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Alegria-Moran R.,University of Chile | Miranda D.,University of Chile | Barnard M.,University of Bristol | Parra A.,Health Vectors | Lapierre L.,University of Chile
Preventive Veterinary Medicine | Year: 2017

Rabies is a zoonotic disease of great impact to public health. According to the World Health Organization, the country of Chile is currently declared free from human rabies transmitted by dogs. An epidemiological characterization and description was conducted using rabies data from 2003 to 2013 held by the National Program for Prevention and Control of Rabies from the Ministry of Health, consisting of bats samples reported as suspect and samples taken by active surveillance (bats brain tissue). Spatial autocorrelation analysis was performed using Local Indicators of Spatial Association (LISA) statistics, particularly Moran's I index, for the detection of spatial clusters. Temporal descriptive analysis was also carried out. Nine hundred and twenty-seven positive cases were reported, presenting an average of 84 cases per year, mainly originated from passive surveillance (98.5%), whilst only 1.5% of cases were reported by active surveillance. Global positivity for the study period was 7.02% and 0.1% in passive and active surveillance respectively. Most of the cases were reported in the central zone of Chile (88.1%), followed by south zone (9.1%) and north zone (2.8%). At a regional level, Metropolitana (40.6%), Valparaíso (19.1%) and Maule (11.8%) regions reported the majority of the cases. Tadarida brasiliensis (92%) presented the majority of the cases reported, with viral variant 4 (82%) being most commonly diagnosed. Only two cases were detected in companion animals. The central zone presented a positive spatial autocorrelation (Moran's I index = 0.1537, 95% CI = 0.1141–0.1933; p-value = 0.02); north and south zones returned non-significant results (Moran's I index = 0.0517 and −0.0117, 95% CI = −0.0358–0.1392 and −0.0780–0.0546, and p-values = 0.21 and 0.34 respectively). The number of rabies cases decreased between May and August (late fall and winter) and tended to increase during the hot season (December to March), confirmed with the evidence from Autocorrelation analysis and the Ljun-Box test (X2 = 234.85 and p-value < 0.0001). Knowledge of animal rabies epidemiologic behaviour becomes relevant when designing prevention and control measures and surveillance programs. This is especially important considering the high impact to Public Health of this disease and that wildlife rabies in bats remains endemic in Chile. © 2017 Elsevier B.V.


God J.M.,Childrens Research Institute | Cameron C.,Childrens Research Institute | Figueroa J.,Childrens Research Institute | Amria S.,Childrens Research Institute | And 6 more authors.
Journal of Immunology | Year: 2015

Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B cell lymphomas. Although many of c-MYC's functions have been elucidated, its effect on the presentation of Ag through the HLA class II pathway has not been reported previously. This is an issue of considerable importance, given the low immunogenicity of many c-MYC - positive tumors. We report in this paper that increased c-MYC expression has a negative effect on the ability of B cell lymphomas to functionally present Ags/peptides to CD4+ T cells. This defect was associated with alterations in the expression of distinct cofactors as well as interactions of antigenic peptides with class II molecules required for the presentation of class II-peptide complexes and T cell engagement. Using early passage Burkitt's lymphoma (BL) tumors and transformed cells, we show that compared with B lymphoblasts, BL cells express decreased levels of the class II editor HLA-DM, lysosomal thiol-reductase GILT, and a 47-kDa enolase-like protein. Functional Ag presentation was partially restored in BL cells treated with a c-MYC inhibitor, demonstrating the impact of this oncogene on Ag recognition. This restoration of HLA class II-mediated Ag presentation in early passage BL tumors/cells was linked to enhanced HLA-DM expression and a concurrent decrease in HLA-DO in BL cells. Taken together, these results reveal c-MYC exerts suppressive effects at several critical checkpoints in Ag presentation, which contribute to the immunoevasive properties of BL tumors. Copyright © 2015 by The American Association of Immunologists, Inc.


Zhao Y.,University of Texas Medical Branch | Valbuena G.,University of Texas Medical Branch | Hidalgo M.,Pontifical Xavierian University | DeSousa R.,Health Vectors | Brasier A.R.,University of Texas Medical Branch
Molecular and Cellular Proteomics | Year: 2016

Rickettsia conorii is the etiologic agent of Mediterranean spotted fever, a re-emerging infectious disease with significant mortality. This Gram-negative, obligately intracellular pathogen is transmitted via tick bites, resulting in disseminated vascular endothelial cell infection with vascular leakage. In the infected human, Rickettsia conorii infects endothelial cells, stimulating expression of cytokines and pro-coagulant factors. However, the integrated proteomic response of human endothelial cells to R. Conorii infection is not known. In this study, we performed quantitative proteomic profiling of primary human umbilical vein endothelial cells (HUVECs) with established R conorii infection versus those stimulated with endotoxin (LPS) alone. We observed differential expression of 55 proteins in HUVEC whole cell lysates. Of these, we observed induction of signal transducer and activator of transcription (STAT)1, MX dynamin-like GTPase (MX1), and ISG15 ubiquitin-like modifier, indicating activation of the JAK-STAT signaling pathway occurs in R. Conoriiinfected HUVECs. The down-regulated proteins included those involved in the pyrimidine and arginine biosynthetic pathways. A highly specific biotinylated cross-linking enrichment protocol was performed to identify dysregulation of 11 integral plasma membrane proteins that included up-regulated expression of a sodium/potassium transporter and down-regulation of β-actin 1. Analysis of Golgi and soluble Golgi fractions identified up-regulated proteins involved in platelet-endothelial adhesion, phospholipase activity, and IFN activity. Thirty four rickettsial proteins were identified with high confidence in the Golgi, plasma membrane, or secreted protein fractions. The host proteins associated with rickettsial infections indicate activation of interferon-STAT signaling pathways; the disruption of cellular adhesion and alteration of antigen presentation pathways in response to rickettsial infections are distinct from those produced by nonspecific LPS stimulation. These patterns of differentially expressed proteins suggest mechanisms of pathogenesis as well as methods for diagnosis and monitoring Rickettsia infections. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Pontifical Xavierian University, Pathology., Health Vectors, University of Texas Medical Branch and SInstitute for Translational science and Pathology
Type: Journal Article | Journal: Molecular & cellular proteomics : MCP | Year: 2016

Rickettsia conorii is the etiologic agent of Mediterranean spotted fever, a re-emerging infectious disease with significant mortality. This Gram-negative, obligately intracellular pathogen is transmitted via tick bites, resulting in disseminated vascular endothelial cell infection with vascular leakage. In the infected human, Rickettsia conorii infects endothelial cells, stimulating expression of cytokines and pro-coagulant factors. However, the integrated proteomic response of human endothelial cells to R. conorii infection is not known. In this study, we performed quantitative proteomic profiling of primary human umbilical vein endothelial cells (HUVECs) with established R conorii infection versus those stimulated with endotoxin (LPS) alone. We observed differential expression of 55 proteins in HUVEC whole cell lysates. Of these, we observed induction of signal transducer and activator of transcription (STAT)1, MX dynamin-like GTPase (MX1), and ISG15 ubiquitin-like modifier, indicating activation of the JAK-STAT signaling pathway occurs in R. conorii-infected HUVECs. The down-regulated proteins included those involved in the pyrimidine and arginine biosynthetic pathways. A highly specific biotinylated cross-linking enrichment protocol was performed to identify dysregulation of 11 integral plasma membrane proteins that included up-regulated expression of a sodium/potassium transporter and down-regulation of -actin 1. Analysis of Golgi and soluble Golgi fractions identified up-regulated proteins involved in platelet-endothelial adhesion, phospholipase activity, and IFN activity. Thirty four rickettsial proteins were identified with high confidence in the Golgi, plasma membrane, or secreted protein fractions. The host proteins associated with rickettsial infections indicate activation of interferon-STAT signaling pathways; the disruption of cellular adhesion and alteration of antigen presentation pathways in response to rickettsial infections are distinct from those produced by nonspecific LPS stimulation. These patterns of differentially expressed proteins suggest mechanisms of pathogenesis as well as methods for diagnosis and monitoring Rickettsia infections.


Wagner F.M.,Ludwig Maximilians University of Munich | Brizic I.,Ludwig Maximilians University of Munich | Prager A.,Ludwig Maximilians University of Munich | Trsan T.,University of Rijeka | And 12 more authors.
PLoS Pathogens | Year: 2013

Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/gL/gO complex has been described. Knock-out of MCMV gO does impair, but not abolish, virus spread indicating that also MCMV might form an alternative gH/gL complex. Here, we show that the MCMV CC chemokine MCK-2 forms a complex with the glycoprotein gH, a complex which is incorporated into the virion. We could additionally show that mutants lacking both, gO and MCK-2 are not able to produce infectious virus. Trans-complementation of these double mutants with either gO or MCK-2 showed that both proteins can promote infection of host cells, although through different entry pathways. MCK-2 has been extensively studied in vivo by others. It has been shown to be involved in attracting cells for virus dissemination and in regulating antiviral host responses. We now show that MCK-2, by forming a complex with gH, strongly promotes infection of macrophages in vitro and in vivo. Thus, MCK-2 may play a dual role in MCMV infection, as a chemokine regulating the host response and attracting specific target cells and as part of a glycoprotein complex promoting entry into cells crucial for virus dissemination. © 2013 Wagner et al.


Milhano N.,Health Vectors | Saito T.B.,University of Texas Medical Branch | Bechelli J.,University of Texas Medical Branch | Fang R.,University of Texas Medical Branch | And 3 more authors.
Medical and Veterinary Entomology | Year: 2015

Animal models have been developed for the study of rickettsial pathogenesis. However, to understand what occurs during the natural route of rickettsial transmission via the tick bite, the role of tick saliva should be considered in these models. To address this, we analysed the role of tick saliva in the transmission of Rickettsia conorii (Rickettsiales: Rickettsiaceae) in a murine host by intradermally (i.d.) inoculating two groups of susceptible C3H/HeJ mice with this Rickettsia, and infesting one group with nymphal Rhipicephalus sanguineus sensu lato (Ixodida: Ixodidae) ticks. Quantification of bacterial loads and mRNA levels of interleukin-1β (IL-1β), IL-10 and NF-κB was performed in C3H/HeJ lung samples by real-time quantitative polymerase chain reaction (PCR) and real-time reverse transcriptase PCR, respectively. Lung histology was examined to evaluate the pathological manifestations of infection. No statistically significant difference in bacterial load in the lungs of mice was observed between these two groups; however, a statistically significant difference was observed in levels of IL-1β and NF-κB, both of which were higher in the group inoculated with rickettsiae but not infected with ticks. Lung histology in both groups of animals revealed infiltration of inflammatory cells. Overall, this study showed that i.d. inoculation of R.conorii caused infection in the lungs of C3H/HeJ mice and tick saliva inhibited proinflammatory effects. © 2015 The Royal Entomological Society.


Hammoud A.A.,University of Bordeaux 1 | Kirstein N.,University of Bordeaux 1 | Mournetas V.,French National Center for Scientific Research | Darracq A.,Lebanese University | And 5 more authors.
PLoS ONE | Year: 2016

Mouse embryonic stem cells (mESCs) are expanded and maintained pluripotent in vitro in the presence of leukemia inhibitory factor (LIF), an IL6 cytokine family member which displays pleiotropic functions, depending on both cell maturity and cell type. LIF withdrawal leads to heterogeneous differentiation of mESCs with a proportion of the differentiated cells apoptosising. During LIF withdrawal, cells sequentially enter a reversible and irreversible phase of differentiation during which LIF addition induces different effects. However the regulators and effectors of LIF-mediated reprogramming are poorly understood. By employing a LIF-dependent 'plasticity' test, that we set up, we show that Klf5, but not JunB is a key LIF effector. Furthermore PI3K signaling, required for the maintenance of mESC pluripotency, has no effect on mESC plasticity while displaying a major role in committed cells by stimulating expression of the mesodermal marker Brachyury at the expense of endoderm and neuroectoderm lineage markers. We also show that the MMP1 metalloproteinase, which can replace LIF for maintenance of pluripotency, mimics LIF in the plasticity window, but less efficiently. Finally, we demonstrate that mESCs maintain plasticity and pluripotency potentials in vitro under hypoxic/physioxic growth conditions at 3% O2 despite lower levels of Pluri and Master gene expression in comparison to 20% O2. © 2016 Hammoud et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Weller P.,University of Duisburg - Essen | Bankfalvi A.,University of Duisburg - Essen | Gu X.,University of Duisburg - Essen | Dominas N.,University of Duisburg - Essen | And 6 more authors.
European Journal of Cancer | Year: 2014

Expression of the forkhead transcription factor (FoxP3) - an established marker of regulatory T cells - has been found in other cell types as well, including tumour cells. Recent studies indicated that high tumour FoxP3 expression might be associated with a poor outcome of patients with several types of solid cancers. Here, we investigated the role of FoxP3 expressed by the tumour cells in the prognosis of larynx and oro-hypopharynx squamous cell carcinoma (LSCC and OHSCC) - two major subtypes of head and neck cancer. To this end, we analysed by immunohistochemistry the expression of tumour FoxP3 in tissues from 83 LSCC and 89 OHSCC patients in relation to overall survival. In multivariate analysis we found that high tumour FoxP3 expression significantly associated with poor survival in OHSCC but not in LSCC patients. In further studies, we combined the prognostic value of FoxP3 with selected markers of inflammation (cyclooxygenase-2; COX2) or with markers of enhanced tumour migration/invasion (AHNAK and CORTACTIN). Interestingly, we found that the combination of FoxP3 and AHNAK (in LSCC) or FoxP3 and CORTACTIN (in OHSCC) had significantly stronger prognostic values than either marker analysed individually. Combination of FoxP3 and COX2 enhanced the prognostic accuracy only in OHSCC. Thus, our study identifies novel individual and combination markers that might have enhanced and distinct prognostic relevance in different subtypes of head and neck cancer. © 2014 Elsevier Ltd. All rights reserved.


A health assessment, prediction, and management system/method includes a first mechanism that acquires and captures a data set comprising an individuals health status, a local computer server having a first platform for the first mechanism to input the data set, and a central server in communication with the local computer having a second platform for the transmittal of the data set from the local computer server to the central server. A second mechanism accesses the data set in the central server, analyzes the data set, and provides an analytical result. The analytical result may include a health score/grade/index generated by the second mechanism and a health risk assessment provided by the second mechanism. A third platform allows the second mechanism to input the data set and the health score/grade/index. An expert system, with self learning/discovery capability is created based on the data set and the health score/grade/index.


PubMed | Health Vectors, University of Texas Medical Branch and University of Évora
Type: Journal Article | Journal: Medical and veterinary entomology | Year: 2015

Animal models have been developed for the study of rickettsial pathogenesis. However, to understand what occurs during the natural route of rickettsial transmission via the tick bite, the role of tick saliva should be considered in these models. To address this, we analysed the role of tick saliva in the transmission of Rickettsia conorii (Rickettsiales: Rickettsiaceae) in a murine host by intradermally (i.d.) inoculating two groups of susceptible C3H/HeJ mice with this Rickettsia, and infesting one group with nymphal Rhipicephalus sanguineus sensu lato (Ixodida: Ixodidae) ticks. Quantification of bacterial loads and mRNA levels of interleukin-1 (IL-1), IL-10 and NF-B was performed in C3H/HeJ lung samples by real-time quantitative polymerase chain reaction (PCR) and real-time reverse transcriptase PCR, respectively. Lung histology was examined to evaluate the pathological manifestations of infection. No statistically significant difference in bacterial load in the lungs of mice was observed between these two groups; however, a statistically significant difference was observed in levels of IL-1 and NF-B, both of which were higher in the group inoculated with rickettsiae but not infected with ticks. Lung histology in both groups of animals revealed infiltration of inflammatory cells. Overall, this study showed that i.d. inoculation of R.conorii caused infection in the lungs of C3H/HeJ mice and tick saliva inhibited proinflammatory effects.

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