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1,800 |
Application of Behavioral Theories to Disaster and Emergency Health Preparedness: A Systematic Review
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Background: Preparedness for disasters and emergencies at individual, community and organizational levels could be more effective tools in mitigating (the growing incidence) of disaster risk and ameliorating their impacts. That is, to play more significant roles in disaster risk reduction (DRR). Preparedness efforts focus on changing human behaviors in ways that reduce people’s risk and increase their ability to cope with hazard consequences. While preparedness initiatives have used behavioral theories to facilitate DRR, many theories have been used and little is known about which behavioral theories are more commonly used, where they have been used, and why they have been preferred over alternative behavioral theories. Given that theories differ with respect to the variables used and the relationship between them, a systematic analysis is an essential first step to answering questions about the relative utility of theories and providing a more robust evidence base for preparedness components of DRR strategies. The goal of this systematic review was to search and summarize evidence by assessing the application of behavioral theories to disaster and emergency health preparedness across the world. Methods: The protocol was prepared in which the study objectives, questions, inclusion and exclusion criteria, and sensitive search strategies were developed and pilot-tested at the beginning of the study. Using selected keywords, articles were searched mainly in PubMed, Scopus, Mosby’s Index (Nursing Index) and Safetylit databases. Articles were assessed based on their titles, abstracts, and their full texts. The data were extracted from selected articles and results were presented using qualitative and quantitative methods. Results: In total, 2040 titles, 450 abstracts and 62 full texts of articles were assessed for eligibility criteria, whilst five articles were archived from other sources, and then finally, 33 articles were selected. The Health Belief Model (HBM), Extended Parallel Process Model (EPPM), Theory of Planned Behavior (TPB) and Social Cognitive Theories were most commonly applied to influenza (H1N1 and H5N1), floods, and earthquake hazards. Studies were predominantly conducted in USA (13 studies). In Asia, where the annual number of disasters and victims exceeds those in other continents, only three studies were identified. Overall, the main constructs of HBM (perceived susceptibility, severity, benefits, and barriers), EPPM (higher threat and higher efficacy), TPB (attitude and subjective norm), and the majority of the constructs utilized in Social Cognitive Theories were associated with preparedness for diverse hazards. However, while all the theories described above describe the relationships between constituent variables, with the exception of research on Social Cognitive Theories, few studies of other theories and models used path analysis to identify the interdependence relationships between the constructs described in the respective theories/models. Similarly, few identified how other mediating variables could influence disaster and emergency preparedness. Conclusions: The existing evidence on the application of behavioral theories and models to disaster and emergency preparedness is chiefly from developed countries. This raises issues regarding their utility in countries, particularly in Asisa and the Middle East, where cultural characteristics are very different to those prevailing in the Western countries in which theories have been developed and tested. The theories and models discussed here have been applied predominantly to disease outbreaks and natural hazards, and information on their utility as guides to preparedness for man-made hazards is lacking. Hence, future studies related to behavioral theories and models addressing preparedness need to target developing countries where disaster risk and the consequent need for preparedness is high. A need for additional work on demonstrating the relationships of variables and constructs, including more clearly articulating roles for mediating effects was also identified in this analysis.
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1,801 |
Determining the Provincial and National Burden of Influenza-Associated Severe Acute Respiratory Illness in South Africa Using a Rapid Assessment Methodology
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Local disease burden data are necessary to set national influenza vaccination policy. In 2010 the population of South Africa was 50 million and the HIV prevalence was 11%. We used a previously developed methodology to determine severe influenza burden in South Africa. Hospitalized severe acute respiratory illness (SARI) incidence was calculated, stratified by HIV status, for four age groups using data from population-based surveillance in one site situated in Gauteng Province for 2009–2011. These rates were adjusted for each of the remaining 8 provinces based on their prevalence of risk factors for pneumonia and healthcare-seeking behavior. We estimated non-hospitalized influenza-associated SARI from healthcare utilization surveys at two sites and used the percent of SARI cases positive for influenza from sentinel surveillance to derive the influenza-associated SARI rate. We applied rates of hospitalized and non-hospitalized influenza-associated SARI to census data to calculate the national number of cases. The percent of SARI cases that tested positive for influenza ranged from 7–17% depending on age group, year, province and HIV status. In 2010, there were an estimated 21,555 total severe influenza cases in HIV-uninfected individuals and 13,876 in HIV-infected individuals. In 2011, there were an estimated 29,892 total severe influenza cases in HIV-uninfected individuals and 17,289 in HIV-infected individuals. The incidence of influenza-associated SARI was highest in children <5 years and was higher in HIV-infected than HIV-uninfected persons in all age groups. Influenza virus was associated with a substantial amount of severe disease, especially in young children and HIV-infected populations in South Africa.
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1,802 |
Down-regulation of IL-8 expression in human airway epithelial cells through helper-dependent adenoviral-mediated RNA interference
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Interleukin (IL)-8 is a potent neutrophil chemotactic factor and a crucial mediator in neutrophil-dependent inflammation. Various cell types produce IL-8, either in response to external stimuli such as cytokines or bacterial infection, or after malignant transformation. Anti-IL-8 strategies have been considered for anti-inflammatory therapy. In this paper we demonstrate that the RNA interference technique can be used to efficiently down-regulate IL-8 protein expression in airway epithelial cells. We used a helper-dependent adenoviral vector to express a small hairpin (sh)RNA targeting human IL-8 in cultured airway epithelial cells (IB3-1, Cftr(−/−); C38, Cftr-corrected) stimulated with TNF-α, IL-1β or heat-inactivated Burkholderia cenocepacia. Stimulated IL-8 expression in IB3-1 and C38 cells was significantly reduced by shRNA expression. The shRNA targeting IL-8 had no effect on the activation of NF-κB, or on the protein levels of IκB or IL-6, suggesting that this anti-IL-8 strategy was highly specific, and therefore may offer potential for the treatment of inflammatory diseases. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/sj.cr.7290275) contains supplementary material, which is available to authorized users.
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1,803 |
Novel circular single-stranded DNA viruses identified in marine invertebrates reveal high sequence diversity and consistent predicted intrinsic disorder patterns within putative structural proteins
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Viral metagenomics has recently revealed the ubiquitous and diverse nature of single-stranded DNA (ssDNA) viruses that encode a conserved replication initiator protein (Rep) in the marine environment. Although eukaryotic circular Rep-encoding ssDNA (CRESS-DNA) viruses were originally thought to only infect plants and vertebrates, recent studies have identified these viruses in a number of invertebrates. To further explore CRESS-DNA viruses in the marine environment, this study surveyed CRESS-DNA viruses in various marine invertebrate species. A total of 27 novel CRESS-DNA genomes, with Reps that share less than 60.1% identity with previously reported viruses, were recovered from 21 invertebrate species, mainly crustaceans. Phylogenetic analysis based on the Rep revealed a novel clade of CRESS-DNA viruses that included approximately one third of the marine invertebrate associated viruses identified here and whose members may represent a novel family. Investigation of putative capsid proteins (Cap) encoded within the eukaryotic CRESS-DNA viral genomes from this study and those in GenBank demonstrated conserved patterns of predicted intrinsically disordered regions (IDRs), which can be used to complement similarity-based searches to identify divergent structural proteins within novel genomes. Overall, this study expands our knowledge of CRESS-DNA viruses associated with invertebrates and explores a new tool to evaluate divergent structural proteins encoded by these viruses.
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1,804 |
Meta-genomic analysis of toilet waste from long distance flights; a step towards global surveillance of infectious diseases and antimicrobial resistance
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Human populations worldwide are increasingly confronted with infectious diseases and antimicrobial resistance spreading faster and appearing more frequently. Knowledge regarding their occurrence and worldwide transmission is important to control outbreaks and prevent epidemics. Here, we performed shotgun sequencing of toilet waste from 18 international airplanes arriving in Copenhagen, Denmark, from nine cities in three world regions. An average of 18.6 Gb (14.8 to 25.7 Gb) of raw Illumina paired end sequence data was generated, cleaned, trimmed and mapped against reference sequence databases for bacteria and antimicrobial resistance genes. An average of 106,839 (0.06%) reads were assigned to resistance genes with genes encoding resistance to tetracycline, macrolide and beta-lactam resistance genes as the most abundant in all samples. We found significantly higher abundance and diversity of genes encoding antimicrobial resistance, including critical important resistance (e.g. bla(CTX-M)) carried on airplanes from South Asia compared to North America. Presence of Salmonella enterica and norovirus were also detected in higher amounts from South Asia, whereas Clostridium difficile was most abundant in samples from North America. Our study provides a first step towards a potential novel strategy for global surveillance enabling simultaneous detection of multiple human health threatening genetic elements, infectious agents and resistance genes.
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1,805 |
Nogo-B protects mice against lipopolysaccharide-induced acute lung injury
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Nogo-B, a member of the reticulon 4 protein family, plays a critical role in tissue repair and acute inflammation. Its role in acute lung injury (ALI) remains unclear. Here, we assessed the function of Nogo-B during tissue injury in a lipopolysaccharide (LPS)-induced ALI mouse model. We found that pulmonary Nogo-B was significantly repressed after LPS instillation in C57BL/6 mice. Over-expression of pulmonary Nogo-B using an adenovirus vector carrying the Nogo-B-RFP-3flag gene (Ad-Nogo-B) significantly prolonged the survival of mice challenged with a lethal dose of LPS. The Ad-Nogo-B-treated mice also had less severe lung injury, less alveolar protein exudation, and a higher number of macrophages but less neutrophil infiltration compared with Ad-RFP-treated mice. Interestingly, microarray analysis showed that the Ad-Nogo-B-treated mice had different gene expression profiles compared with the controls and the prominent expression of genes related to wound healing and the humoral immune response after LPS induction. Of the 49 differently expressed genes, we found that the expression of PTX3 was significantly up-regulated following Nogo-B over-expression as observed in lung tissues and RAW264.7 cells. In conclusion, Nogo-B plays a protective role against LPS-induced ALI, and this effect might be exerted through the modulation of alveolar macrophage recruitment and PTX3 production.
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1,806 |
EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT
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Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway.
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1,807 |
Identification and pathogenicity of a variant porcine epidemic diarrhea virus field strain with reduced virulence
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BACKGROUND: Since 2010, a variant Porcine epidemic diarrhea virus (PEDV), which causes an acute, highly contagious, and devastating viral enteric disease with a high mortality rate in suckling pigs, broke out in China and spread rapidly to neighboring countries, even to the North America. This virus gradually became the main subtype of PEDV worldwide. However, there were no reports of mild pathogenicity of a variant porcine epidemic diarrhea virus in China. FINDINGS: In 2013, a PEDV-positive sample from a sow with very mild clinical sign was used to inoculate in Vero cells to isolate the virus. This PEDV field strain, designated FL2013 strain, was successfully propagated and genetically characterized. The phylogenetic trees based upon either the complete genome or S gene showed that the FL2013 strain belongs to the genogroup G2b. The S gene of FL2013 has a 7-aa deletion (FEKVHVQ) in the C-terminus comparison with the other G2 PEDV sequences. Further comparative pathology study indicated that the FL2013 strain had reduced virulence to newborn piglets. CONCLUSIONS: A novel variant PEDV strain FL2013 with reduced virulence, as determined by the pathological study, was identified from east China. This strain is closely related to the genogroup- 2 PEDV strains prevalent in the U.S. and China currently, but had a short deletion at the 3′- end of the spike gene.
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1,808 |
Bridge hosts, a missing link for disease ecology in multi-host systems
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In ecology, the grouping of species into functional groups has played a valuable role in simplifying ecological complexity. In epidemiology, further clarifications of epidemiological functions are needed: while host roles may be defined, they are often used loosely, partly because of a lack of clarity on the relationships between a host’s function and its epidemiological role. Here we focus on the definition of bridge hosts and their epidemiological consequences. Bridge hosts provide a link through which pathogens can be transmitted from maintenance host populations or communities to receptive populations that people want to protect (i.e., target hosts). A bridge host should (1) be competent for the pathogen or able to mechanically transmit it; and (2) come into direct contact or share habitat with both maintenance and target populations. Demonstration of bridging requires an operational framework that integrates ecological and epidemiological approaches. We illustrate this framework using the example of the transmission of Avian Influenza Viruses across wild bird/poultry interfaces in Africa and discuss a range of other examples that demonstrate the usefulness of our definition for other multi-host systems. Bridge hosts can be particularly important for understanding and managing infectious disease dynamics in multi-host systems at wildlife/domestic/human interfaces, including emerging infections. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13567-015-0217-9) contains supplementary material, which is available to authorized users.
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1,809 |
The Interferon-Inducible Mouse Apolipoprotein L9 and Prohibitins Cooperate to Restrict Theiler’s Virus Replication
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Apolipoprotein L9b (Apol9b) is an interferon-stimulated gene (ISG) that has antiviral activity and is weakly expressed in primary mouse neurons as compared to other cell types. Here, we show that both Apol9 isoforms (Apol9b and Apol9a) inhibit replication of Theiler’s murine encephalomyelitis virus (TMEV) but not replication of vesicular stomatitis virus (VSV), Murid herpesvirus-4 (MuHV-4), or infection by a lentiviral vector. Apol9 genes are strongly expressed in mouse liver and, to a lesser extent, in pancreas, adipose tissue and intestine. Their expression is increased by type I interferon and viral infection. In contrast to genuine apolipoproteins that are involved in lipid transport, ApoL9 has an intracytoplasmic localization and does not seem to be secreted. The cytoplasmic localization of ApoL9 is in line with the observation that ApoL9 inhibits the replication step of TMEV infection. In contrast to human ApoL6, ApoL9 did not sensitize cells to apoptosis, in spite of the presence of a conserved putative BH3 domain, required for antiviral activity. ApoL9a and b isoforms interact with cellular prohibitin 1 (Phb1) and prohibitin 2 (Phb2) and this interaction might contribute to ApoL9 antiviral activity. Knocking down Phb2 slightly increased TMEV replication, irrespective of ApoL9 overexpression. The antiviral activity of prohibitins against TMEV contrasts with the pro-viral activity of prohibitins observed for VSV and reported previously for Dengue 2 (DENV-2), Chikungunya (CHIKV) and influenza H5N1 viruses. ApoL9 is thus an example of ISG displaying a narrow antiviral range, which likely acts in complex with prohibitins to restrict TMEV replication.
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1,810 |
Mid-Season Estimates of Influenza Vaccine Effectiveness against Influenza A(H3N2) Hospitalization in the Elderly in Quebec, Canada, January 2015
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BACKGROUND: The 2014/15 influenza season in Canada was characterized by an early epidemic due to vaccine-mismatched influenza A(H3N2) viruses, disproportionately affecting elderly individuals ≥65-years-old. We assessed vaccine effectiveness (VE) against A(H3N2) hospitalization among elderly individuals during the peak weeks of the 2014/15 epidemic in Quebec, Canada. METHODS: Nasal specimens and clinical/epidemiological data were collected within 7 days of illness onset from elderly patients admitted with respiratory symptoms to one of four participating hospitals between November 30, 2014 and January 13, 2015. Cases tested RT-PCR positive for influenza A(H3N2) and controls tested negative for any influenza. VE was assessed by test-negative case-control design. RESULTS: There were 314 participants including 186 cases (62% vaccinated) and 128 controls (59% vaccinated) included in primary VE analysis. Median age was 81.5 years, two-thirds were admitted from the community and 91% had underlying comorbidity. Crude VE against A(H3N2) hospitalization was -17% (95%CI: -86% to 26%), decreasing to -23% (95%CI: -99 to 23%) with adjustment for age and comorbidity, and to -39% (95%CI: -142 to 20%) with additional adjustment for specimen collection interval, calendar time, type of residence and hospital. In sensitivity analyses, VE estimates were improved toward the null with restriction to participants admitted from the community (-2%; 95%CI: -105 to 49%) or with specimen collection ≤4 days since illness onset (- 8%; 95%CI: -104 to 43%) but further from the null with restriction to participants with comorbidity (-51%; 95%CI: -169 to 15%). CONCLUSION: The 2014/15 mismatched influenza vaccine provided elderly patients with no cross-protection against hospitalization with the A(H3N2) epidemic strain, reinforcing the need for adjunct protective measures among high-risk individuals and improved vaccine options.
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1,811 |
Enhancing Human Immunodeficiency Virus-Specific CD8(+) T Cell Responses with Heteroclitic Peptides
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Human immunodeficiency virus (HIV)-specific CD8(+) T cells play a critical role in containing HIV replication and delaying disease progression. However, HIV-specific CD8(+) T cells become progressively more “exhausted” as chronic HIV infection proceeds. Symptoms of T cell exhaustion range from expression of inhibitory receptors and selective loss of cytokine production capacity through reduced proliferative potential, impaired differentiation into effector cells and increased susceptibility to apoptosis. While effective combination antiretroviral therapy (cART) durably reduces HIV viremia to undetectable levels, this alone does not restore the full pluripotency of HIV-specific CD8(+) T cells. In a number of studies, a subset of peptide epitope variants categorized as heteroclitic, restimulated more potent cellular immune responses in vitro than did the native, immunizing peptides themselves. This property of heteroclitic peptides has been exploited in experimental cancer and chronic viral infection models to promote clearance of transformed cells and persistent viruses. In this review, we consider the possibility that heteroclitic peptides could improve the efficacy of therapeutic vaccines as part of HIV immunotherapy or eradication strategies. We review literature on heteroclitic peptides and illustrate their potential to beneficially modulate the nature of HIV-specific T cell responses toward those found in the small minority of HIV-infected, aviremic cART-naïve persons termed elite controllers or long-term non-progressors. Our review suggests that the efficacy of HIV vaccines could be improved by identification, testing, and incorporation of heteroclitic variants of native HIV peptide epitopes.
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1,812 |
Macrophage Polarization in Virus-Host Interactions
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Macrophage involvement in viral infections and antiviral states is common. However, this involvement has not been well-studied in the paradigm of macrophage polarization, which typically has been categorized by the dichotomy of classical (M1) and alternative (M2) statuses. Recent studies have revealed the complexity of macrophage polarization in response to various cellular mediators and exogenous stimuli by adopting a multipolar view to revisit the differential process of macrophages, especially those re-polarized during viral infections. Here, through examination of viral infections targeting macrophages/monocytic cells, we focus on the direct involvement of macrophage polarization during viral infections. Type I and type III interferons (IFNs) are critical in regulation of viral pathogenesis and host antiviral infection; thus, we propose to incorporate IFN-mediated antiviral states into the framework of macrophage polarization. This view is supported by the multifunctional properties of type I IFNs, which potentially elicit and regulate both M1- and M2-polarization in addition to inducing the antiviral state, and by the discoveries of viral mechanisms to adapt and modulate macrophage polarization. Indeed, several recent studies have demonstrated effective prevention of viral diseases through manipulation of macrophage immune statuses.
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1,813 |
Immunogenicity and Safety of an EB66 Cell-Culture-Derived Influenza A/Indonesia/5/2005(H5N1) AS03-Adjuvanted Vaccine: A Phase 1 Randomized Trial
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BACKGROUND: Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. METHODS: A CC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, “CC-H5N1”) was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. RESULTS: AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. No vaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine. CONCLUSIONS: The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CC-H5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. CLINICAL TRIALS REGISTRATION: NCT01236040.
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1,814 |
Mechanical ventilation with heliox in an animal model of acute respiratory distress syndrome
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BACKGROUND: Heliox has a lower density and higher diffusion capacity compared to oxygen-in-air. We hypothesized that heliox ventilation allows for a reduction in minute volume ventilation and inspiratory pressures needed for adequate gas exchange in an animal model of an acute lung injury. METHODS: After intratracheal instillation of lipopolysaccharide (10 mg/kg), adult rats were randomized to ventilation with either a gas mixture of helium/oxygen (50:50%) or oxygen/air (50:50%). They were mechanically ventilated according to the ARDSnet recommendations with tidal volumes of 6 ml/kg and monitored with a pneumotachometer. Bronchoalveolar lavage fluid was analyzed for markers of lung injury, and embedded lung sections were histologically scored for lung injury. RESULTS: Heliox limited the increase in driving pressures needed to achieve preset tidal volumes, with a concomitant decrease in loss of compliance. Heliox did neither allow for reduced minute volume ventilation in this model nor improve gas exchange. Also, heliox did not reduce lung injury. CONCLUSIONS: Heliox modestly improved respiratory mechanics but did not improve lung injury in this rat model of acute respiratory distress syndrome.
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1,815 |
Identification of Glial Activation Markers by Comparison of Transcriptome Changes between Astrocytes and Microglia following Innate Immune Stimulation
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The activation of astrocytes and microglia is often associated with diseases of the central nervous system (CNS). Understanding how activation alters the transcriptome of these cells may offer valuable insight regarding how activation of these cells mediate neurological damage. Furthermore, identifying common and unique pathways of gene expression during activation may provide new insight into the distinct roles these cells have in the CNS during infection and inflammation. Since recent studies indicate that TLR7 recognizes not only viral RNA but also microRNAs that are released by damaged neurons and elevated during neurological diseases, we first examined the response of glial cells to TLR7 stimulation using microarray analysis. Microglia were found to generate a much stronger response to TLR7 activation than astrocytes, both in the number of genes induced as well as fold induction. Although the primary pathways induced by both cell types were directly linked to immune responses, microglia also induced pathways associated with cellular proliferation, while astrocytes did not. Targeted analysis of a subset of the upregulated genes identified unique mRNA, including Ifi202b which was only upregulated by microglia and was found to be induced during both retroviral and bunyavirus infections in the CNS. In addition, other genes including Birc3 and Gpr84 as well as two expressed sequences AW112010 and BC023105 were found to be induced in both microglia and astrocytes and were upregulated in the CNS following virus infection. Thus, expression of these genes may a useful measurement of glial activation during insult or injury to the CNS.
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1,816 |
Resistance to Rhabdoviridae Infection and Subversion of Antiviral Responses
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Interferon (IFN) treatment induces the expression of hundreds of IFN-stimulated genes (ISGs). However, only a selection of their products have been demonstrated to be responsible for the inhibition of rhabdovirus replication in cultured cells; and only a few have been shown to play a role in mediating the antiviral response in vivo using gene knockout mouse models. IFNs inhibit rhabdovirus replication at different stages via the induction of a variety of ISGs. This review will discuss how individual ISG products confer resistance to rhabdoviruses by blocking viral entry, degrading single stranded viral RNA, inhibiting viral translation or preventing release of virions from the cell. Furthermore, this review will highlight how these viruses counteract the host IFN system.
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1,817 |
Representing virus-host interactions and other multi-organism processes in the Gene Ontology
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BACKGROUND: The Gene Ontology project is a collaborative effort to provide descriptions of gene products in a consistent and computable language, and in a species-independent manner. The Gene Ontology is designed to be applicable to all organisms but up to now has been largely under-utilized for prokaryotes and viruses, in part because of a lack of appropriate ontology terms. METHODS: To address this issue, we have developed a set of Gene Ontology classes that are applicable to microbes and their hosts, improving both coverage and quality in this area of the Gene Ontology. Describing microbial and viral gene products brings with it the additional challenge of capturing both the host and the microbe. Recognising this, we have worked closely with annotation groups to test and optimize the GO classes, and we describe here a set of annotation guidelines that allow the controlled description of two interacting organisms. CONCLUSIONS: Building on the microbial resources already in existence such as ViralZone, UniProtKB keywords and MeGO, this project provides an integrated ontology to describe interactions between microbial species and their hosts, with mappings to the external resources above. Housing this information within the freely-accessible Gene Ontology project allows the classes and annotation structure to be utilized by a large community of biologists and users.
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1,818 |
The Role of Scientific Collections in Scientific Preparedness
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Building on the findings and recommendations of the Interagency Working Group on Scientific Collections, Scientific Collections International (SciColl) aims to improve the rapid access to science collections across disciplines within the federal government and globally, between government agencies and private research institutions. SciColl offered a novel opportunity for the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, to explore the value of scientific research collections under the science preparedness initiative and integrate it as a research resource at each stage in the emergence of the infectious diseases cycle. Under the leadership of SciColl’s executive secretariat at the Smithsonian Institution, and with multiple federal and international partners, a workshop during October 2014 fully explored the intersections of the infectious disease cycle and the role scientific collections could play as an evidentiary scientific resource to mitigate risks associated with emerging infectious diseases.
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1,819 |
Surgical site infection in critically ill patients with secondary and tertiary peritonitis: epidemiology, microbiology and influence in outcomes
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BACKGROUND: Surgical site infection (SSI) remains a significant problem in the postoperative period that can negatively affect clinical outcomes. Microbiology findings are typically similar to other nosocomial infections, with differences dependent on microbiology selection due to antibiotic pressure or the resident flora. However, this is poorly understood in the critical care setting. We therefore aimed to assess the incidence, epidemiology and microbiology of SSI and its association with outcomes in patients with severe peritonitis in the intensive care unit (ICU). METHODS: We prospectively studied 305 consecutive patients admitted to our surgical ICU from 2010 to 2014 with a diagnosis of secondary or tertiary peritonitis. We collected the following data: SSI diagnosis, demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II score, type of surgery, microbiology, antibiotic treatment and outcomes. Microbiological sampling was done by means of swabs. RESULTS: We identified 269 episodes of SSI in 162 patients (53.1 %) aged 64.4 ± 14.3 years, of which 200 episodes occurred in men (64.6 %). The mean APACHE II and SAPS II scores were 19.7 ± 7.8 and 36.5 ± 16.1 respectively. The mean ICU and hospital stays were 19.8 ± 24.8 and 21.7 ± 30 days respectively. Pseudomonas spp. (n = 52, 19.3 %), Escherichia coli (n = 55, 20.4 %) and Candida spp. (n = 46, 17.1 %) were the most frequently isolated microorganisms, but gram-positive cocci (n = 80, 29.7 %) were also frequent. Microorganisms isolated from SSIs were associated with a higher incidence of antibiotic resistance (64.9 %) in ICU patients, but not with higher in-hospital mortality. However, patients who suffered from SSI had longer ICU admissions (odds ratio = 1.024, 95 % confidence interval 1.010–1.039, P = 0.001). CONCLUSIONS: The incidence of SSI in secondary or tertiary peritonitis requiring ICU admission is very high. Physicians may consider antibiotic-resistant pathogens, gram-positive cocci and fungi when choosing empiric antibiotic treatment for SSI, although more studies are needed to confirm our results due to the inherent limitations of the microbiological sampling with swabs performed in our research. The presence of SSI may be associated with prolonged ICU stays, but without any influence on overall mortality.
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1,820 |
Beyond phage display: non-traditional applications of the filamentous bacteriophage as a vaccine carrier, therapeutic biologic, and bioconjugation scaffold
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For the past 25 years, phage display technology has been an invaluable tool for studies of protein–protein interactions. However, the inherent biological, biochemical, and biophysical properties of filamentous bacteriophage, as well as the ease of its genetic manipulation, also make it an attractive platform outside the traditional phage display canon. This review will focus on the unique properties of the filamentous bacteriophage and highlight its diverse applications in current research. Particular emphases are placed on: (i) the advantages of the phage as a vaccine carrier, including its high immunogenicity, relative antigenic simplicity and ability to activate a range of immune responses, (ii) the phage’s potential as a prophylactic and therapeutic agent for infectious and chronic diseases, (iii) the regularity of the virion major coat protein lattice, which enables a variety of bioconjugation and surface chemistry applications, particularly in nanomaterials, and (iv) the phage’s large population sizes and fast generation times, which make it an excellent model system for directed protein evolution. Despite their ubiquity in the biosphere, metagenomics work is just beginning to explore the ecology of filamentous and non-filamentous phage, and their role in the evolution of bacterial populations. Thus, the filamentous phage represents a robust, inexpensive, and versatile microorganism whose bioengineering applications continue to expand in new directions, although its limitations in some spheres impose obstacles to its widespread adoption and use.
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1,821 |
Aeromonas salmonicida Infection Only Moderately Regulates Expression of Factors Contributing to Toll-Like Receptor Signaling but Massively Activates the Cellular and Humoral Branches of Innate Immunity in Rainbow Trout (Oncorhynchus mykiss)
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Toll-like receptors (TLRs) are known to detect a defined spectrum of microbial structures. However, the knowledge about the specificity of teleost Tlr factors for distinct pathogens is limited so far. We measured baseline expression profiles of 18 tlr genes and associated signaling factors in four immune-relevant tissues of rainbow trout Oncorhynchus mykiss. Intraperitoneal injection of a lethal dose of Aeromonas salmonicida subsp. salmonicida induced highly increased levels of cytokine mRNAs during a 72-hour postinfection (hpi) period. In contrast, only the fish-specific tlr22a2 and the downstream factor irak1 featured clearly increased transcript levels, while the mRNA concentrations of many other tlr genes decreased. Flow cytometry quantified cell trafficking after infection indicating a dramatic influx of myeloid cells into the peritoneum and a belated low level immigration of lymphoid cells. T and B lymphocytes were differentiated with RT-qPCR revealing that B lymphocytes emigrated from and T lymphocytes immigrated into head kidney. In conclusion, no specific TLR can be singled out as a dominant receptor for A. salmonicida. The recruitment of cellular factors of innate immunity rather than induced expression of pathogen receptors is hence of key importance for mounting a first immune defense against invading A. salmonicida.
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1,822 |
Epidemic Wave Dynamics Attributable to Urban Community Structure: A Theoretical Characterization of Disease Transmission in a Large Network
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BACKGROUND: Multiple waves of transmission during infectious disease epidemics represent a major public health challenge, but the ecological and behavioral drivers of epidemic resurgence are poorly understood. In theory, community structure—aggregation into highly intraconnected and loosely interconnected social groups—within human populations may lead to punctuated outbreaks as diseases progress from one community to the next. However, this explanation has been largely overlooked in favor of temporal shifts in environmental conditions and human behavior and because of the difficulties associated with estimating large-scale contact patterns. OBJECTIVE: The aim was to characterize naturally arising patterns of human contact that are capable of producing simulated epidemics with multiple wave structures. METHODS: We used an extensive dataset of proximal physical contacts between users of a public Wi-Fi Internet system to evaluate the epidemiological implications of an empirical urban contact network. We characterized the modularity (community structure) of the network and then estimated epidemic dynamics under a percolation-based model of infectious disease spread on the network. We classified simulated epidemics as multiwave using a novel metric and we identified network structures that were critical to the network’s ability to produce multiwave epidemics. RESULTS: We identified robust community structure in a large, empirical urban contact network from which multiwave epidemics may emerge naturally. This pattern was fueled by a special kind of insularity in which locally popular individuals were not the ones forging contacts with more distant social groups. CONCLUSIONS: Our results suggest that ordinary contact patterns can produce multiwave epidemics at the scale of a single urban area without the temporal shifts that are usually assumed to be responsible. Understanding the role of community structure in epidemic dynamics allows officials to anticipate epidemic resurgence without having to forecast future changes in hosts, pathogens, or the environment.
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1,823 |
Basal Autophagy Is Required for Herpes simplex Virus-2 Infection
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Autophagy is a conserved catabolic process of the cell, which plays an important role in regulating plethora of infections. The role of autophagy in Herpes simplex virus-2 (HSV-2) infection is unknown. Here, we found that HSV-2 does not allow induction of an autophagic response to infection, but maintains basal autophagy levels mostly unchanged during productive infection. Thus, we investigated the importance of basal autophagy for HSV-2 infection, using pharmacological autophagy suppression or cells genetically deficient in an autophagy-essential gene (ATG5). Interference with basal autophagy flux in cells significantly reduced viral replication and diminished the infection. These results indicate that basal autophagy plays an indispensable role required for a productive infection. Importantly, this study draws a sharp distinction between induced and basal autophagy, where the former acts as a viral clearance mechanism abrogating infection, while the latter supports infection.
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1,824 |
The role of heterogeneity in contact timing and duration in network models of influenza spread in schools
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Influenza poses a significant health threat to children, and schools may play a critical role in community outbreaks. Mathematical outbreak models require assumptions about contact rates and patterns among students, but the level of temporal granularity required to produce reliable results is unclear. We collected objective contact data from students aged 5–14 at an elementary school and middle school in the state of Utah, USA, and paired those data with a novel, data-based model of influenza transmission in schools. Our simulations produced within-school transmission averages consistent with published estimates. We compared simulated outbreaks over the full resolution dynamic network with simulations on networks with averaged representations of contact timing and duration. For both schools, averaging the timing of contacts over one or two school days caused average outbreak sizes to increase by 1–8%. Averaging both contact timing and pairwise contact durations caused average outbreak sizes to increase by 10% at the middle school and 72% at the elementary school. Averaging contact durations separately across within-class and between-class contacts reduced the increase for the elementary school to 5%. Thus, the effect of ignoring details about contact timing and duration in school contact networks on outbreak size modelling can vary across different schools.
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1,825 |
A Novel Virus Causes Scale Drop Disease in Lates calcarifer
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From 1992 onwards, outbreaks of a previously unknown illness have been reported in Asian seabass (Lates calcarifer) kept in maricultures in Southeast Asia. The most striking symptom of this emerging disease is the loss of scales. It was referred to as scale drop syndrome, but the etiology remained enigmatic. By using a next-generation virus discovery technique, VIDISCA-454, sequences of an unknown virus were detected in serum of diseased fish. The near complete genome sequence of the virus was determined, which shows a unique genome organization, and low levels of identity to known members of the Iridoviridae. Based on homology of a series of putatively encoded proteins, the virus is a novel member of the Megalocytivirus genus of the Iridoviridae family. The virus was isolated and propagated in cell culture, where it caused a cytopathogenic effect in infected Asian seabass kidney and brain cells. Electron microscopy revealed icosahedral virions of about 140 nm, characteristic for the Iridoviridae. In vitro cultured virus induced scale drop syndrome in Asian seabass in vivo and the virus could be reisolated from these infected fish. These findings show that the virus is the causative agent for the scale drop syndrome, as each of Koch’s postulates is fulfilled. We have named the virus Scale Drop Disease Virus. Vaccines prepared from BEI- and formalin inactivated virus, as well as from E. coli produced major capsid protein provide efficacious protection against scale drop disease.
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1,826 |
Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine
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The leishmaniases are a complex of vector-borne diseases caused by protozoan parasites of the genus Leishmania. LEISHDNAVAX is a multi-antigen, T-cell epitope-enriched DNA vaccine candidate against human leishmaniasis. The vaccine candidate has been proven immunogenic and showed prophylactic efficacy in preclinical studies. Here, we describe the safety testing of LEISHDNAVAX in naive mice and rats, complemented by the demonstration of tolerability in Leishmania-infected mice. Biodistribution and persistence were examined following single and repeated intradermal (i.d.) administration to rats. DNA vectors were distributed systemically but did not accumulate upon repeated injections. Although vector DNA was cleared from most other tissues within 60 days after the last injection, it persisted in skin at the site of injection and in draining lymph nodes. Evaluation of single-dose and repeated-dose toxicity of the vaccine candidate after i.d. administration to naive, non-infected mice did not reveal any safety concerns. LEISHDNAVAX was also well tolerated in Leishmania-infected mice. Taken together, our results substantiate a favorable safety profile of LEISHDNAVAX in both naive and infected animals and thus, support the initiation of clinical trials for both preventive and therapeutic applications of the vaccine.
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1,827 |
Affect of Early Life Oxygen Exposure on Proper Lung Development and Response to Respiratory Viral Infections
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Children born preterm often exhibit reduced lung function and increased severity of response to respiratory viruses, suggesting that premature birth has compromised proper development of the respiratory epithelium and innate immune defenses. Increasing evidence suggests that premature birth promotes aberrant lung development likely due to the neonatal oxygen transition occurring before pulmonary development has matured. Given that preterm infants are born at a point of time where their immune system is also still developing, early life oxygen exposure may also be disrupting proper development of innate immunity. Here, we review current literature in hopes of stimulating research that enhances understanding of how the oxygen environment at birth influences lung development and host defense. This knowledge may help identify those children at risk for disease and ideally culminate in the development of novel therapies that improve their health.
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1,828 |
NMR and MD Studies Reveal That the Isolated Dengue NS3 Protease Is an Intrinsically Disordered Chymotrypsin Fold Which Absolutely Requests NS2B for Correct Folding and Functional Dynamics
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Dengue genome encodes a two component protease complex (NS2B-NS3pro) essential for the viral maturation/infectivity, thus representing a key drug target. Previously, due to its “complete insolubility”, the isolated NS3pro could not be experimentally studied and it remains elusive what structure it adopts without NS2B and why NS2B is indispensable. Here as facilitated by our previous discovery, the isolated NS3pro has been surprisingly deciphered by NMR to be the first intrinsically-disordered chymotrypsin-like fold, which exists in a loosely-packed state with non-native long-range interactions as revealed by paramagnetic relaxation enhancement (PRE). The disordered NS3pro appears to be needed for binding a human host factor to trigger the membrane remodeling. Moreover, we have in vitro refolded the NS3pro in complex with either NS2B (48–100) or the full-length NS2B (1–130) anchored into the LMPC micelle, and the two complexes have similar activities but different dynamics. We also performed molecular dynamics (MD) simulations and the results revealed that NS2B shows the highest structural fluctuations in the complex, thus providing the dynamic basis for the observation on its conformational exchange between open and closed states. Remarkably, the NS2B cofactor plays a central role in maintaining the correlated motion network required for the catalysis as we previously decoded for the SARS 3CL protease. Indeed, a truncated NS2B (48–100;Δ77–84) with the flexible loop deleted is able to trap the NS2B-NS3pro complex in a highly dynamic and catalytically-impotent state. Taken together, our study implies potential strategies to perturb the NS2B-NS3pro interface for design of inhibitors for treating dengue infection.
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1,829 |
Phenotypic and Genetic Characterization of Avian Influenza H5N2 Viruses with Intra- and Inter-Duck Variations in Taiwan
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BACKGROUND: Human infections with avian influenza viruses (AIVs) have frequently raised global concerns of emerging, interspecies-transmissible viruses with pandemic potential. Waterfowl, the predominant reservoir of influenza viruses in nature, harbor precursors of different genetic lineages that have contributed to novel pandemic influenza viruses in the past. METHODS: Two duck influenza H5N2 viruses, DV518 and DV413, isolated through virological surveillance at a live-poultry market in Taiwan, showed phylogenetic relatedness but exhibited different replication capabilities in mammalian Madin-Darby Canine Kidney (MDCK) cells. This study characterizes the replication properties of the two duck H5N2 viruses and the determinants involved. RESULTS: The DV518 virus replicated more efficiently than DV413 in both MDCK and chicken DF1 cells. Interestingly, the infection of MDCK cells by DV518 formed heterogeneous plaques with great differences in size [large (L) and small (S)], and the two viral strains (p518-L and p518-S) obtained from plaque purification exhibited distinguishable replication kinetics in MDCK cells. Nonetheless, both plaque-purified DV518 strains still maintained their growth advantages over the plaque-purified p413 strain. Moreover, three amino acid substitutions in PA (P224S), PB2 (E72D), and M1 (A128T) were identified in intra-duck variations (p518-L vs p518-S), whereas other changes in HA (N170D), NA (I56T), and NP (Y289H) were present in inter-duck variations (DV518 vs DV413). Both p518-L and p518-S strains had the N170D substitution in HA, which might be related to their greater binding to MDCK cells. Additionally, polymerase activity assays on 293T cells demonstrated the role of vRNP in modulating the replication capability of the duck p518-L viruses in mammalian cells. CONCLUSION: These results demonstrate that intra-host phenotypic variation occurs even within an individual duck. In view of recent human infections by low pathogenic AIVs, this study suggests possible determinants involved in the stepwise selection of virus variants from the duck influenza virus population which may facilitate inter-species transmission.
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1,830 |
Tropism and Induction of Cytokines in Human Embryonic-Stem Cells-Derived Neural Progenitors upon Inoculation with Highly- Pathogenic Avian H5N1 Influenza Virus
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Central nervous system (CNS) dysfunction caused by neurovirulent influenza viruses is a dreaded complication of infection, and may play a role in some neurodegenerative conditions, such as Parkinson-like diseases and encephalitis lethargica. Although CNS infection by highly pathogenic H5N1 virus has been demonstrated, it is unknown whether H5N1 infects neural progenitor cells, nor whether such infection plays a role in the neuroinflammation and neurodegeneration. To pursue this question, we infected human neural progenitor cells (hNPCs) differentiated from human embryonic stem cells in vitro with H5N1 virus, and studied the resulting cytopathology, cytokine expression, and genes involved in the differentiation. Human embryonic stem cells (BG01) were maintained and differentiated into the neural progenitors, and then infected by H5N1 virus (A/Chicken/Thailand/CUK2/04) at a multiplicity of infection of 1. At 6, 24, 48, and 72 hours post-infection (hpi), cytopathic effects were observed. Then cells were characterized by immunofluorescence and electron microscopy, supernatants quantified for virus titers, and sampled cells studied for candidate genes.The hNPCs were susceptible to H5N1 virus infection as determined by morphological observation and immunofluorescence. The infection was characterized by a significant up-regulation of TNF-α gene expression, while expressions of IFN-α2, IFN-β1, IFN-γ and IL-6 remained unchanged compared to mock-infected controls. Moreover, H5N1 infection did not appear to alter expression of neuronal and astrocytic markers of hNPCs, such as β-III tubulin and GFAP, respectively. The results indicate that hNPCs support H5N1 virus infection and may play a role in the neuroinflammation during acute viral encephalitis.
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1,831 |
Safety and Immunogenicity of a Subvirion Monovalent Unadjuvanted Inactivated Influenza A(H3N2) Variant Vaccine in Healthy Persons ≥18 Years Old
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BACKGROUND: Variant influenza A(H3N2) viruses (H3N2v) have transmitted recently from pigs to humans in the United States. Vaccines strategies are needed. METHODS: Healthy adults received 2 doses of subvirion H3N2v vaccine (15 µg of hemagglutinin/dose) 21 days apart in this open-label trial. Serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody (Ab) titers were measured before and 8 and 21 days after each dose. Memory B-cell (MBC) responses were assessed. RESULTS: Vaccine was well tolerated. A total of 40% of subjects had an HAI Ab titer of ≥40 before vaccination. Eight-seven percent (95% confidence interval [CI], 79%–93%) and 73% (95% CI, 63%–81%) of subjects 18–64 years old (98 subjects) and ≥65 years old (90 subjects), respectively, had an HAI titer of ≥40 21 days after dose 1 (P = .01); 51% (95% CI, 41%–61%) and 52% (95% CI, 41%–62%) of younger and older subjects, respectively, developed ≥4-fold rises in titer (P = not significant). Neut Ab response patterns were similar. Geometric mean titers were higher in younger subjects. Dose 2 provided no significant enhancement in responses. Cross-reactive MBCs were detected before vaccination and expanded after vaccination. Preexisting H3N2v-specific MBCs positively correlated with early increases in vaccine-induced Ab. CONCLUSIONS: In most healthy adults, one 15-µg dose of vaccine elicited levels of HAI Abs associated with protection. Studies in children and elderly individuals are indicated to define the immunization needs of these groups. CLINICAL TRIALS REGISTRATION: NCT01746082.
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1,832 |
Comparative Analysis of Transcriptional Profiles of Adult Schistosoma japonicum from Different Laboratory Animals and the Natural Host, Water Buffalo
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BACKGROUND: Schistosomiasis is one of the most widely distributed parasitic diseases in the world. Schistosoma japonicum, a zoonotic parasite with a wide range of mammalian hosts, is one of the major pathogens of this disease. Although numerous studies on schistosomiasis japonica have been performed using laboratory animal models, systematic comparative analysis of whole-genome expression profiles in parasites from different laboratory animals and nature mammalian hosts is lacking to date. METHODOLOGY/PRINCIPAL FINDINGS: Adult schistosomes were obtained from laboratory animals BALB/c mice, C57BL/6 mice, New Zealand white rabbits and the natural host, water buffaloes. The gene expression profiles of schistosomes from these animals were obtained and compared by genome-wide oligonucleotide microarray analysis. The results revealed that the gene expression profiles of schistosomes from different laboratory animals and buffaloes were highly consistent (r>0.98) genome-wide. Meanwhile, a total of 450 genes were identified to be differentially expressed in schistosomes which can be clustered into six groups. Pathway analysis revealed that these genes were mainly involved in multiple signal transduction pathways, amino acid, energy, nucleotide and lipid metabolism. We also identified a group of 1,540 abundantly and stably expressed gene products in adult worms, including a panel of 179 Schistosoma- or Platyhelminthes-specific genes that may be essential for parasitism and may be regarded as novel potential anti-parasite intervention targets for future research. CONCLUSIONS/SIGNIFICANCE: This study provides a comprehensive database of gene expression profiles of schistosomes derived from different laboratory animals and water buffaloes. An expanded number of genes potentially affecting the development of schistosomes in different animals were identified. These findings lay the foundation for schistosomiasis research in different laboratory animals and natural hosts at the transcriptional level and provide a valuable resource for screening anti-schistosomal intervention targets.
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1,833 |
Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy
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Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.
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1,834 |
GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders
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BACKGROUND: The majority of cases with severe pulmonary alveolar proteinosis (PAP) are caused by auto-antibodies against GM-CSF. A multitude of genetic and exogenous causes are responsible for few other cases. Goal of this study was to determine the prevalence of GATA2 deficiency in children and adults with PAP and hematologic disorders. METHODS: Of 21 patients with GM-CSF-autoantibody negative PAP, 13 had no other organ involvement and 8 had some form of hematologic disorder. The latter were sequenced for GATA2. RESULTS: Age at start of PAP ranged from 0.3 to 64 years, 4 patients were children. In half of the subjects GATA2-sequence variations were found, two of which were considered disease causing. Those two patients had the typical phenotype of GATA2 deficiency, one of whom additionally showed a previously undescribed feature – a cholesterol pneumonia. Hematologic disorders included chronic myeloic leukemia, juvenile myelo-monocytic leukemia, lymphoblastic leukemia, sideroblastic anemia and two cases of myelodysplastic syndrome (MDS). A 4 year old child with MDS and DiGeorge Syndrome Type 2 was rescued with repetitive whole lung lavages and her PAP was cured with heterologous stem cell transplant. CONCLUSIONS: In children and adults with severe GM-CSF negative PAP a close cooperation between pneumologists and hemato-oncologists is needed to diagnose the underlying diseases, some of which are caused by mutations of transcription factor GATA2. Treatment with whole lung lavages as well as stem cell transplant may be successful.
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1,835 |
Improving health aid for a better planet: The planning, monitoring and evaluation tool (PLANET)
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BACKGROUND: International development assistance for health (DAH) quadrupled between 1990 and 2012, from US$ 5.6 billion to US$ 28.1 billion. This generates an increasing need for transparent and replicable tools that could be used to set investment priorities, monitor the distribution of funding in real time, and evaluate the impact of those investments. METHODS: In this paper we present a methodology that addresses these three challenges. We call this approach PLANET, which stands for planning, monitoring and evaluation tool. Fundamentally, PLANET is based on crowdsourcing approach to obtaining information relevant to deployment of large–scale programs. Information is contributed in real time by a diverse group of participants involved in the program delivery. FINDINGS: PLANET relies on real–time information from three levels of participants in large–scale programs: funders, managers and recipients. At each level, information is solicited to assess five key risks that are most relevant to each level of operations. The risks at the level of funders involve systematic neglect of certain areas, focus on donor’s interests over that of program recipients, ineffective co–ordination between donors, questionable mechanisms of delivery and excessive loss of funding to “middle men”. At the level of managers, the risks are corruption, lack of capacity and/or competence, lack of information and /or communication, undue avoidance of governmental structures / preference to non–governmental organizations and exclusion of local expertise. At the level of primary recipients, the risks are corruption, parallel operations / “verticalization”, misalignment with local priorities and lack of community involvement, issues with ethics, equity and/or acceptability, and low likelihood of sustainability beyond the end of the program’s implementation. INTERPRETATION: PLANET is intended as an additional tool available to policy–makers to prioritize, monitor and evaluate large–scale development programs. In this, it should complement tools such as LiST (for health care/interventions), EQUIST (for health care/interventions) and CHNRI (for health research), which also rely on information from local experts and on local context to set priorities in a transparent, user–friendly, replicable, quantifiable and specific, algorithmic–like manner.
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1,836 |
The Fecal Virome of Children with Hand, Foot, and Mouth Disease that Tested PCR Negative for Pathogenic Enteroviruses
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Hand, foot, and mouth disease (HFMD) affects infant and young children. A viral metagenomic approach was used to identify the eukaryotic viruses in fecal samples from 29 Thai children with clinical diagnosis of HFMD collected during the 2012 outbreak. These children had previously tested negative by PCR for enterovirus 71 and coxsackievirus A16 and A6. Deep sequencing revealed nine virus families: Picornaviridae, Astroviridae, Parvoviridae, Caliciviridae, Paramyxoviridae, Adenoviridae, Reoviridae, Picobirnaviridae, and Polyomaviridae. The highest number of viral sequences belonged to human rhinovirus C, astrovirus-MLB2, and coxsackievirus A21. Our study provides an overview of virus community and highlights a broad diversity of viruses found in feces from children with HFMD.
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1,837 |
Concentration, Size Distribution, and Infectivity of Airborne Particles Carrying Swine Viruses
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When pathogens become airborne, they travel associated with particles of different size and composition. Particle size determines the distance across which pathogens can be transported, as well as the site of deposition and the survivability of the pathogen. Despite the importance of this information, the size distribution of particles bearing viruses emitted by infectious animals remains unknown. In this study we characterized the concentration and size distribution of inhalable particles that transport influenza A virus (IAV), porcine reproductive and respiratory syndrome virus (PRRSV), and porcine epidemic diarrhea virus (PEDV) generated by acutely infected pigs and assessed virus viability for each particle size range. Aerosols from experimentally infected pigs were sampled for 24 days using an Andersen cascade impactor able to separate particles by size (ranging from 0.4 to 10 micrometer (μm) in diameter). Air samples collected for the first 9, 20 and the last 3 days of the study were analyzed for IAV, PRRSV and PEDV, respectively, using quantitative reverse transcription polymerase chain reaction (RT-PCR) and quantified as geometric mean copies/m(3) within each size range. IAV was detected in all particle size ranges in quantities ranging from 5.5x10(2) (in particles ranging from 1.1 to 2.1μm) to 4.3x10(5) RNA copies/m(3) in the largest particles (9.0–10.0μm). PRRSV was detected in all size ranges except particles between 0.7 and 2.1μm in quantities ranging from 6x10(2) (0.4–0.7μm) to 5.1x10(4) RNA copies/m(3) (9.0–10.0μm). PEDV, an enteric virus, was detected in all particle sizes and in higher quantities than IAV and PRRSV (p < 0.0001) ranging from 1.3x10(6) (0.4–0.7μm) to 3.5x10(8) RNA copies/m(3) (9.0–10.0μm). Infectious status was demonstrated for the 3 viruses, and in the case of IAV and PRRSV, viruses were isolated from particles larger than 2.1μm. In summary, our results indicated that airborne PEDV, IAV and PRRSV can be found in a wide range of particle sizes. However, virus viability is particle size dependent.
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1,838 |
Japanese Encephalitis in Assam, India: Need to Increase Healthcare Workers’ Understanding to Improve Health Care
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INTRODUCTION: Japanese encephalitis (JE) is a major cause of high morbidity and mortality in several states across India. However, in 2014, a sharp rise was observed in the number of cases of JE in north-eastern Assam state, and 51% of the total cases of JE in India were reported from the Assam in the same year. In this regard, a study was conducted to evaluate the knowledge and attitudes of healthcare workers in Darrang, a district of Assam highly affected by JE. METHODS: A cross sectional study was conducted for 2 months among HCWs in the major district hospital of Darrang, Assam. A pre-tested, self-administered questionnaire was used to collect data from the participants. Convenience sampling approach was used to collect data from different departments of the hospitals. Descriptive and logistic regression analyses were used to express the results. RESULTS: The knowledge of HCWs regarding JE was poor with a mean knowledge score of 11.02±2.39 (out of 17), while their attitudes were positive with a mean attitudes score of 43.16± 2.47 (ranging from 13 to 52). Overall, 40.4% and 74.3% of participants demonstrated good knowledge and positive attitudes respectively. Cut-off score for good knowledge and positive attitudes toward JE was set as ≥12 and >40 respectively. Older participants (40–49 years) and experienced workers (>10 years) were significantly associated with good knowledge as compared to their referent group (p<0.05), while knowledge of nurses and other orderlies were significantly lower than physicians (p<0.01). Similar factors were associated with the positive attitudes of the participants with the exception of experience. Television was the major source of information regarding JE reported by HCWs (79%). CONCLUSION: Although the knowledge was not optimized, HCWs exhibited positive attitudes towards JE. Future research is required to design, implement and evaluate interventions to improve the knowledge of JE among HCWs.
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1,839 |
Highlighting Indication of extracorporeal membrane oxygenation in endocrine emergencies
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Extracorporeal membrane oxygenation (ECMO) has been repeatedly used to rescue patients with cardiopulmonary arrest. However, its clinical utility in endocrine emergencies remains unclear. Herein, we describe a case series of 12 patients presenting with refractory shock secondary to endocrine emergencies who were rescued by ECMO support. Patients were identified between 2005 and 2012 from our ECMO registry. The diagnostic distribution was as follows: pheochromocytoma crisis (n = 4), thyroid storm (n = 5), and diabetic ketoacidosis (n = 3). The initial presentation of pheochromocytoma crisis was indistinguishable from acute myocardial infarction (AMI) and frequently accompanied by paroxysmal hypertension and limb ischemia. Thyroid storm was characterized by hyperbilirubinemia and severe gastrointestinal bleeding, whereas neurological symptoms were common in diabetic ketoacidosis. The clinical outcomes of patients with endocrine emergencies were compared with those of 80 cases with AMI who received ECMO because of cardiogenic shock. The cardiac function and the general conditions showed a significantly faster recovery in patients with endocrine emergencies than in those with AMI. We conclude that ECMO support can be clinically useful in endocrine emergencies. The screening of endocrine diseases should be considered during the resuscitation of patients with refractory circulatory shock.
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1,840 |
Pneumonia among adults hospitalized with laboratory-confirmed seasonal influenza virus infection—United States, 2005–2008
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BACKGROUND: Influenza and pneumonia combined are the leading causes of death due to infectious diseases in the United States. We describe factors associated with pneumonia among adults hospitalized with influenza. METHODS: Through the Emerging Infections Program, we identified adults ≥ 18 years, who were hospitalized with laboratory-confirmed influenza during October 2005 through April 2008, and had a chest radiograph (CXR) performed. Pneumonia was defined as the presence of a CXR infiltrate and either an ICD-9-CM code or discharge summary diagnosis of pneumonia. RESULTS: Among 4,765 adults hospitalized with influenza, 1392 (29 %) had pneumonia. In multivariable analysis, factors associated with pneumonia included: age ≥ 75 years, adjusted odds ratio (AOR) 1.27 (95 % confidence interval 1.10–1.46), white race AOR 1.24 (1.03–1.49), nursing home residence AOR 1.37 (1.14–1.66), chronic lung disease AOR 1.37 (1.18–1.59), immunosuppression AOR 1.45 (1.19–1.78), and asthma AOR 0.76 (0.62–0.92). Patients with pneumonia were significantly more likely to require intensive care unit (ICU) admission (27 % vs. 10 %), mechanical ventilation (18 % vs. 5 %), and to die (9 % vs. 2 %). CONCLUSIONS: Pneumonia was present in nearly one-third of adults hospitalized with influenza and was associated with ICU admission and death. Among patients hospitalized with influenza, older patients and those with certain underlying conditions are more likely to have pneumonia. Pneumonia is common among adults hospitalized with influenza and should be evaluated and treated promptly. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-015-1004-y) contains supplementary material, which is available to authorized users.
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1,841 |
Genomic analysis of codon usage shows influence of mutation pressure, natural selection, and host features on Marburg virus evolution
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BACKGROUND: The Marburg virus (MARV) has a negative-sense single-stranded RNA genome, belongs to the family Filoviridae, and is responsible for several outbreaks of highly fatal hemorrhagic fever. Codon usage patterns of viruses reflect a series of evolutionary changes that enable viruses to shape their survival rates and fitness toward the external environment and, most importantly, their hosts. To understand the evolution of MARV at the codon level, we report a comprehensive analysis of synonymous codon usage patterns in MARV genomes. Multiple codon analysis approaches and statistical methods were performed to determine overall codon usage patterns, biases in codon usage, and influence of various factors, including mutation pressure, natural selection, and its two hosts, Homo sapiens and Rousettus aegyptiacus. RESULTS: Nucleotide composition and relative synonymous codon usage (RSCU) analysis revealed that MARV shows mutation bias and prefers U- and A-ended codons to code amino acids. Effective number of codons analysis indicated that overall codon usage among MARV genomes is slightly biased. The Parity Rule 2 plot analysis showed that GC and AU nucleotides were not used proportionally which accounts for the presence of natural selection. Codon usage patterns of MARV were also found to be influenced by its hosts. This indicates that MARV have evolved codon usage patterns that are specific to both of its hosts. Moreover, selection pressure from R. aegyptiacus on the MARV RSCU patterns was found to be dominant compared with that from H. sapiens. Overall, mutation pressure was found to be the most important and dominant force that shapes codon usage patterns in MARV. CONCLUSIONS: To our knowledge, this is the first detailed codon usage analysis of MARV and extends our understanding of the mechanisms that contribute to codon usage and evolution of MARV. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12862-015-0456-4) contains supplementary material, which is available to authorized users.
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1,842 |
Shedding of Infectious Borna Disease Virus-1 in Living Bicolored White-Toothed Shrews
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BACKGROUND: Many RNA viruses arise from animal reservoirs, namely bats, rodents and insectivores but mechanisms of virus maintenance and transmission still need to be addressed. The bicolored white-toothed shrew (Crocidura leucodon) has recently been identified as reservoir of the neurotropic Borna disease virus 1 (BoDV-1). PRINCIPAL FINDINGS: Six out of eleven wild living bicoloured white-toothed shrews were trapped and revealed to be naturally infected with BoDV-1. All shrews were monitored in captivity in a long-term study over a time period up to 600 days that differed between the individual shrews. Interestingly, all six animals showed an asymptomatic course of infection despite virus shedding via various routes indicating a highly adapted host-pathogen interaction. Infectious virus and viral RNA were demonstrated in saliva, urine, skin swabs, lacrimal fluid and faeces, both during the first 8 weeks of the investigation period and for long time shedding after more than 250 days in captivity. CONCLUSIONS: The various ways of shedding ensure successful virus maintenance in the reservoir population but also transmission to accidental hosts such as horses and sheep. Naturally BoDV-1-infected living shrews serve as excellent tool to unravel host and pathogen factors responsible for persistent viral co-existence in reservoir species while maintaining their physiological integrity despite high viral load in many organ systems.
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1,843 |
Upstream Disaster Management to Support People Experiencing Homelessness
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The unique context of day-to-day living for people who are chronically homeless or living with housing insecurity puts them at high risk during community disasters. The impacts of extreme events, such as flooding, storms, riots, and other sources of community disruption, underscore the importance of preparedness efforts and fostering community resilience. This study is part of larger initiative focused on enhancing resilience and preparedness among high risk populations. The purpose of this study was to explore critical issues and strategies to promote resilience and disaster preparedness among people who are homeless in Canada. A sample of interviews (n=21) from key informants across Canada was analyzed to explore existing programs and supports for homeless populations. The data was selected from a larger sample of (n=43) interviews focused on programs and supports for people who are at heightened risk for negative impacts during disasters. Qualitative content analysis was used to extract emergent themes and develop a model of multi-level collaboration to support disaster resilience among people who are homeless. The results indicate there is a need for more upstream continuity planning, collaboration and communication between the emergency management sector and community service organizations that support people who are homeless. Prioritization and investment in the social determinants of health and community supports is necessary to promote resilience among this high-risk population. The findings from this study highlight the importance of acknowledging community support organizations as assets in disaster preparedness. Day-to-day resilience is an ongoing theme for people who are chronically homeless or living with housing insecurity. Upstream investment to build adaptive capacity and collaborate with community organizations is an important strategy to enhance community resilience.
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1,844 |
Transcriptional slippage in the positive-sense RNA virus family Potyviridae
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The family Potyviridae encompasses ∼30% of plant viruses and is responsible for significant economic losses worldwide. Recently, a small overlapping coding sequence, termed pipo, was found to be conserved in the genomes of all potyvirids. PIPO is expressed as part of a frameshift protein, P3N-PIPO, which is essential for virus cell-to-cell movement. However, the frameshift expression mechanism has hitherto remained unknown. Here, we demonstrate that transcriptional slippage, specific to the viral RNA polymerase, results in a population of transcripts with an additional “A” inserted within a highly conserved GAAAAAA sequence, thus enabling expression of P3N-PIPO. The slippage efficiency is ∼2% in Turnip mosaic virus and slippage is inhibited by mutations in the GAAAAAA sequence. While utilization of transcriptional slippage is well known in negative-sense RNA viruses such as Ebola, mumps and measles, to our knowledge this is the first report of its widespread utilization for gene expression in positive-sense RNA viruses.
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1,845 |
Serotype 1 and 8 Pneumococci Evade Sensing by Inflammasomes in Human Lung Tissue
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Streptococcus pneumoniae is a major cause of pneumonia, sepsis and meningitis. The pore-forming toxin pneumolysin is a key virulence factor of S. pneumoniae, which can be sensed by the NLRP3 inflammasome. Among the over 90 serotypes, serotype 1 pneumococci (particularly MLST306) have emerged across the globe as a major cause of invasive disease. The cause for its particularity is, however, incompletely understood. We therefore examined pneumococcal infection in human cells and a human lung organ culture system mimicking infection of the lower respiratory tract. We demonstrate that different pneumococcal serotypes differentially activate inflammasome-dependent IL-1β production in human lung tissue and cells. Whereas serotype 2, 3, 6B, 9N pneumococci expressing fully haemolytic pneumolysins activate NLRP3 inflammasome-dependent responses, serotype 1 and 8 strains expressing non-haemolytic toxins are poor activators of IL-1β production. Accordingly, purified haemolytic pneumolysin but not serotype 1-associated non-haemolytic toxin activates strong IL-1β production in human lungs. Our data suggest that the evasion of inflammasome-dependent innate immune responses by serotype 1 pneumococci might contribute to their ability to cause invasive diseases in humans.
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1,846 |
Different Blood Cell-Derived Transcriptome Signatures in Cows Exposed to Vaccination Pre- or Postpartum
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Periparturient cows have been found to reveal immunosuppression, frequently associated with increased susceptibility to uterine and mammary infections. To improve understanding of the causes and molecular regulatory mechanisms accounting for this phenomenon around calving, we examined the effect of an antigen challenge on gene expression modulation on cows prior to (BC) or after calving (AC) using whole transcriptome sequencing (RNAseq). The transcriptome analysis of the cows’ blood identified a substantially higher number of loci affected in BC cows (2,235) in response to vaccination compared to AC cows (208) and revealed a divergent transcriptional profile specific for each group. In BC cows, a variety of loci involved in immune defense and cellular signaling processes were transcriptionally activated, whereas protein biosynthesis and posttranslational processes were tremendously impaired in response to vaccination. Furthermore, energy metabolism in the blood cells of BC cows was shifted from oxidative phosphorylation to the glycolytic system. In AC cows, the number and variety of regulated pathways involved in immunomodulation and maintenance of immnunocompetence are considerably lower after vaccination, and upregulation of arginine degradation was suggested as an immunosuppressive mechanism. Elevated transcript levels of erythrocyte-specific genes involved in gas exchange processes were a specific transcriptional signature in AC cows pointing to hematopoiesis activation. The divergent and substantially lower magnitude of transcriptional modulation in response to vaccination in AC cows provides evidence for a suppressed immune capacity of early lactating cows on the molecular level and demonstrates that an efficient immune response of cows is related to their physiological and metabolic status.
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1,847 |
A Multiple Antigenic Peptide Mimicking Peptidoglycan Induced T Cell Responses to Protect Mice from Systemic Infection with Staphylococcus aureus
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Due to the enormous capacity of Staphylococcus aureus to acquire antibiotic resistance, it becomes imperative to develop vaccines for decreasing the risk of its life-threatening infections. Peptidoglycan (PGN) is a conserved and major component of S. aureus cell wall. However, it has not been used as a vaccine candidate since it is a thymus-independent antigen. In this study, we synthesized a multiple antigenic peptide, named MAP27, which comprised four copies of a peptide that mimics the epitope of PGN. After immunization with MAP27 five times and boosting with heat-inactivated bacterium one time, anti-MAP27 serum bound directly to S. aureus or PGN. Immunization with MAP27 decreased the bacterial burden in organs of BALB/c mice and significantly prolonged their survival time after S. aureus lethal-challenge. The percentage of IFN-γ(+)CD3(+) T cells and IL-17(+)CD4(+) T cells in spleen, as well as the levels of IFN-γ, IL-17A/F and CCL3 in spleen and lung, significantly increased in the MAP27-immunized mice after infection. Moreover, in vitro incubation of heat-inactivated S. aureus with splenocytes isolated from MAP27-immunized mice stimulated the production of IFN-γ and IL-17A/F. Our findings demonstrated that MAP27, as a thymus-dependent antigen, is efficient at eliciting T cell-mediated responses to protect mice from S. aureus infection. This study sheds light on a possible strategy to design vaccines against S. aureus.
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1,848 |
Severe Measles Infection: The Spectrum of Disease in 36 Critically Ill Adult Patients
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France has recently witnessed a nationwide outbreak of measles. Data on severe forms of measles in adults are lacking. We sought to describe the epidemiologic, clinical, treatment, and prognostic aspects of the disease in adult patients who required admission to an intensive care unit (ICU). We performed a retrospective analysis of a cohort of 36 adults admitted to a total of 64 ICUs throughout France for complications of measles from January 1, 2009, to December 31, 2011. All cases of measles were confirmed by serologic testing and/or reverse transcription polymerase chain reaction. The cohort consisted of 21 male and 15 female patients, with a median age of 29.2 years (25th–75th interquartile range [IQR], 27.2–34.2 yr) and a median Simplified Acute Physiology Score (SAPS II) of 13 (IQR, 9–18). Among the 26 patients whose measles vaccination status was documented, none had received 2 injections. One patient had developed measles during childhood. Underlying comorbid conditions included chronic respiratory disease in 9 patients, immunosuppression in 7 patients, and obesity in 3 patients, while measles affected 5 pregnant women. Respiratory complications induced by measles infection led to ICU admission in 32 cases, and measles-related neurologic complications led to ICU admission in 2 cases. Two patients were admitted due to concurrent respiratory and neurologic complications. Bacterial superinfection of measles-related airway infection was suspected in 28 patients and was documented in 8. Four cases of community-acquired pneumonia, 6 cases of ventilator-associated pneumonia, 1 case of tracheobronchitis, and 2 cases of sinusitis were microbiologically substantiated. Of 11 patients who required mechanical ventilation, 9 developed acute respiratory distress syndrome (ARDS). Among the patients with ARDS, extraalveolar air leak complications occurred in 4 cases. Five patients died, all of whom were severely immunocompromised. On follow-up, 1 patient had severe chronic respiratory failure related to lung fibrosis, and 2 patients had mild lower limb paraparesis along with bladder dysfunction, both of which were ascribable to measles-induced encephalitis and myelitis. Among the 5 pregnant patients, the course of measles infection was uneventful, albeit 1 patient underwent emergent cesarean delivery because of fetal growth restriction. Measles is a disease with protean and potentially deceptive clinical manifestations, especially in the immunocompromised patient. Measles-associated pneumonitis and its complications, and less commonly postinfectious encephalomyelitis, are the main source of morbidity and mortality. In contrast with the usually benign course of the disease in immunocompetent patients, measles occurring in immunocompromised patients gives rise to lethal complications including ARDS, with or without bacterial superinfection. Other patients potentially at high risk for severe measles are young adults and pregnant women. Measles pneumonitis may predispose to air leak disease in patients using mechanical ventilation. To date, vaccination remains the most potent tool to control measles infection.
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1,849 |
Inhibitory effects of magnolol and honokiol on human calcitonin aggregation
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Amyloid formation is associated with multiple amyloidosis diseases. Human calcitonin (hCT) is a typical amyloidogenic peptide, its aggregation is associated with medullary carcinoma of the thyroid (MTC), and also limits its clinical application. Magnolia officinalis is a traditional Chinese herbal medicine; its two major polyphenol components, magnolol (Mag) and honokiol (Hon), have displayed multiple functions. Polyphenols like flavonoids and their derivatives have been extensively studied as amyloid inhibitors. However, the anti-amyloidogenic property of a biphenyl backbone containing polyphenols such as Mag and Hon has not been reported. In this study, these two compounds were tested for their effects on hCT aggregation. We found that Mag and Hon both inhibited the amyloid formation of hCT, whereas Mag showed a stronger inhibitory effect; moreover, they both dose-dependently disassembled preformed hCT aggregates. Further immuno-dot blot and dynamic light scattering studies suggested Mag and Hon suppressed the aggregation of hCT both at the oligomerization and the fibrillation stages, while MTT-based and dye-leakage assays demonstrated that Mag and Hon effectively reduced cytotoxicity caused by hCT aggregates. Furthermore, isothermal titration calorimetry indicated Mag and Hon both interact with hCT. Together, our study suggested a potential anti-amyloidogenic property of these two compounds and their structure related derivatives.
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1,850 |
Identification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus
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Avian influenza viruses of the H5N1 subtype pose a serious global health threat due to the high mortality (>60%) associated with the disease caused by these viruses and the lack of protective antibodies to these viruses in the general population. The factors that enable avian H5N1 influenza viruses to replicate in humans are not completely understood. Here we use a high-throughput screening approach to identify novel mutations in the polymerase genes of an avian H5N1 virus that confer efficient polymerase activity in mammalian cells. Several of the identified mutations (which have previously been found in natural isolates) increase viral replication in mammalian cells and virulence in infected mice compared with the wild-type virus. The identification of amino-acid mutations in avian H5N1 influenza virus polymerase complexes that confer increased replication and virulence in mammals is important for the identification of circulating H5N1 viruses with an increased potential to infect humans. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/ncomms8491) contains supplementary material, which is available to authorized users.
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1,851 |
One Health – a strategy for resilience in a changing arctic
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The circumpolar north is uniquely vulnerable to the health impacts of climate change. While international Arctic collaboration on health has enhanced partnerships and advanced the health of inhabitants, significant challenges lie ahead. One Health is an approach that considers the connections between the environment, plant, animal and human health. Understanding this is increasingly critical in assessing the impact of global climate change on the health of Arctic inhabitants. The effects of climate change are complex and difficult to predict with certainty. Health risks include changes in the distribution of infectious disease, expansion of zoonotic diseases and vectors, changing migration patterns, impacts on food security and changes in water availability and quality, among others. A regional network of diverse stakeholder and transdisciplinary specialists from circumpolar nations and Indigenous groups can advance the understanding of complex climate-driven health risks and provide community-based strategies for early identification, prevention and adaption of health risks in human, animals and environment. We propose a regional One Health approach for assessing interactions at the Arctic human–animal–environment interface to enhance the understanding of, and response to, the complexities of climate change on the health of the Arctic inhabitants.
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1,852 |
Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy
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BACKGROUND: Addition of high-dose cytarabine (HDCA) to the conventional cyclophosphamide/total-body irradiation (CY/TBI) regimen significantly improved prognosis after cord blood transplantation (CBT) for adult acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The efficacy of HDCA in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), however, has not yet been elucidated. FINDINGS: We conducted a cohort study to compare the prognosis of HDCA/CY/TBI (N = 435) and CY/TBI (N = 1667) in BMT/PBSCT for AML/MDS using a Japanese transplant registry database. The median age was 38 years, and 86.0 % of the patients had AML. Unrelated donors comprised 54.6 %, and 63.9 % of donors were human leukocyte antigen (HLA)-matched. Overall survival (OS) was not improved in the HDCA/CY/TBI group (adjusted hazard ratio (HR), 1.14; p = 0.13). Neutrophil engraftment was inferior (HR, 0.80; p < 0.01), and the incidence of hemorrhagic cystitis and thrombotic microangiopathy increased in HDCA/CY/TBI (HR, 1.47 and 1.60; p = 0.06 and 0.04, respectively), leading to significantly higher non-relapse mortality (NRM; HR, 1.48; p < 0.01). Post-transplant relapse and tumor-related mortality were not suppressed by the addition of HDCA. CONCLUSIONS: This study indicated the inefficacy of HDCA/CY/TBI in BMT/PBSCT for AML/MDS. Our results should be validated in large-scale prospective studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-015-0201-x) contains supplementary material, which is available to authorized users.
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1,853 |
Nutritional Impact of Dietary Plasma Proteins in Animals Undergoing Experimental Challenge and Implications for Patients with Inflammatory Bowel Disorders: A Meta-analysis(1)(2)
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Studies administering plasma protein isolates (PPIs) to experimentally challenged animals have reported improvements in growth, food intake, and overall condition when compared with animals fed control diets, due in part to improvements in gut barrier function, normalization of cytokine signals, and support of enteric immune function. These and early clinical studies suggest that nutritional therapy with PPIs may similarly assist in restoring homeostasis to gut barrier function in humans experiencing mild or more acute enteropathic symptomatology such as irritable bowel syndrome and inflammatory bowel disease. This meta-analysis evaluated the ability of PPIs to promote weight gain and food intake in weanling animals, primarily piglets, after oral challenge with various enteric pathogens or bacterial toxins. MEDLINE, EMBASE, and PubMed were searched from 1980 through August 2012 for specified terms and keywords. Twenty-nine articles retrieved through this process were evaluated; 11 studies including 13 experiments were selected for inclusion in the analysis. The meta-analysis included descriptive analyses and methods for combining P values for the primary endpoint, average daily growth (ADG) at week 1, and secondary endpoints including ADG, average daily feed intake (ADFI), and gain to feed ratio (G:F) at weeks 1 and 2 and at the end of study. Primary and secondary endpoint analyses of growth (ADG, ADFI, and G:F) were significant (P < 0.01). The proinflammatory cytokines interleukin (IL) 1β, IL-6, and tumor necrosis factor α were significantly lower in animals fed dietary PPIs. Additional research in patients experiencing symptoms of enteropathy will further characterize the benefits of PPIs in clinical populations.
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1,854 |
Targeted Collection of Plasmid DNA in Large and Growing Animal Muscles 6 Weeks after DNA Vaccination with and without Electroporation
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DNA vaccination has been developed in the last two decades in human and animal species as a promising alternative to conventional vaccination. It consists in the injection, in the muscle, for example, of plasmid DNA encoding the vaccinating polypeptide. Electroporation which forces the entrance of the plasmid DNA in cells at the injection point has been described as a powerful and promising strategy to enhance DNA vaccine efficacy. Due to the fact that the vaccine is composed of DNA, close attention on the fate of the plasmid DNA upon vaccination has to be taken into account, especially at the injection point. To perform such studies, the muscle injection point has to be precisely recovered and collected several weeks after injection. This is even more difficult for large and growing animals. A technique has been developed to localize precisely and collect efficiently the muscle injection points in growing piglets 6 weeks after DNA vaccination accompanied or not by electroporation. Electroporation did not significantly increase the level of remaining plasmids compared to nonelectroporated piglets, and, in all the cases, the levels were below the limit recommended by the FDA to research integration events of plasmid DNA into the host DNA.
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1,855 |
Controlled Microwave Heating Accelerates Rolling Circle Amplification
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Rolling circle amplification (RCA) generates single-stranded DNAs or RNA, and the diverse applications of this isothermal technique range from the sensitive detection of nucleic acids to analysis of single nucleotide polymorphisms. Microwave chemistry is widely applied to increase reaction rate as well as product yield and purity. The objectives of the present research were to apply microwave heating to RCA and indicate factors that contribute to the microwave selective heating effect. The microwave reaction temperature was strictly controlled using a microwave applicator optimized for enzymatic-scale reactions. Here, we showed that microwave-assisted RCA reactions catalyzed by either of the four thermostable DNA polymerases were accelerated over 4-folds compared with conventional RCA. Furthermore, the temperatures of the individual buffer components were specifically influenced by microwave heating. We concluded that microwave heating accelerated isothermal RCA of DNA because of the differential heating mechanisms of microwaves on the temperatures of reaction components, although the overall reaction temperatures were the same.
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1,856 |
Development of a Rapid Detection Method for Potato virus X by Reverse Transcription Loop-Mediated Isothermal Amplification
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The primary step for efficient control of viral diseases is the development of simple, rapid, and sensitive virus detection. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) has been used to detect viral RNA molecules because of its simplicity and high sensitivity for a number of viruses. RT-LAMP for the detection of Potato virus X (PVX) was developed and compared with conventional reverse transcription polymerase chain reaction (RT-PCR) to demonstrate its advantages over RT-PCR. RT-LAMP reactions were conducted with or without a set of loop primers since one out of six primers showed PVX specificity. Based on real-time monitoring, RT-LAMP detected PVX around 30 min, compared to 120 min for RT-PCR. By adding a fluorescent reagent during the reaction, the extra step of visualization by gel electrophoresis was not necessary. RT-LAMP was conducted using simple inexpensive instruments and a regular incubator to evaluate whether RNA could be amplified at a constant temperature instead of using an expensive thermal cycler. This study shows the potential of RT-LAMP for the diagnosis of viral diseases and PVX epidemiology because of its simplicity and rapidness compared to RT-PCR.
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1,857 |
Evolutionary History of the Photolyase/Cryptochrome Superfamily in Eukaryotes
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BACKGROUND: Photolyases and cryptochromes are evolutionarily related flavoproteins, which however perform distinct physiological functions. Photolyases (PHR) are evolutionarily ancient enzymes. They are activated by light and repair DNA damage caused by UV radiation. Although cryptochromes share structural similarity with DNA photolyases, they lack DNA repair activity. Cryptochrome (CRY) is one of the key elements of the circadian system in animals. In plants, CRY acts as a blue light receptor to entrain circadian rhythms, and mediates a variety of light responses, such as the regulation of flowering and seedling growth. RESULTS: We performed a comprehensive evolutionary analysis of the CRY/PHR superfamily. The superfamily consists of 7 major subfamilies: CPD class I and CPD class II photolyases, (6–4) photolyases, CRY-DASH, plant PHR2, plant CRY and animal CRY. Although the whole superfamily evolved primarily under strong purifying selection (average ω = 0.0168), some subfamilies did experience strong episodic positive selection during their evolution. Photolyases were lost in higher animals that suggests natural selection apparently became weaker in the late stage of evolutionary history. The evolutionary time estimates suggested that plant and animal CRYs evolved in the Neoproterozoic Era (~1000–541 Mya), which might be a result of adaptation to the major climate and global light regime changes occurred in that period of the Earth’s geological history.
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1,858 |
Comparative Analysis of Host Cell Entry of Ebola Virus From Sierra Leone, 2014, and Zaire, 1976
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The ongoing Ebola virus (EBOV) disease (EVD) epidemic in Western Africa is the largest EVD outbreak recorded to date and requires the rapid development and deployment of antiviral measures. The viral glycoprotein (GP) facilitates host cell entry and, jointly with cellular interaction partners, constitutes a potential target for antiviral intervention. However, it is unknown whether the GPs of the currently and previously circulating EBOVs use the same mechanisms for cellular entry and are thus susceptible to inhibition by the same antivirals and cellular defenses. Here, we show that the GPs of the EBOVs circulating in 1976 and 2014 transduce the same spectrum of target cells, use the same cellular factors for host cell entry, and are comparably susceptible to blockade by antiviral interferon-induced transmembrane proteins and neutralizing antibody KZ52. Thus, the viruses responsible for the ongoing EVD epidemic should be fully susceptible to established antiviral strategies targeting GP and cellular entry factors.
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1,859 |
Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus
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Previously, recombinant vesicular stomatitis virus (rVSV) pseudotypes expressing Ebolavirus glycoproteins (GPs) in place of the VSV G protein demonstrated protection of nonhuman primates from lethal homologous Ebolavirus challenge. Those pseudotype vectors contained no additional attenuating mutations in the rVSV genome. Here we describe rVSV vectors containing a full complement of VSV genes and expressing the Ebola virus (EBOV) GP from an additional transcription unit. These rVSV vectors contain the same combination of attenuating mutations used previously in the clinical development pathway of an rVSV/human immunodeficiency virus type 1 vaccine. One of these rVSV vectors (N4CT1-EBOVGP1), which expresses membrane-anchored EBOV GP from the first position in the genome (GP1), elicited a balanced cellular and humoral GP-specific immune response in mice. Guinea pigs immunized with a single dose of this vector were protected from any signs of disease following lethal EBOV challenge, while control animals died in 7–9 days. Subsequently, N4CT1-EBOVGP1 demonstrated complete, single-dose protection of 2 macaques following lethal EBOV challenge. A single sham-vaccinated macaque died from disease due to EBOV infection. These results demonstrate that highly attenuated rVSV vectors expressing EBOV GP may provide safer alternatives to current EBOV vaccines.
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1,860 |
Changes in the Swine Gut Microbiota in Response to Porcine Epidemic Diarrhea Infection
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The gastrointestinal tract of mammals is a complex ecosystem with distinct environments and comprises hundreds of different types of bacterial cells. The gut microbiota may play a critical role in the gut health of the host. We herein attempted to identify a microbiota shift that may be affected by porcine epidemic diarrhea (PED). We observed significant differences in microbiota between the control and PED virus (PEDV)-infected groups at both the phylum and genus level. Most commensal bacteria (i.e. Psychrobacter, Prevotella, and Faecalibacterium) in the healthy gastrointestinal tract were decreased due to dysbiosis induced by PEDV infection.
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1,861 |
Protection conferred by live infectious bronchitis vaccine viruses against variant Middle East IS/885/00-like and IS/1494/06-like isolates in commercial broiler chicks
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The ability of the infectious bronchitis H120 (a Massachusetts strain) and CR88 (a 793B strain) live attenuated vaccine viruses to protect from two Middle East infectious bronchitis virus isolates, IS/885/00-like (IS/885) and IS/1494/06-like (IS/1494) in broiler chicks was investigated. Day-old chicks were separated into three groups, (I) vaccinated with H120 at day-old followed by CR88 at 14 days-old, (II) vaccinated with H120 and CR88 simultaneously at day-old and again with CR88 at 14 days-old, (III) control unvaccinated. At 30 days-old, each of the groups was challenged with virulent IS/885 or IS/1494. Protection was evaluated based on the clinical signs, tracheal and kidney gross lesions and tracheal ciliostasis. Results showed that administering combined live H120 and CR88 vaccines simultaneously at day-old followed by CR88 vaccine at 14 days-old gave more than 80 per cent tracheal ciliary protection from both of the Middle East isolates. In addition, this programme conferred 100 per cent protection from clinical signs and tracheal or kidney lesions. The other vaccination programme, H120 at day-old followed by CR88 at 14 days-old, the tracheal ciliary protection conferred were 60 per cent and 80 per cent from IS/885/00-like and IS/1494/06-like, respectively.
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1,862 |
The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis
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Viral fulminant hepatitis (FH) is a severe disease with high mortality resulting from excessive inflammation in the infected liver. Clinical interventions have been inefficient due to the lack of knowledge for inflammatory pathogenesis in the virus-infected liver. We show that wild-type mice infected with murine hepatitis virus strain-3 (MHV-3), a model for viral FH, manifest with severe disease and high mortality in association with a significant elevation in IL-1β expression in the serum and liver. Whereas, the viral infection in IL-1β receptor-I deficient (IL-1R1 (-/-)) or IL-1R antagonist (IL-1Ra) treated mice, show reductions in virus replication, disease progress and mortality. IL-1R1 deficiency appears to debilitate the virus-induced fibrinogen-like protein-2 (FGL2) production in macrophages and CD45(+)Gr-1(high) neutrophil infiltration in the liver. The quick release of reactive oxygen species (ROS) by the infected macrophages suggests a plausible viral initiation of NLRP3 inflammasome activation. Further experiments show that mice deficient of p47 (phox), a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit that controls acute ROS production, present with reductions in NLRP3 inflammasome activation and subsequent IL-1β secretion during viral infection, which appears to be responsible for acquiring resilience to viral FH. Moreover, viral infected animals in deficiencies of NLRP3 and Caspase-1, two essential components of the inflammasome complex, also have reduced IL-1β induction along with ameliorated hepatitis. Our results demonstrate that the ROS/NLRP3/IL-1β axis institutes an essential signaling pathway, which is over activated and directly causes the severe liver disease during viral infection, which sheds light on development of efficient treatments for human viral FH and other severe inflammatory diseases.
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1,863 |
Live Poultry Exposure and Public Response to Influenza A(H7N9) in Urban and Rural China during Two Epidemic Waves in 2013-2014
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BACKGROUND: The novel influenza A(H7N9) virus has caused 2013 spring and 2013–2014 winter waves of human infections since its first emergence in China in March 2013. Exposure to live poultry is a risk factor for H7N9 infection. Public psychobehavioral responses often change during progression of an epidemic. METHODS: We conducted population-based surveys in southern China to examine human exposure to live poultry, and population psychological response and behavioral changes in the two waves. In Guangzhou, an urban area of Guangdong province, we collected data using telephone surveys with random digit dialing in May-June 2013 and again in December 2013 to January 2014. In Zijin county, a rural area of the same province, we used door-to-door surveys under a stratified sampling design in July 2013 and again in December 2013 to January 2014. All responses were weighted by age and sex to the respective adult populations. FINDINGS: Around half of the urban respondents (53.8%) reported having visited LPMs in the previous year in the first survey, around double that reported in the second survey (27.7%). In the rural surveys, around half of the participants reported raising backyard poultry in the past year in the first survey, increasing to 83.2% participants in the second survey. One third of urban subjects supported the permanent closure of LPMs in the first and second surveys, and factors associated with support for closure included female sex, higher level of worry towards H7N9, and worry induced by a hypothetical influenza-like illness. CONCLUSIONS: Our study indicated high human exposure to live poultry and low support for permanent closure of markets in both urban and rural residents regardless of increased worry during the epidemic.
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1,864 |
ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry
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Interferon stimulated genes (ISGs) target viruses at various stages of their infectious life cycles, including at the earliest stage of viral entry. Here we identify ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2) as a gene upregulated by type I IFN treatment in a STAT1-dependent manner. ADAP2 functions as a GTPase-activating protein (GAP) for Arf6 and binds to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3)) and PI(3,4)P(2). We show that overexpression of ADAP2 suppresses dengue virus (DENV) and vesicular stomatitis virus (VSV) infection in an Arf6 GAP activity-dependent manner, while exerting no effect on coxsackievirus B (CVB) or Sendai virus (SeV) replication. We further show that ADAP2 expression induces macropinocytosis and that ADAP2 strongly associates with actin-enriched membrane ruffles and with Rab8a- and LAMP1-, but not EEA1- or Rab7-, positive vesicles. Utilizing two techniques—light-sensitive neutral red (NR)-containing DENV and fluorescence assays for virus internalization—we show that ADAP2 primarily restricts DENV infection at the stage of virion entry and/or intracellular trafficking and that incoming DENV and VSV particles associate with ADAP2 during their entry. Taken together, this study identifies ADAP2 as an ISG that exerts antiviral effects against RNA viruses by altering Arf6-mediated trafficking to disrupt viral entry.
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1,865 |
Early real-time estimation of the basic reproduction number of emerging or reemerging infectious diseases in a community with heterogeneous contact pattern: Using data from Hong Kong 2009 H1N1 Pandemic Influenza as an illustrative example
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Emerging and re-emerging infections such as SARS (2003) and pandemic H1N1 (2009) have caused concern for public health researchers and policy makers due to the increased burden of these diseases on health care systems. This concern has prompted the use of mathematical models to evaluate strategies to control disease spread, making these models invaluable tools to identify optimal intervention strategies. A particularly important quantity in infectious disease epidemiology is the basic reproduction number, R(0.) Estimation of this quantity is crucial for effective control responses in the early phase of an epidemic. In our previous study, an approach for estimating the basic reproduction number in real time was developed. This approach uses case notification data and the structure of potential transmission contacts to accurately estimate R(0) from the limited amount of information available at the early stage of an outbreak. Based on this approach, we extend the existing methodology; the most recent method features intra- and inter-age groups contact heterogeneity. Given the number of newly reported cases at the early stage of the outbreak, with parsimony assumptions on removal distribution and infectivity profile of the diseases, experiments to estimate real time R(0) under different levels of intra- and inter-group contact heterogeneity using two age groups are presented. We show that the new method converges more quickly to the actual value of R(0) than the previous one, in particular when there is high-level intra-group and inter-group contact heterogeneity. With the age specific contact patterns, number of newly reported cases, removal distribution, and information about the natural history of the 2009 pandemic influenza in Hong Kong, we also use the extended model to estimate R(0) and age-specific R(0).
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1,866 |
Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a mouse model of diabetes
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AIMS/HYPOTHESIS: We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. METHODS: Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied. RESULTS: Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1–7 receptor [MasR]) expression, and normalised urinary Ang 1–7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-β1 and Tgf-βrII gene expression. Furthermore, hnRNP F overexpression prevented TGF-β1 signalling and TGF-β1 inhibition of Ace-2 gene expression. CONCLUSIONS/INTERPRETATION: These data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-β1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3700-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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1,867 |
Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study
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INTRODUCTION: Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). METHODS: We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients <18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen’s κ. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria. RESULTS: Of the 706 patients, 301 (42.6 %) met both definitions. The inter-rater agreement (κ ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician’s diagnosis of severe sepsis, only 69 % (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria. CONCLUSIONS: Physician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13054-015-1055-x) contains supplementary material, which is available to authorized users.
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1,868 |
Mosquito Rasputin interacts with chikungunya virus nsP3 and determines the infection rate in Aedes albopictus
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BACKGROUND: Chikungunya virus (CHIKV) is an arthritogenic alphavirus (family Togaviridae), transmitted by Aedes species mosquitoes. CHIKV re-emerged in 2004 with multiple outbreaks worldwide and recently reached the Americas where it has infected over a million individuals in a rapidly expanding epidemic. While alphavirus replication is well understood in general, the specific function (s) of non-structural protein nsP3 remain elusive. CHIKV nsP3 modulates the mammalian stress response by preventing stress granule formation through sequestration of G3BP. In mosquitoes, nsP3 is a determinant of vector specificity, but its functional interaction with mosquito proteins is unclear. METHODS: In this research we studied the domains required for localization of CHIKV nsP3 in insect cells and demonstrated its molecular interaction with Rasputin (Rin), the mosquito homologue of G3BP. The biological involvement of Rin in CHIKV infection was investigated in live Ae. albopictus mosquitoes. RESULTS: In insect cells, nsP3 localized as cytoplasmic granules, which was dependent on the central domain and the C-terminal variable region but independent of the N-terminal macrodomain. Ae. albopictus Rin displayed a diffuse, cytoplasmic localization, but was effectively sequestered into nsP3-granules upon nsP3 co-expression. Site-directed mutagenesis showed that the Rin-nsP3 interaction involved the NTF2-like domain of Rin and two conserved TFGD repeats in the C-terminal variable domain of nsP3. Although in vitro silencing of Rin did not impact nsP3 localization or CHIKV replication in cell culture, Rin depletion in vivo significantly decreased the CHIKV infection rate and transmissibility in Ae.albopictus. CONCLUSIONS: We identified the nsP3 hypervariable C-terminal domain as a critical factor for granular localization and sequestration of mosquito Rin. Our study offers novel insight into a conserved virus-mosquito interaction at the molecular level, and reveals a strong proviral role for G3BP homologue Rin in live mosquitoes, making the nsP3-Rin interaction a putative target to interfere with the CHIKV transmission cycle.
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1,869 |
Survey of Ixodes pacificus Ticks in California Reveals a Diversity of Microorganisms and a Novel and Widespread Anaplasmataceae Species
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Ixodes pacificus ticks can harbor a wide range of human and animal pathogens. To survey the prevalence of tick-borne known and putative pathogens, we tested 982 individual adult and nymphal I. pacificus ticks collected throughout California between 2007 and 2009 using a broad-range PCR and electrospray ionization mass spectrometry (PCR/ESI-MS) assay designed to detect a wide range of tick-borne microorganisms. Overall, 1.4% of the ticks were found to be infected with Borrelia burgdorferi, 2.0% were infected with Borrelia miyamotoi and 0.3% were infected with Anaplasma phagocytophilum. In addition, 3.0% were infected with Babesia odocoilei. About 1.2% of the ticks were co-infected with more than one pathogen or putative pathogen. In addition, we identified a novel Anaplasmataceae species that we characterized by sequencing of its 16S rRNA, groEL, gltA, and rpoB genes. Sequence analysis indicated that this organism is phylogenetically distinct from known Anaplasma species with its closest genetic near neighbors coming from Asia. The prevalence of this novel Anaplasmataceae species was as high as 21% at one site, and it was detected in 4.9% of ticks tested statewide. Based upon this genetic characterization we propose that this organism be called ‘Candidatus Cryptoplasma californiense’. Knowledge of this novel microbe will provide awareness for the community about the breadth of the I. pacificus microbiome, the concept that this bacterium could be more widely spread; and an opportunity to explore whether this bacterium also contributes to human or animal disease burden.
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1,870 |
High-Throughput Ligand Discovery Reveals a Sitewise Gradient of Diversity in Broadly Evolved Hydrophilic Fibronectin Domains
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Discovering new binding function via a combinatorial library in small protein scaffolds requires balance between appropriate mutations to introduce favorable intermolecular interactions while maintaining intramolecular integrity. Sitewise constraints exist in a non-spatial gradient from diverse to conserved in evolved antibody repertoires; yet non-antibody scaffolds generally do not implement this strategy in combinatorial libraries. Despite the fact that biased amino acid distributions, typically elevated in tyrosine, serine, and glycine, have gained wider use in synthetic scaffolds, these distributions are still predominantly applied uniformly to diversified sites. While select sites in fibronectin domains and DARPins have shown benefit from sitewise designs, they have not been deeply evaluated. Inspired by this disparity between diversity distributions in natural libraries and synthetic scaffold libraries, we hypothesized that binders resulting from discovery and evolution would exhibit a non-spatial, sitewise gradient of amino acid diversity. To identify sitewise diversities consistent with efficient evolution in the context of a hydrophilic fibronectin domain, >10(5) binders to six targets were evolved and sequenced. Evolutionarily favorable amino acid distributions at 25 sites reveal Shannon entropies (range: 0.3–3.9; median: 2.1; standard deviation: 1.1) supporting the diversity gradient hypothesis. Sitewise constraints in evolved sequences are consistent with complementarity, stability, and consensus biases. Implementation of sitewise constrained diversity enables direct selection of nanomolar affinity binders validating an efficient strategy to balance inter- and intra-molecular interaction demands at each site.
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1,871 |
What’s Past is Prologue: A Scoping Review of Recent Public Health and Global Health Informatics Literature
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Objective: To categorize and describe the public health informatics (PHI) and global health informatics (GHI) literature between 2012 and 2014. Methods: We conducted a semi-systematic review of articles published between January 2012 and September 2014 where information and communications technologies (ICT) was a primary subject of the study or a main component of the study methodology. Additional inclusion and exclusion criteria were used to filter PHI and GHI articles from the larger biomedical informatics domain. Articles were identified using MEDLINE as well as personal bibliographies from members of the American Medical Informatics Association PHI and GHI working groups. Results: A total of 85 PHI articles and 282 GHI articles were identified. While systems in PHI continue to support surveillance activities, we identified a shift towards support for prevention, environmental health, and public health care services. Furthermore, articles from the U.S. reveal a shift towards PHI applications at state and local levels. GHI articles focused on telemedicine, mHealth and eHealth applications. The development of adequate infrastructure to support ICT remains a challenge, although we identified a small but growing set of articles that measure the impact of ICT on clinical outcomes. Discussion: There is evidence of growth with respect to both implementation of information systems within the public health enterprise as well as a widening of scope within each informatics discipline. Yet the articles also illuminate the need for more primary research studies on what works and what does not as both searches yielded small numbers of primary, empirical articles. Conclusion: While the body of knowledge around PHI and GHI continues to mature, additional studies of higher quality are needed to generate the robust evidence base needed to support continued investment in ICT by governmental health agencies.
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1,872 |
Vaccine Induced Herd Immunity for Control of Respiratory Syncytial Virus Disease in a Low-Income Country Setting
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BACKGROUND: Respiratory syncytial virus (RSV) is globally ubiquitous, and infection during the first six months of life is a major risk for severe disease and hospital admission; consequently RSV is the most important viral cause of respiratory morbidity and mortality in young children. Development of vaccines for young infants is complicated by the presence of maternal antibodies and immunological immaturity, but vaccines targeted at older children avoid these problems. Vaccine development for young infants has been unsuccessful, but this is not the case for older children (> 6m). Would vaccinating older children have a significant public health impact? We developed a mathematical model to explore the benefits of a vaccine against RSV. METHODS AND FINDINGS: We have used a deterministic age structured model capturing the key epidemiological characteristics of RSV and performed a statistical maximum-likelihood fit to age-specific hospitalization data from a developing country setting. To explore the effects of vaccination under different mixing assumptions, we included two versions of contact matrices: one from a social contact diary study, and the second a synthesised construction based on demographic data. Vaccination is assumed to elicit an immune response equivalent to primary infection. Our results show that immunisation of young children (5–10m) is likely to be a highly effective method of protection of infants (<6m) against hospitalisation. The majority benefit is derived from indirect protection (herd immunity). A full sensitivity and uncertainty analysis using Latin Hypercube Sampling of the parameter space shows that our results are robust to model structure and model parameters. CONCLUSIONS: This result suggests that vaccinating older infants and children against RSV can have a major public health benefit.
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1,873 |
The 15N and 46R Residues of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Nucleocapsid Protein Enhance Regulatory T Lymphocytes Proliferation
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Porcine reproductive and respiratory syndrome virus (PRRSV) negatively modulates host immune responses, resulting in persistent infection and immunosuppression. PRRSV infection increases the number of PRRSV-specific regulatory T lymphocytes (Tregs) in infected pigs. However, the target antigens for Tregs proliferation in PRRSV infection have not been fully understood. In this study, we demonstrated that the highly pathogenic PRRSV (HP-PRRSV) induced more CD4(+)CD25(+)Foxp3(+) Tregs than classical PRRSV (C-PRRSV) strain. Of the recombinant GP5, M and N proteins of HP-PRRSV expressed in baculovirus expression systems, only N protein induced Tregs proliferation. The Tregs assays showed that three amino-acid regions, 15–21, 42–48 and 88–94, in N protein played an important role in induction of Tregs proliferation with synthetic peptides covering the whole length of N protein. By using reverse genetic methods, it was firstly found that the 15N and 46R residues in PRRSV N protein were critical for induction of Tregs proliferation. The phenotype of induced Tregs closely resembled that of transforming-growth-factor-β-secreting T helper 3 Tregs in swine. These data should be useful for understanding the mechanism of immunity to PRRSV and development of infection control strategies in the future.
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1,874 |
Evidence for the Convergence Model: The Emergence of Highly Pathogenic Avian Influenza (H5N1) in Viet Nam
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Building on a series of ground breaking reviews that first defined and drew attention to emerging infectious diseases (EID), the ‘convergence model’ was proposed to explain the multifactorial causality of disease emergence. The model broadly hypothesizes disease emergence is driven by the co-incidence of genetic, physical environmental, ecological, and social factors. We developed and tested a model of the emergence of highly pathogenic avian influenza (HPAI) H5N1 based on suspected convergence factors that are mainly associated with land-use change. Building on previous geospatial statistical studies that identified natural and human risk factors associated with urbanization, we added new factors to test whether causal mechanisms and pathogenic landscapes could be more specifically identified. Our findings suggest that urbanization spatially combines risk factors to produce particular types of peri-urban landscapes with significantly higher HPAI H5N1 emergence risk. The work highlights that peri-urban areas of Viet Nam have higher levels of chicken densities, duck and geese flock size diversities, and fraction of land under rice or aquaculture than rural and urban areas. We also found that land-use diversity, a surrogate measure for potential mixing of host populations and other factors that likely influence viral transmission, significantly improves the model’s predictability. Similarly, landscapes where intensive and extensive forms of poultry production overlap were found at greater risk. These results support the convergence hypothesis in general and demonstrate the potential to improve EID prevention and control by combing geospatial monitoring of these factors along with pathogen surveillance programs.
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1,875 |
A cascade reaction network mimicking the basic functional steps of acquired immune response
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Biological systems use complex ‘information processing cores’ composed of molecular networks to coordinate their external environment and internal states. An example of this is the acquired, or adaptive, immune system (AIS), which is composed of both humoral and cell-mediated components. Here we report the step-by-step construction of a prototype mimic of the AIS which we call Adaptive Immune Response Simulator (AIRS). DNA and enzymes are used as simple artificial analogues of the components of the AIS to create a system which responds to specific molecular stimuli in vitro. We show that this network of reactions can function in a manner which is superficially similar to the most basic responses of the vertebrate acquired immune system, including reaction sequences that mimic both humoral and cellular responses. As such, AIRS provides guidelines for the design and engineering of artificial reaction networks and molecular devices.
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1,876 |
A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models
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Human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2) are the etiologic agents of AIDS. Most HIV-1 infected individuals worldwide are women, who acquire HIV infections during sexual contact. Blocking HIV mucosal transmission and local spread in the female lower genital tract is important in preventing infection and ultimately eliminating the pandemic. Microbicides work by destroying the microbes or preventing them from establishing an infection. Thus, a number of different types of microbicides are under investigation, however, the lack of their solubility and bioavailability, and toxicity has been major hurdles. Herein, we report the development of multifunctional chitosan-lipid nanocomplexes that can effectively deliver plasmids encoding siRNA(s) as microbicides without adverse effects and provide significant protection against HIV in both in vitro and in vivo models. Chitosan or chitosan-lipid (chlipid) was complexed with a cocktail of plasmids encoding HIV-1-specific siRNAs (psiRNAs) and evaluated for their efficacy in HEK-293 cells, PBMCs derived from nonhuman primates, 3-dimensional human vaginal ectocervical tissue (3D-VEC) model and also in non-human primate model. Moreover, prophylactic administration of the chlipid to deliver a psiRNA cocktail intravaginally with a cream formulation in a non-human primate model showed substantial reduction of SHIV (simian/human immunodeficiency virus SF162) viral titers. Taken together, these studies demonstrate the potential of chlipid-siRNA nanocomplexes as a potential genetic microbicide against HIV infections.
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1,877 |
Use of Padlock Probes and Rolling Circle Amplification (RCA) for Rapid Identification of Trichophyton Species, Related to Human and Animal Disorder
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BACKGROUND: The high degree of phenotypic similarity among Trichophyton species makes their identification difficult. OBJECTIVES: The current study aims to establish the use of rolling circle amplification (RCA) based on internal transcribed spacer ribosomal DNA (ITS rDNA) as a powerful, simple, and rapid procedure for distinguishing closely related organisms, and specifically to identify Trichophyton species, which cause human and animal disorders. MATERIALS AND METHODS: A total of sixty-one isolates belonging to three species of Trichophyton were identified to the species level based on microscopic and macroscopic examinations and their ITS rDNA regions were sequenced. Three specific circular oligonucleotide probes targeting the ITS1 and ITS2 regions were designed to differentiate Trichophyton rubrum, T. mentagrophytes, and T. tonsurans. RESULTS: Of the 61 putative Trichophyton clinical isolates, 52 were identified to the species level. The most common species was T. mentagrophytes var. interdigitale (31 isolates), followed by T. rubrum (11 isolates), T. tonsurans (9 isolates), and T. violaceum (1 isolates); moreover, 9 isolates were identified as non-Trichophyton species. The RCA method correctly identified four Trichophyton species and was 100% specific for each species. Neither cross-reaction between the examined species of Trichophyton nor false positive or false negative results were observed. CONCLUSIONS: Species identification of Trichophyton is crucially important for epidemiological and phylogenetic purposes and for genotype delineation. RCA based on ITS polymorphisms can be used to generate identification barcodes and as an alternative to DNA sequencing; it is a very fast, specific, and economical tool for species identification.
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1,878 |
Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg?
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In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten “challenge” are the most reliable markers. Immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of SNCD patients may be useful. In our experience, tTG-mRNA was similarly increased in seropositive celiac disease (CD) and suspected SNCD, and strongly correlated with the IELs count. This increase is found even in the IELs’ range of 15–25/100 enterocytes, suggesting that there may be a “grey zone” of gluten-related disorders. An immune deregulation (severely lacking B-cell differentiation) underlies the association of SNCD with immunoglobulin deficiencies. Therefore, CD may be linked to autoimmune disorders and immune deficits (common variable immunodeficiency (CVID)/IgA selective deficiency). CVID is a heterogeneous group of antibodies dysfunction, whose association with CD is demonstrated only by the response to a gluten-free diet (GFD). We hypothesized a familial inheritance between CD and CVID. Selective IgA deficiency, commonly associated with CD, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare (<300 cases) and associated to CD in 5% of cases. We diagnosed SNCD in a patient affected by sIgMD using the tTG-mRNA assay. One-year GFD induced IgM restoration. This evidence, supporting a link between SNCD and immunoglobulin deficiencies, suggests that we should take a closer look at this association.
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1,879 |
Metagenomic ventures into outer sequence space
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Sequencing DNA or RNA directly from the environment often results in many sequencing reads that have no homologs in the database. These are referred to as “unknowns," and reflect the vast unexplored microbial sequence space of our biosphere, also known as “biological dark matter." However, unknowns also exist because metagenomic datasets are not optimally mined. There is a pressure on researchers to publish and move on, and the unknown sequences are often left for what they are, and conclusions drawn based on reads with annotated homologs. This can cause abundant and widespread genomes to be overlooked, such as the recently discovered human gut bacteriophage crAssphage. The unknowns may be enriched for bacteriophage sequences, the most abundant and genetically diverse component of the biosphere and of sequence space. However, it remains an open question, what is the actual size of biological sequence space? The de novo assembly of shotgun metagenomes is the most powerful tool to address this question.
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1,880 |
Enhancing production of ergosterol in Pichia pastoris GS115 by over-expression of 3-hydroxy-3-methylglutaryl CoA reductase from Glycyrrhiza uralensis
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The rate-limiting enzyme in the mevalonic acid (MVA) pathway which can lead to triterpenoid saponin glycyrrhizic acid (GA) is 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR). In order to reveal the effect of copy number variation in the HMGR gene on the MVA pathway, the HMGR gene from Glycyrrhiza uralensis Fisch. (GuHMGR) was cloned and over-expressed in Pichia pastoris GS115. Six recombinant P. pastoris strains containing different copy numbers of the GuHMGR gene were obtained and the content of ergosterol was analyzed by HPLC. The results showed that all the recombinant P. pastoris strains contained more ergosterol than the negative control and the strains with 8 and 44 copies contained significantly more ergosterol than the other strains. However, as the copy number increased, the content of ergosterol showed an increasing–decreasing–increasing pattern. This study provides a rationale for increasing the content of GA through over-expressing the GuHMGR gene in cultivars of G. uralensis.
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1,881 |
Disparities in Spatial Prevalence of Feline Retroviruses due to Data Aggregation: A Case of the Modifiable Areal Unit Problem
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The knowledge of the spatial distribution feline immunodeficiency virus and feline leukemia virus infections, which are untreatable, can inform on their risk factors and high-risk areas to enhance control. However, when spatial analysis involves aggregated spatial data, results may be influenced by the spatial scale of aggregation, an effect known as the modifiable areal unit problem (MAUP). In this study, area level risk factors for both infections in 28,914 cats tested with ELISA were investigated by multivariable spatial Poisson regression models along with MAUP effect on spatial clustering and cluster detection (for postal codes, counties, and states) by Moran's I test and spatial scan test, respectively. The study results indicate that the significance and magnitude of the association of risk factors with both infections varied with aggregation scale. Further more, Moran's I test only identified spatial clustering at postal code and county levels of aggregation. Similarly, the spatial scan test indicated that the number, size, and location of clusters varied over aggregation scales. In conclusion, the association between infection and area was influenced by the choice of spatial scale and indicates the importance of study design and data analysis with respect to specific research questions.
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1,882 |
The Large Scale Machine Learning in an Artificial Society: Prediction of the Ebola Outbreak in Beijing
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Ebola virus disease (EVD) distinguishes its feature as high infectivity and mortality. Thus, it is urgent for governments to draw up emergency plans against Ebola. However, it is hard to predict the possible epidemic situations in practice. Luckily, in recent years, computational experiments based on artificial society appeared, providing a new approach to study the propagation of EVD and analyze the corresponding interventions. Therefore, the rationality of artificial society is the key to the accuracy and reliability of experiment results. Individuals' behaviors along with travel mode directly affect the propagation among individuals. Firstly, artificial Beijing is reconstructed based on geodemographics and machine learning is involved to optimize individuals' behaviors. Meanwhile, Ebola course model and propagation model are built, according to the parameters in West Africa. Subsequently, propagation mechanism of EVD is analyzed, epidemic scenario is predicted, and corresponding interventions are presented. Finally, by simulating the emergency responses of Chinese government, the conclusion is finally drawn that Ebola is impossible to outbreak in large scale in the city of Beijing.
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1,883 |
Lack of Association between Toxocara Exposure and Suicide Attempts in Psychiatric Patients
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Infection with Toxocara may affect the central nervous system. A high seroprevalence of Toxocara infection has been reported in psychiatric patients. To the best of our knowledge, there is no previous report about an association of Toxocara infection with suicide attempts. Therefore, we sought to determine whether Toxocara exposure is associated with suicide attempts in psychiatric patients. We studied 282 psychiatric outpatients (156 with suicide attempts and 126 without suicide attempts). Sera of patients were analyzed for the presence of anti-Toxocara IgG antibodies by using a commercially available enzyme immunoassay. One of the 156 (0.6%) suicide attempters and 1 (0.8%) of the 126 controls were positive for anti-Toxocara IgG antibodies (OR = 0.80; 95% CI: 0.04–13.02; P = 1.00). Toxocara seropositivity was significantly higher (P = 0.01) in male patients with consumption of raw dried goat meat than male patients without this consumption. Results suggest that Toxocara exposure is not associated with suicide attempts in psychiatric outpatients in Durango City, Mexico. However, further studies with larger samples sizes to confirm our results should be conducted. Too few patients were seropositive to assess further associations of Toxocara exposure with sociodemographic, clinical, and behavioral characteristics of the psychiatric patients.
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1,884 |
Possible Role of Rickettsia felis in Acute Febrile Illness among Children in Gabon
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Rickettsia felis has been reported to be a cause of fever in sub-Saharan Africa, but this association has been poorly evaluated in Gabon. We assessed the prevalence of this bacterium among children <15 years of age in 4 areas of Gabon; the locations were in urban, semiurban, and rural areas. DNA samples from 410 febrile children and 60 afebrile children were analyzed by quantitative PCR. Overall, the prevalence of R. felis among febrile and afebrile children was 10.2% (42/410 children) and 3.3% (2/60 children), respectively. Prevalence differed among febrile children living in areas that are urban (Franceville, 1.3% [1/77]), semiurban (Koulamoutou, 2.1% [3/141]), and rural (Lastourville, 11.2% [15/134]; Fougamou, 39.7% [23/58]). Furthermore, in a rural area (Fougamou), R. felis was significantly more prevalent in febrile (39.7% [23/58]) than afebrile children (5.0% [1/20]). Additional studies are needed to better understand the pathogenic role of R. felis in this part of the world.
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1,885 |
Influenza Transmission in the Mother-Infant Dyad Leads to Severe Disease, Mammary Gland Infection, and Pathogenesis by Regulating Host Responses
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Seasonal influenza viruses are typically restricted to the human upper respiratory tract whereas influenza viruses with greater pathogenic potential often also target extra-pulmonary organs. Infants, pregnant women, and breastfeeding mothers are highly susceptible to severe respiratory disease following influenza virus infection but the mechanisms of disease severity in the mother-infant dyad are poorly understood. Here we investigated 2009 H1N1 influenza virus infection and transmission in breastfeeding mothers and infants utilizing our developed infant-mother ferret influenza model. Infants acquired severe disease and mortality following infection. Transmission of the virus from infants to mother ferrets led to infection in the lungs and mother mortality. Live virus was also found in mammary gland tissue and expressed milk of the mothers which eventually led to milk cessation. Histopathology showed destruction of acini glandular architecture with the absence of milk. The virus was localized in mammary epithelial cells of positive glands. To understand the molecular mechanisms of mammary gland infection, we performed global transcript analysis which showed downregulation of milk production genes such as Prolactin and increased breast involution pathways indicated by a STAT5 to STAT3 signaling shift. Genes associated with cancer development were also significantly increased including JUN, FOS and M2 macrophage markers. Immune responses within the mammary gland were characterized by decreased lymphocyte-associated genes CD3e, IL2Ra, CD4 with IL1β upregulation. Direct inoculation of H1N1 into the mammary gland led to infant respiratory infection and infant mortality suggesting the influenza virus was able to replicate in mammary tissue and transmission is possible through breastfeeding. In vitro infection studies with human breast cells showed susceptibility to H1N1 virus infection. Together, we have shown that the host-pathogen interactions of influenza virus infection in the mother-infant dyad initiate immunological and oncogenic signaling cascades within the mammary gland. These findings suggest the mammary gland may have a greater role in infection and immunity than previously thought.
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1,886 |
Ring finger protein 166 potentiates RNA virus-induced interferon-β production via enhancing the ubiquitination of TRAF3 and TRAF6
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Host cells orchestrate the production of IFN-β upon detecting invading viral pathogens. Here, we report that Ring finger protein 166 (RNF166) potentiates RNA virus-triggered IFN-β production. Overexpression of RNF166 rather than its homologous proteins RNF114, RNF125, and RNF138, enhanced Sendai virus (SeV)-induced activation of the IFN-β promoter. Knockdown of endogenous RNF166, but not other RNFs, inhibited the IFN-β production induced by SeV and encephalomyocarditis virus. RNF166 interacted with TRAF3 and TRAF6. SeV-induced ubiquitination of TRAF3 and TRAF6 was suppressed when endogenous RNF166 rather than RNF114/138 was knocked down. These findings suggest that RNF166 positively regulates RNA virus-triggered IFN-β production by enhancing the ubiquitination of TRAF3 and TRAF6.
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1,887 |
Estimates of the Demand for Mechanical Ventilation in the United States During an Influenza Pandemic
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An outbreak in China in April 2013 of human illnesses due to avian influenza A(H7N9) virus provided reason for US public health officials to revisit existing national pandemic response plans. We built a spreadsheet model to examine the potential demand for invasive mechanical ventilation (excluding “rescue therapy” ventilation). We considered scenarios of either 20% or 30% gross influenza clinical attack rate (CAR), with a “low severity” scenario with case fatality rates (CFR) of 0.05%–0.1%, or a “high severity” scenario (CFR: 0.25%–0.5%). We used rates-of-influenza-related illness to calculate the numbers of potential clinical cases, hospitalizations, admissions to intensive care units, and need for mechanical ventilation. We assumed 10 days ventilator use per ventilated patient, 13% of total ventilator demand will occur at peak, and a 33.7% weighted average mortality risk while on a ventilator. At peak, for a 20% CAR, low severity scenario, an additional 7000 to 11 000 ventilators will be needed, averting a pandemic total of 35 000 to 55 000 deaths. A 30% CAR, high severity scenario, will need approximately 35 000 to 60 500 additional ventilators, averting a pandemic total 178 000 to 308 000 deaths. Estimates of deaths averted may not be realized because successful ventilation also depends on sufficient numbers of suitably trained staff, needed supplies (eg, drugs, reliable oxygen sources, suction apparatus, circuits, and monitoring equipment) and timely ability to match access to ventilators with critically ill cases. There is a clear challenge to plan and prepare to meet demands for mechanical ventilators for a future severe pandemic.
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1,888 |
Pronounced Seasonal Changes in the Movement Ecology of a Highly Gregarious Central-Place Forager, the African Straw-Coloured Fruit Bat (Eidolon helvum)
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BACKGROUND: Straw-coloured fruit bats (Eidolon helvum) migrate over vast distances across the African continent, probably following seasonal bursts of resource availability. This causes enormous fluctuations in population size, which in turn may influence the bats’ impact on local ecosystems. We studied the movement ecology of this central-place forager with state-of-the-art GPS/acceleration loggers and concurrently monitored the seasonal fluctuation of the colony in Accra, Ghana. Habitat use on the landscape scale was assessed with remote sensing data as well as ground-truthing of foraging areas. PRINCIPAL FINDINGS: During the wet season population low (~ 4000 individuals), bats foraged locally (3.5–36.7 km) in urban areas with low tree cover. Major food sources during this period were fruits of introduced trees. Foraging distances almost tripled (24.1–87.9 km) during the dry season population peak (~ 150,000 individuals), but this was not compensated for by reduced resting periods. Dry season foraging areas were random with regard to urban footprint and tree cover, and food consisted almost exclusively of nectar and pollen of native trees. CONCLUSIONS AND SIGNIFICANCE: Our study suggests that straw-coloured fruit bats disperse seeds in the range of hundreds of meters up to dozens of kilometres, and pollinate trees for up to 88 km. Straw-coloured fruit bats forage over much larger distances compared to most other Old World fruit bats, thus providing vital ecosystem services across extensive landscapes. We recommend increased efforts aimed at maintaining E. helvum populations throughout Africa since their keystone role in various ecosystems is likely to increase due to the escalating loss of other seed dispersers as well as continued urbanization and habitat fragmentation.
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1,889 |
Efficacy of a nonsurgical treatment regimen in patients with bisphosphonate-related osteonecrosis of the jaws in Saudi Arabia
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OBJECTIVES: The objective of this study was to evaluate the effectiveness of a nonsurgical treatment regimen in the long-term control of necrotic areas of the jaws and pain in such patients. METHODS: A total of 96 patients suffering from the disease were included in this study. All patients received nonsurgical treatment regimen for 10 days, and repeated every 3 months for 2 years. The size of the osteonecrotic lesions was measured and the pain level was self-assessed with a visual analog scale. RESULTS: The patients showed a statistically significant (F = 16.1; p < .01; r(2) = .95) gradual decrease in the size of exposed bone areas during the nonsurgical therapy (from 12.5 to 8.8 mm). Pain scores ranged from 0 to 3 score scale. Complete resolution of the disease was observed in some patients. CONCLUSIONS: This conservative nonsurgical treatment regimen seems to provide successful treatment in reduction of the sizes of exposed bone areas in the majority of patients.
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1,890 |
The population health approach: A qualitative study of conceptual and operational definitions for leaders in Canadian healthcare
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OBJECTIVES: The population health approach is increasingly recognized for its role in health system reform; however, its broad scope and definition have been criticized for being a barrier to clear communication. This qualitative study examined the way senior healthcare leaders in Canada conceptualize and operationalize the population health approach in planning and decision-making. FINDINGS: Core elements of the population health approach included focusing on health and wellness rather than illness, taking a population rather than individual orientation, understanding needs and solutions through community outreach, addressing health disparities/health in vulnerable groups, addressing the social determinants of health and inter-sectoral action and partnerships. CONCLUSION: The population health approach is increasingly recognized for its role in reducing healthcare demand and contributing to health system sustainability. This study demonstrated the growing need to clarify terminology among multiform partners to establish a foundation for future healthcare integration and inter-sectoral action.
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1,891 |
Expression and Purification of the Uropathogenic Escherichia coli PapG Protein and its Surface Absorption on Lactobacillus reuteri: Implications for Surface Display System Vaccines
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BACKGROUND: Uropathogenic Escherichia coli (UPEC) is one of the most common bacteria that can cause urinary tract infections (UTIs). Unfortunately, no human vaccine against UTIs has been developed. Therefore, it is necessary to develop an efficient and safe vaccine that is able to induce mucosal and systemic immune responses. The use of lactic acid bacteria as a delivery system is a promising method to induce the immune system. OBJECTIVES: The aim of this study was to establish Lactobacillus reuteri harboring the E. coli PapG antigen on its surface. MATERIALS AND METHODS: In this study, the gene encoding PapG was fused to the AcmA gene (which encodes an anchor protein in Lactobacillus) and cloned into the pEX A vector. The PapG.AcmA fusion gene was digested with BamHI and NdeI and sub-cloned into the pET21a expression vector at the digestion sites. Subsequently, the recombinant plasmids (pET21a-PapG.AcmA and pET21a-PapG) were transformed into the E. coli Origami strain using the calcium chloride method and the fusion protein was expressed under 1 mM IPTG induction. The expression of the fusion protein was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. Purification of the PapG and PapG.AcmA proteins was carried out using a Ni-NTA column, and surface adsorption was estimated on Lactobacillus. Finally, surface localization of the fusion protein was verified by an enzyme-linked immunosorbent assay (ELISA). RESULTS: The PapG.AcmA fusion was successfully sub-cloned in the pET21a expression vector. The expression of PapG and PapG.AcmA proteins in the E. coli Origami strain was indicated as protein bands in SDS-PAGE and confirmed by western blotting. In addition, the fusion protein was displayed on the surface of L. reuteri. CONCLUSIONS: In conclusion, we developed a method to express the PapG.AcmA protein on the surface of Lactobacillus. This is the first report on the successful application of lactic acid bacteria displaying the PapG.AcmA fusion protein. It will be interesting to determine the immune responses against the PapG protein in near future using this surface display strategy.
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1,892 |
Estimating the Potential Effects of a Vaccine Program Against an Emerging Influenza Pandemic—United States
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Background. Human illness from influenza A(H7N9) was identified in March 2013, and candidate vaccine viruses were soon developed. To understand factors that may impact influenza vaccination programs, we developed a model to evaluate hospitalizations and deaths averted considering various scenarios. Methods. We utilized a model incorporating epidemic curves with clinical attack rates of 20% or 30% in a single wave of illness, case hospitalization ratios of 0.5% or 4.2%, and case fatality ratios of 0.08% or 0.53%. We considered scenarios that achieved 80% vaccination coverage, various starts of vaccination programs (16 or 8 weeks before, the same week of, or 8 or 16 weeks after start of pandemic), an administration rate of 10 or 30 million doses per week (the latter rate is an untested assumption), and 2 levels of vaccine effectiveness (2 doses of vaccine required; either 62% or 80% effective for persons aged <60 years, and either 43% or 60% effective for persons aged ≥60 years). Results. The start date of vaccination campaigns most influenced impact; 141 000–2 200 000 hospitalizations and 11 000–281 000 deaths were averted when campaigns started before a pandemic, and <100–1 300 000 hospitalizations and 0–165 000 deaths were averted for programs beginning the same time as or after the introduction of the pandemic virus. The rate of vaccine administration and vaccine effectiveness did not influence campaign impact as much as timing of the start of campaign. Conclusions. Our findings suggest that efforts to improve the timeliness of vaccine production will provide the greatest impacts for future pandemic vaccination programs.
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1,893 |
Identification of a Natural Viral RNA Motif That Optimizes Sensing of Viral RNA by RIG-I
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Stimulation of the antiviral response depends on the sensing of viral pathogen-associated molecular patterns (PAMPs) by specialized cellular proteins. During infection with RNA viruses, 5′-di- or -triphosphates accompanying specific single or double-stranded RNA motifs trigger signaling of intracellular RIG-I-like receptors (RLRs) and initiate the antiviral response. Although these molecular signatures are present during the replication of many viruses, it is unknown whether they are sufficient for strong activation of RLRs during infection. Immunostimulatory defective viral genomes (iDVGs) from Sendai virus (SeV) are among the most potent natural viral triggers of antiviral immunity. Here we describe an RNA motif (DVG(70-114)) that is essential for the potent immunostimulatory activity of 5′-triphosphate-containing SeV iDVGs. DVG(70-114) enhances viral sensing by the host cell independently of the long stretches of complementary RNA flanking the iDVGs, and it retains its stimulatory potential when transferred to otherwise inert viral RNA. In vitro analysis showed that DVG(70-114) augments the binding of RIG-I to viral RNA and promotes enhanced RIG-I polymerization, thereby facilitating the onset of the antiviral response. Together, our results define a new natural viral PAMP enhancer motif that promotes viral recognition by RLRs and confers potent immunostimulatory activity to viral RNA.
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1,894 |
Wnt3a mitigates acute lung injury by reducing P2X7 receptor-mediated alveolar epithelial type I cell death
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Acute lung injury (ALI) is characterized by pulmonary endothelial and epithelial cell damage, and loss of the alveolar–capillary barrier. We have previously shown that P2X7 receptor (P2X7R), a cell death receptor, is specifically expressed in alveolar epithelial type I cells (AEC I). In this study, we hypothesized that P2X7R-mediated purinergic signaling and its interaction with Wnt/β-catenin signaling contributes to AEC I death. We examined the effect of P2X7R agonist 2′-3′-O-(4-benzoylbenzoyl)-ATP (BzATP) and Wnt agonist Wnt3a on AEC I death in vitro and in vivo. We also assessed the therapeutic potential of Wnt3a in a clinically relevant ALI model of intratracheal lipopolysaccharide (LPS) exposure in ventilated mice. We found that the activation of P2X7R by BzATP caused the death of AEC I by suppressing Wnt/β-catenin signaling through stimulating glycogen synthase kinase-3β (GSK-3β) and proteasome. On the other hand, the activation of Wnt/β-catenin signaling by Wnt3a, GSK-3β inhibitor, or proteasome inhibitor blocked the P2X7R-mediated cell death. More importantly, Wnt3a attenuated the AEC I damage caused by intratracheal instillation of BzATP in rats or LPS in ventilated mice. Our results suggest that Wnt3a overrides the effect of P2X7R on the Wnt/β-catenin signaling to prevent the AEC I death and restrict the severity of ALI.
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1,895 |
Origin of Long-Term Storage Stability and Nitric Oxide Release Behavior of CarboSil Polymer Doped with S-Nitroso-N-acetyl-d-penicillamine
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[Image: see text] The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-d-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC–MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer–crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4–4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.
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1,896 |
Influence of H7N9 virus infection and associated treatment on human gut microbiota
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Between March and June, 2013, forty H7N9 patients were hospitalized in our hospital. Next-generation sequencing technologies have been used to sequence the fecal DNA samples of the patient, the within sample diversity analysis, enterotyping, functional gene and metagenomic species analysis have been carried on both the patients and healthy controls. The influence of associated treatment in H7N9 infected patients is dramatic and was firstly revealed in species level due to deep sequencing technology. We found that most of the MetaGenomic Species (MGS) enriched in the control samples were Roseburia inulinivorans DSM 16841, butyrate producing bacterium SS3/4 and most of MGS enriched in the H7N9 patients were Clostridium sp. 7 2 43FAA and Enterococcus faecium. It was concluded that H7N9 viral infection and antibiotic administration have a significant effect on the microbiota community with decreased diversity and overgrowth of the bacteria such as Escherichia coli and Enterococcus faecium. Enterotype analysis showed that the communities were unstable. Treatment including antivirals, probiotics and antibiotics helps to improve the microbiota diversity and the abundance of beneficial bacteria in the gut.
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1,897 |
Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS?
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Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.
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1,898 |
Anti-cytokine autoantibodies in postherpetic neuralgia
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BACKGROUND: The mechanisms by which varicella zoster virus (VZV) reactivation causes postherpetic neuralgia (PHN), a debilitating chronic pain condition, have not been fully elucidated. Based on previous studies identifying a causative role for anti-cytokine autoantibodies in patients with opportunistic infections, we explored this possibility in PHN. METHODS: Sera from herpes zoster (HZ) patients without and with PHN (N = 115 and 83, respectively) were examined for the presence of autoantibodies against multiple cytokines, and other known autoantigens. In addition, a cohort of patients with complex regional pain syndrome or neuropathic pain was tested for autoantibodies against selected cytokines. Antibody levels against VZV, Epstein Barr virus, and herpes simplex virus-2 were also measured in the HZ and PHN patients. Patient sera with high levels of anti-cytokine autoantibodies were functionally tested for in vitro neutralizing activity. RESULTS: Six PHN subjects demonstrated markedly elevated levels of single, autoantibodies against interferon-α, interferon-γ, GM-CSF, or interleukin-6. In contrast, the HZ and the pain control group showed low or no autoantibodies, respectively, against these four cytokines. Further analysis revealed that one PHN patient with high levels of anti-interleukin-6 autoantibodies had a markedly depressed antibody level to VZV, potentially reflecting poor T cell immunity against VZV. In vitro functional testing revealed that three of the five anti-cytokine autoantibody positive PHN subjects had neutralizing autoantibodies against interferon-α, GM-CSF or interleukin-6. In contrast, none of the HZ patients without PHN had neutralizing autoantibodies. CONCLUSIONS: These results suggest the possibility that sporadic anti-cytokine autoantibodies in some subjects may cause an autoimmune immunodeficiency syndrome leading to uncontrolled VZV reactivation, nerve damage and subsequent PHN.
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1,899 |
Characterization of a New Pathogenic Acanthamoeba Species, A. byersi n. sp., Isolated from a Human with Fatal Amoebic Encephalitis
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Acanthamoeba spp. are free‐living amoebae that are ubiquitous in natural environments. They can cause cutaneous, nasopharyngeal, and disseminated infection, leading to granulomatous amebic encephalitis (GAE) in immunocompromised individuals. In addition, they can cause amoebic keratitis in contact lens wearers. Acanthamoeba GAE is almost always fatal because of difficulty and delay in diagnosis and lack of optimal antimicrobial therapy. Here, we report the description of an unusual strain isolated from skin and brain of a GAE patient. The amoebae displayed large trophozoites and star‐shaped cysts, characteristics for acanthamoebas belonging to morphology Group 1. However, its unique morphology and growth characteristics differentiated this new strain from other Group 1 species. DNA sequence analysis, secondary structure prediction, and phylogenetic analysis of the 18S rRNA gene confirmed that this new strain belonged to Group 1, but that it was distinct from the other sequence types within that group. Thus, we hereby propose the establishment of a new species, Acanthamoeba byersi n. sp. as well as a new sequence type, T18, for this new strain. To our knowledge, this is the first report of a Group 1 Acanthamoeba that is indisputably pathogenic in humans.
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