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1,500 | Rapid RNA Exchange in Aqueous Two-Phase System and Coacervate Droplets | Compartmentalization in a prebiotic setting is an important aspect of early cell formation and is crucial for the development of an artificial protocell system that effectively couples genotype and phenotype. Aqueous two-phase systems (ATPSs) and complex coacervates are phase separation phenomena that lead to the selective partitioning of biomolecules and have recently been proposed as membrane-free protocell models. We show in this study through fluorescence recovery after photobleaching (FRAP) microscopy that despite the ability of such systems to effectively concentrate RNA, there is a high rate of RNA exchange between phases in dextran/polyethylene glycol ATPS and ATP/poly-L-lysine coacervate droplets. In contrast to fatty acid vesicles, these systems would not allow effective segregation and consequent evolution of RNA, thus rendering these systems ineffective as model protocells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11084-014-9355-8) contains supplementary material, which is available to authorized users. |
1,501 | Mimiviridae, Marseilleviridae, and virophages as emerging human pathogens causing healthcare-associated infections | Aim: During the last decade it became obvious that viruses belonging to Mimiviridae and Marseilleviridae families (order Megavirales), may be potential causative agents of pneumonia. Thus, we have performed a review of the association of Mimiviridae, Marseilleviridae, and virophages with pneumonia, particularly healthcare-associated pneumonia, and other infections of the respiratory tract. Results and discussion: According to the analysis of the published articles, viruses belonging to Mimiviridae family can be potential agents of both community-acquired and healthcare-associated pneumonia. In particular, these viruses may be associated with poor outcome in patients of intensive care units. The exact mechanism of their pathogenicity, however, still remains unclear. The discrepancies between the results obtained by serological and genomic methods could be explained by the high polymorphism of nucleotide sequences of Mimiviridae family representatives. Further investigations on the Mimiviridae pathogenicity and on the determination of Mimiviridae-caused pneumonia risk groups are required. However, the pathogenicity of the viruses belonging to Marseilleviridae family and virophages is unclear up to now. |
1,502 | Genetic Variants of CD209 Associated with Kawasaki Disease Susceptibility | BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis with unknown etiology mainly affecting children in Asian countries. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN, CD209) in humans was showed to trigger an anti-inflammatory cascade and associated with KD susceptibility. This study was conducted to investigate the association between genetic polymorphisms of CD209 and the risk KD. METHODS: A total of 948 subjects (381 KD and 567 controls) were recruited. Nine tagging SNPs (rs8112310, rs4804800, rs11465421, rs1544766, rs4804801, rs2287886, rs735239, rs735240, rs4804804) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. RESULTS: Significant associations were found between CD209 polymorphisms (rs4804800, rs2287886, rs735240) and the risk of KD. Haplotype analysis for CD209 polymorphisms showed that A/A/G haplotype (P = 0.0002, OR = 1.61) and G/A/G haplotype (P = 0.0365, OR = 1.52) had higher risk of KD as compared with G/G/A haplotype in rs2287886/rs735239/rs735240 pairwise allele analysis. There were no significant association in KD with regards to CAL formation and IVIG treatment responses. CONCLUSION: CD209 polymorphisms were responsible for the susceptibility of KD, but not CAL formation and IVIG treatment responsiveness. |
1,503 | Tumour necrosis factor, interleukin-6 and interleukin-10 are possibly involved in Plasmodium vivax-associated thrombocytopaenia in southern Pakistani population | BACKGROUND: In Pakistan, Plasmodium vivax is endemic causing approximately 70% of the malaria cases. A number of haematological changes, especially thrombocytopaenia have been reported for P. vivax. Several host factors including cell-mediated immune cells, such as IL-1, IL-6 and IL-10 have been documented for P. vivax-induced thrombocytopaenia. However, study on correlation of cytokines and thrombocytopaenia in P. vivax, particularly in patients with severe signs and symptoms has not been reported from Pakistan. METHODS: A case control study to correlate TNF, IL-6 and IL-10 in healthy controls and thrombocytopaenic P. vivax-infected patients (both uncomplicated and complicated cases) from southern Pakistan was carried out during January 2009 to December 2011. One Hundred and eighty two patients presenting with microscopy-confirmed asexual P. vivax mono-infection and 100 healthy controls were enrolled in the study at Aga Khan University Hospital, Karachi. Enzyme-linked immunosorbent assay (ELISA) was performed for determination of TNF, IL-6 and IL-10 levels. RESULTS: Out of 182 cases, mild thrombocytopaenia (platelet count 100,000-150,000 mm(3)) was observed in ten (5.5%), moderate (50,000-100,000 mm(3)) in 93 (51.1%), and profound thrombocytopaenia (<50,000 mm(3)) was detected in 79 (43.4%) patients. IL-6 and IL-10 levels were found approximately three-fold higher in the mild cases compared to healthy controls. Two-fold increase in TNF and IL-10 (p < 0.0001) was observed in profound thrombocytopaenic when compared with moderate cases, while IL-6 was not found to be significantly elevated. CONCLUSION: Cytokines may have a possible role in P. vivax-induced thrombocytopaenia in Pakistani population. Findings from this study give first insight from Pakistan on the role of cytokines in P.vivax-associated thrombocytopaenia. However, further studies are required to understand the relevance of cytokines in manifestations of thrombocytopaenia in P. vivax malaria. |
1,504 | ERKs and mitochondria-related pathways are essential for glycyrrhizic acid-mediated neuroprotection against glutamate-induced toxicity in differentiated PC12 cells | The present study focuses on the neuroprotective effect of glycyrrhizic acid (GA, a major compound separated from Glycyrrhiza Radix, which is a crude Chinese traditional drug) against glutamate-induced cytotoxicity in differentiated PC12 (DPC12) cells. The results showed that GA treatment improved cell viability and ameliorated abnormal glutamate-induced alterations in mitochondria in DPC12 cells. GA reversed glutamate-suppressed B-cell lymphoma 2 levels, inhibited glutamate-enhanced expressions of Bax and cleaved caspase 3, and reduced cytochrome C (Cyto C) release. Exposure to glutamate strongly inhibited phosphorylation of AKT (protein kinase B) and extracellular signal-regulated kinases (ERKs); however, GA pretreatment enhanced activation of ERKs but not AKT. The presence of PD98059 (a mitogen-activated protein/extracellular signal-regulated kinase kinase [MEK] inhibitor) but not LY294002 (a phosphoinositide 3-kinase [PI3K] inhibitor) diminished the potency of GA for improving viability of glutamate-exposed DPC12 cells. These results indicated that ERKs and mitochondria-related pathways are essential for the neuroprotective effect of GA against glutamate-induced toxicity in DPC12 cells. The present study provides experimental evidence supporting GA as a potential therapeutic agent for use in the treatment of neurodegenerative diseases. |
1,505 | Membrane Interacting Regions of Dengue Virus NS2A Protein | [Image: see text] The Dengue virus (DENV) NS2A protein, essential for viral replication, is a poorly characterized membrane protein. NS2A displays both protein/protein and membrane/protein interactions, yet neither its functions in the viral cycle nor its active regions are known with certainty. To highlight the different membrane-active regions of NS2A, we characterized the effects of peptides derived from a peptide library encompassing this protein’s full length on different membranes by measuring their membrane leakage induction and modulation of lipid phase behavior. Following this initial screening, one region, peptide dens25, had interesting effects on membranes; therefore, we sought to thoroughly characterize this region’s interaction with membranes. This peptide presents an interfacial/hydrophobic pattern characteristic of a membrane-proximal segment. We show that dens25 strongly interacts with membranes that contain a large proportion of lipid molecules with a formal negative charge, and that this effect has a major electrostatic contribution. Considering its membrane modulating capabilities, this region might be involved in membrane rearrangements and thus be important for the viral cycle. |
1,506 | FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination | BACKGROUND: FTY720 (fingolimod) is the first oral drug approved by the Food and Drug Administration for treatment of patients with the relapsing-remitting form of the human demyelinating disease multiple sclerosis. Evidence suggests that the therapeutic benefit of FTY720 occurs by preventing the egress of lymphocytes from lymph nodes thereby inhibiting the infiltration of disease-causing lymphocytes into the central nervous system (CNS). We hypothesized that FTY720 treatment would affect lymphocyte migration to the CNS and influence disease severity in a mouse model of viral-induced neurologic disease. METHODS: Mice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus. Infected animals were treated with increasing doses (1, 3 and 10 mg/kg) of FTY720 and morbidity and mortality recorded. Infiltration of inflammatory virus-specific T cells (tetramer staining) into the CNS of FTY720-treated mice was determined using flow cytometry. The effects of FTY720 treatment on virus-specific T cell proliferation, cytokine production and cytolytic activity were also determined. The severity of neuroinflammation and demyelination in FTY720-treated mice was examined by flow cytometry and histopathologically, respectively, in the spinal cords of the mice. RESULTS: Administration of FTY720 to JHMV-infected mice resulted in increased clinical disease severity and mortality. These results correlated with impaired ability to control viral replication (P < 0.05) within the CNS at days 7 and 14 post-infection, which was associated with diminished accumulation of virus-specific CD4+ and CD8+ T cells (P < 0.05) into the CNS. Reduced neuroinflammation in FTY720-treated mice correlated with increased retention of T lymphocytes within draining cervical lymph nodes (P < 0.05). Treatment with FTY720 did not affect virus-specific T cell proliferation, expression of IFN-γ, TNF-α or cytolytic activity. FTY720-treated mice exhibited a reduction in the severity of demyelination associated with dampened neuroinflammation. CONCLUSION: These findings indicate that FTY720 mutes effective anti-viral immune responses through impacting migration and accumulation of virus-specific T cells within the CNS during acute viral-induced encephalomyelitis. FTY720 treatment reduces the severity of neuroinflammatory-mediated demyelination by restricting the access of disease-causing lymphocytes into the CNS but is not associated with viral recrudescence in this model. |
1,507 | The role of viral persistence in flavivirus biology | In nature, vector-borne flaviviruses are persistently cycled between either the tick or mosquito vector and small mammals such as rodents, skunks, and swine. These viruses account for considerable human morbidity and mortality worldwide. Increasing and substantial evidence of viral persistence in humans, which includes the isolation of RNA by RT-PCR and infectious virus by culture, continues to be reported. Viral persistence can also be established in vitro in various human, animal, arachnid and insect cell lines in culture. Although some research has focused on the potential roles of defective virus particles, evasion of the immune response through the manipulation of autophagy and/or apoptosis, the precise mechanism of flavivirus persistence is still not well understood. We propose additional research for further understanding of how viral persistence is established in different systems. Avenues for additional studies include determining if the multifunctional flavivirus protein NS5 has a role in viral persistence, the development of relevant animal models of viral persistence as well as investigating the host responses that allow vector borne flavivirus replication without detrimental effects on infected cells. Such studies might shed more light on the viral-host relationships, and could be used to unravel the mechanisms for establishment of persistence. |
1,508 | Characterisation of novel microRNAs in the Black flying fox (Pteropus alecto) by deep sequencing | BACKGROUND: Bats are a major source of new and emerging viral diseases. Despite the fact that bats carry and shed highly pathogenic viruses including Ebola, Nipah and SARS, they rarely display clinical symptoms of infection. Host factors influencing viral replication are poorly understood in bats and are likely to include both pre- and post-transcriptional regulatory mechanisms. MicroRNAs are a major mechanism of post-transcriptional gene regulation, however very little is known about them in bats. RESULTS: This study describes 399 microRNAs identified by deep sequencing of small RNA isolated from tissues of the Black flying fox, Pteropus alecto, a confirmed natural reservoir of the human pathogens Hendra virus and Australian bat lyssavirus. Of the microRNAs identified, more than 100 are unique amongst vertebrates, including a subset containing mutations in critical seed regions. Clusters of rapidly-evolving microRNAs were identified, as well as microRNAs predicted to target genes involved in antiviral immunity, the DNA damage response, apoptosis and autophagy. Closer inspection of the predicted targets for several highly supported novel miRNA candidates suggests putative roles in host-virus interaction. CONCLUSIONS: MicroRNAs are likely to play major roles in regulating virus-host interaction in bats, via dampening of inflammatory responses (limiting the effects of immunopathology), and directly limiting the extent of viral replication, either through restricting the availability of essential factors or by controlling apoptosis. Characterisation of the bat microRNA repertoire is an essential step towards understanding transcriptional regulation during viral infection, and will assist in the identification of mechanisms that enable bats to act as natural virus reservoirs. This in turn will facilitate the development of antiviral strategies for use in humans and other species. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-682) contains supplementary material, which is available to authorized users. |
1,509 | Life‐history traits predict perennial species response to fire in a desert ecosystem | The Mojave Desert of North America has become fire‐prone in recent decades due to invasive annual grasses that fuel wildfires following years of high rainfall. Perennial species are poorly adapted to fire in this system, and post‐fire shifts in species composition have been substantial but variable across community types. To generalize across a range of conditions, we investigated whether simple life‐history traits could predict how species responded to fire. Further, we classified species into plant functional types (PFTs) based on combinations of life‐history traits and evaluated whether these groups exhibited a consistent fire‐response. Six life‐history traits varied significantly between burned and unburned areas in short (up to 4 years) or long‐term (up to 52 years) post‐fire datasets, including growth form, lifespan, seed size, seed dispersal, height, and leaf longevity. Forbs and grasses consistently increased in abundance after fire, while cacti were reduced and woody species exhibited a variable response. Woody species were classified into three PFTs based on combinations of life‐history traits. Species in Group 1 increased in abundance after fire and were characterized by short lifespans, small, wind‐dispersed seeds, low height, and deciduous leaves. Species in Group 2 were reduced by fire and distinguished from Group 1 by longer lifespans and evergreen leaves. Group 3 species, which also decreased after fire, were characterized by long lifespans, large non‐wind dispersed seeds, and taller heights. Our results show that PFTs based on life‐history traits can reliably predict the responses of most species to fire in the Mojave Desert. Dominant, long‐lived species of this region possess a combination of traits limiting their ability to recover, presenting a clear example of how a novel disturbance regime may shift selective environmental pressures to favor alternative life‐history strategies. |
1,510 | Progress and challenges of disaster health management in China: a scoping review | BACKGROUND: Despite the importance of an effective health system response to various disasters, relevant research is still in its infancy, especially in middle- and low-income countries. OBJECTIVE: This paper provides an overview of the status of disaster health management in China, with its aim to promote the effectiveness of the health response for reducing disaster-related mortality and morbidity. DESIGN: A scoping review method was used to address the recent progress of and challenges to disaster health management in China. Major health electronic databases were searched to identify English and Chinese literature that were relevant to the research aims. RESULTS: The review found that since 2003 considerable progress has been achieved in the health disaster response system in China. However, there remain challenges that hinder effective health disaster responses, including low standards of disaster-resistant infrastructure safety, the lack of specific disaster plans, poor emergency coordination between hospitals, lack of portable diagnostic equipment and underdeveloped triage skills, surge capacity, and psychological interventions. Additional challenges include the fragmentation of the emergency health service system, a lack of specific legislation for emergencies, disparities in the distribution of funding, and inadequate cost-effective considerations for disaster rescue. CONCLUSIONS: One solution identified to address these challenges appears to be through corresponding policy strategies at multiple levels (e.g. community, hospital, and healthcare system level). |
1,511 | Multiyear Persistence of 2 Pandemic A/H1N1 Influenza Virus Lineages in West Africa | Our understanding of the global ecology of influenza viruses is impeded by historically low levels of viral surveillance in Africa. Increased genetic sequencing of African A/H1N1 pandemic influenza viruses during 2009–2013 revealed multiyear persistence of 2 viral lineages within West Africa, raising questions about the roles of reduced air traffic and the asynchrony of seasonal influenza epidemics among West African countries in the evolution of independent lineages. The potential for novel influenza virus lineages to evolve within Africa warrants intensified influenza surveillance in Africa and other understudied areas. |
1,512 | Autoreactivity to Glucose Regulated Protein 78 Links Emphysema and Osteoporosis in Smokers | RATIONALE: Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders. OBJECTIVES: To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers. METHODS: Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays. MEASUREMENTS AND MAIN RESULTS: Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7–5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7–13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively). CONCLUSIONS: Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders. |
1,513 | Isolation and characterization of 11 novel microsatellite loci in a West African leaf-nosed bat, Hipposideros aff. ruber | BACKGROUND: Noack’s leaf-nosed bat, Hipposideros ruber, is a cryptic species within the Hipposideros caffer species complex. Despite a widespread distribution in Africa and being host to potentially zoonotic viruses, the genetic structure and ecology of H. ruber is poorly known. Here we describe the development of 11 novel polymorphic microsatellite loci to facilitate the investigation of genetic structure. FINDINGS: We selected 20 microsatellite sequences identified from high throughput sequence reads and PCR amplified these for 38 individuals, yielding 11 consistently amplifying and scorable loci. The number of alleles per locus ranged from two to 12, and observed heterozygosities from 0.00 to 0.865. No evidence of linkage disequilibrium was observed, and nine of the markers showed no departure from Hardy-Weinberg equilibrium. We demonstrate successful amplification in two closely related species and two divergent lineages of the H. caffer species complex. CONCLUSIONS: These new markers will provide a valuable tool to investigate genetic structure in the poorly understood Hipposideros caffer species complex. |
1,514 | Bioassay Directed Isolation and Biological Evaluation of Compounds Isolated from Rubus fairholmianus Gard. | The in vitro and in silico analysis of Rubus fairholmianus acetone extract for antioxidant, antiproliferative, and anti-inflammatory activity led to the isolation of six compounds. Amongst all the six isolated compounds tested, 1-(2-hydroxyphenyl)-4-methylpentan-1-one (compound 1) and 2-[(3-methylbutoxy) carbonyl] benzoic acid (compound 2) were found to be more active in inhibiting BRCA and COX target proteins, which also showed the better results for DPPH and ABTS radical scavenging assays. The promising results of this investigation emphasize the importance of using R. fairholmianus in the treatment of radical generated disorders mainly cancer and other inflammatory diseases. |
1,515 | Rapid identification of novel antigens of Salmonella Enteritidis by microarray-based immunoscreening | We report on an approach to rapidly screen thousands of Salmonella Enteritidis proteins with the goal of identifying novel immunodominant proteins. We used a microarray-based system that warrants high throughput and easy handling. Seven immunogenic candidates were selected after screening. Comparative analyses by ELISA and microarrays manifested their immunodominant character. The large repetitive protein (SEN4030) that plays a role as a putative adhesin in initial cell surface interaction and is highly specific to Salmonella is considered to be the most suitable protein for a diagnostic approach. The results further demonstrate that the strategy applied herein is convenient for specifically identifying immunogenic proteins of pathogenic microorganisms. Consequently, it enables a sound assessment of promising candidates for diagnostic applications and vaccine development. Moreover, the elucidation of immunogenic proteins may assist in unveiling unknown virulence-associated factors, thus furthering the understanding of the underlying pathogenicity of Salmonella in general, and of S. Enteritidis, one of the most frequently detected serovars of this pathogen, in particular. [Figure: see text] |
1,516 | Multiplex isothermal solid-phase recombinase polymerase amplification for the specific and fast DNA-based detection of three bacterial pathogens | We report on the development of an on-chip RPA (recombinase polymerase amplification) with simultaneous multiplex isothermal amplification and detection on a solid surface. The isothermal RPA was applied to amplify specific target sequences from the pathogens Neisseria gonorrhoeae, Salmonella enterica and methicillin-resistant Staphylococcus aureus (MRSA) using genomic DNA. Additionally, a positive plasmid control was established as an internal control. The four targets were amplified simultaneously in a quadruplex reaction. The amplicon is labeled during on-chip RPA by reverse oligonucleotide primers coupled to a fluorophore. Both amplification and spatially resolved signal generation take place on immobilized forward primers bount to expoxy-silanized glass surfaces in a pump-driven hybridization chamber. The combination of microarray technology and sensitive isothermal nucleic acid amplification at 38 °C allows for a multiparameter analysis on a rather small area. The on-chip RPA was characterized in terms of reaction time, sensitivity and inhibitory conditions. A successful enzymatic reaction is completed in <20 min and results in detection limits of 10 colony-forming units for methicillin-resistant Staphylococcus aureus and Salmonella enterica and 100 colony-forming units for Neisseria gonorrhoeae. The results show this method to be useful with respect to point-of-care testing and to enable simplified and miniaturized nucleic acid-based diagnostics. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00604-014-1198-5) contains supplementary material, which is available to authorized users. |
1,517 | Neuroinflammation in Pulmonary Hypertension: Concept, Facts, and Relevance | Pulmonary hypertension (PH) is a progressive lung disease characterized by elevated pressure in the lung vasculature, resulting in right-sided heart failure and premature death. The pathogenesis of PH is complex and multifactorial, involving a dysregulated autonomic nervous system and immune response. Inflammatory mechanisms have been linked to the development and progression of PH; however, these are usually restricted to systemic and/or local lung tissue. Inflammation within the CNS, often referred to as neuroinflammation involves activation of the microglia, the innate immune cells that are found specifically in the brain and spinal cord. Microglial activation results in the release of several cytokines and chemokines that trigger neuroinflammation, and has been implicated in the pathogenesis of several disease conditions such as Alzheimer’s, Parkinson’s, hypertension, atherosclerosis, and metabolic disorders. In this review, we introduce the concept of neuroinflammation in the context of PH, and discuss possible strategies that could be developed for PH therapy based on this concept. |
1,518 | Full-Length Genomic Analysis of Korean Porcine Sapelovirus Strains | Porcine sapelovirus (PSV), a species of the genus Sapelovirus within the family Picornaviridae, is associated with diarrhea, pneumonia, severe neurological disorders, and reproductive failure in pigs. However, the structural features of the complete PSV genome remain largely unknown. To analyze the structural features of PSV genomes, the full-length nucleotide sequences of three Korean PSV strains were determined and analyzed using bioinformatic techniques in comparison with other known PSV strains. The Korean PSV genomes ranged from 7,542 to 7,566 nucleotides excluding the 3′ poly(A) tail, and showed the typical picornavirus genome organization; 5′untranslated region (UTR)-L-VP4-VP2-VP3-VP1-2A-2B-2C-3A-3B-3C-3D-3′UTR. Three distinct cis-active RNA elements, the internal ribosome entry site (IRES) in the 5′UTR, a cis-replication element (CRE) in the 2C coding region and 3′UTR were identified and their structures were predicted. Interestingly, the structural features of the CRE and 3′UTR were different between PSV strains. The availability of these first complete genome sequences for PSV strains will facilitate future investigations of the molecular pathogenesis and evolutionary characteristics of PSV. |
1,519 | Association of Cytokines in Individuals Sensitive and Insensitive to Dust Mites in a Brazilian Population | INTRODUCTION: Allergic reaction to dust mites is a relatively common condition among children, triggering cutaneous and respiratory responses that have a great impact on the health of this population. Anaphylactic hypersensitivity is characterized by an exacerbated response involving the production of regulatory cytokines responsible for stimulating the production of IgE antibodies. OBJECTIVE: To investigate an association of variants in cytokine genes (IL1A (−889), IL1B (−511, +3962), IL1R (1970), IL1RA (11100), IL4RA (+1902), IL12 (−1188), IFNG (+874), TGFB1 (codon 10, codon 25), TNFA (−308, −238), IL2 (−330, +166), IL4 (−1098, −590, −33), IL6 (−174, nt565), and IL10 (−1082, −819, −592)) between patients sensitive to dust mites and a control group. METHODS: A total of 254 patients were grouped as atopic and non-atopic according to sensitivity as evaluated by the Prick Test and to cytokine genotyping by the polymerase chain reaction-sequence specific primers (PCR-SSP) method using the Cytokine Genotyping Kit. RESULTS: A comparison between individuals allergic to Dermatophagoides farinae, Dermatophagoides pteronyssinus, and Blomia tropicalis and a non-atopic control group showed significant differences between allele and genotype frequencies in the regulatory regions of cytokine genes, with important evidence for IL4 (−590) in T/C (10.2% vs. 43.1%, odd ratio [OR] = 0.15, p = 5.2 10(−8), pc = 0.0000011, and 95% confidence interval [95%CI] = 0.07–0.32) and T/T genotypes (42.9% vs. 13.8%, OR = 4.69, p = 2.5 10(−6), pc = 0.000055, and 95%CI = 2.42–9.09). Other associations were observed in the pro-inflammatory cytokines IL1A (−889) (T/T, C, and T) and IL2 (−330) (G/T and T/T) and the anti-inflammatory cytokines IL4RA (+1902) (A and G), IL4 (−590) (T/C, T/T, C, and T), and IL10 (−592) (A/A, C/A, A, and C). CONCLUSION: Our results suggest a possible association between single nucleotide polymorphisms (SNPs) in cytokine genes and hypersensitivity to dust mites. |
1,520 | Metagenomic Assay for Identification of Microbial Pathogens in Tumor Tissues | Screening for thousands of viruses and other pathogenic microorganisms, including bacteria, fungi, and parasites, in human tumor tissues will provide a better understanding of the contributory role of the microbiome in the predisposition for, causes of, and therapeutic responses to the associated cancer. Metagenomic assays designed to perform these tasks will have to include rapid and economical processing of large numbers of samples, supported by straightforward data analysis pipeline and flexible sample preparation options for multiple input tissue types from individual patients, mammals, or environmental samples. To meet these requirements, the PathoChip platform was developed by targeting viral, prokaryotic, and eukaryotic genomes with multiple DNA probes in a microarray format that can be combined with a variety of upstream sample preparation protocols and downstream data analysis. PathoChip screening of DNA plus RNA from formalin-fixed, paraffin-embedded tumor tissues demonstrated the utility of this platform, and the detection of oncogenic viruses was validated using independent PCR and deep sequencing methods. These studies demonstrate the use of the PathoChip technology combined with PCR and deep sequencing as a valuable strategy for detecting the presence of pathogens in human cancers and other diseases. |
1,521 | Docetaxel induces moderate ovarian toxicity in mice, primarily affecting granulosa cells of early growing follicles | Advances in cancer therapy have focused attention on the quality of life of cancer survivors. Since infertility is a major concern following chemotherapy, it is important to characterize the drug-specific damage to the reproductive system to help find appropriate protective strategies. This study investigates the damage on neonatal mouse ovary maintained in vitro for 6 days, and exposed for 24 h (on Day 2) to clinically relevant doses of Docetaxel (DOC; low: 0.1 µM, mid: 1 µM, high: 10 µM). Furthermore, the study explores the putative protective action exerted by Tri-iodothyronine (T3; 10(−7) M). At the end of culture, morphological analyses and follicle counts showed that DOC negatively impacts on early growing follicles, decreasing primary follicle number and severely affecting health at the transitional and primary stages. Poor follicle health was mainly due to effects on granulosa cells, indicating that the effects of DOC on oocytes were likely to be secondary to granulosa cell damage. DOC damages growing follicles specifically, with no direct effect on the primordial follicle reserve. Immunostaining and western blotting showed that DOC induces activation of intrinsic, type II apoptosis in ovarian somatic cells; increasing the levels of cleaved caspase 3, cleaved caspase 8, Bax and cleaved poly(ADP-ribose) polymerase, while also inducing movement of cytochrome C from mitochondria into the cytosol. T3 did not prevent the damage induced by the low dose of DOC. These results demonstrated that DOC induces a gonadotoxic effect on the mouse ovary through induction of somatic cell apoptosis, with no evidence of direct effects on the oocyte, and that the damaging effect is not mitigated by T3. |
1,522 | Anxiety and Depression: Linkages with Viral Diseases | Anxiety and mood disorders are common in the general population in countries around the world. This article provides a review of the recent literature on anxiety and depressive disorders with a focus on linkages with several important viral diseases. Although the majority of studies have been conducted in developed countries such as the United States and Great Britain, some studies have been carried out in less developed nations where only a small percentage of persons with mental illness receive treatment for their condition. The studies summarized in this review indicate that there are important linkages between anxiety and depression and viral diseases such as influenza A (H1N1) and other influenza viruses, varicella-zoster virus, herpes simplex virus, human immunodeficiency virus/acquired immune deficiency syndrome, and hepatitis C. Additional studies are needed to further clarify the mechanisms for interactions between mental health and communicable diseases, in order to assist patients and further prevention and control efforts. |
1,523 | Associations of hand-washing frequency with incidence of acute respiratory tract infection and influenza-like illness in adults: a population-based study in Sweden | BACKGROUND: Frequent hand-washing is standard advice for avoidance of respiratory tract infections, but the evidence for a preventive effect in a general community setting is sparse. We therefore set out to quantify, in a population-based adult general population cohort, the possible protection against acute respiratory tract infections (ARIs) conferred by a person’s self-perceived hand-washing frequency. METHODS: During the pandemic influenza season from September 2009 through May 2010, a cohort of 4365 adult residents of Stockholm County, Sweden, reported respiratory illnesses in real-time. A questionnaire about typical contact and hand-washing behaviour was administered at the end of the period (response rate 70%). RESULTS: There was no significant decrease in ARI rates among adults with increased daily hand-washing frequency: Compared to 2–4 times/day, 5–9 times was associated with an adjusted ARI rate ratio (RR) of 1.08 (95% confidence interval [CI] 0.87-1.33), 10–19 times with RR = 1.22 (CI 0.97-1.53), and ≥20 times with RR = 1.03 (CI 0.81-1.32). A similar lack of effect was seen for influenza-like illness, and in all investigated subgroups. We found no clear effect modification by contact behaviour. Health care workers exhibited rate ratio point estimates below unity, but no dose-risk trend. CONCLUSIONS: Our results suggest that increases in what adult laymen perceive as being adequate hand-washing may not significantly reduce the risk of ARIs. This might have implications for the design of public health campaigns in the face of threatening outbreaks of respiratory infections. However, the generalizability of our results to non-pandemic circumstances should be further explored. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2334-14-509) contains supplementary material, which is available to authorized users. |
1,524 | High-Throughput Sequencing and De Novo Assembly of the Isatis indigotica Transcriptome | BACKGROUND: Isatis indigotica, the source of the traditional Chinese medicine Radix isatidis (Ban-Lan-Gen), is an extremely important economical crop in China. To facilitate biological, biochemical and molecular research on the medicinal chemicals in I. indigotica, here we report the first I. indigotica transcriptome generated by RNA sequencing (RNA-seq). RESULTS: RNA-seq library was created using RNA extracted from a mixed sample including leaf and root. A total of 33,238 unigenes were assembled from more than 28 million of high quality short reads. The quality of the assembly was experimentally examined by cDNA sequencing of seven randomly selected unigenes. Based on blast search 28,184 unigenes had a hit in at least one of the protein and nucleotide databases used in this study, and 8 unigenes were found to be associated with biosynthesis of indole and its derivatives. According to Gene Ontology classification, 22,365 unigenes were categorized into 48 functional groups. Furthermore, Clusters of Orthologous Group and Swiss-Port annotation were assigned for 7,707 and 18,679 unigenes, respectively. Analysis of repeat motifs identified 6,400 simple sequence repeat markers in 4,509 unigenes. CONCLUSION: Our data provide a comprehensive sequence resource for molecular study of I. indigotica. Our results will facilitate studies on the functions of genes involved in the indole alkaloid biosynthesis pathway and on metabolism of nitrogen and indole alkaloids in I. indigotica and its related species. |
1,525 | Comparison of Antibodies Hydrolyzing Myelin Basic Protein from the Cerebrospinal Fluid and Serum of Patients with Multiple Sclerosis | It was found that antibodies (Abs) against myelin basic protein (MBP) are the major components of the antibody response in multiple sclerosis (MS) patients. We have recently shown that IgGs from sera of MS patients are active in the hydrolysis of MBP. However, in literature there are no available data concerning possible MBP-hydrolyzing Abs in cerebrospinal fluid (CSF) of MS patients. We have shown that the average content of IgGs in their sera is about 195-fold higher than that in their CSF. Here we have compared, for the first time, the average content of lambda- and kappa-IgGs as well as IgGs of four different subclasses (IgG1-IgG4) in CSF and sera of MS patients. The average relative content of lambda-IgGs and kappa –IgGs in the case of CSFs (8.0 and 92.0%) and sera (12.3 and 87.7%) are comparable, while IgG1, IgG2, IgG3, and IgG4: CSF - 40.4, 49.0, 8.2, and 2.5% of total IgGs, respectively and the sera - 53.6, 36.0, 5.6, and 4.8%, decreased in different order. Electrophoretically and immunologically homogeneous IgGs were obtained by sequential affinity chromatography of the CSF proteins on protein G-Sepharose and FPLC gel filtration. We present first evidence showing that IgGs from CSF efficiently hydrolyze MBP and that their average specific catalytic activity is unpredictably ∼54-fold higher than that of Abs from sera of the same MS patients. Some possible reasons of these findings are discussed. We suggest that anti-MBP abzymes of CSF may promote important neuropathologic mechanisms in this chronic inflammatory disorder and in MS pathogenesis development. |
1,526 | Procalcitonin guidance for reduction of antibiotic use in patients hospitalized with severe acute exacerbations of asthma: a randomized controlled study with 12-month follow-up | INTRODUCTION: Patients with severe acute exacerbations of asthma often receive inappropriate antibiotic treatment. We aimed to determine whether serum procalcitonin (PCT) levels can effectively and safely reduce antibiotic exposure in patients experiencing exacerbations of asthma. METHODS: In this randomized controlled trial, a total of 216 patients requiring hospitalization for severe acute exacerbations of asthma were screened for eligibility to participate and 169 completed the 12-month follow-up visit. Patients were randomized to either PCT-guided (PCT group) or standard (control group) antimicrobial therapy. In the control group, patients received antibiotics according to the attending physician’s discretion; in the PCT group, patients received antibiotics according to an algorithm based on serum PCT levels. The primary end point was antibiotic exposure; secondary end points were clinical recovery, length of hospital stay, clinical and laboratory parameters, spirometry, number of asthma exacerbations, emergency room visits, hospitalizations and need for corticosteroid use due to asthma. RESULTS: PCT guidance reduced antibiotic prescription (48.9% versus 87.8%, respectively; P < 0.001) and antibiotic exposure (relative risk, 0.56; 95% confidence interval, 0.44 to 0.70; P < 0.001) compared to standard therapy. There were no significant differences in clinical recovery, length of hospital stay or clinical, laboratory and spirometry outcomes in both groups. Number of asthma exacerbations, emergency room visits, hospitalizations and need for corticosteroid use due to asthma were similar during the 12-month follow-up period. CONCLUSION: A PCT-guided strategy allows antibiotic exposure to be reduced in patients with severe acute exacerbation of asthma without apparent harm. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-TRC-12002534 (registered 26 September 2012) |
1,527 | Graph-distance distribution of the Boltzmann ensemble of RNA secondary structures | BACKGROUND: Large RNA molecules are often composed of multiple functional domains whose spatial arrangement strongly influences their function. Pre-mRNA splicing, for instance, relies on the spatial proximity of the splice junctions that can be separated by very long introns. Similar effects appear in the processing of RNA virus genomes. Albeit a crude measure, the distribution of spatial distances in thermodynamic equilibrium harbors useful information on the shape of the molecule that in turn can give insights into the interplay of its functional domains. RESULT: Spatial distance can be approximated by the graph-distance in RNA secondary structure. We show here that the equilibrium distribution of graph-distances between a fixed pair of nucleotides can be computed in polynomial time by means of dynamic programming. While a naïve implementation would yield recursions with a very high time complexity of O(n(6)D(5)) for sequence length n and D distinct distance values, it is possible to reduce this to O(n(4)) for practical applications in which predominantly small distances are of of interest. Further reductions, however, seem to be difficult. Therefore, we introduced sampling approaches that are much easier to implement. They are also theoretically favorable for several real-life applications, in particular since these primarily concern long-range interactions in very large RNA molecules. CONCLUSIONS: The graph-distance distribution can be computed using a dynamic programming approach. Although a crude approximation of reality, our initial results indicate that the graph-distance can be related to the smFRET data. The additional file and the software of our paper are available from http://www.rna.uni-jena.de/RNAgraphdist.html. |
1,528 | A systematic review of studies on forecasting the dynamics of influenza outbreaks | Forecasting the dynamics of influenza outbreaks could be useful for decision-making regarding the allocation of public health resources. Reliable forecasts could also aid in the selection and implementation of interventions to reduce morbidity and mortality due to influenza illness. This paper reviews methods for influenza forecasting proposed during previous influenza outbreaks and those evaluated in hindsight. We discuss the various approaches, in addition to the variability in measures of accuracy and precision of predicted measures. PubMed and Google Scholar searches for articles on influenza forecasting retrieved sixteen studies that matched the study criteria. We focused on studies that aimed at forecasting influenza outbreaks at the local, regional, national, or global level. The selected studies spanned a wide range of regions including USA, Sweden, Hong Kong, Japan, Singapore, United Kingdom, Canada, France, and Cuba. The methods were also applied to forecast a single measure or multiple measures. Typical measures predicted included peak timing, peak height, daily/weekly case counts, and outbreak magnitude. Due to differences in measures used to assess accuracy, a single estimate of predictive error for each of the measures was difficult to obtain. However, collectively, the results suggest that these diverse approaches to influenza forecasting are capable of capturing specific outbreak measures with some degree of accuracy given reliable data and correct disease assumptions. Nonetheless, several of these approaches need to be evaluated and their performance quantified in real-time predictions. |
1,529 | Genetic diversity and molecular epidemiology of human rhinoviruses in South Africa | BACKGROUND: Rhinoviruses (RV) are a well-established cause of respiratory illness. RV-C has been associated with more severe illness. We aimed to characterize and compare the clinical presentations and disease severity of different RV type circulating in South Africa. METHOD: We performed two analyses of RV-positive specimens identified through surveillance in South Africa across all age groups. First, RV-positive specimens identified through severe acute respiratory illness (SARI) surveillance in four provinces was randomly selected from 2009 to 2010 for molecular characterization. Second, RV-positive specimens identified through SARI, influenza-like illness (ILI) and control surveillance at hospitals and outpatient clinics in during 2012–2013 were used to determine the association of RV type with severe disease. Selected specimens were sequenced, and phylogenetic analysis was performed. RESULTS: Among the 599 sequenced specimens from 2009 to 2010 and 2012 to 2013, RV-A (285, 48%) and RV-C (247, 41%) were more commonly identified than RV-B (67, 11%), with no seasonality and a high genetic diversity. A higher prevalence of RV infection was identified in cases with SARI [515/962 (26%); aRRR = 1·6; 95% CI 1·21; 2·2] and ILI [356/962 (28%); aRRR = 1·9; 95% CI 1·37; 2·6] compared with asymptomatic controls (91/962, 22%). There was no difference in disease severity between the different type when comparing SARI, ILI and controls. CONCLUSION: All three type of RV were identified in South Africa, although RV-A and RV-C were more common than RV-B. RV was associated with symptomatic respiratory illness; however, there was no association between RV type and disease severity. |
1,530 | Chimeric NP Non Coding Regions between Type A and C Influenza Viruses Reveal Their Role in Translation Regulation | Exchange of the non coding regions of the NP segment between type A and C influenza viruses was used to demonstrate the importance not only of the proximal panhandle, but also of the initial distal panhandle strength in type specificity. Both elements were found to be compulsory to rescue infectious virus by reverse genetics systems. Interestingly, in type A influenza virus infectious context, the length of the NP segment 5′ NC region once transcribed into mRNA was found to impact its translation, and the level of produced NP protein consequently affected the level of viral genome replication. |
1,531 | Lack of a 5.9 kDa Peptide C-Terminal Fragment of Fibrinogen α Chain Precedes Fibrosis Progression in Patients with Liver Disease | Early detection of fibrosis progression is of major relevance for the diagnosis and management of patients with liver disease. This study was designed to find non-invasive biomarkers for fibrosis in a clinical context where this process occurs rapidly, HCV-positive patients who underwent liver transplantation (LT). We analyzed 93 LT patients with HCV recurrence, 41 non-LT patients with liver disease showing a fibrosis stage F≥1 and 9 patients without HCV recurrence who received antiviral treatment before LT, as control group. Blood obtained from 16 healthy subjects was also analyzed. Serum samples were fractionated by ion exchange chromatography and their proteomic profile was analyzed by SELDI-TOF-MS. Characterization of the peptide of interest was performed by ion chromatography and electrophoresis, followed by tandem mass spectrometry identification. Marked differences were observed between the serum proteome profile of LT patients with early fibrosis recurrence and non-recurrent LT patients. A robust peak intensity located at 5905 m/z was the distinguishing feature of non-recurrent LT patients. However, the same peak was barely detected in recurrent LT patients. Similar results were found when comparing samples of healthy subjects with those of non-LT fibrotic patients, indicating that our findings were not related to either LT or HCV infection. Using tandem mass-spectrometry, we identified the protein peak as a C-terminal fragment of the fibrinogen α chain. Cell culture experiments demonstrated that TGF-β reduces α-fibrinogen mRNA expression and 5905 m/z peak intensity in HepG2 cells, suggesting that TGF-β activity regulates the circulating levels of this protein fragment. In conclusion, we identified a 5.9 kDa C-terminal fragment of the fibrinogen α chain as an early serum biomarker of fibrogenic processes in patients with liver disease. |
1,532 | Nerve growth factor reduces amiloride‐sensitive Na(+) transport in human airway epithelial cells | Nerve growth factor (NGF) is overexpressed in patients with inflammatory lung diseases, including virus infections. Airway surface liquid (ASL), which is regulated by epithelial cell ion transport, is essential for normal lung function. No information is available regarding the effect of NGF on ion transport of airway epithelium. To investigate whether NGF can affect ion transport, human primary air‐interface cultured epithelial cells were placed in Ussing chambers to obtain transepithelial voltage (−7.1 ± 3.4 mV), short‐circuit current (I(sc), 5.9 ± 1.0 μA), and transepithelial resistance (750 Ω·cm(2)), and to measure responses to ion transport inhibitors. Amiloride (apical, 3.5 × 10(−5) mol/L) decreased I(sc) by 55.3%. Apically applied NGF (1 ng/mL) reduced I(sc) by 5.3% in 5 min; basolaterally applied NGF had no effect. The response to amiloride was reduced (41.6%) in the presence of NGF. K‐252a (10 nmol/L, apical) did not itself affect Na(+) transport, but it attenuated the NGF‐induced reduction in Na(+) transport, indicating the participation of the trkA receptor in the NGF‐induced reduction in Na(+) transport. PD‐98059 (30 μmol/L, apical and basolateral) did not itself affect Na(+) transport, but attenuated the NGF‐induced reduction in Na(+) transport, indicating that trkA activated the Erk 1/2 signaling cascade. NGF stimulated phosphorylation of Erk 1/2 and the β‐subunit of ENaC. K‐252a and PD‐98059 inhibited these responses. NGF had no effect on I(sc) in the presence of apical nystatin (50 μmol/L). These results indicate that NGF inhibits Na(+) transport through a trkA‐Erk 1/2‐activated signaling pathway linked to ENaC phosphorylation. |
1,533 | Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection | BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-β). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1β, IL-4, IL-5, IL-6, IL-12(p40), IFN-γ, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1β, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-γ. Silencing of retinoic acid–inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-014-0041-4) contains supplementary material, which is available to authorized users. |
1,534 | Passive Broad-Spectrum Influenza Immunoprophylaxis | Influenza is a perennial problem affecting millions of people annually with the everpresent threat of devastating pandemics. Active prophylaxis by vaccination against influenza virus is currently the main countermeasure supplemented with antivirals. However, disadvantages of this strategy include the impact of antigenic drift, necessitating constant updating of vaccine strain composition, and emerging antiviral drug resistance. The development of other options for influenza prophylaxis, particularly with broad acting agents able to provide protection in the period between the onset of a pandemic and the development of a strain specific vaccine, is of great interest. Exploitation of broad-spectrum mediators could provide barricade protection in the early critical phase of influenza virus outbreaks. Passive immunity has the potential to provide immediate antiviral effects, inhibiting virus replication, reducing virus shedding, and thereby protecting vulnerable populations in the event of an impending influenza pandemic. Here, we review passive broad-spectrum influenza prophylaxis options with a focus on harnessing natural host defenses, including interferons and antibodies. |
1,535 | The interconnected and cross-border nature of risks posed by infectious diseases | Infectious diseases can constitute public health emergencies of international concern when a pathogen arises, acquires new characteristics, or is deliberately released, leading to the potential for loss of human lives as well as societal disruption. A wide range of risk drivers are now known to lead to and/or exacerbate the emergence and spread of infectious disease, including global trade and travel, the overuse of antibiotics, intensive agriculture, climate change, high population densities, and inadequate infrastructures, such as water treatment facilities. Where multiple risk drivers interact, the potential impact of a disease outbreak is amplified. The varying temporal and geographic frequency with which infectious disease events occur adds yet another layer of complexity to the issue. Mitigating the emergence and spread of infectious disease necessitates mapping and prioritising the interdependencies between public health and other sectors. Conversely, during an international public health emergency, significant disruption occurs not only to healthcare systems but also to a potentially wide range of sectors, including trade, tourism, energy, civil protection, transport, agriculture, and so on. At the same time, dealing with a disease outbreak may require a range of critical sectors for support. There is a need to move beyond narrow models of risk to better account for the interdependencies between health and other sectors so as to be able to better mitigate and respond to the risks posed by emerging infectious disease. |
1,536 | The calcium-dependent ribonuclease XendoU promotes ER network formation through local RNA degradation | How cells shape and remodel organelles in response to cellular signals is a poorly understood process. Using Xenopus laevis egg extract, we found that increases in cytosolic calcium lead to the activation of an endogenous ribonuclease, XendoU. A fraction of XendoU localizes to the endoplasmic reticulum (ER) and is required for nuclear envelope assembly and ER network formation in a catalysis-dependent manner. Using a purified vesicle fusion assay, we show that XendoU functions on the surface of ER membranes to promote RNA cleavage and ribonucleoprotein (RNP) removal. Additionally, RNA removal from the surface of vesicles by RNase treatment leads to increased ER network formation. Using human tissue culture cells, we found that hEndoU localizes to the ER, where it promotes the formation of ER tubules in a catalysis-dependent manner. Together, these results demonstrate that calcium-activated removal of RNA from membranes by XendoU promotes and refines ER remodeling and the formation of tubular ER. |
1,537 | Review: The Important Bacterial Zoonoses in “One Health” Concept | An infectious disease that is transmitted from animals to humans, sometimes by a vector, is called zoonosis. The focus of this review article is on the most common emerging and re-emerging bacterial zoonotic diseases. The role of “One Health” approach, public health education, and some measures that can be taken to prevent zoonotic bacterial infections are discussed. Key points: A zoonotic bacterial disease is a disease that can be very commonly transmitted between animals and humans. Global climate changes, overuse of antimicrobials in medicine, more intensified farm settings, and closer interactions with animals facilitate emergence or re-emergence of bacterial zoonotic infections. The global “One Health” approach, which requires interdisciplinary collaborations and communications in all aspects of health care for humans, animals, and the environment, will support public health in general. New strategies for continuous dissemination of multidisciplinary research findings related to zoonotic bacterial diseases are hence needed. |
1,538 | Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes | The blood–brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. Interleukin-1β (IL-1β), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases. |
1,539 | IFITM3 Polymorphism rs12252-C Restricts Influenza A Viruses | The IFITM3 polymorphism rs12252-C, which encodes an IFITM3 isoform (Δ21 IFITM3) lacking 21 amino acids at the amino terminus, has been controversially associated with poor clinical outcomes in patients with H1N1 influenza A virus (IAV) infections. In vitro studies have shown that Δ21 IFITM3 loses its ability to restrict H1N1 IAV. Subsequent research has also revealed that tyrosine 20 is the key determinant for IFITM3 endocytic trafficking, which is essential for the efficient anti-viral activity of IFITM3. In contrast to previous studies, we demonstrated that both Δ21 IFITM3 and an IFITM3 variant (Y20A IFITM3), in which tyrosine 20 is substituted with alanine, strongly restricted entry mediated by IAV H1, H3, H5, and H7 proteins. Δ21 IFITM3 also efficiently suppressed replication of H1N1 and, to a lesser extent, H3N2 IAV. Δ21 IFITM3 and Y20A IFITM3 had broader subcellular distributions than full-length IFITM3 but an abundant amount of both IFITM3 variants still localized to late endosomes and lysosomes. Our data indicate that tyrosine 20 partially regulates the subcellular localization of IFITM3 but is not functionally essential for IFITM3-mediated IAV restriction. They also suggested that mechanisms, other than viral entry restriction, might contribute to variations in clinical outcomes of H1N1 influenza associated with rs12252-C. |
1,540 | Intestinal current measurement versus nasal potential difference measurements for diagnosis of cystic fibrosis: a case–control study | BACKGROUND: Nasal potential difference (NPD) and intestinal current measurement (ICM) are functional CFTR tests that are used as adjunctive diagnostic tools for cystic fibrosis (CF). Smoking has a systemic negative impact on CFTR function. A diagnostic comparison between NPD and ICM and the impact of smoking on both CFTR tests has not been done. METHODS: The sweat chloride test, NPD, and ICM were performed in 18 patients with CF (sweat chloride >60 mmol/l), including 6 pancreatic sufficient (PS) patients, and 13 healthy controls, including 8 smokers. The NPD CFTR response to Cl-free and isoproterenol perfusion (Δ0Cl(-) + Iso) was compared to the ICM CFTR response to forskolin/IBMX, carbachol, and histamine (ΔI(sc, forskolin/IBMX+ carbachol+histamine)). RESULTS: The mean NPD CFTR response and ICM CFTR response between patients with CF and healthy controls was significantly different (p <0.001), but not between patients with CF who were PS and those who were pancreatic insufficient (PI). Smokers have a decreased CFTR response measured by NPD (p = 0.049). For ICM there is a trend towards decreased CFTR response (NS). Three healthy control smokers had NPD responses within the CF-range. In contrast to NPD, there was no overlap of the ICM response between patients with CF and controls. CONCLUSIONS: ICM is superior to NPD in distinguishing between patients with CF who have a sweat chloride > 60 mmol/l and healthy controls, including smokers. Neither NPD nor ICM differentiated between patients with CF who were PS from those who were PI. Smoking has a negative impact on CFTR function in healthy controls measured by NPD and challenges the diagnostic interpretation of NPD, but not ICM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2466-14-156) contains supplementary material, which is available to authorized users. |
1,541 | The Evolutionary History and Spatiotemporal Dynamics of the Fever, Thrombocytopenia and Leukocytopenia Syndrome Virus (FTLSV) in China | BACKGROUND: In 2007, a novel bunyavirus was found in Henan Province, China and named fever, thrombocytopenia and leukocytopenia syndrome virus (FTLSV); since then, FTLSV has been found in ticks and animals in many Chinese provinces. Human-to-human transmission has been documented, indicating that FTLSV should be considered a potential public health threat. Determining the historical spread of FTLSV could help curtail its spread and prevent future movement of this virus. METHOD/PRINCIPAL FINDINGS: To examine the pattern of FTLSV evolution and the origin of outbreak strains, as well to examine the rate of evolution, the genome of 12 FTLSV strains were sequenced and a phylogenetic and Bayesian phylogeographic analysis of all available FTLSV sequences in China were performed. Analysis based on the FTLSV L segment suggests that the virus likely originated somewhere in Huaiyangshan circa 1790 (95% highest probability density interval: 1756–1817) and began spreading around 1806 (95% highest probability density interval: 1773–1834). Analysis also indicates that when FTLSV arrived in Jiangsu province from Huaiyangshan, Jiangsu Province became another source for the spread of the disease. Bayesian factor test analysis identified three major transmission routes: Huaiyangshan to Jiangsu, Jiangsu to Liaoning, and Jiangsu to Shandong. The speed of FTLSV movement has increased in recent decades, likely facilitated by modern human activity and ecosystem changes. In addition, evidence of RNA segment reassortment was found in FTLSV; purifying selection appears to have been the dominant force in the evolution of this virus. CONCLUSION: Results presented in the manuscript suggest that the Huaiyangshan area is likely be the origin of FTLSV in China and identified probable viral migration routes. These results provide new insights into the origin and spread of FTLSV in China, and provide a foundation for future virological surveillance and control. |
1,542 | Antibody-Validated Proteins in Inflamed Islets of Fulminant Type 1 Diabetes Profiled by Laser-Capture Microdissection Followed by Mass Spectrometry | BACKGROUND: There are no reports of proteomic analyses of inflamed islets in type 1 diabetes. PROCEDURES: Proteins expressed in the islets of enterovirus-associated fulminant type 1 diabetes (FT1DM) with extensive insulitis were identified by laser-capture microdissection mass spectrometry using formalin-fixed paraffin-embedded pancreatic tissues. RESULTS: Thirty-eight proteins were identified solely in FT1DM islets, most of which have not been previously linked to type 1 diabetes. Five protein-protein interacting clusters were identified, and the cellular localization of selected proteins was validated immunohistochemically. Migratory activity-related proteins, including plastin-2 (LCP1), moesin (MSN), lamin-B1 (LMNB1), Ras GTPase-activating-like protein (IQGAP1) and others, were identified in CD8(+) T cells and CD68(+) macrophages infiltrated to inflamed FT1DM islets. Proteins involved in successive signaling in innate/adaptive immunity were identified, including SAM domain and HD domain-containing protein 1 (SAMHD1), Ras GTPase-activating-like protein (IQGAP1), proteasome activator complex subunit 1 (PSME1), HLA class I histocompatibility antigen (HLA-C), and signal transducer and activator of transcription 1-alpha/beta (STAT1). Angiogenic (thymidine phosphorylase (TYMP)) and anti-angiogenic (tryptophan-tRNA ligase (WARS)) factors were identified in migrating CD8(+) T cells and CD68(+) macrophages. Proteins related to virus replication and cell proliferation, including probable ATP-dependent RNA helicase DEAD box helicase 5 (DDX5) and heterogeneous nuclear ribonucleoprotein H (HNRNPH1), were identified. The anti-apoptotic protein T-complex protein 1 subunit epsilon (CCT5), the anti-oxidative enzyme 6-phosphogluconate dehydrogenase (PDG), and the anti-viral and anti-apoptotic proteins serpin B6 (SERPINB6) and heat shock 70 kDa protein1-like (HSPA1L), were identified in FT1DM-affected islet cells. CONCLUSION: The identified FT1DM-characterizing proteins include those involved in aggressive beta cell destruction through massive immune cell migration and proteins involved in angiogenesis and islet vasculature bleeding, cell repair, and anti-inflammatory processes. Several target proteins for future type 1 diabetes interventions were identified. |
1,543 | Procalcitonin versus C-reactive protein: Usefulness as biomarker of sepsis in ICU patient | BACKGROUND: Early diagnosis and appropriate therapy of sepsis is a daily challenge in intensive care units (ICUs) despite the advances in critical care medicine. Procalcitonin (PCT); an innovative laboratory marker, has been recently proven valuable worldwide in this regard. OBJECTIVES: This study was undertaken to evaluate the utility of PCT in a resource constrained country like ours when compared to the traditional inflammatory markers like C - reactive protein (CRP) to introduce PCT as a routine biochemical tool in regional hospitals. MATERIALS AND METHODS: PCT and CRP were simultaneously measured and compared in 73 medico-surgical ICU patients according to the American College of Chest Physicians (ACCP) criteria based study groups. RESULTS: The clinical presentation of 75% cases revealed a range of systemic inflammatory responses (SIRS). The diagnostic accuracy of PCT was higher (75%) with greater specificity (72%), sensitivity (76%), positive and negative predictive values (89% and 50%), positive likelihood ratio (2.75) as well as the smaller negative likelihood ratio (0.33). Both serum PCT and CRP values in cases with sepsis, severe sepsis and septic shock were significantly higher from that of the cases with SIRS and no SIRS (P < 0.01). CONCLUSION: PCT is found to be superior to CRP in terms of accuracy in identification and to assess the severity of sepsis even though both markers cannot be used in differentiating infectious from noninfectious clinical syndrome. |
1,544 | Adaptive Management and the Value of Information: Learning Via Intervention in Epidemiology | Optimal intervention for disease outbreaks is often impeded by severe scientific uncertainty. Adaptive management (AM), long-used in natural resource management, is a structured decision-making approach to solving dynamic problems that accounts for the value of resolving uncertainty via real-time evaluation of alternative models. We propose an AM approach to design and evaluate intervention strategies in epidemiology, using real-time surveillance to resolve model uncertainty as management proceeds, with foot-and-mouth disease (FMD) culling and measles vaccination as case studies. We use simulations of alternative intervention strategies under competing models to quantify the effect of model uncertainty on decision making, in terms of the value of information, and quantify the benefit of adaptive versus static intervention strategies. Culling decisions during the 2001 UK FMD outbreak were contentious due to uncertainty about the spatial scale of transmission. The expected benefit of resolving this uncertainty prior to a new outbreak on a UK-like landscape would be £45–£60 million relative to the strategy that minimizes livestock losses averaged over alternate transmission models. AM during the outbreak would be expected to recover up to £20.1 million of this expected benefit. AM would also recommend a more conservative initial approach (culling of infected premises and dangerous contact farms) than would a fixed strategy (which would additionally require culling of contiguous premises). For optimal targeting of measles vaccination, based on an outbreak in Malawi in 2010, AM allows better distribution of resources across the affected region; its utility depends on uncertainty about both the at-risk population and logistical capacity. When daily vaccination rates are highly constrained, the optimal initial strategy is to conduct a small, quick campaign; a reduction in expected burden of approximately 10,000 cases could result if campaign targets can be updated on the basis of the true susceptible population. Formal incorporation of a policy to update future management actions in response to information gained in the course of an outbreak can change the optimal initial response and result in significant cost savings. AM provides a framework for using multiple models to facilitate public-health decision making and an objective basis for updating management actions in response to improved scientific understanding. |
1,545 | Identification of Antigenic Proteins of the Nosocomial Pathogen Klebsiella pneumoniae | The continuous expansion of nosocomial infections around the globe has become a precarious situation. Key challenges include mounting dissemination of multiple resistances to antibiotics, the easy transmission and the growing mortality rates of hospital-acquired bacterial diseases. Thus, new ways to rapidly detect these infections are vital. Consequently, researchers around the globe pursue innovative approaches for point-of-care devices. In many cases the specific interaction of an antigen and a corresponding antibody is pivotal. However, the knowledge about suitable antigens is lacking. The aim of this study was to identify novel antigens as specific diagnostic markers. Additionally, these proteins might be aptly used for the generation of vaccines to improve current treatment options. Hence, a cDNA-based expression library was constructed and screened via microarrays to detect novel antigens of Klebsiella pneumoniae, a prominent agent of nosocomial infections well-known for its extensive antibiotics resistance, especially by extended-spectrum beta-lactamases (ESBL). After screening 1536 clones, 14 previously unknown immunogenic proteins were identified. Subsequently, each protein was expressed in full-length and its immunodominant character examined by ELISA and microarray analyses. Consequently, six proteins were selected for epitope mapping and three thereof possessed linear epitopes. After specificity analysis, homology survey and 3d structural modelling, one epitope sequence GAVVALSTTFA of KPN_00363, an ion channel protein, was identified harboring specificity for K. pneumoniae. The remaining epitopes showed ambiguous results regarding the specificity for K. pneumoniae. The approach adopted herein has been successfully utilized to discover novel antigens of Campylobacter jejuni and Salmonella enterica antigens before. Now, we have transferred this knowledge to the key nosocomial agent, K. pneumoniae. By identifying several novel antigens and their linear epitope sites, we have paved the way for crucial future research and applications including the design of point-of-care devices, vaccine development and serological screenings for a highly relevant nosocomial pathogen. |
1,546 | Integrin β3 Is Required in Infection and Proliferation of Classical Swine Fever Virus | Classical Swine Fever (CSF) is a highly infectious fatal pig disease, resulting in huge economic loss to the swine industry. Integrins are membrane-bound signal mediators, expressed on a variety of cell surfaces and are known as receptors or co-receptors for many viruses. However, the role of integrin β3 in CSFV infection is unknown. Here, through quantitive PCR, immunofluorescence (IFC) and immunocytohistochemistry (ICC), we revealed that ST (swine testicles epithelial) cells have a prominent advantage in CSFV proliferation as compared to EC (swine umbilical vein endothelial cell), IEC (swine intestinal epithelial cell) and PK (porcine kidney epithelial) cells. Meanwhile, ST cells had remarkably more integrin β3 expression as compared to EC, IEC and PK cells, which was positively correlated with CSFV infection and proliferation. Integrin β3 was up-regulated post CSFV infection in all the four cell lines, while the CSFV proliferation rate was decreased in integrin β3 function-blocked cells. ShRNA1755 dramatically decreased integrin β3, with a deficiency of 96% at the mRNA level and 80% at the protein level. CSFV proliferation was dramatically reduced in integrin β3 constantly-defected cells (ICDC), with the deficiencies of 92.6%, 99% and 81.7% at 24 h, 48 h and 72 h post CSFV infection, respectively. These results demonstrate that integrin β3 is required in CSFV infection and proliferation, which provide a new insight into the mechanism of CSFV infection. |
1,547 | Growth Patterns and Scaling Laws Governing AIDS Epidemic in Brazilian Cities | Brazil holds approximately 1/3 of population living infected with AIDS (acquired immunodeficiency syndrome) in Central and South Americas, and it was also the first developing country to implement a large-scale control and intervention program against AIDS epidemic. In this scenario, we investigate the temporal evolution and current status of the AIDS epidemic in Brazil. Specifically, we analyze records of annual absolute frequency of cases for more than 5000 cities for the first 33 years of the infection in Brazil. We found that (i) the annual absolute frequencies exhibit a logistic-type growth with an exponential regime in the first few years of the AIDS spreading; (ii) the actual reproduction number decaying as a power law; (iii) the distribution of the annual absolute frequencies among cities decays with a power law behavior; (iv) the annual absolute frequencies and the number of inhabitants have an allometric relationship; (v) the temporal evolution of the annual absolute frequencies have different profile depending on the average annual absolute frequencies in the cities. These findings yield a general quantitative description of the AIDS infection dynamics in Brazil since the beginning. They also provide clues about the effectiveness of treatment and control programs against the infection, that has had a different impact depending on the number of inhabitants of cities. In this framework, our results give insights into the overall dynamics of AIDS epidemic, which may contribute to select empirically accurate models. |
1,548 | Functional ultrastructure of the plant nucleolus | Nucleoli are nuclear domains present in almost all eukaryotic cells. They not only specialize in the production of ribosomal subunits but also play roles in many fundamental cellular activities. Concerning ribosome biosynthesis, particular stages of this process, i.e., ribosomal DNA transcription, primary RNA transcript processing, and ribosome assembly proceed in precisely defined nucleolar subdomains. Although eukaryotic nucleoli are conservative in respect of their main function, clear morphological differences between these structures can be noticed between individual kingdoms. In most cases, a plant nucleolus shows well-ordered structure in which four main ultrastructural components can be distinguished: fibrillar centers, dense fibrillar component, granular component, and nucleolar vacuoles. Nucleolar chromatin is an additional crucial structural component of this organelle. Nucleolonema, although it is not always an unequivocally distinguished nucleolar domain, has often been described as a well-grounded morphological element, especially of plant nucleoli. The ratios and morphology of particular subcompartments of a nucleolus can change depending on its metabolic activity which in turn is correlated with the physiological state of a cell, cell type, cell cycle phase, as well as with environmental influence. Precise attribution of functions to particular nucleolar subregions in the process of ribosome biosynthesis is now possible using various approaches. The presented description of plant nucleolar morphology summarizes previous knowledge regarding the function of nucleoli as well as of their particular subdomains not only in the course of ribosome biosynthesis. |
1,549 | Knowledge, attitudes and practices relating to influenza A(H7N9) risk among live poultry traders in Guangzhou City, China | BACKGROUND: Live poultry traders (LPTs) have greater risk to avian influenza due to occupational exposure to poultry. This study investigated knowledge, attitudes and practices of LPTs relating to influenza A (H7N9). METHODS: Using multi-stage cluster sampling, 306 LPTs were interviewed in Guangzhou by a standardized questionnaire between mid-May to June, 2013. Hierarchical logistic regression models were used to identify factors associated with preventive practices and attitudes towards various control measures implemented in live poultry markets against H7N9. RESULTS: Only 46.1% of the respondents recognized risks associated with contacts with bird secretions or droppings, and only 22.9% perceived personally "likely/very likely" to contract H7N9 infection. Around 60% of the respondents complied with hand-washing and wearing gloves, and only 20% reported wearing face masks. Only 16.3% of the respondents agreed on introducing central slaughtering of poultry. Being younger, involving in slaughtering poultry, having longer working hours, less access to H7N9-related information and poorer knowledge, and perceiving lower personal susceptibility to H7N9 infection were negatively associated with preventive practices. Comparing with previous studies conducted when human cases of H5N1 avian influenza infection was first identified in Guangdong, LPTs' perceived susceptibility to novel influenza viruses increased significantly but acceptance for central slaughtering of poultry remained low. CONCLUSIONS: Information on avian influenza provided through multiple communication tools may be necessary to promote knowledge among poultry traders. Familiarity with risk may have led to the lower perceived vulnerability to avian influenza and less protective actions among the LPTs particularly for those involving more risky exposure to live poultry. Reasons for the consistently low acceptance for central slaughtering of poultry await further exploration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0554-8) contains supplementary material, which is available to authorized users. |
1,550 | An Internet-Based Epidemiological Investigation of the Outbreak of H7N9 Avian Influenza A in China Since Early 2013 | BACKGROUND: In early 2013, a new type of avian influenza, H7N9, emerged in China. It quickly became an issue of great public concern and a widely discussed topic on the Internet. A considerable volume of relevant information was made publicly available on the Internet through various sources. OBJECTIVE: This study aimed to describe the outbreak of H7N9 in China based on data openly available on the Internet and to validate our investigation by comparing our findings with a well-conducted conventional field epidemiologic study. METHODS: We searched publicly accessible Internet data on the H7N9 outbreak primarily from government and major mass media websites in China up to February 10, 2014. Two researchers independently extracted, compared, and confirmed the information of each confirmed H7N9 case using a self-designed data extraction form. We summarized the epidemiological and clinical characteristics of confirmed H7N9 cases and compared them with those from the field study. RESULTS: According to our data updated until February 10, 2014, 334 confirmed H7N9 cases were identified. The median age was 58 years and 67.0% (219/327) were males. Cases were reported in 15 regions in China. Five family clusters were found. Of the 16.8% (56/334) of the cases with relevant data, 69.6% (39/56) reported a history of exposure to animals. Of the 1751 persons with a close contact with a confirmed case, 0.6% (11/1751) of them developed respiratory symptoms during the 7-day surveillance period. In the 97.9% (327/334) of the cases with relevant data, 21.7% (71/327) died, 20.8% (68/327) were discharged from a hospital, and 57.5% (188/327) were of uncertain status. We compared our findings before February 10, 2014 and those before December 1, 2013 with those from the conventional field study, which had the latter cutoff date of ours in data collection. Our study showed most epidemiological and clinical characteristics were similar to those in the field study, except for case fatality (71/327, 21.7% for our data before February 10; 45/138, 32.6% for our data before December 1; 47/139, 33.8% for the field study), time from illness onset to first medical care (4 days, 3 days, and 1 day), and time from illness onset to death (16.5 days, 17 days, and 21 days). CONCLUSIONS: Findings from our Internet-based investigation were similar to those from the conventional field study in most epidemiological and clinical aspects of the outbreak. Importantly, publicly available Internet data are open to any interested researchers and can thus greatly facilitate the investigation and control of such outbreaks. With improved efforts for Internet data provision, Internet-based investigation has a great potential to become a quick, economical, novel approach to investigating sudden issues of great public concern that involve a relatively small number of cases like this H7N9 outbreak. |
1,551 | Autoimmune and Neoplastic Thyroid Diseases Associated with Hepatitis C Chronic Infection | Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographic signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender versus healthy controls, or hepatitis B virus infected patients. In patients with “HCV-associated mixed cryoglobulinemia” (MC + HCV), a higher prevalence of thyroid autoimmune disorders was shown not only compared to controls, but also versus HCV patients without cryoglobulinemia. Patients with MC + HCV or HCV chronic infection show a higher prevalence of papillary thyroid cancer than controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC + HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine, but normal levels of Th2 (C-C motif) ligand 2 chemokine, than patients without thyroiditis. HCV thyroid infection could act by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes that secrete interferon-γ and tumor necrosis factor-α. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, which may lead to the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function, particularly where nodules occur, is recommended in HCV patients. |
1,552 | Interferon Lambda: Opportunities, Risks, and Uncertainties in the Fight Against HCV | Innate immunity is key to the fight against the daily onslaught from viruses that our bodies are subjected to. Essential to this response are the interferons (IFNs) that prime our cells to block viral pathogens. Recent evidence suggests that the Type III (λ) IFNs are intimately associated with the immune response to hepatitis C virus (HCV) infection. Genome-wide association studies have identified polymorphisms within the IFN-λ gene locus that correlate with response to IFNα-based antiviral therapy and with spontaneous clearance of HCV infection. The mechanisms for these correlations are incompletely understood. Restricted expression of the IFN-λ receptor, and the ability of IFN-λ to induce IFN-stimulated genes in HCV-infected cells, suggest potential roles for IFN-λ in HCV therapy even in this era of directly acting antivirals. This review summarizes our current understanding of the IFN-λ family and the role of λ IFNs in the natural history of HCV infection. |
1,553 | Arenavirus Stable Signal Peptide Is the Keystone Subunit for Glycoprotein Complex Organization | The rodent arenavirus glycoprotein complex encodes a stable signal peptide (SSP) that is an essential structural component of mature virions. The SSP, GP1, and GP2 subunits of the trimeric glycoprotein complex noncovalently interact to stud the surface of virions and initiate arenavirus infectivity. Nascent glycoprotein production undergoes two proteolytic cleavage events: first within the endoplasmic reticulum (ER) to cleave SSP from the remaining precursor GP1/2 (glycoprotein complex [GPC]) glycoprotein and second within the Golgi stacks by the cellular SKI-1/S1P for GP1/2 processing to yield GP1 and GP2 subunits. Cleaved SSP is not degraded but retained as an essential glycoprotein subunit. Here, we defined functions of the 58-amino-acid lymphocytic choriomeningitis virus (LCMV) SSP in regard to glycoprotein complex processing and maturation. Using molecular biology techniques, confocal microscopy, and flow cytometry, we detected SSP at the plasma membrane of transfected cells. Further, we identified a sorting signal (FLLL) near the carboxyl terminus of SSP that is required for glycoprotein maturation and trafficking. In the absence of SSP, the glycoprotein accumulated within the ER and was unable to undergo processing by SKI-1/S1P. Mutation of this highly conserved FLLL motif showed impaired glycoprotein processing and secretory pathway trafficking, as well as defective surface expression and pH-dependent membrane fusion. Immunoprecipitation of SSP confirmed an interaction between the signal peptide and the GP2 subunit; however, mutations within this FLLL motif disrupted the association of the GP1 subunit with the remaining glycoprotein complex. |
1,554 | Study of the effect on shelter cat intakes and euthanasia from a shelter neuter return project of 10,080 cats from March 2010 to June 2014 | Cat impoundments were increasing at the municipal San Jose animal shelter in 2009, despite long-term successful low cost sterilization programs and attempts to lower the euthanasia rate of treatable-rehabilitatable impounds beginning in 2008. San Jose Animal Care and Services implemented a new strategy designed to control overall feral cat reproduction by altering and returning feral cats entering the shelter system, rather than euthanizing the cats. The purpose of this case study was to determine how the program affected the shelter cat intakes over time. In just over four years, 10,080 individual healthy adult feral cats, out of 11,423 impounded at the shelter during this time frame, were altered and returned to their site of capture. Included in the 11,423 cats were 862 cats impounded from one to four additional times for a total of 958 (9.5%) recaptures of the previously altered 10,080 cats. The remaining 385 healthy feral cats were euthanized at the shelter from March 2010 to June 2014. Four years into the program, researchers observed cat and kitten impounds decreased 29.1%; euthanasia decreased from over 70% of intakes in 2009, to 23% in 2014. Euthanasia in the shelter for Upper Respiratory Disease decreased 99%; dead cat pick up off the streets declined 20%. Dog impounds did not similarly decline over the four years. No other laws or program changes were implemented since the beginning of the program. |
1,555 | Factors Influencing the Measurement of Plasma/Serum Surfactant Protein D Levels by ELISA | BACKGROUND: Extensive variations in human surfactant protein D (SP-D) levels in circulation as measured by ELISA exist in the published literature. In order to determine the source of these variations, factors influencing the measurement by ELISA were explored. MATERIALS AND METHODS: Peripheral blood from healthy individuals was collected into various vacutainers during the same blood draw. Recombinant SP-D was diluted into different matrices and used for a standard curve. Samples were analyzed by capture ELISA using one of two distinct detection antibodies. RESULTS: The type of matrix had some effects on detection of recombinant SP-D. The type of anticoagulant used and dilution factor had very little effect, except for in plasma collected in EDTA vacutainers. The extent of variation in published values seemed to be due to the ELISA configuration employed, and, in agreement with this, we found that by switching the detection antibody, there was a 50% decrease in the extrapolated SP-D value of serum and plasma samples. Storage of samples resulted in slight changes in measured SP-D levels. CONCLUSIONS: The ELISA configuration employed to measure circulating levels of SP-D has a significant effect on the extrapolated values. In both configurations tested, the use of EDTA as a coagulant resulted in inconsistent values, and we, therefore, suggest the avoidance of this anticoagulant when assaying for SP-D by ELISA. While the demonstrated effects of several factors on measurement of SP-D may not account for all the disparities amongst the previous studies, they stress that variations in methodologies for measuring the same protein can result in very inconsistent results. |
1,556 | Toll-Like Receptor Responses to Peste des petits ruminants Virus in Goats and Water Buffalo | Ovine rinderpest or goat plague is an economically important and contagious viral disease of sheep and goats, caused by the Peste des petits ruminants virus (PPRV). Differences in susceptibility to goat plague among different breeds and water buffalo exist. The host innate immune system discriminates between pathogen associated molecular patterns and self antigens through surveillance receptors known as Toll like receptors (TLR). We investigated the role of TLR and cytokines in differential susceptibility of goat breeds and water buffalo to PPRV. We examined the replication of PPRV in peripheral blood mononuclear cells (PBMC) of Indian domestic goats and water buffalo and demonstrated that the levels of TLR3 and TLR7 and downstream signalling molecules correlation with susceptibility vs resistance. Naturally susceptible goat breeds, Barbari and Tellichery, had dampened innate immune responses to PPRV and increased viral loads with lower basal expression levels of TLR 3/7. Upon stimulation of PBMC with synthetic TLR3 and TLR7 agonists or PPRV, the levels of proinflammatory cytokines were found to be significantly higher while immunosuppressive interleukin (IL) 10 levels were lower in PPRV resistant Kanni and Salem Black breeds and water buffalo at transcriptional level, correlating with reduced viralloads in infected PBMC. Water buffalo produced higher levels of interferon (IFN) α in comparison with goats at transcriptional and translational levels. Pre-treatment of Vero cells with human IFNα resulted in reduction of PPRV replication, confirming the role of IFNα in limiting PPRV replication. Treatment with IRS66, a TLR7 antagonist, resulted in the reduction of IFNα levels, with increased PPRV replication confirming the role of TLR7. Single nucleotide polymorphism analysis of TLR7 of these goat breeds did not show any marked nucleotide differences that might account for susceptibility vs resistance to PPRV. Analyzing other host genetic factors might provide further insights on susceptibility to PPRV and genetic polymorphisms in the host. |
1,557 | Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells Derived Exosomes on in vitro Stimulated T Cells | In the recent years, it has been demonstrated that the biological activity of mesenchymal stem cells (MSCs) is mediated through the release of paracrine factors. Many of these factors are released into exosomes, which are small membranous vesicles that participate in cell–cell communication. Exosomes from MSCs are thought to have similar functions to MSCs such as repairing and regeneration of damaged tissue, but little is known about the immunomodulatory effect of these vesicles. Based on an extensive bibliography where the immunomodulatory capacity of MSCs has been demonstrated, here we hypothesized that released exosomes from MSCs may have an immunomodulatory role on the differentiation, activation and function of different lymphocyte subsets. According to this hypothesis, in vitro experiments were performed to characterize the immunomodulatory effect of human adipose MSCs derived exosomes (exo-hASCs) on in vitro stimulated T cells. The phenotypic characterization of cytotoxic and helper T cells (activation and differentiation markers) together with functional assays (proliferation and IFN-γ production) demonstrated that exo-hASCs exerted an inhibitory effect in the differentiation and activation of T cells as well as a reduced T cell proliferation and IFN-γ release on in vitro stimulated cells. In summary, here we demonstrate that MSCs-derived exosomes are a cell-derived product that could be considered as a therapeutic agent for the treatment of inflammation-related diseases. |
1,558 | Achieving compliance with the International Health Regulations by overseas territories of the United Kingdom of Great Britain and Northern Ireland | The 2005 International Health Regulations (IHR) came into force for all Member States of the World Health Organization (WHO) in June 2007 and the deadline for achieving compliance was June 2012. The purpose of the IHR is to prevent, protect against, control – and provide a public health response to – international spread of disease. The territory of the United Kingdom of Great Britain and Northern Ireland and that of several other Member States, such as China, Denmark, France, the Netherlands and the United States of America, include overseas territories, which cover a total population of approximately 15 million people. Member States have a responsibility to ensure that all parts of their territory comply with the IHR. Since WHO has not provided specific guidance on compliance in the special circumstances of the overseas territories of Member States, compliance by these territories is an issue for self-assessment by Member States themselves. To date, no reports have been published on the assessment of IHR compliance in countries with overseas territories. We describe a gap analysis done in the United Kingdom to assess IHR compliance of its overseas territories. The findings and conclusions are broadly applicable to other countries with overseas territories which may have yet to assess their compliance with the IHR. Such assessments are needed to ensure compliance across all parts of a Member States’ territory and to increase global health security. |
1,559 | Bone Marrow Dendritic Cells from Mice with an Altered Microbiota Provide Interleukin 17A-Dependent Protection against Entamoeba histolytica Colitis | There is an emerging paradigm that the human microbiome is central to many aspects of health and may have a role in preventing enteric infection. Entamoeba histolytica is a major cause of amebic diarrhea in developing countries. It colonizes the colon lumen in close proximity to the gut microbiota. Interestingly, not all individuals are equally susceptible to E. histolytica infection. Therefore, as the microbiota is highly variable within individuals, we sought to determine if a component of the microbiota could regulate susceptibility to infection. In studies utilizing a murine model, we demonstrated that colonization of the gut with the commensal Clostridia-related bacteria known as segmented filamentous bacteria (SFB) is protective during E. histolytica infection. SFB colonization in this model was associated with elevated cecal levels of interleukin 17A (IL-17A), dendritic cells, and neutrophils. Bone marrow-derived dendritic cells (BMDCs) from SFB-colonized mice had higher levels of IL-23 production in response to stimulation with trophozoites. Adoptive transfer of BMDCs from an SFB(+) to an SFB(−) mouse was sufficient to provide protection against E. histolytica. IL-17A induction during BMDC transfer was necessary for this protection. This work demonstrates that intestinal colonization with a specific commensal bacterium can provide protection during amebiasis in a murine model. Most importantly, this work demonstrates that the microbiome can mediate protection against an enteric infection via extraintestinal effects on bone marrow-derived dendritic cells. |
1,560 | Specificity and Effector Functions of Human RSV-Specific IgG from Bovine Milk | BACKGROUND: Respiratory syncytial virus (RSV) infection is the second most important cause of death in the first year of life, and early RSV infections are associated with the development of asthma. Breastfeeding and serum IgG have been shown to protect against RSV infection. Yet, many infants depend on bovine milk-based nutrition, which at present lacks intact immunoglobulins. OBJECTIVE: To investigate whether IgG purified from bovine milk (bIgG) can modulate immune responses against human RSV. METHODS: ELISAs were performed to analyse binding of bIgG to human respiratory pathogens. bIgG or hRSV was coated to plates to assess dose-dependent binding of bIgG to human Fcγ receptors (FcγR) or bIgG-mediated binding of myeloid cells to hRSV respectively. S. Epidermidis and RSV were used to test bIgG-mediated binding and internalisation of pathogens by myeloid cells. Finally, the ability of bIgG to neutralise infection of HEp2 cells by hRSV was evaluated. RESULTS: bIgG recognised human RSV, influenza haemagglutinin and Haemophilus influenza. bIgG bound to FcγRII on neutrophils, monocytes and macrophages, but not to FcγRI and FcγRIII, and could bind simultaneously to hRSV and human FcγRII on neutrophils. In addition, human neutrophils and dendritic cells internalised pathogens that were opsonised with bIgG. Finally, bIgG could prevent infection of HEp2 cells by hRSV. CONCLUSIONS: The data presented here show that bIgG binds to hRSV and other human respiratory pathogens and induces effector functions through binding to human FcγRII on phagocytes. Thus bovine IgG may contribute to immune protection against RSV. |
1,561 | Requirement of CRTC1 coactivator for hepatitis B virus transcription | Transcription of hepatitis B virus (HBV) from the covalently closed circular DNA (cccDNA) template is essential for its replication. Suppressing the level and transcriptional activity of cccDNA might have anti-HBV effect. Although cellular transcription factors, such as CREB, which mediate HBV transcription, have been well described, transcriptional coactivators that facilitate this process are incompletely understood. In this study we showed that CREB-regulated transcriptional coactivator 1 (CRTC1) is required for HBV transcription and replication. The steady-state levels of CRTC1 protein were elevated in HBV-positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 or its homolog CRTC2 or CRTC3 in hepatoma cells stimulated the activity of the preS2/S promoter of HBV, whereas overexpression of a dominant inactive form of CRTC1 inhibited HBV transcription. CRTC1 interacts with CREB and they are mutually required for the recruitment to the preS2/S promoter on cccDNA and for the activation of HBV transcription. Accumulation of pregenomic RNA (pgRNA) and cccDNA was observed when CRTC1 or its homologs were overexpressed, whereas the levels of pgRNA, cccDNA and secreted HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Our work reveals an essential role of CRTC1 coactivator in facilitating and supporting HBV transcription and replication. |
1,562 | Archaeal DnaG contains a conserved N-terminal RNA-binding domain and enables tailing of rRNA by the exosome | The archaeal exosome is a phosphorolytic 3′–5′ exoribonuclease complex. In a reverse reaction it synthesizes A-rich RNA tails. Its RNA-binding cap comprises the eukaryotic orthologs Rrp4 and Csl4, and an archaea-specific subunit annotated as DnaG. In Sulfolobus solfataricus DnaG and Rrp4 but not Csl4 show preference for poly(rA). Archaeal DnaG contains N- and C-terminal domains (NTD and CTD) of unknown function flanking a TOPRIM domain. We found that the NT and TOPRIM domains have comparable, high conservation in all archaea, while the CTD conservation correlates with the presence of exosome. We show that the NTD is a novel RNA-binding domain with poly(rA)-preference cooperating with the TOPRIM domain in binding of RNA. Consistently, a fusion protein containing full-length Csl4 and NTD of DnaG led to enhanced degradation of A-rich RNA by the exosome. We also found that DnaG strongly binds native and in vitro transcribed rRNA and enables its polynucleotidylation by the exosome. Furthermore, rRNA-derived transcripts with heteropolymeric tails were degraded faster by the exosome than their non-tailed variants. Based on our data, we propose that archaeal DnaG is an RNA-binding protein, which, in the context of the exosome, is involved in targeting of stable RNA for degradation. |
1,563 | Mapping overlapping functional elements embedded within the protein-coding regions of RNA viruses | Identification of the full complement of genes and other functional elements in any virus is crucial to fully understand its molecular biology and guide the development of effective control strategies. RNA viruses have compact multifunctional genomes that frequently contain overlapping genes and non-coding functional elements embedded within protein-coding sequences. Overlapping features often escape detection because it can be difficult to disentangle the multiple roles of the constituent nucleotides via mutational analyses, while high-throughput experimental techniques are often unable to distinguish functional elements from incidental features. However, RNA viruses evolve very rapidly so that, even within a single species, substitutions rapidly accumulate at neutral or near-neutral sites providing great potential for comparative genomics to distinguish the signature of purifying selection. Computationally identified features can then be efficiently targeted for experimental analysis. Here we analyze alignments of protein-coding virus sequences to identify regions where there is a statistically significant reduction in the degree of variability at synonymous sites, a characteristic signature of overlapping functional elements. Having previously tested this technique by experimental verification of discoveries in selected viruses, we now analyze sequence alignments for ∼700 RNA virus species to identify hundreds of such regions, many of which have not been previously described. |
1,564 | Activation of Innate Immune-Response Genes in Little Brown Bats (Myotis lucifugus) Infected with the Fungus Pseudogymnoascus destructans | Recently bats have been associated with the emergence of diseases, both as reservoirs for several new viral diseases in humans and other animals and, in the northern Americas, as hosts for a devastating fungal disease that threatens to drive several bat species to regional extinction. However, despite these catastrophic events little Information is available on bat defences or how they interact with their pathogens. Even less is known about the response of bats to infection during torpor or long-term hibernation. Using tissue samples collected at the termination of an experiment to explore the pathogenesis of White Nose Syndrome in Little Brown Bats, we determined if hibernating bats infected with the fungus Pseudogymnoascus destructans could respond to infection by activating genes responsible for innate immune and stress responses. Lesions due to fungal infection and, in some cases, secondary bacterial infections, were restricted to the skin. However, we were unable to obtain sufficient amounts of RNA from these sites. We therefore examined lungs for response at an epithelial surface not linked to the primary site of infection. We found that bats responded to infection with a significant increase in lungs of transcripts for Cathelicidin (an anti-microbial peptide) as well as the immune modulators tumor necrosis factor alpha and interleukins 10 and 23. In conclusion, hibernating bats can respond to experimental P. destructans infection by activating expression of innate immune response genes. |
1,565 | Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection | INTRODUCTION: Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Components of the innate immune response may be crucial in the first days of the infection. The collectins surfactant protein (SP)-A1, -A2, and -D and mannose-binding lectin (MBL) neutralize IAV infectivity, although only SP-A2 can establish an efficient neutralization of poorly glycosylated pandemic IAV strains. METHODS: We studied the role of polymorphic variants at the genes of MBL (MBL2), SP-A1 (SFTPA1), SP-A2 (SFTPA2), and SP-D (SFTPD) in 93 patients with H1N1 pandemic 2009 (H1N1pdm) infection. RESULTS: Multivariate analysis showed that two frequent SFTPA2 missense alleles (rs1965708-C and rs1059046-A) and the SFTPA2 haplotype 1A(0) were associated with a need for mechanical ventilation, acute respiratory failure, and acute respiratory distress syndrome. The SFTPA2 haplotype 1A(1) was a protective variant. Kaplan-Meier analysis and Cox regression also showed that diplotypes not containing the 1A(1) haplotype were associated with a significantly shorter time to ICU admission in hospitalized patients. In addition, rs1965708-C (P = 0.0007), rs1059046-A (P = 0.0007), and haplotype 1A(0) (P = 0.0004) were associated, in a dose-dependent fashion, with lower PaO(2)/FiO(2) ratio, whereas haplotype 1A(1) was associated with a higher PaO(2)/FiO(2) ratio (P = 0.001). CONCLUSIONS: Our data suggest an effect of genetic variants of SFTPA2 on the severity of H1N1pdm infection and could pave the way for a potential treatment with haplotype-specific (1A(1)) SP-A2 for future IAV pandemics. |
1,566 | Immune Responses to Non-Tumor Antigens in the Central Nervous System | The central nervous system (CNS), once viewed as an immune-privileged site protected by the blood–brain barrier (BBB), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells. Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non-tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity. |
1,567 | A model-based information sharing protocol for profile Hidden Markov Models used for HIV-1 recombination detection | BACKGROUND: In many applications, a family of nucleotide or protein sequences classified into several subfamilies has to be modeled. Profile Hidden Markov Models (pHMMs) are widely used for this task, modeling each subfamily separately by one pHMM. However, a major drawback of this approach is the difficulty of dealing with subfamilies composed of very few sequences. One of the most crucial bioinformatical tasks affected by the problem of small-size subfamilies is the subtyping of human immunodeficiency virus type 1 (HIV-1) sequences, i.e., HIV-1 subtypes for which only a small number of sequences is known. RESULTS: To deal with small samples for particular subfamilies of HIV-1, we introduce a novel model-based information sharing protocol. It estimates the emission probabilities of the pHMM modeling a particular subfamily not only based on the nucleotide frequencies of the respective subfamily but also incorporating the nucleotide frequencies of all available subfamilies. To this end, the underlying probabilistic model mimics the pattern of commonality and variation between the subtypes with regards to the biological characteristics of HI viruses. In order to implement the proposed protocol, we make use of an existing HMM architecture and its associated inference engine. CONCLUSIONS: We apply the modified algorithm to classify HIV-1 sequence data in the form of partial HIV-1 sequences and semi-artificial recombinants. Thereby, we demonstrate that the performance of pHMMs can be significantly improved by the proposed technique. Moreover, we show that our algorithm performs significantly better than Simplot and Bootscanning. |
1,568 | Role of Oct4 in the early embryo development | Oct4 is a key component of the pluripotency regulatory network, and its reciprocal interaction with Cdx2 has been shown to be a determinant of either the self-renewal of embryonic stem cells (ESCs) or their differentiation into trophoblast. Oct4 of maternal origin is postulated to play critical role in defining totipotency and inducing pluripotency during embryonic development. However, the genetic elimination of maternal Oct4 using a Cre-lox approach in mouse revealed that the establishment of totipotency in maternal Oct4–depleted embryos was not affected, and that these embryos could complete full-term development without any obvious defect. These results indicate that Oct4 is not essential for the initiation of pluripotency, in contrast to its critical role in maintaining pluripotency. This conclusion is further supported by the formation of Oct4-GFP– and Nanog- expressing inner cell masses (ICMs) in embryos with complete inactivation of both maternal and zygotic Oct4 expression and the reprogramming of fibroblasts into fully pluripotent cells by Oct4-deficient oocytes. |
1,569 | Atomistic Detailed Mechanism and Weak Cation-Conducting Activity of HIV-1 Vpu Revealed by Free Energy Calculations | The viral protein U (Vpu) encoded by HIV-1 has been shown to assist in the detachment of virion particles from infected cells. Vpu forms cation-specific ion channels in host cells, and has been proposed as a potential drug target. An understanding of the mechanism of ion transport through Vpu is desirable, but remains limited because of the unavailability of an experimental structure of the channel. Using a structure of the pentameric form of Vpu – modeled and validated based on available experimental data – umbrella sampling molecular dynamics simulations (cumulative simulation time of more than 0.4 µs) were employed to elucidate the energetics and the molecular mechanism of ion transport in Vpu. Free energy profiles corresponding to the permeation of Na(+) and K(+) were found to be similar to each other indicating lack of ion selection, consistent with previous experimental studies. The Ser23 residue is shown to enhance ion transport via two mechanisms: creating a weak binding site, and increasing the effective hydrophilic length of the channel, both of which have previously been hypothesized in experiments. A two-dimensional free energy landscape has been computed to model multiple ion permeation, based on which a mechanism for ion conduction is proposed. It is shown that only one ion can pass through the channel at a time. This, along with a stretch of hydrophobic residues in the transmembrane domain of Vpu, explains the slow kinetics of ion conduction. The results are consistent with previous conductance studies that showed Vpu to be a weakly conducting ion channel. |
1,570 | RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders | Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively. The boundary between such classifications has recently been blurred by the discovery of repeat-associated non-AUG (RAN) translation reported in spinocerebellar ataxia type 8, myotonic dystrophy type 1, fragile X tremor/ataxia syndrome and C9ORF72 amyotrophic lateral sclerosis and frontotemporal dementia. This noncanonical translation requires no AUG start codon and can initiate in multiple frames of CAG, CGG and GGGGCC repeats of the sense and antisense strands of disease-relevant transcripts. RNA structures formed by the repeats have been suggested as possible triggers; however, the precise mechanism of the translation initiation remains elusive. Templates containing expansions of microsatellites have also been shown to challenge translation elongation, as frameshifting has been recognized across CAG repeats in spinocerebellar ataxia type 3 and Huntington's disease. Determining the critical requirements for RAN translation and frameshifting is essential to decipher the mechanisms that govern these processes. The contribution of unusual translation products to pathogenesis needs to be better understood. In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions. |
1,571 | Identification of novel multitargeted PPARα/γ/δ pan agonists by core hopping of rosiglitazone | The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research. |
1,572 | Sequencing, Annotation and Analysis of the Syrian Hamster (Mesocricetus auratus) Transcriptome | BACKGROUND: The Syrian hamster (golden hamster, Mesocricetus auratus) is gaining importance as a new experimental animal model for multiple pathogens, including emerging zoonotic diseases such as Ebola. Nevertheless there are currently no publicly available transcriptome reference sequences or genome for this species. RESULTS: A cDNA library derived from mRNA and snRNA isolated and pooled from the brains, lungs, spleens, kidneys, livers, and hearts of three adult female Syrian hamsters was sequenced. Sequence reads were assembled into 62,482 contigs and 111,796 reads remained unassembled (singletons). This combined contig/singleton dataset, designated as the Syrian hamster transcriptome, represents a total of 60,117,204 nucleotides. Our Mesocricetus auratus Syrian hamster transcriptome mapped to 11,648 mouse transcripts representing 9,562 distinct genes, and mapped to a similar number of transcripts and genes in the rat. We identified 214 quasi-complete transcripts based on mouse annotations. Canonical pathways involved in a broad spectrum of fundamental biological processes were significantly represented in the library. The Syrian hamster transcriptome was aligned to the current release of the Chinese hamster ovary (CHO) cell transcriptome and genome to improve the genomic annotation of this species. Finally, our Syrian hamster transcriptome was aligned against 14 other rodents, primate and laurasiatheria species to gain insights about the genetic relatedness and placement of this species. CONCLUSIONS: This Syrian hamster transcriptome dataset significantly improves our knowledge of the Syrian hamster's transcriptome, especially towards its future use in infectious disease research. Moreover, this library is an important resource for the wider scientific community to help improve genome annotation of the Syrian hamster and other closely related species. Furthermore, these data provide the basis for development of expression microarrays that can be used in functional genomics studies. |
1,573 | Hijacking of an autophagy-like process is critical for the life cycle of a DNA virus infecting oceanic algal blooms | Marine photosynthetic microorganisms are the basis of marine food webs and are responsible for nearly 50% of the global primary production. Emiliania huxleyi forms massive oceanic blooms that are routinely terminated by large double-stranded DNA coccolithoviruses. The cellular mechanisms that govern the replication cycle of these giant viruses are largely unknown. We used diverse techniques, including fluorescence microscopy, transmission electron microscopy, cryoelectron tomography, immunolabeling and biochemical methodologies to investigate the role of autophagy in host–virus interactions. Hallmarks of autophagy are induced during the lytic phase of E. huxleyi viral infection, concomitant with up-regulation of autophagy-related genes (ATG genes). Pretreatment of the infected cells with an autophagy inhibitor causes a major reduction in the production of extracellular viral particles, without reducing viral DNA replication within the cell. The host-encoded Atg8 protein was detected within purified virions, demonstrating the pivotal role of the autophagy-like process in viral assembly and egress. We show that autophagy, which is classically considered as a defense mechanism, is essential for viral propagation and for facilitating a high burst size. This cellular mechanism may have a major impact on the fate of the viral-infected blooms, and therefore on the cycling of nutrients within the marine ecosystem. |
1,574 | Human Bocavirus: Lessons Learned to Date | Human bocavirus (HBoV) was identified as the second human parvovirus with pathogenic potential in 2005 in respiratory samples from children suffering from viral respiratory infections of unknown etiology. Since its first description, a large number of clinical studies have been performed that address the clinical significance of HBoV detection and the molecular biology of the virus. This review summarizes the most important steps taken in HBoV research to date and addresses open questions that need to be answered in the future to provide a better understanding of the role of a virus that is difficult to grow in cell culture and is suspected to be a pathogen, although it has not yet fulfilled Koch’s postulates. |
1,575 | PTB Binds to the 3’ Untranslated Region of the Human Astrovirus Type 8: A Possible Role in Viral Replication | The 3′ untranslated region (3′UTR) of human astroviruses (HAstV) consists of two hairpin structures (helix I and II) joined by a linker harboring a conserved PTB/hnRNP1 binding site. The identification and characterization of cellular proteins that interact with the 3′UTR of HAstV-8 virus will help to uncover cellular requirements for viral functions. To this end, mobility shift assays and UV cross-linking were performed with uninfected and HAstV-8-infected cell extracts and HAstV-8 3′UTR probes. Two RNA-protein complexes (CI and CII) were recruited into the 3′UTR. Complex CII formation was compromised with cold homologous RNA, and seven proteins of 35, 40, 45, 50, 52, 57/60 and 75 kDa were cross-linked to the 3′UTR. Supermobility shift assays indicated that PTB/hnRNP1 is part of this complex, and 3′UTR-crosslinked PTB/hnRNP1 was immunoprecipitated from HAstV-8 infected cell-membrane extracts. Also, immunofluorescence analyses revealed that PTB/hnRNP1 is distributed in the nucleus and cytoplasm of uninfected cells, but it is mainly localized perinuclearly in the cytoplasm of HAstV-8 infected cells. Furthermore, the minimal 3′UTR sequences recognized by recombinant PTB are those conforming helix I, and an intact PTB/hnRNP1-binding site. Finally, small interfering RNA-mediated PTB/hnRNP1 silencing reduced synthesis viral genome and virus yield in CaCo2 cells, suggesting that PTB/hnRNP1 is required for HAstV replication. In conclusion, PTB/hnRNP1 binds to the 3′UTR HAstV-8 and is required or participates in viral replication. |
1,576 | Frequency and Fitness Consequences of Bacteriophage Φ6 Host Range Mutations | Viruses readily mutate and gain the ability to infect novel hosts, but few data are available regarding the number of possible host range-expanding mutations allowing infection of any given novel host, and the fitness consequences of these mutations on original and novel hosts. To gain insight into the process of host range expansion, we isolated and sequenced 69 independent mutants of the dsRNA bacteriophage Φ6 able to infect the novel host, Pseudomonas pseudoalcaligenes. In total, we found at least 17 unique suites of mutations among these 69 mutants. We assayed fitness for 13 of 17 mutant genotypes on P. pseudoalcaligenes and the standard laboratory host, P. phaseolicola. Mutants exhibited significantly lower fitnesses on P. pseudoalcaligenes compared to P. phaseolicola. Furthermore, 12 of the 13 assayed mutants showed reduced fitness on P. phaseolicola compared to wildtype Φ6, confirming the prevalence of antagonistic pleiotropy during host range expansion. Further experiments revealed that the mechanistic basis of these fitness differences was likely variation in host attachment ability. In addition, using computational protein modeling, we show that host-range expanding mutations occurred in hotspots on the surface of the phage's host attachment protein opposite a putative hydrophobic anchoring domain. |
1,577 | A systematic review of barriers to data sharing in public health | BACKGROUND: In the current information age, the use of data has become essential for decision making in public health at the local, national, and global level. Despite a global commitment to the use and sharing of public health data, this can be challenging in reality. No systematic framework or global operational guidelines have been created for data sharing in public health. Barriers at different levels have limited data sharing but have only been anecdotally discussed or in the context of specific case studies. Incomplete systematic evidence on the scope and variety of these barriers has limited opportunities to maximize the value and use of public health data for science and policy. METHODS: We conducted a systematic literature review of potential barriers to public health data sharing. Documents that described barriers to sharing of routinely collected public health data were eligible for inclusion and reviewed independently by a team of experts. We grouped identified barriers in a taxonomy for a focused international dialogue on solutions. RESULTS: Twenty potential barriers were identified and classified in six categories: technical, motivational, economic, political, legal and ethical. The first three categories are deeply rooted in well-known challenges of health information systems for which structural solutions have yet to be found; the last three have solutions that lie in an international dialogue aimed at generating consensus on policies and instruments for data sharing. CONCLUSIONS: The simultaneous effect of multiple interacting barriers ranging from technical to intangible issues has greatly complicated advances in public health data sharing. A systematic framework of barriers to data sharing in public health will be essential to accelerate the use of valuable information for the global good. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2458-14-1144) contains supplementary material, which is available to authorized users. |
1,578 | The discriminative capacity of soluble Toll-like receptor (sTLR)2 and sTLR4 in inflammatory diseases | BACKGROUND: The extracellular domains of cytokine receptors are released during inflammation, but little is known about the shedding of Toll-like receptors (TLR) and whether they can be used as diagnostic biomarkers. METHODS: The release of sTLR2 and sTLR4 was studied in in-vitro stimulations, as well as in-vivo during experimental human endotoxemia (n = 11, 2 ng/kg LPS), and in plasma of 394 patients with infections (infectious mononucleosis, measles, respiratory tract infections, bacterial sepsis and candidemia) or non-infectious inflammation (Crohn’s disease, gout, rheumatoid arthritis, autoinflammatory syndromes and pancreatitis). Using C-statistics, the value of sTLR2 and sTLR4 levels for discrimination between infections and non-infectious inflammatory diseases, as well as between viral and bacterial infections was analyzed. RESULTS: In-vitro, peripheral blood mononuclear cells released sTLR2 and sTLR4 by exposure to microbial ligands. During experimental human endotoxemia, plasma concentrations peaked after 2 hours (sTLR4) and 4 hours (sTLR2). sTLR4 did not correlate with cytokines, but sTLR2 correlated positively with TNFα (r(s) = 0.80, P < 0.05), IL-6 (r(s) = 0.65, P < 0.05), and IL-1Ra (r(s) = 0.57, P = 0.06), and negatively with IL-10 (r(s) = -0.58, P = 0.06), respectively. sTLR4 had a similar area under the ROC curve [AUC] for differentiating infectious and non-infectious inflammation compared to CRP: 0.72 (95% CI 0.66-0.79) versus 0.74 (95% CI 0.69-0.80) [P = 0.80], while sTLR2 had a lower AUC: 0.60 (95% CI 0.54-0.66) [P = 0.0004]. CRP differentiated bacterial infections better from viral infections than sTLR2 and sTLR4: AUC 0.94 (95% CI 0.90-0.96) versus 0.58 (95% CI 0.51-0.64) and 0.75 (95% CI 0.70-0.80), respectively [P < 0.0001 for both]. CONCLUSIONS: sTLRs are released into the circulation, and suggest the possibility to use sTLRs as diagnostic tool in inflammatory conditions. |
1,579 | Drug sales data analysis for outbreak detection of infectious diseases: a systematic literature review | BACKGROUND: This systematic literature review aimed to summarize evidence for the added value of drug sales data analysis for the surveillance of infectious diseases. METHODS: A search for relevant publications was conducted in Pubmed, Embase, Scopus, Cochrane Library, African Index Medicus and Lilacs databases. Retrieved studies were evaluated in terms of objectives, diseases studied, data sources, methodologies and performance for real-time surveillance. Most studies compared drug sales data to reference surveillance data using correlation measurements or indicators of outbreak detection performance (sensitivity, specificity, timeliness of the detection). RESULTS: We screened 3266 articles and included 27 in the review. Most studies focused on acute respiratory and gastroenteritis infections. Nineteen studies retrospectively compared drug sales data to reference clinical data, and significant correlations were observed in 17 of them. Four studies found that over-the-counter drug sales preceded clinical data in terms of incidence increase. Five studies developed and evaluated statistical algorithms for selecting drug groups to monitor specific diseases. Another three studies developed models to predict incidence increase from drug sales. CONCLUSIONS: Drug sales data analyses appear to be a useful tool for surveillance of gastrointestinal and respiratory disease, and OTC drugs have the potential for early outbreak detection. Their utility remains to be investigated for other diseases, in particular those poorly surveyed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0604-2) contains supplementary material, which is available to authorized users. |
1,580 | Tuberculosis care for pregnant women: a systematic review | BACKGROUND: Tuberculosis (TB) during pregnancy may lead to severe consequences affecting both mother and child. Prenatal care could be a very good opportunity for TB care, especially for women who have limited access to health services. The aim of this review was to gather and evaluate studies on TB care for pregnant women. METHODS: We used a combination of the terms “tuberculosis” and “pregnancy”, limited to human, to search for published articles. Studies reflecting original data and focusing on TB care for pregnant women were included. All references retrieved were collected using the Reference Manager software (Version 11). RESULTS: Thirty five studies were selected for review and their data showed that diagnosis was often delayed because TB symptoms during pregnancy were not typical. TB prophylaxis and anti-TB therapy appeared to be safe and effective for pregnant women and their babies when suitable follow up and early initiation were present, but the compliance rate to TB prophylaxis is still low due to lack of follow up and referral services. TB care practices in the reviewed studies were in line in principle with the WHO International Standards for Tuberculosis Care (ISTC). CONCLUSIONS: Integration of TB care within prenatal care would improve TB diagnosis and treatment for pregnant women. To improve the quality of TB care, it is necessary to develop national level guidelines based on the ISTC with detailed guidelines for pregnant women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0617-x) contains supplementary material, which is available to authorized users. |
1,581 | Cell Surface Protein Disulfide Isomerase Regulates Natriuretic Peptide Generation of Cyclic Guanosine Monophosphate | RATIONALE: The family of natriuretic peptides (NPs), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), exert important and diverse actions for cardiovascular and renal homeostasis. The autocrine and paracrine functions of the NPs are primarily mediated through the cellular membrane bound guanylyl cyclase-linked receptors GC-A (NPR-A) and GC-B (NPR-B). As the ligands and receptors each contain disulfide bonds, a regulatory role for the cell surface protein disulfide isomerase (PDI) was investigated. OBJECTIVE: We utilized complementary in vitro and in vivo models to determine the potential role of PDI in regulating the ability of the NPs to generate its second messenger, cyclic guanosine monophosphate. METHODS AND RESULTS: Inhibition of PDI attenuated the ability of ANP, BNP and CNP to generate cGMP in human mesangial cells (HMCs), human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs), each of which were shown to express PDI. In LLC-PK1 cells, where PDI expression was undetectable by immunoblotting, PDI inhibition had a minimal effect on cGMP generation. Addition of PDI to cultured LLC-PK1 cells increased intracellular cGMP generation mediated by ANP. Inhibition of PDI in vivo attenuated NP-mediated generation of cGMP by ANP. Surface Plasmon Resonance demonstrated modest and differential binding of the natriuretic peptides with immobilized PDI in a cell free system. However, PDI was shown to co-localize on the surface of cells with GC-A and GC-B by co-immunoprecpitation and immunohistochemistry. CONCLUSION: These data demonstrate for the first time that cell surface PDI expression and function regulate the capacity of natriuretic peptides to generate cGMP through interaction with their receptors. |
1,582 | Silencing airway epithelial cell-derived hepcidin exacerbates sepsis-induced acute lung injury | INTRODUCTION: The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infections and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury. METHODS: Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the seven-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated. RESULTS: The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice. CONCLUSIONS: Airway epithelial cell-derived hepcidin plays an important role in CLP-induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages. |
1,583 | Autopsy analyses in acute exacerbation of idiopathic pulmonary fibrosis | BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. However, few studies have so far reviewed analyses of autopsy findings in patients with AE-IPF. METHODS: We retrospectively reviewed 52 consecutive patients with AE-IPF who underwent autopsies at five university hospitals and one municipal hospital between 1999 and 2013. The following variables were abstracted from the medical records: demographic and clinical data, autopsy findings and complications during the clinical course until death. RESULTS: The median age at autopsy was 71 years (range 47–86 years), and the subjects included 38 (73.1%) males. High-dose corticosteroid therapy was initiated in 45 (86.5%) patients after AE-IPF. The underling fibrotic lesion was classified as having the usual interstitial pneumonia (UIP) pattern in all cases. Furthermore, 41 (78.8%) patients had diffuse alveolar damage (DAD), 15 (28.8%) exhibited pulmonary hemorrhage, nine (17.3%) developed pulmonary thromboembolism and six (11.5%) were diagnosed with lung carcinoma. In addition, six (11.5%) patients developed pneumothorax prior to death and 26 (53.1%) developed diabetes that required insulin treatment after the administration of high-dose corticosteroid therapy. In addition, 15 (28.8%) patients presented with bronchopneumonia during their clinical course and/or until death, including fungal (seven, 13.5%), cytomegalovirus (six, 11.5%) and bacterial (five, 9.6%) infections. CONCLUSIONS: The pathological findings in patients with AE-IPF represent not only DAD, but also a variety of pathological conditions. Therefore, making a diagnosis of AE-IPF is often difficult, and the use of cautious diagnostic approaches is required for appropriate treatment. |
1,584 | Emergent severe acute respiratory distress syndrome caused by adenovirus type 55 in immunocompetent adults in 2013: a prospective observational study | INTRODUCTION: Since 2008, severe cases of emerging human adenovirus type 55 (HAdV-55) in immunocompetent adults have been reported sporadically in China. The clinical features and outcomes of the most critically ill patients with severe acute respiratory distress syndrome (ARDS) caused by HAdV-55 requiring invasive mechanical ventilation (IMV) and/or extracorporeal membrane oxygenation (ECMO) are lacking. METHODS: We conducted a prospective, single-center observational study of pneumonia with ARDS in immunocompetent adults admitted to our respiratory ICU. We prospectively collected and analyzed clinical, laboratory, radiological characteristics, sequential tests of viral load in respiratory tract and blood, treatments and outcomes. RESULTS: The results for a total of five consecutive patients with severe ARDS with confirmed HAdV-55 infection were included. All five patients were immunocompetent young men with a median age of 32 years. The mean time from onset to dyspnea was 5 days. Arterial blood gas analysis at ICU admission revealed profound hypoxia. Mean partial oxygen pressure/fraction of inspired oxygen was 58.1. Mean durations from onset to a single-lobe consolidation shown on chest X-rays (CXRs) and, from the first positive CXR to bilateral multilobar lung infiltrates, were 2 days and 4.8 days, respectively. The viral load was higher than 1 × 10(8) copies in three patients and was 1 × 10(4) in one patient. It was negative in the only patient who survived. The mean duration for noninvasive positive pressure ventilation (NPPV) failure and IMV failure were 30.8 hours and 6.2 days, respectively. Four patients received venovenous ECMO. Four (80%) of the five patients died despite receiving appropriate respiratory support. CONCLUSIONS: HAdV-55 may cause severe ARDS in immunocompetent young men. Persistent high fever, dyspnea and rapid progression to respiratory failure within 2 weeks, together with bilateral consolidations and infiltrates, are the most frequent clinical manifestations of HAdV-55-induced severe ARDS. Viral load monitoring may help predict disease severity and outcome. The NPPV and IMV failure rates were very high, but ECMO may still be the respiratory support therapy of choice. TRIAL REGISTRATION: Clinicaltrials.gov NCT01585922. Registered 20 April 2012 |
1,585 | Comparison of Contact Patterns Relevant for Transmission of Respiratory Pathogens in Thailand and the Netherlands Using Respondent-Driven Sampling | Understanding infection dynamics of respiratory diseases requires the identification and quantification of behavioural, social and environmental factors that permit the transmission of these infections between humans. Little empirical information is available about contact patterns within real-world social networks, let alone on differences in these contact networks between populations that differ considerably on a socio-cultural level. Here we compared contact network data that were collected in the Netherlands and Thailand using a similar online respondent-driven method. By asking participants to recruit contact persons we studied network links relevant for the transmission of respiratory infections. We studied correlations between recruiter and recruited contacts to investigate mixing patterns in the observed social network components. In both countries, mixing patterns were assortative by demographic variables and random by total numbers of contacts. However, in Thailand participants reported overall more contacts which resulted in higher effective contact rates. Our findings provide new insights on numbers of contacts and mixing patterns in two different populations. These data could be used to improve parameterisation of mathematical models used to design control strategies. Although the spread of infections through populations depends on more factors, found similarities suggest that spread may be similar in the Netherlands and Thailand. |
1,586 | Spatial Analysis of the Distribution, Risk Factors and Access to Medical Resources of Patients with Hepatitis B in Shenzhen, China | Considering the high morbidity of hepatitis B in China, many epidemiological studies based on classic medical statistical analysis have been started but lack spatial information. However, spatial information such as the spatial distribution, autocorrelation and risk factors of the disease is of great help in studying patients with hepatitis B. This study examined 2851 cases of hepatitis B that were hospitalized in Shenzhen in 2010 and studied the spatial distribution, risk factors and spatial access to health services using spatial interpolation, Pearson correlation analysis and the improved two-step floating catchment area method. The results showed that the spatial distribution of hepatitis B, along with risk factors as well as spatial access to the regional medical resources, was uneven and mainly concentrated in the south and southwest of Shenzhen in 2010. In addition, the distribution characteristics of hepatitis B revealed a positive correlation between four types of service establishments and risk factors for the disease. The Pearson correlation coefficients are 0.566, 0.515, 0.626, 0.538 corresponding to bath centres, beauty salons, massage parlours and pedicure parlours (p < 0.05). Additionally, the allocation of medical resources for hepatitis B is adequate, as most patients could be treated at nearby hospitals. |
1,587 | Use of simple clinical and laboratory predictors to differentiate influenza from dengue and other febrile illnesses in the emergency room | BACKGROUND: Clinical differentiation of influenza from dengue and other febrile illnesses (OFI) is difficult, and available rapid diagnostic tests have limited sensitivity. METHODS: We conducted a retrospective study to compare clinical and laboratory findings between (i) influenza and dengue and (ii) influenza and OFI. RESULTS: Of 849 enrolled patients, the mean time between illness onset and hospital presentation was 1.7, 3.7, and 3 days for influenza, dengue, and OFI, respectively. Among pediatric patients (≤18 years) (445 influenza, 24 dengue, and 130 OFI), we identified absence of rashes, no leukopenia, and no marked thrombocytopenia (platelet counts <100 × 10(9) cells/L) as predictors to distinguish influenza from dengue, whereas rhinorrhea, malaise, sore throat, and mild thrombocytopenia (platelet counts 100-149 × 10(9)/L) were predictors that differentiated influenza from OFI. Among adults (>18 years) (81 influenza, 124 dengue, and 45 OFI), no leukopenia and no marked thrombocytopenia distinguished influenza from dengue, while rhinorrhea and malaise differentiated influenza from OFI. A diagnostic algorithm developed to distinguish influenza from dengue using rash, leukopenia, and marked thrombocytopenia showed >90% sensitivity to identify influenza in pediatric patients. CONCLUSIONS: This study identified simple clinical and laboratory parameters that can assist clinicians to distinguish influenza from dengue and OFI. These findings may help clinicians diagnose influenza and facilitate appropriate management of affected patients, particularly in resource-poor settings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0623-z) contains supplementary material, which is available to authorized users. |
1,588 | Characterizing Influenza surveillance systems performance: application of a Bayesian hierarchical statistical model to Hong Kong surveillance data | BACKGROUND: Infectious disease surveillance is a process the product of which reflects both actual disease trends and public awareness of the disease. Decisions made by patients, health care providers, and public health professionals about seeking and providing health care and about reporting cases to health authorities are all influenced by the information environment, which changes constantly. Biases are therefore imbedded in surveillance systems; these biases need to be characterized to provide better situational awareness for decision-making purposes. Our goal is to develop a statistical framework to characterize influenza surveillance systems, particularly their correlation with the information environment. METHODS: We identified Hong Kong influenza surveillance data systems covering healthcare providers, laboratories, daycare centers and residential care homes for the elderly. A Bayesian hierarchical statistical model was developed to examine the statistical relationships between the influenza surveillance data and the information environment represented by alerts from HealthMap and web queries from Google. Different models were fitted for non-pandemic and pandemic periods and model goodness-of-fit was assessed using common model selection procedures. RESULTS: Some surveillance systems — especially ad hoc systems developed in response to the pandemic flu outbreak — are more correlated with the information environment than others. General practitioner (percentage of influenza-like-illness related patient visits among all patient visits) and laboratory (percentage of specimen tested positive) seem to proportionally reflect the actual disease trends and are less representative of the information environment. Surveillance systems using influenza-specific code for reporting tend to reflect biases of both healthcare seekers and providers. CONCLUSIONS: This study shows certain influenza surveillance systems are less correlated with the information environment than others, and therefore, might represent more reliable indicators of disease activity in future outbreaks. Although the patterns identified in this study might change in future outbreaks, the potential susceptibility of surveillance data is likely to persist in the future, and should be considered when interpreting surveillance data. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2458-14-850) contains supplementary material, which is available to authorized users. |
1,589 | Persistent viremia by a novel parvovirus in a slow loris (Nycticebus coucang) with diffuse histiocytic sarcoma | Cancer is one of the leading health concerns for human and animal health. Since the tumorigenesis process is not completely understood and it is known that some viruses can induce carcinogenesis, it is highly important to identify novel oncoviruses and extensively study underlying oncogenic mechanisms. Here, we investigated a case of diffuse histiocytic sarcoma in a 22 year old slow loris (Nycticebus coucang), using a broad spectrum virus discovery technique. A novel parvovirus was discovered and the phylogenetic analysis performed on its fully sequenced genome demonstrated that it represents the first member of a novel genus. The possible causative correlation between this virus and the malignancy was further investigated and 20 serum and 61 organ samples from 25 animals (N. coucang and N. pygmaeus) were screened for the novel virus but only samples collected from the originally infected animal were positive. The virus was present in all tested organs (intestine, liver, spleen, kidneys, and lungs) and in all banked serum samples collected up to 8 years before death. All attempts to identify a latent viral form (integrated or episomal) were unsuccessful and the increase of variation in the viral sequences during the years was consistent with absence of latency. Since it is well known that parvoviruses are dependent on cell division to successfully replicate, we hypothesized that the virus could have benefitted from the constantly dividing cancer cells and may not have been the cause of the histiocytic sarcoma. It is also possible to conjecture that the virus had a role in delaying the tumor progression and this report might bring new exciting opportunities in recognizing viruses to be used in cancer virotherapy. |
1,590 | Associations of IFN-γ rs2430561 T/A, IL28B rs12979860 C/T and ERα rs2077647 T/C polymorphisms with outcomes of hepatitis B virus infection: a meta-analysis | Several studies investigated associations of IFN-γ rs2430561 T/A, IL28B rs12979860 C/T and ERα rs2077647 T/C gene polymorphisms with outcomes of hepatitis B virus (HBV) infection, but the results were controversial. Therefore, we performed a meta-analysis of all published observational studies to address this inconsistency. Literature was searched in online database and a systematic review was conducted based on the search results. A total of 24 studies were included and dichotomous data were presented as odds ratio (OR) with a 95% confidence interval (CI). The rs2430561 T allele was associated with reduced persistent HBV infection risk (T vs. A: OR, 0.690; 95% CI, [0.490, 0.971]), while the rs2077647 T allele significantly increased the risk of persistent HBV infection (T vs. C: OR, 1.678; 95% CI, [1.212, 2.323]). Rs 2077647 CC might play a role in protecting individuals against HBV persistence (TT vs. CC: OR, 4.109; 95% CI, [2.609, 6.473]). Furthermore, carriers of the rs2430561 TT genotype were more likely to clear HBV spontaneously compared with those of the AA genotype (TT vs. AA: OR, 0.555; 95% CI, [0.359, 0.856]). For rs12979860 C/T polymorphism, no significant correlation with HBV infection outcomes was found. In subgroup analyses, the results were similar to those of overall analysis. However, for rs2077647 TT vs. TC+CC, significantly increased risks were observed in the Asian and hospital-based population, but not in the overall analysis. IFN-γ rs2430561 T/A and ERα rs2077647 T/C genetic polymorphisms were associated with outcomes of HBV infection, but no association was found between IL28B rs12979860 C/T and HBV infection. |
1,591 | Molecular Detection, Phylogenetic Analysis, and Identification of Transcription Motifs in Feline Leukemia Virus from Naturally Infected Cats in Malaysia | A nested PCR assay was used to determine the viral RNA and proviral DNA status of naturally infected cats. Selected samples that were FeLV-positive by PCR were subjected to sequencing, phylogenetic analysis, and motifs search. Of the 39 samples that were positive for FeLV p27 antigen, 87.2% (34/39) were confirmed positive with nested PCR. FeLV proviral DNA was detected in 38 (97.3%) of p27-antigen negative samples. Malaysian FeLV isolates are found to be highly similar with a homology of 91% to 100%. Phylogenetic analysis revealed that Malaysian FeLV isolates divided into two clusters, with a majority (86.2%) sharing similarity with FeLV-K01803 and fewer isolates (13.8%) with FeLV-GM1 strain. Different enhancer motifs including NF-GMa, Krox-20/WT1I-del2, BAF1, AP-2, TBP, TFIIF-beta, TRF, and TFIID are found to occur either in single, duplicate, triplicate, or sets of 5 in different positions within the U3-LTR-gag region. The present result confirms the occurrence of FeLV viral RNA and provirus DNA in naturally infected cats. Malaysian FeLV isolates are highly similar, and a majority of them are closely related to a UK isolate. This study provides the first molecular based information on FeLV in Malaysia. Additionally, different enhancer motifs likely associated with FeLV related pathogenesis have been identified. |
1,592 | MiR-23a Facilitates the Replication of HSV-1 through the Suppression of Interferon Regulatory Factor 1 | MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression. It has been reported that miRNAs are involved in host-virus interaction, but evidence that cellular miRNAs promote virus replication has been limited. Here, we found that miR-23a promoted the replication of human herpes simplex virus type 1 (HSV-1) in HeLa cells, as demonstrated by a plaque-formation assay and quantitative real-time PCR. Furthermore, interferon regulatory factor 1 (IRF1), an innate antiviral molecule, is targeted by miR-23a to facilitate viral replication. MiR-23a binds to the 3′UTR of IRF1 and down-regulates its expression. Suppression of IRF1 expression reduced RSAD2 gene expression, augmenting HSV-1 replication. Ectopic expression of IRF1 abrogated the promotion of HSV-1 replication induced by miR-23a. Notably, IRF1 contributes to innate antiviral immunity by binding to IRF-response elements to regulate the expression of interferon-stimulated genes (ISGs) and apoptosis, revealing a complex interaction between miR-23a and HSV-1. MiR-23a thus contributes to HSV-1 replication through the regulation of the IRF1-mediated antiviral signal pathway, which suggests that miR-23a may represent a promising target for antiviral treatments. |
1,593 | Rapid Identification of Black Grain Eumycetoma Causative Agents Using Rolling Circle Amplification | Accurate identification of mycetoma causative agent is a priority for treatment. However, current identification tools are far from being satisfactory for both reliable diagnosis and epidemiological investigations. A rapid, simple, and highly efficient molecular based method for identification of agents of black grain eumycetoma is introduced, aiming to improve diagnostic in endemic areas. Rolling Circle Amplification (RCA) uses species-specific padlock probes and isothermal DNA amplification. The tests were based on ITS sequences and developed for Falciformispora senegalensis, F. tompkinsii, Madurella fahalii, M. mycetomatis, M. pseudomycetomatis, M. tropicana, Medicopsis romeroi, and Trematosphaeria grisea. With the isothermal RCA assay, 62 isolates were successfully identified with 100% specificity and no cross reactivity or false results. The main advantage of this technique is the low-cost, high specificity, and simplicity. In addition, it is highly reproducible and can be performed within a single day. |
1,594 | Molecular Evolution of Peste des Petits Ruminants Virus | Despite safe and efficacious vaccines against peste des petits ruminants virus (PPRV), this virus has emerged as the cause of a highly contagious disease with serious economic consequences for small ruminant agriculture across Asia, the Middle East, and Africa. We used complete and partial genome sequences of all 4 lineages of the virus to investigate evolutionary and epidemiologic dynamics of PPRV. A Bayesian phylogenetic analysis of all PPRV lineages mapped the time to most recent common ancestor and initial divergence of PPRV to a lineage III isolate at the beginning of 20th century. A phylogeographic approach estimated the probability for root location of an ancestral PPRV and individual lineages as being Nigeria for PPRV, Senegal for lineage I, Nigeria/Ghana for lineage II, Sudan for lineage III, and India for lineage IV. Substitution rates are critical parameters for understanding virus evolution because restrictions in genetic variation can lead to lower adaptability and pathogenicity. |
1,595 | Emergence of travel: Associated dengue fever in a non-endemic, hilly state | BACKGROUND: We assessed the occurrence of dengue fever in association with travel in a non-endemic hilly region. The clinical presentation and laboratory parameters of febrile patients with a travel history to an endemic region were studied, and the role of the laboratory in the diagnosis was affirmed. MATERIALS AND METHODS: Febrile patients presenting with clinical features defining dengue with a history of travel to an endemic area constituted the study group. Serum samples were tested for dengue-specific NS1 antigen and IgM, IgG antibodies. The demographic data were retrieved from the hospital information system. A hematological and biochemical workup was done and the results analyzed using percentage, proportion, mean, and median. RESULTS: Out of 189 febrile patients, 58 were reactive to serological tests for dengue, with 47 (81%) males. The presenting features were chills and rigors, myalgia, cough, sweating, and vomiting. Thrombocytopenia (74.35%), lymphopenia (52.94%), and leucopenia (47.05%) were present in early disease, with AST >34 IU/L in 58.97% of the patients. The NS1 antigen was detectable between three and seven days of fever and the IgM antibodies after five days. The positivities to only NS1, both NS1 and IgM, and IgM alone were 60.34, 27.58, and 10.34%, respectively, and the median duration of fever was five, seven, and ten days, respectively. One case of dengue hemorrhagic fever and one of probable secondary dengue infection with detectable IgG were encountered. CONCLUSION: Dengue fever remains unsuspected in febrile cases in non-endemic regions. History of travel is an essential criterion to suspect dengue. A non-specific clinical presentation eludes diagnosis. Serological tests for antigen and antibodies, and hematological and biochemical markers are vital for distinguishing the diagnosis. |
1,596 | A sustained deficiency of mitochondrial respiratory complex III induces an apoptotic cell death through the p53-mediated inhibition of pro-survival activities of the activating transcription factor 4 | Generation of energy in mitochondria is subjected to physiological regulation at many levels, and its malfunction may result in mitochondrial diseases. Mitochondrial dysfunction is associated with different environmental influences or certain genetic conditions, and can be artificially induced by inhibitors acting at different steps of the mitochondrial electron transport chain (ETC). We found that a short-term (5 h) inhibition of ETC complex III with myxothiazol results in the phosphorylation of translation initiation factor eIF2α and upregulation of mRNA for the activating transcription factor 4 (ATF4) and several ATF4-regulated genes. The changes are characteristic for the adaptive integrated stress response (ISR), which is known to be triggered by unfolded proteins, nutrient and metabolic deficiency, and mitochondrial dysfunctions. However, after a prolonged incubation with myxothiazol (13–17 h), levels of ATF4 mRNA and ATF4-regulated transcripts were found substantially suppressed. The suppression was dependent on the p53 response, which is triggered by the impairment of the complex III-dependent de novo biosynthesis of pyrimidines by mitochondrial dihydroorotate dehydrogenase. The initial adaptive induction of ATF4/ISR acted to promote viability of cells by attenuating apoptosis. In contrast, the induction of p53 upon a sustained inhibition of ETC complex III produced a pro-apoptotic effect, which was additionally stimulated by the p53-mediated abrogation of the pro-survival activities of the ISR. Interestingly, a sustained inhibition of ETC complex I by piericidine did not induce the p53 response and stably maintained the pro-survival activation of ATF4/ISR. We conclude that a downregulation of mitochondrial ETC generally induces adaptive pro-survival responses, which are specifically abrogated by the suicidal p53 response triggered by the genetic risks of the pyrimidine nucleotide deficiency. |
1,597 | 3D QSAR Studies, Pharmacophore Modeling and Virtual Screening on a Series of Steroidal Aromatase Inhibitors | Aromatase inhibitors are the most important targets in treatment of estrogen-dependent cancers. In order to search for potent steroidal aromatase inhibitors (SAIs) with lower side effects and overcome cellular resistance, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of SAIs to build 3D QSAR models. The reliable and predictive CoMFA and CoMSIA models were obtained with statistical results (CoMFA: q(2) = 0.636, r(2)(ncv) = 0.988, r(2)(pred) = 0.658; CoMSIA: q(2) = 0.843, r(2)(ncv) = 0.989, r(2)(pred) = 0.601). This 3D QSAR approach provides significant insights that can be used to develop novel and potent SAIs. In addition, Genetic algorithm with linear assignment of hypermolecular alignment of database (GALAHAD) was used to derive 3D pharmacophore models. The selected pharmacophore model contains two acceptor atoms and four hydrophobic centers, which was used as a 3D query for virtual screening against NCI2000 database. Six hit compounds were obtained and their biological activities were further predicted by the CoMFA and CoMSIA models, which are expected to design potent and novel SAIs. |
1,598 | Mortality attributable to Plasmodium vivax malaria: a clinical audit from Papua, Indonesia | BACKGROUND: Plasmodium vivax causes almost half of all malaria cases in Asia and is recognised as a significant cause of morbidity. In recent years it has been associated with severe and fatal disease. The extent to which P. vivax contributes to death is not known. METHODS: To define the epidemiology of mortality attributable to vivax malaria in southern Papua, Indonesia, a retrospective clinical records-based audit was conducted of all deaths in patients with vivax malaria at a tertiary referral hospital. RESULTS: Between January 2004 and September 2009, hospital surveillance identified 3,495 inpatients with P. vivax monoinfection and 65 (1.9%) patients who subsequently died. Charts for 54 of these 65 patients could be reviewed, 40 (74%) of whom had pure P. vivax infections on cross-checking. Using pre-defined conservative criteria, vivax malaria was the primary cause of death in 6 cases, a major contributor in 17 cases and a minor contributor in a further 13 cases. Extreme anaemia was the most common primary cause of death. Malnutrition, sepsis with respiratory and gastrointestinal manifestations, and chronic diseases were the commonest attributed causes of death for patients in the latter two categories. There were an estimated 293,763 cases of pure P. vivax infection in the community during the study period giving an overall minimum case fatality of 0.12 per 1,000 infections. The corresponding case fatality in hospitalised patients was 10.3 per 1,000 infections. CONCLUSIONS: Although uncommonly directly fatal, vivax malaria is an important indirect cause of death in southern Papua in patients with malnutrition, sepsis syndrome and chronic diseases, including HIV infection. |
1,599 | Lipid interactions during virus entry and infection | For entry and infection viruses have developed numerous strategies to subjugate indispensable cellular factors and functions. Host cell lipids and cellular lipid synthesis machinery are no exception. Not only do viruses exploit existing lipid signalling and modifications for virus entry and trafficking, they also reprogram lipid synthesis, metabolism, and compartmentalization for assembly and egress. Here we review these various concepts and highlight recent progress in understanding viral interactions with host cell lipids during entry and assembly. |
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