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PMID:28615210
Autor:Loftus MS; Verville N; Kedes DH
Endereço:Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Título:A Conserved Leucine Zipper Motif in Gammaherpesvirus ORF52 Is Critical for Distinct Microtubule Rearrangements.
Fonte:J Virol; 91(17), 2017 Sep 01.
ISSN:1098-5514
País de publicação:United States
Idioma:eng
Resumo:Productive viral infection often depends on the manipulation of the cytoskeleton. Herpesviruses, including rhesus monkey rhadinovirus (RRV) and its close homolog, the oncogenic human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8), exploit microtubule (MT)-based retrograde transport to deliver their genomes to the nucleus. Subsequently, during the lytic phase of the life cycle, the maturing viral particles undergo orchestrated translocation to specialized regions within the cytoplasm, leading to tegumentation, secondary envelopment, and then egress. As a result, we hypothesized that RRV might induce changes in the cytoskeleton at both early and late stages of infection. Using confocal imaging, we found that RRV infection led to the thickening and acetylation of MTs emanating from the MT-organizing center (MTOC) shortly after viral entry and more pronounced and diffuse MT reorganization during peak stages of lytic gene expression and virion production. We subsequently identified open reading frame 52 (ORF52), a multifunctional and abundant tegument protein, as being the only virally encoded component responsible for these cytoskeletal changes. Mutational and modeling analyses indicated that an evolutionarily conserved, truncated leucine zipper motif near the N terminus as well as a strictly conserved arginine residue toward the C terminus of ORF52 play critical roles in its ability to rearrange the architecture of the MT cytoskeleton. Taken together, our findings combined with data from previous studies describing diverse roles for ORF52 suggest that it likely binds to different cellular components, thereby allowing context-dependent modulation of function. A thorough understanding of the processes governing viral infection includes knowledge of how viruses manipulate their intracellular milieu, including the cytoskeleton. Altering the dynamics of actin or MT polymerization, for example, is a common strategy employed by viruses to ensure efficient entry, maturation, and egress as well as the avoidance of antiviral defenses through the sequestration of key cellular factors. We found that infection with RRV, a homolog of the human pathogen KSHV, led to perinuclear wrapping by acetylated MT bundles and identified ORF52 as the viral protein underlying these changes. Remarkably, incoming virions were able to supply sufficient ORF52 to induce MT thickening and acetylation near the MTOC, potentially aiding in the delivery viral genomes to the nucleus. Although the function of MT alterations during late stages of infection requires further study, ORF52 shares functional and structural similarities with alphaherpesvirus VP22, underscoring the evolutionary importance of MT cytoskeletal manipulations for this virus family.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Viral Proteins)


  2 / 36456 MEDLINE  
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PMID:28350824
Autor:Byrum SD; Burdine MS; Orr L; Mackintosh SG; Authier S; Pouliot M; Hauer-Jensen M; Tackett AJ
Endereço:Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Título:Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.
Fonte:PLoS One; 12(3):e0174771, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Biomarkers); 0 (Blood Proteins); 0 (Proteome)


  3 / 36456 MEDLINE  
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PMID:28757306
Autor:Park SH; Russ BE; McMahon DBT; Koyano KW; Berman RA; Leopold DA
Endereço:Section on Cognitive Neurophysiology and Imaging, National Institute of Mental Health, 49 Convent Dr., Bethesda, MD 20892, USA; Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: soohyun.park@nih.gov.
Título:Functional Subpopulations of Neurons in a Macaque Face Patch Revealed by Single-Unit fMRI Mapping.
Fonte:Neuron; 95(4):971-981.e5, 2017 Aug 16.
ISSN:1097-4199
País de publicação:United States
Idioma:eng
Resumo:Neurons within fMRI-defined face patches of the macaque brain exhibit shared categorical responses to flashed images but diverge in their responses under more natural viewing conditions. Here we investigate functional diversity among neurons in the anterior fundus (AF) face patch, combining whole-brain fMRI with longitudinal single-unit recordings in a local population (<1 mm ). For each cell, we computed a whole-brain correlation map based on its shared time course with voxels throughout the brain during naturalistic movie viewing. Based on this mapping, neighboring neurons showed markedly different affiliation with distant visually responsive areas and fell coarsely into subpopulations. Of these, only one subpopulation (∼16% of neurons) yielded similar correlation maps to the local fMRI signal. The results employ the readout of large-scale fMRI networks and, by indicating multiple functional domains within a single voxel, present a new view of functional diversity within a local neural population.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:S88TT14065 (Oxygen)


  4 / 36456 MEDLINE  
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PMID:28066727
Autor:Feng M; Guo S; Fan S; Zeng X; Zhang Y; Liao Y; Wang J; Zhao T; Wang L; Che Y; Wang J; Ma N; Liu L; Yue L; Li Q
Endereço:Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College Kunming, China.
Título:The Preferential Infection of Astrocytes by Enterovirus 71 Plays a Key Role in the Viral Neurogenic Pathogenesis.
Fonte:Front Cell Infect Microbiol; 6:192, 2016.
ISSN:2235-2988
País de publicação:Switzerland
Idioma:eng
Resumo:The pathological manifestations of fatal cases of human hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) are characterized by inflammatory damage to the central nervous system (CNS). Here, the dynamic distribution of EV71 in the CNS and the subsequent pathological characteristics within different regions of neonatal rhesus macaque brain tissue were studied using a chimeric EV71 expressing green fluorescence protein. The results were compared with brain tissue obtained from the autopsies of deceased EV71-infected HFMD patients. These observations suggested that the virus was prevalent in areas around the blood vessels and nerve nuclei in the brain stem and showed a preference for astrocytes in the CNS. Interestingly, infected astrocytes within the and human and macaque systems exhibited increased expression of excitatory neurotransmitters and cytokines that also stimulated the neuronal secretion of the excitatory neurotransmitters noradrenalin and adrenalin, and this process most likely plays a role in the pathophysiological events that occur during EV71 infection.
Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE
Nome de substância:0 (Cytokines); X4W3ENH1CV (Norepinephrine); YKH834O4BH (Epinephrine)


  5 / 36456 MEDLINE  
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PMID:28414332
Autor:He Z; Han D; Efimova O; Guijarro P; Yu Q; Oleksiak A; Jiang S; Anokhin K; Velichkovsky B; Grünewald S; Khaitovich P
Endereço:CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, SIBS, CAS, Shanghai, China.
Título:Comprehensive transcriptome analysis of neocortical layers in humans, chimpanzees and macaques.
Fonte:Nat Neurosci; 20(6):886-895, 2017 Jun.
ISSN:1546-1726
País de publicação:United States
Idioma:eng
Resumo:While human cognitive abilities are clearly unique, underlying changes in brain organization and function remain unresolved. Here we characterized the transcriptome of the cortical layers and adjacent white matter in the prefrontal cortexes of humans, chimpanzees and rhesus macaques using unsupervised sectioning followed by RNA sequencing. More than 20% of detected genes were expressed predominantly in one layer, yielding 2,320 human layer markers. While the bulk of the layer markers were conserved among species, 376 switched their expression to another layer in humans. By contrast, only 133 of such changes were detected in the chimpanzee brain, suggesting acceleration of cortical reorganization on the human evolutionary lineage. Immunohistochemistry experiments further showed that human-specific expression changes were not limited to neurons but affected a broad spectrum of cortical cell types. Thus, despite apparent histological conservation, human neocortical organization has undergone substantial changes affecting more than 5% of its transcriptome.
Tipo de publicação: JOURNAL ARTICLE


  6 / 36456 MEDLINE  
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PMID:28288127
Autor:Moeller S; Crapse T; Chang L; Tsao DY
Endereço:Division of Biology and Biological Engineering, Computation and Neural Systems, California Institute of Technology, Pasadena, California, USA.
Título:The effect of face patch microstimulation on perception of faces and objects.
Fonte:Nat Neurosci; 20(5):743-752, 2017 May.
ISSN:1546-1726
País de publicação:United States
Idioma:eng
Resumo:What is the range of stimuli encoded by face-selective regions of the brain? We asked how electrical microstimulation of face patches in macaque inferotemporal cortex affects perception of faces and objects. We found that microstimulation strongly distorted face percepts and that this effect depended on precise targeting to the center of face patches. While microstimulation had no effect on the percept of many non-face objects, it did affect the percept of some, including non-face objects whose shape is consistent with a face (for example, apples) as well as somewhat facelike abstract images (for example, cartoon houses). Microstimulation even perturbed the percept of certain objects that did not activate the stimulated face patch at all. Overall, these results indicate that representation of facial identity is localized to face patches, but activity in these patches can also affect perception of face-compatible non-face objects, including objects normally represented in other parts of inferotemporal cortex.
Tipo de publicação: JOURNAL ARTICLE


  7 / 36456 MEDLINE  
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PMID:28232617
Autor:Kwun J; Burghuber C; Manook M; Iwakoshi N; Gibby A; Hong JJ; Knechtle S
Endereço:Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
Título:Humoral Compensation after Bortezomib Treatment of Allosensitized Recipients.
Fonte:J Am Soc Nephrol; 28(7):1991-1996, 2017 Jul.
ISSN:1533-3450
País de publicação:United States
Idioma:eng
Resumo:The efficacy of bortezomib monotherapy in desensitizing kidney transplant candidates with preformed donor-specific antibodies remains unclear. We evaluated the effect of bortezomib on preformed antibodies and upstream components of the B cell response in a primate model sensitized by fully mismatched allogeneic skin transplants to provide mechanistic insights regarding the use of bortezomib as a means of desensitization. Bortezomib treatment given intravenously twice weekly for 1 month (1.3 mg/m per dose) clearly reduced the numbers of antibody-producing cells and CD38 CD19 CD20 plasma cells in the bone marrow ( <0.05), but donor-specific alloantibody levels did not decrease. We observed a rapid but transient induction of circulating IgG B cells and an increased number of proliferating B cells in the lymph nodes after 1 month of treatment. Notably, bortezomib treatment induced germinal center B cell and follicular helper T cell expansion in the lymph nodes. These data suggest that bortezomib-induced plasma cell depletion triggers humoral compensation.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:69G8BD63PP (Bortezomib)


  8 / 36456 MEDLINE  
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PMID:28771513
Autor:Florek NW; Kamlangdee A; Mutschler JP; Kingstad-Bakke B; Schultz-Darken N; Broman KW; Osorio JE; Friedrich TC
Endereço:Department of Pathobiological Sciences, University of Wisconsin-Madison, School of Veterinary Medicine, Madison, Wisconsin, United States of America.
Título:A modified vaccinia Ankara vaccine vector expressing a mosaic H5 hemagglutinin reduces viral shedding in rhesus macaques.
Fonte:PLoS One; 12(8):e0181738, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:The rapid antigenic evolution of influenza viruses requires frequent vaccine reformulations. Due to the economic burden of continuous vaccine reformulation and the threat of new pandemics, there is intense interest in developing vaccines capable of eliciting broadly cross-reactive immunity to influenza viruses. We recently constructed a "mosaic" hemagglutinin (HA) based on subtype 5 HA (H5) and designed to stimulate cellular and humoral immunity to multiple influenza virus subtypes. Modified vaccinia Ankara (MVA) expressing this H5 mosaic (MVA-H5M) protected mice against multiple homosubtypic H5N1 strains and a heterosubtypic H1N1 virus. To assess its potential as a human vaccine we evaluated the ability of MVA-H5M to provide heterosubtypic immunity to influenza viruses in a non-human primate model. Rhesus macaques received an initial dose of either MVA-H5M or plasmid DNA encoding H5M, followed by a boost of MVA-H5M, and then were challenged, together with naïve controls, with the heterosubtypic virus A/California/04/2009 (H1N1pdm). Macaques receiving either vaccine regimen cleared H1N1pdm challenge faster than naïve controls. Vaccination with H5M elicited antibodies that bound H1N1pdm HA, but did not neutralize the H1N1pdm challenge virus. Plasma from vaccinated macaques activated NK cells in the presence of H1N1pdm HA, suggesting that vaccination elicited cross-reactive antibodies capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Although HA-specific T cell responses to the MVA-H5M vaccine were weak, responses after challenge were stronger in vaccinated macaques than in control animals. Together these data suggest that mosaic HA antigens may provide a means for inducing broadly cross-reactive immunity to influenza viruses.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Hemagglutinin Glycoproteins, Influenza Virus); 0 (hemagglutinin, avian influenza A virus)


  9 / 36456 MEDLINE  
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PMID:28358858
Autor:Wang C; Du X; He S; Yuan Y; Han P; Wang D; Chen Y; Liu J; Tian B; Yang G; Yi S; Gao F; Zhong Z; Li H; Cheng J; Lu Y
Endereço:Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
Título:A preclinical evaluation of alternative site for islet allotransplantation.
Fonte:PLoS One; 12(3):e0174505, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:The bone marrow cavity (BMC) has recently been identified as an alternative site to the liver for islet transplantation. This study aimed to compare the BMC with the liver as an islet allotransplantation site in diabetic monkeys. Diabetes was induced in Rhesus monkeys using streptozocin, and the monkeys were then divided into the following three groups: Group1 (islets transplanted in the liver with immunosuppressant), Group 2 (islets transplanted in the tibial BMC), and Group 3 (islets transplanted in the tibial BMC with immunosuppressant). The C-peptide and blood glucose levels were preoperatively measured. An intravenous glucose tolerance test (IVGTT) was conducted to assess graft function, and complete blood cell counts were performed to assess cell population changes. Cytokine expression was measured using an enzyme-linked immune sorbent assay (ELISA) and MILLIPLEX. Five monkeys in Group 3 exhibited a significantly increased insulin-independent time compared with the other groups (Group 1: 78.2 ± 19.0 days; Group 2: 58.8 ± 17.0 days; Group 3: 189.6 ± 26.2 days) and demonstrated increases in plasma C-peptide 4 months after transplantation. The infusion procedure was not associated with adverse effects. Functional islets in the BMC were observed 225 days after transplantation using the dithizone (DTZ) and insulin/glucagon stains. Our results showed that allogeneic islets transplanted in the BMC of diabetic Rhesus monkeys remained alive and functional for a longer time than those transplanted in the liver. This study was the first successful demonstration of allogeneic islet engraftment in the BMC of non-human primates (NHPs).
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Blood Glucose); 0 (C-Peptide); 0 (Immunosuppressive Agents)


  10 / 36456 MEDLINE  
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PMID:28182750
Autor:Pichyangkul S; Spring MD; Yongvanitchit K; Kum-Arb U; Limsalakpetch A; Im-Erbsin R; Ubalee R; Vanachayangkul P; Remarque EJ; Angov E; Smith PL; Saunders DL
Endereço:Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Título:Chemoprophylaxis with sporozoite immunization in P. knowlesi rhesus monkeys confers protection and elicits sporozoite-specific memory T cells in the liver.
Fonte:PLoS One; 12(2):e0171826, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Whole malaria sporozoite vaccine regimens are promising new strategies, and some candidates have demonstrated high rates of durable clinical protection associated with memory T cell responses. Little is known about the anatomical distribution of memory T cells following whole sporozoite vaccines, and immunization of nonhuman primates can be used as a relevant model for humans. We conducted a chemoprophylaxis with sporozoite (CPS) immunization in P. knowlesi rhesus monkeys and challenged via mosquito bites. Half of CPS immunized animals developed complete protection, with a marked delay in parasitemia demonstrated in the other half. Antibody responses to whole sporozoites, CSP, and AMA1, but not CelTOS were detected. Peripheral blood T cell responses to whole sporozoites, but not CSP and AMA1 peptides were observed. Unlike peripheral blood, there was a high frequency of sporozoite-specific memory T cells observed in the liver and bone marrow. Interestingly, sporozoite-specific CD4+ and CD8+ memory T cells in the liver highly expressed chemokine receptors CCR5 and CXCR6, both of which are known for liver sinusoid homing. The majority of liver sporozoite-specific memory T cells expressed CD69, a phenotypic marker of tissue-resident memory (TRM) cells, which are well positioned to rapidly control liver-stage infection. Vaccine strategies that aim to elicit large number of liver TRM cells may efficiently increase the efficacy and durability of response against pre-erythrocytic parasites.
Tipo de publicação: JOURNAL ARTICLE



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