manuscript provides a resource and platform for fundamental and translational research into a major urban malaria vector. Chromosome-based investigations provide unique perspectives on Anopheles chromosome evolution. RNA-seq analysis and studies of immunity genes offer new insights into mosquito biology and mosquito-parasite interactions.
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- 2014
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26. Hydraulic fracturing: paving the way for a sustainable future?
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Chen J, Al-Wadei MH, Kennedy RC, and Terry PD
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- Extraction and Processing Industry legislation & jurisprudence, Groundwater, Natural Gas, United States, Conservation of Energy Resources, Environment, Extraction and Processing Industry trends, Water Quality
- Abstract
With the introduction of hydraulic fracturing technology, the United States has become the largest natural gas producer in the world with a substantial portion of the production coming from shale plays. In this review, we examined current hydraulic fracturing literature including associated wastewater management on quantity and quality of groundwater. We conclude that proper documentation/reporting systems for wastewater discharge and spills need to be enforced at the federal, state, and industrial level. Furthermore, Underground Injection Control (UIC) requirements under SDWA should be extended to hydraulic fracturing operations regardless if diesel fuel is used as a fracturing fluid or not. One of the biggest barriers that hinder the advancement of our knowledge on the hydraulic fracturing process is the lack of transparency of chemicals used in the practice. Federal laws mandating hydraulic companies to disclose fracturing fluid composition and concentration not only to federal and state regulatory agencies but also to health care professionals would encourage this practice. The full disclosure of fracturing chemicals will allow future research to fill knowledge gaps for a better understanding of the impacts of hydraulic fracturing on human health and the environment.
- Published
- 2014
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27. A test of agent-based models as a tool for predicting patterns of pathogen transmission in complex landscapes.
- Author
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Lane-deGraaf KE, Kennedy RC, Arifin SM, Madey GR, Fuentes A, and Hollocher H
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- Animal Distribution, Animals, Computer Simulation, Ecology methods, Gene Flow, Geographic Information Systems, Macaca genetics, Entamoeba pathogenicity, Entamoebiasis transmission, Environment, Macaca parasitology, Models, Biological
- Abstract
Background: Landscape complexity can mitigate or facilitate host dispersal, influencing patterns of pathogen transmission. Spatial transmission of pathogens through landscapes, therefore, presents an important but not fully elucidated aspect of transmission dynamics. Using an agent-based model (LiNK) that incorporates GIS data, we examined the effects of landscape information on the spatial patterns of host movement and pathogen transmission in a system of long-tailed macaques and their gut parasites. We first examined the role of the landscape to identify any individual or additive effects on host movement. We then compared modeled dispersal distance to patterns of actual macaque gene flow to both confirm our model's predictions and to understand the role of individual land uses on dispersal. Finally, we compared the rate and the spread of two gastrointestinal parasites, Entamoeba histolytica and E. dispar, to understand how landscape complexity influences spatial patterns of pathogen transmission., Results: LiNK captured emergent properties of the landscape, finding that interaction effects between landscape layers could mitigate the rate of infection in a non-additive way. We also found that the inclusion of landscape information facilitated an accurate prediction of macaque dispersal patterns across a complex landscape, as confirmed by Mantel tests comparing genetic and simulated dispersed distances. Finally, we demonstrated that landscape heterogeneity proved a significant barrier for a highly virulent pathogen, limiting the dispersal ability of hosts and thus its own transmission into distant populations., Conclusions: Landscape complexity plays a significant role in determining the path of host dispersal and patterns of pathogen transmission. Incorporating landscape heterogeneity and host behavior into disease management decisions can be important in targeting response efforts, identifying cryptic transmission opportunities, and reducing or understanding potential for unintended ecological and evolutionary consequences. The inclusion of these data into models of pathogen transmission patterns improves our understanding of these dynamics, ultimately proving beneficial for sound public health policy.
- Published
- 2013
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28. Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.
- Author
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Hunt CA, Kennedy RC, Kim SH, and Ropella GE
- Subjects
- Drug Interactions physiology, Evidence-Based Medicine, Pharmaceutical Preparations chemistry, Pharmaceutical Preparations economics, Pharmaceutical Preparations metabolism, Research, Uncertainty, Models, Molecular
- Abstract
A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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29. The role of gamma interferon in DNA vaccine-induced tumor immunity targeting simian virus 40 large tumor antigen.
- Author
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Aldrich JF, Shearer MH, Lowe DB, Winn RE, Jumper CA, Kennedy RC, and Bright RK
- Subjects
- Animals, Antigens, Polyomavirus Transforming genetics, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic immunology, Cells, Cultured, Female, Interferon-gamma metabolism, Kidney Neoplasms immunology, Kidney Neoplasms pathology, Killer Cells, Natural immunology, Lung Neoplasms immunology, Lung Neoplasms secondary, Mice, Mice, Inbred BALB C, Plasmids, Polyomavirus Infections genetics, Spleen immunology, Th1 Cells immunology, Tumor Virus Infections genetics, Antigens, Polyomavirus Transforming immunology, Interferon-gamma immunology, Polyomavirus Infections immunology, Simian virus 40 immunology, Tumor Virus Infections immunology, Vaccines, DNA immunology
- Abstract
The central role of CD4+ T lymphocytes in mediating DNA vaccine-induced tumor immunity against the viral oncoprotein simian virus 40 (SV40) large tumor antigen (Tag) has previously been described by our laboratory. In the present study, we extend our previous findings by examining the roles of IFN-γ and Th1-associated effector cells within the context of DNA immunization in a murine model of pulmonary metastasis. Immunization of BALB/c mice with plasmid DNA encoding SV40 Tag (pCMV-Tag) generated IFN-γ-secreting T lymphocytes that produced this cytokine upon in vitro stimulation with mKSA tumor cells. The role of IFN-γ as a mediator of protection against mKSA tumor development was assessed via in vivo IFN-γ neutralization, and these experiments demonstrated a requirement for this cytokine in the induction immune phase. Neutralization of IFN-γ was associated with a reduction in Th1 cytokine-producing CD4+ and CD8+ splenocytes, as assessed by flow cytometry analysis, and provided further evidence for the role of CD4+ T lymphocytes as drivers of the cellular immune response. Depletion of NK cells and CD8+ T lymphocytes demonstrated the expendability of these cell types individually, but showed a requirement for a resident cytotoxic cell population within the immune effector phase. Our findings demonstrate the importance of IFN-γ in the induction of protective immunity stimulated by pCMV-Tag DNA-based vaccine and help to clarify the general mechanisms by which DNA vaccines trigger immunity to tumor cells.
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- 2013
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30. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study.
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Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, and Zonder JA
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bendamustine Hydrochloride, Dexamethasone adverse effects, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm drug effects, Feasibility Studies, Female, Humans, Lenalidomide, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Multiple Myeloma pathology, Nitrogen Mustard Compounds adverse effects, Recurrence, Thalidomide administration & dosage, Thalidomide adverse effects, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dexamethasone administration & dosage, Multiple Myeloma drug therapy, Nitrogen Mustard Compounds administration & dosage, Thalidomide analogs & derivatives
- Abstract
This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m(2) (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.
- Published
- 2012
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31. Preclinical prophylactic efficacy testing of Sm-p80-based vaccine in a nonhuman primate model of Schistosoma mansoni infection and immunoglobulin G and E responses to Sm-p80 in human serum samples from an area where schistosomiasis is endemic.
- Author
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Ahmad G, Zhang W, Torben W, Ahrorov A, Damian RT, Wolf RF, White GL, Carey DW, Mwinzi PN, Ganley-Leal L, Kennedy RC, and Siddiqui AA
- Subjects
- Animals, Antigens, Helminth administration & dosage, Cytokines metabolism, Disease Models, Animal, Female, Humans, Immunoglobulin E blood, Immunoglobulin G blood, Male, Papio, Primate Diseases immunology, Primate Diseases prevention & control, Serum immunology, Vaccination methods, Vaccines, DNA administration & dosage, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, Antibodies, Helminth blood, Antigens, Helminth immunology, Endemic Diseases, Schistosoma mansoni immunology, Schistosomiasis mansoni immunology, Schistosomiasis mansoni prevention & control, Vaccines, DNA immunology
- Abstract
The prophylactic efficacy of a schistosome antigen (Sm-p80) was tested in a nonhuman primate model, the baboon. Using a total of 28 baboons, different vaccination strategies were used including recombinant Sm-p80 protein formulated in Toll-like receptor 7 and Toll-like receptor 9 agonists, and DNA priming followed by boosting with protein plus adjuvants. Recombinant protein approaches provided levels of prophylactic efficacy of 52%-58%, whereas prime-boost approaches conferred 38%-47% protection in baboons. An appropriately balanced pro-inflammatory (T-helper 17 [Th17] and Th1) and anti-inflammatory (Th2) type of response was generated; the Th1 and Th17 types of immune responses appear to be indicative of increased prophylactic efficacy. Production and expression of several cytokines (interleukin 2 [IL-2], interferon γ, IL-12α, IL-1β, IL-6, and IL-22) were up-regulated in vaccinated animals. Human correlate studies revealed Sm-p80 reactivity with immunoglobulin G in human serum samples from schistosome-infected individuals. In addition, a complete lack of prevailing Sm-p80-specific immunoglobulin E in a high-risk or infected population was observed, thus minimizing the risk of hypersensitivity reaction following vaccination with Sm-p80 in humans. This study provided the proof of concept to move Sm-p80 forward into further preclinical development leading to human clinical trials.
- Published
- 2011
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32. CD4+ T lymphocytes are critical mediators of tumor immunity to simian virus 40 large tumor antigen induced by vaccination with plasmid DNA.
- Author
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Aldrich JF, Lowe DB, Shearer MH, Winn RE, Jumper CA, Bright RK, and Kennedy RC
- Subjects
- Animals, Antibodies, Viral biosynthesis, Enzyme-Linked Immunosorbent Assay, Female, Mice, Mice, Inbred BALB C, Vaccines, DNA administration & dosage, Antigens, Viral, Tumor immunology, CD4-Positive T-Lymphocytes immunology, Neoplasms, Experimental immunology, Plasmids, Simian virus 40 immunology, Vaccines, DNA immunology
- Abstract
A mechanistic analysis of tumor immunity directed toward the viral oncoprotein simian virus 40 (SV40) large tumor antigen (Tag) has previously been described by our laboratory for scenarios of recombinant Tag immunization in BALB/c mice. In the present study, we performed a preliminary characterization of the immune components necessary for systemic tumor immunity induced upon immunization with plasmid DNA encoding SV40 Tag as a transgene (pCMV-Tag). Antibody responses to SV40 Tag were observed via indirect enzyme-linked immunosorbent assay following three intramuscular (i.m.) injections of pCMV-Tag and were typified by a mixed Th1/Th2 response. Complete tumor immunity within a murine model of pulmonary metastasis was achieved upon two i.m. injections of pCMV-Tag, as assessed by examination of tumor foci in mouse lungs, without a detectable antibody response to SV40 Tag. Induction-phase and effector-phase depletions of T cell subsets were performed in vivo via administration of depleting rat monoclonal antibodies, and these experiments demonstrated that CD4(+) T lymphocytes are required in both phases of the adaptive immune response. Conversely, depletion of CD8(+) T lymphocytes did not impair tumor immunity in either immune phase and resulted in the premature production of antibodies to SV40 Tag. Our findings are unique in that a dominant role could be ascribed to CD4(+) T lymphocytes within a model of DNA vaccine-induced tumor immunity to Tag-expressing tumor cells. Additionally, our findings provide insight into the general mechanisms of vaccine-induced tumor immunity directed toward tumors bearing distinct tumor-associated antigens.
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- 2011
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33. An automated homology-based approach for identifying transposable elements.
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Kennedy RC, Unger MF, Christley S, Collins FH, and Madey GR
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- Animals, Base Sequence, Conserved Sequence, Eukaryota genetics, Gene Library, Humans, DNA Transposable Elements, Genome, Sequence Homology, Nucleic Acid
- Abstract
Background: Transposable elements (TEs) are mobile sequences found in nearly all eukaryotic genomes. They have the ability to move and replicate within a genome, often influencing genome evolution and gene expression. The identification of TEs is an important part of every genome project. The number of sequenced genomes is rapidly rising, and the need to identify TEs within them is also growing. The ability to do this automatically and effectively in a manner similar to the methods used for genes is of increasing importance. There exist many difficulties in identifying TEs, including their tendency to degrade over time and that many do not adhere to a conserved structure. In this work, we describe a homology-based approach for the automatic identification of high-quality consensus TEs, aimed for use in the analysis of newly sequenced genomes., Results: We describe a homology-based approach for the automatic identification of TEs in genomes. Our modular approach is dependent on a thorough and high-quality library of representative TEs. The implementation of the approach, named TESeeker, is BLAST-based, but also makes use of the CAP3 assembly program and the ClustalW2 multiple sequence alignment tool, as well as numerous BioPerl scripts. We apply our approach to newly sequenced genomes and successfully identify consensus TEs that are up to 99% identical to manually annotated TEs., Conclusions: While TEs are known to be a major force in the evolution of genomes, the automatic identification of TEs in genomes is far from mature. In particular, there is a lack of automated homology-based approaches that produce high-quality TEs. Our approach is able to generate high-quality consensus TE sequences automatically, requiring the user to only provide a few basic parameters. This approach is intentionally modular, allowing researchers to use components separately or iteratively. Our approach is most effective for TEs with intact reading frames. The implementation, TESeeker, is available for download as a virtual appliance, while the library of representative TEs is available as a separate download., (© 2011 Kennedy et al; licensee BioMed Central Ltd.)
- Published
- 2011
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34. Sequencing of Culex quinquefasciatus establishes a platform for mosquito comparative genomics.
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Arensburger P, Megy K, Waterhouse RM, Abrudan J, Amedeo P, Antelo B, Bartholomay L, Bidwell S, Caler E, Camara F, Campbell CL, Campbell KS, Casola C, Castro MT, Chandramouliswaran I, Chapman SB, Christley S, Costas J, Eisenstadt E, Feschotte C, Fraser-Liggett C, Guigo R, Haas B, Hammond M, Hansson BS, Hemingway J, Hill SR, Howarth C, Ignell R, Kennedy RC, Kodira CD, Lobo NF, Mao C, Mayhew G, Michel K, Mori A, Liu N, Naveira H, Nene V, Nguyen N, Pearson MD, Pritham EJ, Puiu D, Qi Y, Ranson H, Ribeiro JM, Roberston HM, Severson DW, Shumway M, Stanke M, Strausberg RL, Sun C, Sutton G, Tu ZJ, Tubio JM, Unger MF, Vanlandingham DL, Vilella AJ, White O, White JR, Wondji CS, Wortman J, Zdobnov EM, Birren B, Christensen BM, Collins FH, Cornel A, Dimopoulos G, Hannick LI, Higgs S, Lanzaro GC, Lawson D, Lee NH, Muskavitch MA, Raikhel AS, and Atkinson PW
- Subjects
- Aedes genetics, Animals, Anopheles genetics, Chromosome Mapping, Culex classification, Culex physiology, DNA Transposable Elements, Insect Proteins genetics, Insect Proteins physiology, Insect Vectors genetics, Molecular Sequence Data, Multigene Family, Phylogeny, Receptors, Odorant genetics, Retroelements, Chromosomes genetics, Culex genetics, Genes, Insect, Genome, Sequence Analysis, DNA
- Abstract
Culex quinquefasciatus (the southern house mosquito) is an important mosquito vector of viruses such as West Nile virus and St. Louis encephalitis virus, as well as of nematodes that cause lymphatic filariasis. C. quinquefasciatus is one species within the Culex pipiens species complex and can be found throughout tropical and temperate climates of the world. The ability of C. quinquefasciatus to take blood meals from birds, livestock, and humans contributes to its ability to vector pathogens between species. Here, we describe the genomic sequence of C. quinquefasciatus: Its repertoire of 18,883 protein-coding genes is 22% larger than that of Aedes aegypti and 52% larger than that of Anopheles gambiae with multiple gene-family expansions, including olfactory and gustatory receptors, salivary gland genes, and genes associated with xenobiotic detoxification.
- Published
- 2010
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35. Role of the innate immune response and tumor immunity associated with simian virus 40 large tumor antigen.
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Lowe DB, Shearer MH, Aldrich JF, Winn RE, Jumper CA, and Kennedy RC
- Subjects
- Animals, Antibodies, Neoplasm biosynthesis, Cell Line, Tumor, Cytotoxicity, Immunologic, Immunotherapy, In Vitro Techniques, Interleukin-2 pharmacology, Killer Cells, Natural immunology, Lung Neoplasms secondary, Lung Neoplasms therapy, Mice, Mice, Inbred BALB C, Poly I-C pharmacology, Rabbits, Th1 Cells immunology, Toll-Like Receptors metabolism, Antigens, Polyomavirus Transforming immunology, Immunity, Innate, Lung Neoplasms immunology
- Abstract
We examined properties of the innate immune response against the tumor-specific antigen simian virus 40 (SV40) large tumor antigen (Tag) following experimental pulmonary metastasis in naive mice. Approximately 14 days after mKSA tumor cell challenge, expression of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha), interleukin-2 (IL-2), and RANTES was upregulated in splenocytes harvested from mice, as assessed by flow cytometry and antibody array assays. This response was hypothesized to activate and induce tumor-directed NK cell lysis since IL-2-stimulated NK cells mediated tumor cell destruction in vitro. The necessary function of NK cells was further validated in vivo through selected antibody depletion of NK cells, which resulted in an overwhelming lung tumor burden relative to that in animals receiving a control rabbit IgG depletion regimen. Interestingly, mice achieved increased protection from experimental pulmonary metastasis when NK cells were further activated indirectly through in vivo administration of poly(I:C), a Toll-like receptor 3 (TLR3) agonist. In a separate study, mice receiving treatments of poly(I:C) and recombinant SV40 Tag protein immunization mounted effective tumor immunity in an established experimental pulmonary metastasis setting. Initiating broad-based immunity with poly(I:C) was observed to induce a Th1 bias in the SV40 Tag antibody response that led to successful antitumor responses not observed in animals treated only with poly(I:C) or SV40 Tag. These data have direct implications for immunotherapeutic strategies incorporating methods to elicit inflammatory reactions, particularly NK cell-driven lysis, against malignant cell types that express a tumor-specific antigen such as SV40 Tag.
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- 2010
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36. Genome sequences of the human body louse and its primary endosymbiont provide insights into the permanent parasitic lifestyle.
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Kirkness EF, Haas BJ, Sun W, Braig HR, Perotti MA, Clark JM, Lee SH, Robertson HM, Kennedy RC, Elhaik E, Gerlach D, Kriventseva EV, Elsik CG, Graur D, Hill CA, Veenstra JA, Walenz B, Tubío JM, Ribeiro JM, Rozas J, Johnston JS, Reese JT, Popadic A, Tojo M, Raoult D, Reed DL, Tomoyasu Y, Kraus E, Mittapalli O, Margam VM, Li HM, Meyer JM, Johnson RM, Romero-Severson J, Vanzee JP, Alvarez-Ponce D, Vieira FG, Aguadé M, Guirao-Rico S, Anzola JM, Yoon KS, Strycharz JP, Unger MF, Christley S, Lobo NF, Seufferheld MJ, Wang N, Dasch GA, Struchiner CJ, Madey G, Hannick LI, Bidwell S, Joardar V, Caler E, Shao R, Barker SC, Cameron S, Bruggner RV, Regier A, Johnson J, Viswanathan L, Utterback TR, Sutton GG, Lawson D, Waterhouse RM, Venter JC, Strausberg RL, Berenbaum MR, Collins FH, Zdobnov EM, and Pittendrigh BR
- Subjects
- Animals, Enterobacteriaceae genetics, Genes, Bacterial genetics, Genes, Insect genetics, Genomics methods, Humans, Lice Infestations parasitology, Molecular Sequence Data, Sequence Analysis, DNA, Symbiosis, Genome, Bacterial genetics, Genome, Insect genetics, Pediculus genetics, Pediculus microbiology
- Abstract
As an obligatory parasite of humans, the body louse (Pediculus humanus humanus) is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. Here, we present genome sequences of the body louse and its primary bacterial endosymbiont Candidatus Riesia pediculicola. The body louse has the smallest known insect genome, spanning 108 Mb. Despite its status as an obligate parasite, it retains a remarkably complete basal insect repertoire of 10,773 protein-coding genes and 57 microRNAs. Representing hemimetabolous insects, the genome of the body louse thus provides a reference for studies of holometabolous insects. Compared with other insect genomes, the body louse genome contains significantly fewer genes associated with environmental sensing and response, including odorant and gustatory receptors and detoxifying enzymes. The unique architecture of the 18 minicircular mitochondrial chromosomes of the body louse may be linked to the loss of the gene encoding the mitochondrial single-stranded DNA binding protein. The genome of the obligatory louse endosymbiont Candidatus Riesia pediculicola encodes less than 600 genes on a short, linear chromosome and a circular plasmid. The plasmid harbors a unique arrangement of genes required for the synthesis of pantothenate, an essential vitamin deficient in the louse diet. The human body louse, its primary endosymbiont, and the bacterial pathogens that it vectors all possess genomes reduced in size compared with their free-living close relatives. Thus, the body louse genome project offers unique information and tools to use in advancing understanding of coevolution among vectors, symbionts, and pathogens.
- Published
- 2010
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- View/download PDF
37. Research in visually induced motion sickness.
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Kennedy RS, Drexler J, and Kennedy RC
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- Computer Terminals, Humans, Randomized Controlled Trials as Topic, Surveys and Questionnaires, Time Factors, Motion Sickness etiology, Photic Stimulation adverse effects, Research
- Abstract
While humans have experienced motion sickness symptoms in response to inertial motion from early history through the present day, motion sickness symptoms also occur from exposure to some types of visual displays. Even in the absence of physical motion, symptoms may result from visually perceived motion, which are often classified as effects of visually induced motion sickness (VIMS). This paper provides a brief discussion of general motion sickness and then reviews findings from three lines of recent VIMS investigations that we have conducted., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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38. Sm-p80-based DNA vaccine provides baboons with levels of protection against Schistosoma mansoni infection comparable to those achieved by the irradiated cercarial vaccine.
- Author
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Zhang W, Ahmad G, Torben W, Noor Z, Le L, Damian RT, Wolf RF, White GL, Chavez-Suarez M, Podesta RB, Kennedy RC, and Siddiqui AA
- Subjects
- Animals, Antibodies, Helminth blood, Antigens, Helminth genetics, CHO Cells, COS Cells, Cell Proliferation, Chlorocebus aethiops, Cricetinae, Cricetulus, Enzyme-Linked Immunosorbent Assay, Helminth Proteins genetics, Helminth Proteins immunology, Immunoglobulin G blood, Interleukin-4 metabolism, Intestines parasitology, Leukocytes, Mononuclear metabolism, Liver parasitology, Parasite Egg Count, Schistosoma mansoni genetics, Schistosomiasis mansoni immunology, T-Lymphocytes immunology, Vaccines, DNA administration & dosage, Antigens, Helminth immunology, Papio immunology, Schistosoma mansoni immunology, Schistosomiasis mansoni prevention & control, Vaccines, DNA immunology
- Abstract
To date, no vaccine is available to prevent human schistosomiasis. We have targeted a protein of Schistosoma mansoni that plays an important role in the surface membrane renewal process, a mechanism widely believed to be utilized by the parasite as an immune evasion strategy. Sm-p80 antigen is a promising vaccine target because of its documented immunogenicity, protective efficacy, and antifecundity effects observed in both experimental murine and nonhuman primate models of this infectious disease. In the present study, we report that, in a vector approved for human use (VR1020), an Sm-p80-based DNA vaccine formulation confers a 46% reduction in the worm burden in a baboon (Papio anubis) model. Baboons vaccinated with Sm-p80-VR1020 had a 28% decrease in egg production after challenge with the infectious parasite. Sm-p80-VR1020 vaccine elicited robust immune responses to specific antigen Sm-p80, including immunoglobulin (Ig) G, its subtypes IgG1 and IgG2, and IgA and IgM in vaccinated animals. When stimulated in vitro with recombinant Sm-p80, peripheral blood mononuclear cells and splenocytes from baboons vaccinated with Sm-p80-VR1020 produced considerably higher levels of T helper 1 response-enhancing cytokines (interleukin [IL]-2 and interferon-gamma) than T helper 2 (Th2) response-enhancing cytokines (IL-4 and IL-10). Peripheral blood mononuclear cells produced a significantly higher number of spot-forming units for interferon-gamma than for IL-4 in enzyme-linked immunosorbent spot assays. A mixed T helper 1/T helper 2 type of humoral and T cell responses was generated after immunization with Sm-p80-VR1020. These findings again highlight the potential of Sm-p80 as a promising vaccine candidate for schistosomiasis.
- Published
- 2010
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- View/download PDF
39. Vaccines and immunotherapeutics for the treatment of malignant disease.
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Aldrich JF, Lowe DB, Shearer MH, Winn RE, Jumper CA, and Kennedy RC
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- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antigens, Neoplasm administration & dosage, Antigens, Neoplasm immunology, Cancer Vaccines genetics, Cancer Vaccines immunology, Cytokines administration & dosage, Cytokines immunology, Dendritic Cells immunology, Dogs, Humans, Mice, Cancer Vaccines therapeutic use, Immunotherapy methods, Neoplasms immunology, Neoplasms therapy
- Abstract
The employment of the immune system to treat malignant disease represents an active area of biomedical research. The specificity of the immune response and potential for establishing long-term tumor immunity compels researchers to continue investigations into immunotherapeutic approaches for cancer. A number of immunotherapeutic strategies have arisen for the treatment of malignant disease, including various vaccination schemes, cytokine therapy, adoptive cellular therapy, and monoclonal antibody therapy. This paper describes each of these strategies and discusses some of the associated successes and limitations. Emphasis is placed on the integration of techniques to promote optimal scenarios for eliminating cancer.
- Published
- 2010
- Full Text
- View/download PDF
40. Tumor immunity against a simian virus 40 oncoprotein requires CD8+ T lymphocytes in the effector immune phase.
- Author
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Lowe DB, Shearer MH, Jumper CA, Bright RK, and Kennedy RC
- Subjects
- Animals, Antibodies, Viral blood, Antigens, Polyomavirus Transforming administration & dosage, Cell Line, Transformed, Immunity, Humoral, Immunization, Kidney cytology, Kidney virology, Lung Neoplasms mortality, Lung Neoplasms prevention & control, Lymphocyte Depletion, Mice, Mice, Inbred BALB C, Neoplasm Transplantation, T-Lymphocytes, Cytotoxic, Th1 Cells immunology, Tumor Virus Infections mortality, Tumor Virus Infections prevention & control, Antigens, Polyomavirus Transforming immunology, CD8-Positive T-Lymphocytes immunology, Lung Neoplasms immunology, Simian virus 40 immunology, Tumor Virus Infections immunology
- Abstract
The required activities of CD4(+) T cells and antibody against the virally encoded oncoprotein simian virus 40 (SV40) Tag have previously been demonstrated by our laboratory to be mediators in achieving antitumor responses and tumor protection through antibody-dependent cell-mediated cytotoxicity (ADCC). In this study, we further characterize the necessary immune cell components that lead to systemic tumor immunity within an experimental pulmonary metastatic model as the result of SV40 Tag immunization and antibody production. Immunized animals depleted of CD8(+) T cells at the onset of experimental tumor cell challenge developed lung tumor foci and had an overall decreased survival due to lung tumor burden, suggesting a role for CD8(+) T cells in the effector phase of the immune response. Lymphocytes and splenocytes harvested from SV40 Tag-immunized mice experimentally inoculated with tumor cells synthesized increased in vitro levels of the Th1 cytokine gamma interferon (IFN-gamma), as assessed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry assays. CD8(+) T-cell activity was also heightened in SV40 Tag-immunized and tumor cell-challenged mice, based upon intracellular production of perforin, confirming the cytolytic properties of CD8(+) T cells against tumor cell challenge. Altogether, these data point to the role of recombinant SV40 Tag protein immunization in initiating a cytotoxic T-lymphocyte (CTL) response during tumor cell dissemination and growth. The downstream activity of CD8(+) T cells within this model is likely initiated from SV40 Tag-specific antibody mediating ADCC tumor cell destruction.
- Published
- 2010
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- View/download PDF
41. Protective and antifecundity effects of Sm-p80-based DNA vaccine formulation against Schistosoma mansoni in a nonhuman primate model.
- Author
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Ahmad G, Zhang W, Torben W, Damian RT, Wolf RF, White GL, Chavez-Suarez M, Kennedy RC, and Siddiqui AA
- Subjects
- Animals, Antibodies, Protozoan immunology, Antigens, Helminth genetics, Cell Line, Chlorocebus aethiops, Cricetinae, Cytokines biosynthesis, Cytokines immunology, Female, Male, Models, Animal, Ovum immunology, Schistosoma mansoni genetics, Schistosoma mansoni metabolism, Schistosomiasis mansoni immunology, T-Lymphocytes immunology, Vaccines, DNA genetics, Antigens, Helminth immunology, Antigens, Helminth metabolism, Fertility, Papio immunology, Schistosoma mansoni immunology, Schistosomiasis mansoni prevention & control, Vaccines, DNA immunology
- Abstract
Schistosomiasis is an important parasitic disease for which there is no available vaccine. We have focused on a functionally important antigen of Schistosoma mansoni, Sm-p80, as a vaccine candidate because of its consistent immunogenicity, protective potential and antifecundity effect observed in murine models; and for its pivotal role in the immune evasion process. In the present study we report that an Sm-p80-based DNA vaccine formulation confers 38% reduction in worm burden in a nonhuman primate model, the baboon (Papio anubis). Animals immunized with Sm-p80-pcDNA3 exhibited a decrease in egg production by 32%. Sm-p80 DNA elicited specific immune responses that include IgG; its subtypes IgG1 and IgG2; and IgM in vaccinated animals. Peripheral blood mononuclear cells (PBMCs) from immunized animals when stimulated in vitro with Sm-p80 produced appreciably more Th1 response enhancing cytokines (IL-2, IFN-gamma) than Th2 response enhancing cytokines (IL-4, IL-10). PBMCs produced appreciably more spot-forming units for INF-gamma than for IL-4 in enzyme-linked immunosorbent spot (ELISPOT) assays. Overall it appears that even though a mixed (Th1/Th2) type of humoral antibody response was generated following immunization with Sm-p80; the dominant protective immune response is Th1 type. These data reinforce the potential of Sm-p80 as an excellent vaccine candidate for schistosomiasis.
- Published
- 2009
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- View/download PDF
42. Characterization of PEDF: a multi-functional serpin family protein.
- Author
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Filleur S, Nelius T, de Riese W, and Kennedy RC
- Subjects
- Angiogenesis Inhibitors, Eye Proteins metabolism, Eye Proteins therapeutic use, Humans, Nerve Growth Factors metabolism, Nerve Growth Factors therapeutic use, Receptors, Neuropeptide metabolism, Serpins metabolism, Serpins therapeutic use, Eye Proteins physiology, Nerve Growth Factors physiology, Serpins physiology
- Abstract
Pigment epithelium-derived factor (PEDF) is a 50 kDa secreted glycoprotein that belongs to the non-inhibitory serpin family group. PEDF has been described as a natural angiogenesis inhibitor with neurotrophic and immune-modulation properties; it balances angiogenesis in the eye and blocks tumor progression. The mechanisms underlying most of these events are not completely clear; however, it appears that PEDF acts via multiple high affinity ligands and cell receptors. In this review article, we will summarize the current knowledge on the biochemical properties of PEDF and its receptors, the multimodal activities of PEDF and finally address the therapeutic potential of PEDF in treating angiogenesis-, neurodegeneration- and inflammation-related diseases.
- Published
- 2009
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43. Sperm protein 17 is a suitable target for adoptive T-cell-based immunotherapy in human ovarian cancer.
- Author
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Chiriva-Internati M, Weidanz JA, Yu Y, Frezza EE, Jenkins MR, Kennedy RC, Cobos E, and Kast WM
- Subjects
- Animals, Antigens, Surface metabolism, Calmodulin-Binding Proteins, Carrier Proteins metabolism, Cell Line, Tumor, Female, Humans, Male, Membrane Proteins, Mice, Mice, Inbred NOD, Mice, SCID, Ovarian Neoplasms pathology, T-Lymphocytes, Cytotoxic immunology, Antigens, Surface immunology, Carrier Proteins immunology, Immunotherapy, Adoptive methods, Ovarian Neoplasms immunology, Ovarian Neoplasms therapy, T-Lymphocytes, Cytotoxic transplantation
- Abstract
For ovarian cancer (OC) patients with advanced or metastatic disease, standard treatments (chemotherapy and radiotherapy) are not very effective and have undesirable side effects. Newer and more promising approaches in cancer treatment use components of the immune system. In this study, we applied an adoptive immunotherapy-based approach using a cancer testis antigen, sperm protein 17, as a target for the treatment of human metastatic OC in a NOD.CB17-PrkDCcid/J (nonobese, diabetic severe combined immunodeficient) mouse model. We used the human SK-OV-3A2.A3 OC cell line, endogenously expressing sperm protein 17, to induce tumor growth in mice. We provide direct evidence, for the first time, that in vitro cultured, monoclonal, cytotoxic T lymphocytes (derived either from advanced OC patients or from healthy donors), specific for sperm protein 17, can eradicate human metastatic OC cells. In addition, we observed no evidence of autoimmunity after histologic examination of the tissue sections adding to the safety profile of our approach.
- Published
- 2008
- Full Text
- View/download PDF
44. Evidence of simian virus 40 exposure in a colony of captive baboons.
- Author
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Westfall LW, Shearer MH, Jumper CA, White GL, Papin JF, Eberle R, Butel JS, Bright RK, and Kennedy RC
- Subjects
- Amino Acid Sequence, Animals, Animals, Laboratory immunology, Animals, Laboratory virology, Antibodies, Viral blood, Antigens, Viral, Tumor genetics, Antigens, Viral, Tumor isolation & purification, Base Sequence, DNA Primers genetics, DNA, Viral genetics, Enzyme-Linked Immunosorbent Assay, Female, Male, Molecular Sequence Data, Monkey Diseases immunology, Monkey Diseases virology, Papio immunology, Papio anubis immunology, Papio anubis virology, Papio cynocephalus immunology, Papio cynocephalus virology, Papio ursinus immunology, Papio ursinus virology, Polymerase Chain Reaction, Polyomavirus Infections immunology, Polyomavirus Infections veterinary, Polyomavirus Infections virology, Sequence Homology, Nucleic Acid, Seroepidemiologic Studies, Simian virus 40 genetics, Simian virus 40 immunology, Tumor Virus Infections immunology, Tumor Virus Infections veterinary, Tumor Virus Infections virology, Papio virology, Simian virus 40 isolation & purification
- Abstract
Simian virus 40 (SV40) is a polyomavirus for which non-human primates are the permissive host. The baboon (Papio spp.) is an old world monkey that is used in a variety of research investigations; however, natural infection of SV40 among baboons has not been thoroughly examined or reported. Initially, we were interested in determining the prevalence of SV40 infection among a captive colony of baboons based on the presence of antibodies to SV40 large T-antigen (Tag). An overall seroprevalence rate of >50% was found after screening sera from 142 baboons in the colony based on ELISA. Endpoint titer values for serum antibody binding to SV40 Tag reached as high as 1280 for 5 out of 142 baboons. Peptide binding assays revealed that a range of SV40 Tag epitopes are immunogenic in the baboon, and that individual animals differ in their humoral immune responses to SV40 Tag based on epitope recognition. Specificity to SV40 Tag and not some other primate polyomavirus encoded large Tag was further examined by serologic reactivity to peptide epitopes unique to SV40 Tag. Additional serology was performed to assess SV40 Tag reactivity by Western blot and whether antibodies were capable of neutralizing SV40 infectivity in vitro. Although antibodies with high levels of SV40 neutralization were observed in a number of the baboons, there was a lack of correlation between viral neutralization and antibodies to SV40 Tag. Further examination using molecular-based diagnosis and SV40 Tag specific real-time quantitative PCR determined that some of the baboons appeared to be exposed to SV40. DNA sequence analysis of the PCR products confirmed that SV40 Tag specific sequences were detected in baboons.
- Published
- 2008
- Full Text
- View/download PDF
45. Experimental vaccines in animal models for schistosomiasis.
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Siddiqui AA, Ahmad G, Damian RT, and Kennedy RC
- Subjects
- Animals, Antigens, Helminth immunology, Child, Child, Preschool, Humans, Mice, Papio, Schistosomiasis parasitology, Disease Models, Animal, Schistosomiasis prevention & control, Vaccines administration & dosage, Vaccines immunology
- Abstract
Considerable morbidity and mortality results from the affliction of an estimated 200 million people worldwide by several species of schistosomes; 779 million are exposed to the disease in 74 different countries. Even though anti-parasitic drugs and other control measures, including public hygiene and snail control are available, the advent of an effective vaccine still remains the most potentially powerful means for the control of this disease. The putative vaccine could be administered to small children prior to the time when their contact with infected water is maximal, so as to prevent severe infection in the subsequent years. This review attempts to summarize the status of schistosome vaccine development with special emphasis on functionally important vaccine candidates. The importance of utilizing both murine and nonhuman primate models as a prerequisite for clinical trials is discussed.
- Published
- 2008
- Full Text
- View/download PDF
46. Health and social problems encountered by treated and untreated obstetric fistula patients in rural Ethiopia.
- Author
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Muleta M, Hamlin EC, Fantahun M, Kennedy RC, and Tafesse B
- Subjects
- Adaptation, Psychological, Adolescent, Adult, Attitude to Health, Cross-Sectional Studies, Ethiopia, Female, Humans, Middle Aged, Pregnancy, Rural Population, Social Support, Socioeconomic Factors, Obstetric Labor Complications, Rectovaginal Fistula complications, Social Alienation, Vesicovaginal Fistula complications
- Abstract
Objective: To assess health, social, and psychological problems encountered by women with treated and untreated obstetric fistula (OF)., Methods: A cross-sectional study consisting of quantitative and qualitative components was conducted in seven administrative regions of rural Ethiopia. Fifty-two women with OF were interviewed on the subjects of their socioeconomic status and history of the development of OF. Qualitative in-depth interviews were conducted with 27 of the untreated women and seven of the treated women., Results: A total of 19 153 houses were surveyed, and 55 women with fistulae were identified, of whom 52 were interviewed. Thirty-six of the interviewed women (69.2%) were divorced, 10 (19.2%) were not allowed to eat with family members, and 23 (44.2%) were not members of any community associations. Of the 48 women with feelings of depression, 28 (54.2%) had suicidal ideation. Twenty-four women attributed their development of a fistula to evil spirits, to a curse, or to sin. The in-depth interviews revealed that treatment improved family and social life; however, some health, social, and sexual problems remained., Conclusion: Women with OF encounter health, psychological, and social consequences that are not completely resolved by repairing the fistula. The care of women with OF should go beyond surgical treatment and should include support for their reintegration into the community with proper follow-up.
- Published
- 2008
- Full Text
- View/download PDF
47. Obstetric fistula in rural Ethiopia.
- Author
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Muleta M, Fantahun M, Tafesse B, Hamlin EC, and Kennedy RC
- Subjects
- Adolescent, Adult, Cross-Sectional Studies, Emergency Service, Hospital, Ethiopia epidemiology, Female, Fistula, Health Care Surveys, Health Services Accessibility, Humans, Middle Aged, Obstetric Labor Complications, Pregnancy, Prevalence, Risk Factors, Surveys and Questionnaires, Vesicovaginal Fistula etiology, Vesicovaginal Fistula prevention & control, Maternal Health Services, Rural Population, Vesicovaginal Fistula epidemiology, Women's Health
- Abstract
Objectives: To determine the prevalence of obstetric fistula in rural Ethiopia and identify the circumstances and barriers to care that enhance development of obstetric fistula and its health and social consequences., Design: A cross-sectional study., Setting: The study was conducted in seven out of eleven administrative regions of Ethiopia by visiting randomly selected houses in rural areas and identifying women who have or had obstetric fistula and interviewing them., Results: A total of 19,153 houses were visited. Untreated fistula prevalence was about 1.5 per 1000 amounting to approximately 26,819 women. Most of the patients were young women who delivered for the first time. Marriage took place early in life mostly through family arrangements or abduction. The median number of days in labour was three to eight., Conclusion: Promotive measures such as increasing age at marriage, and identification and treatment of patients should be intensified. There is a great need in improving accessibility and affordability of basic and emergency obstetric services for rural communities. Curving the situation in the long run requires dealing with the problem of poverty and improvement in the status of women.
- Published
- 2007
- Full Text
- View/download PDF
48. Towards progress on DNA vaccines for cancer.
- Author
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Lowe DB, Shearer MH, Jumper CA, and Kennedy RC
- Subjects
- Humans, Immunotherapy, Cancer Vaccines immunology, Neoplasms immunology, Neoplasms therapy, Vaccines, DNA immunology
- Abstract
Cancer immunotherapy faces many obstacles that include eliciting immune reactions to self antigens as well as overcoming tumor-derived immunosuppressive networks and evasion tactics. Within the vaccine arsenal for inhibiting cancer proliferation, plasmid DNA represents a novel immunization strategy that is capable of eliciting both humoral and cellular arms of the immune response in addition to being safely administered and easily engineered and manufactured. Unfortunately, while DNA vaccines have performed well in preventing and treating malignancies in animal models, their overall application in human clinical trials has not impacted cancer regression to date. Since the establishment of these early trials, progress has been made in terms of increasing DNA vaccine immunogenicity and subverting the suppressive properties of tumor cells. Therefore, the success of future plasmid DNA use in cancer patients will depend on combinatorial strategies that enhance and direct the DNA vaccine immune response while also targeting tumor evasion mechanisms.
- Published
- 2007
- Full Text
- View/download PDF
49. Inhibition of prostate carcinogenesis by combined active immunoprophylaxis.
- Author
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De Giovanni C, Croci S, Nicoletti G, Landuzzi L, Palladini A, Pannellini T, Borgia L, Iezzi M, Di Carlo E, Orengo AM, Kennedy RC, Lollini PL, Nanni P, and Musiani P
- Subjects
- Animals, Antibody Formation immunology, Cancer Vaccines, Cell Line, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Survival Rate, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic pathology, Prostatic Neoplasms immunology, Prostatic Neoplasms prevention & control
- Abstract
The aim of this study is to investigate whether an active immunoprophylactic approach combining specific antigens and adjuvant stimuli would be able to inhibit prostate carcinogenesis in transgenic TRAMP mice. A vaccine consisting of allogeneic large T antigen (TAg)-positive SV40-transformed cells combined with systemic recombinant IL-12 was administered to TRAMP mice, starting from when they were still tumor-free at 5-6 weeks of age. The combined vaccine significantly inhibited prostate carcinogenesis, giving a more than doubled median latency time of prostatic tumors (53 weeks in comparison to 26 weeks in control mice). Vaccination with cells alone or IL-12 treatment alone was poorly effective (median latency of 30 and 39 weeks, respectively). The combined vaccine induced a very high CD4 response biased toward the Th1 pathway, with the induction of a humoral response that included TAg-specific antibodies. Therefore, such active immunoprophylactic approach based on the combination of allogeneic SV40 TAg-positive cells and systemic administration of recombinant IL-12 significantly delayed autochthonous urogenital carcinogenesis driven by SV40 TAg in TRAMP mice.
- Published
- 2007
- Full Text
- View/download PDF
50. Genome sequence of Aedes aegypti, a major arbovirus vector.
- Author
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Nene V, Wortman JR, Lawson D, Haas B, Kodira C, Tu ZJ, Loftus B, Xi Z, Megy K, Grabherr M, Ren Q, Zdobnov EM, Lobo NF, Campbell KS, Brown SE, Bonaldo MF, Zhu J, Sinkins SP, Hogenkamp DG, Amedeo P, Arensburger P, Atkinson PW, Bidwell S, Biedler J, Birney E, Bruggner RV, Costas J, Coy MR, Crabtree J, Crawford M, Debruyn B, Decaprio D, Eiglmeier K, Eisenstadt E, El-Dorry H, Gelbart WM, Gomes SL, Hammond M, Hannick LI, Hogan JR, Holmes MH, Jaffe D, Johnston JS, Kennedy RC, Koo H, Kravitz S, Kriventseva EV, Kulp D, Labutti K, Lee E, Li S, Lovin DD, Mao C, Mauceli E, Menck CF, Miller JR, Montgomery P, Mori A, Nascimento AL, Naveira HF, Nusbaum C, O'leary S, Orvis J, Pertea M, Quesneville H, Reidenbach KR, Rogers YH, Roth CW, Schneider JR, Schatz M, Shumway M, Stanke M, Stinson EO, Tubio JM, Vanzee JP, Verjovski-Almeida S, Werner D, White O, Wyder S, Zeng Q, Zhao Q, Zhao Y, Hill CA, Raikhel AS, Soares MB, Knudson DL, Lee NH, Galagan J, Salzberg SL, Paulsen IT, Dimopoulos G, Collins FH, Birren B, Fraser-Liggett CM, and Severson DW
- Subjects
- Aedes metabolism, Animals, Anopheles genetics, Anopheles metabolism, Arboviruses, Base Sequence, DNA Transposable Elements, Dengue prevention & control, Dengue transmission, Drosophila melanogaster genetics, Female, Genes, Insect, Humans, Insect Proteins genetics, Insect Vectors metabolism, Male, Membrane Transport Proteins genetics, Molecular Sequence Data, Multigene Family, Protein Structure, Tertiary genetics, Sequence Analysis, DNA, Sex Characteristics, Sex Determination Processes, Species Specificity, Synteny, Transcription, Genetic, Yellow Fever prevention & control, Yellow Fever transmission, Aedes genetics, Genome, Insect, Insect Vectors genetics
- Abstract
We present a draft sequence of the genome of Aedes aegypti, the primary vector for yellow fever and dengue fever, which at approximately 1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae. Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of approximately 4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster. Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of approximately 2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.
- Published
- 2007
- Full Text
- View/download PDF
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