niryuu/sni-each-converted huggingface dataset:
Since the pilots' strike of 1989, the Australian tourism industry has experienced a series of 'shocks' or crises which have included the 1991 Gulf War, the Asian economic crisis in 1997, the dotcom crash of 2000, the collapse of the HIH Insurance Company, the World Trade Centre attacks and the demise of Ansett Airlines in 2001, the Bali bombings in 2002 and the Iraq War and the outbreak of the SARS (severe acute respiratory syndrome) epidemic in 2003. In 2002, a research project was carried out in a range of sectors of the Australian tourism industry to investigate the impact of the collapse of the HIH Insurance Company, the World Trade Centre attacks and the demise of Ansett Airlines on these organisations and the range of responses adopted to these events. This paper describes the preparedness of organisations to respond to these events; the personnel or human resource (HR) strategies implemented and the postscript, the organisational learning which had occurred. Interview findings indicate that there was little preparation for such events, a widespread reluctance to retrench staff, and limited organisational learning had taken place. r
Output: Crisis management in the Australian tourism industry: Preparedness, personnel and postscript
NF-jB, a family of transcription factors involved in different cell functions and immune responses is targeted by viruses. The mechanism of NF-jB signalling and its role in replication of EAV have not been investigated. We demonstrate that EAV infection in BHK-21 cells activates NF-jB, and this activation was found to be mediated through the MyD88 pathway. Infection of IKKb -/murine embryo fibroblasts (MEFs), which are deficient in NF-jB signalling, resulted in lower virus titre, less cytopathic effect, and reduced expression of viral proteins. These findings implicate the MyD88 pathway in EAV-induced NF-jB activation and suggest that NF-jB activation is essential for efficient replication of EAV.
Output: NF-jB activation by equine arteritis virus is MyD88 dependent and promotes viral replication
The principal component analysis based on the physicochemical properties of amino acid residues is applied to DNA and RNA polymerases to assign the sequence motifs for the polymerization activities of these proteins. After the reconfirmation of the sequence motifs of families A and B of DNA polymerases indicated previously, it elucidates the sequence motifs for the polymerization activity of DNA polymerase III (family C) by the similarity to the polymerization center of multimeric DNA dependent RNA polymerases. This identification proceeds to clarify the sequence motifs for polymerization activities of primases; eukaryotic and archaebacterial primases carry motifs similar to those of family C, while the motifs of eubacterial primase fall into the category of the motifs in family B DNA polymerases such as K, N, O and II. This finding means that DNA dependent RNA polymerases are also divided into groups corresponding to three families, A, B and C, because the monomeric DNA dependent RNA polymerases in phages are reconfirmed to carry sequence motifs similar to those of family A DNA polymerases. Furthermore, the three families of polymerization motifs are found to fall within the variation range of polymerization motifs displayed by many RNA dependent RNA polymerases, suggesting a close evolutionary relation between them. The sequence motifs for polymerization activities of reverse transcriptase and telomerase seem to be the intermediate between family A DNA polymerase and some RNA dependent RNA polymerases, e.g., from Leviviridae. On the contrary, the sequence fragments similar to the nucleotidyltransferase superfamily including DNA polymerase L are not found in any RNA dependent RNA polymerase, suggesting their other lineage of polymerization motifs. ß 1999 Elsevier Science B.V. All rights reserved. 0167-4838 / 99 / $^see front matter ß 1999 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 -4 8 3 8 ( 9 9 ) 0 0 1 8 7 -9 * Corresponding
Output: Similarity relations of DNA and RNA polymerases investigated by the principal component analysis of amino acid sequences
Several studies have shown that cell-mediated immune responses play a crucial role in controlling viral replication. As such, a candidate SARS vaccine should elicit broad CD8+ T-cell immune responses. Several groups of mice were immunized alone or in combination with SARSnucleocapsid immunogen. A high level of specific SARS-CD8+ T-cell response was demonstrated in mice that received DNA encoding the SARS-nucleocapsid, protein and XIAP as an adjuvant. We also observed that co-administration of a plasmid expressing nucleocapsid, recombinant protein and montanide/CpG induces high antibody titers in immunized mice. Moreover, this vaccine approach merits further investigation as a potential candidate vaccine against SARS.
Output: Genetic Vaccines and Therapy A combined nucleocapsid vaccine induces vigorous SARS-CD8+ T-cell immune responses
Newcastle disease virus (NDV) causes severe economic losses through severe morbidity and mortality and poses a significant threat to the global poultry industry. Significant efforts have been made to develop novel vaccines and therapeutics; however, the interaction of NDV with the host is not yet fully understood. Interferons (IFNs), an integral component of innate immune signaling, act as the first line of defense against invading viruses. Compared with the mammalian repertoire of IFNs, limited information is available on the antiviral potential of IFNs in chickens. Here, we expressed chicken IFN-γ (chIFN-γ) using a baculovirus expression vector system, characterized its antiviral potential against NDV, and determined its antiviral potential. Priming of chicken embryo fibroblasts with chIFN-γ elicited an antiviral environment in primary cells, which was mainly due to interferon-stimulated genes (ISGs). A genome-wide transcriptomics approach was used to elucidate the possible signaling pathways associated with IFN-γ-induced immune responses. RNAsequencing (RNA-seq) data revealed significant induction of ISG-associated pathways, activated temporal expression of ISGs, antiviral mediators, and transcriptional regulators in a cascade of antiviral responses. Collectively, we found that IFN-γ significantly elicited an antiviral response against NDV infection. These data provide a foundation for chIFN-γ-mediated antiviral responses and underpin functional annotation of these important chIFN-γ-induced antiviral influencers.
Output: IFN-γ establishes interferon-stimulated gene-mediated antiviral state against Newcastle disease virus in chicken fibroblasts
Common cold viruses create significant health and financial burdens, and understanding key loci of transmission would help focus control strategies. This study (1) examines factors that influence when individuals transition from a negative to positive test (acquisition) or a positive to negative test (loss) of rhinovirus (HRV) and other respiratory tract viruses in 26 households followed weekly for one year, (2) investigates evidence for intrahousehold and interhousehold transmission and the characteristics of individuals implicated in transmission, and (3) builds data-based simulation models to identify factors that most strongly affect patterns of prevalence. We detected HRV, coronavirus, paramyxovirus, influenza and bocavirus with the FilmArray polymerase chain reaction (PCR) platform (BioFire Diagnostics, LLC). We used logistic regression to find covariates affecting acquisition or loss of HRV including demographic characteristics of individuals, their household, their current infection status, and prevalence within their household and across the population. We apply generalized linear mixed models to test robustness of results. Acquisition of HRV was less probable in older individuals and those infected with a coronavirus, and higher with a higher proportion of other household members infected. Loss of HRV is reduced with a higher proportion of other household members infected. Within households, only children and symptomatic individuals show evidence for transmission, while between households only a higher number of infected older children (ages 5-19) increases the probability of acquisition. Coronaviruses, paramyxoviruses and bocavirus also show evidence of intrahousehold transmission. Simulations show that age-dependent susceptibility and transmission have the largest effects on mean HRV prevalence.
Output: Transmission of rhinovirus in the Utah BIG- LoVE families: Consequences of age and household structure
Egyptian poultry suffer from frequent respiratory disease outbreaks associated with Infectious Bronchitis Virus (IBV) variant 2 strains (Egy/VarII). Different vaccination programs using imported vaccines have failed to protect the flocks from field challenge. Recent studies confirmed a successful protection using homologous strains as live attenuated vaccines. In this study, a newly developed live attenuated IB-VAR2 vaccine representing the GI-23 Middle East IBV lineage was evaluated in day-old commercial broilers in an IBV-endemic area. A commercial broiler flock was vaccinated with the IB-VAR2 vaccine at day-old age followed by IB-H120 at day 16. The vaccinated flock was monitored on a weekly basis till the slaughter age. The health status and growth performance were monitored, and selected viral pathogen real-time RT-PCR (rRT-PCR) detection was conducted on a weekly basis. Finally, the flock was compared to a nearby farm with only the classical IB-H120 vaccination program. Results showed that the IB-VAR2 vaccine was tolerable in day-old broiler chicks. The IBV virus rRT-PCR detection was limited to the trachea as compared to its nephropathogenic parent virus. Respiratory disease problems and high mortalities were reported in the IB-H120-only vaccinated flock. An exposure to a wild-type Egy/VarII strain was confirmed in both flocks as indicated by partial IBV S1 gene sequence. Even though the IB-VAR2-vaccinated flock performance was better than the flock that received only IB-H120, the IBV ELISA (enzyme-linked immunosorbent assay) and log2 Haemagglutination inhibition (HI) antibody mean titers remained high (3128 ± 2713 and ≥9 log2, respectively) until the 28th day of age. The current study demonstrates the safety and effectiveness of IB-VAR2 as a live attenuated vaccine in day-old commercial broilers. Also, the combination of IB-VAR2 and classical IBV vaccines confers a broader protective immune response against IBV in endemic areas.
Output: Field Efficacy of an Attenuated Infectious Bronchitis Variant 2 Virus Vaccine in Commercial Broiler Chickens
Steady state alveolar macrophages (AM) are long-lived lung-resident macrophages with sentinel function. Evidence suggests that AM precursors originate during embryogenesis and populate lungs without replenishment by circulating leukocytes. However, their presence and persistence are unclear following human lung transplantation (LTx). Our goal was to examine donor AM longevity and evaluate whether AM of recipient origin seeds the transplanted lungs. Origin of AM was accessed using donor-recipient HLA mismatches. We demonstrate that 94-100% of AM present in bronchoalveolar lavage (BAL) were donor derived and importantly AM of recipient origin were not detected. Further, analysis of BAL cells up to 3.5 yrs post-LTx revealed that majority of AM (>87%) was donor derived. Elicitation of de novo donor specific antibody (DSA) is a major post-LTx complication and a risk factor for development of chronic rejection. The donor AM responded to anti-HLA framework Ab with secretion of inflammatory cytokines. Further, in an experimental murine model, we demonstrate that adoptive transfer of allogeneic AM stimulated humoral and cellular immune responses to alloantigen and lung-associated self-antigens and led to bronchiolar obstruction. Therefore, donor derived AM play an essential role in the DSA induced inflammatory cascade leading to obliterative airway disease of the transplanted lungs.
Output: Long-term persistence of donor alveolar macrophages in human lung transplant recipients that influences donor specific immune responses HHS Public Access
Hepatitis C virus (HCV) is believed to assemble by budding into membranes of the early secretory pathway, consistent with the membrane location where the viral envelope glycoproteins E1 and E2 accumulate when expressed. Coronavirus assembly also takes place at pre-Golgi membranes. Here, we generated coronavirus-like particles carrying in their envelope chimeric HCV glycoproteins composed of the ectodomains of E1 and E2, each fused to the transmembrane plus endodomain of the mouse hepatitis coronavirus spike glycoprotein. The chimeric particle system will enable structural and functional studies of the HCV glycoproteins. * . This flavivirus causes chronic liver disease for which treatment options are limited and no vaccine is yet available. The study of its biology has been severely hampered by the lack of viral culture systems, a situation that has recently changed by the generation of infectious HCV genomes that replicate efficiently in cell culture [21, 37, 38] . Little is still known about the biogenesis and structure of HCV particles. The virus is composed of a core (C) protein -that packages the positive-stranded RNA genome -and envelope proteins, E1 and E2, which are generated by cleavage
Output: Assembly of HCV E1 and E2 glycoproteins into coronavirus VLPs Brief Report
Effective isolation of nucleic acids from samples containing viral materials is an essential step for accurate diagnosis of viral infections. The necessity of this critical step before analytical identification and diagnosis of viral infections is paramount to screening programs and to identifying and monitoring epidemics and pandemics. With molecular assays rapidly evolving into routine practice, clinical laboratories face several challenges, including presence of small amounts of viral nucleic acids in abundant levels of genomic DNA and total RNA, processing of various sample types, and carry-over of polymerase chain reaction inhibitors, which could significantly affect polymerase chain reaction and microarray results. MagaZorb nucleic acid isolation technology overcomes these challenges and offers a simple and reliable method for isolation of highquality and high-yield nucleic acids. Although the MagaZorb technology is readily adaptable to automated platforms, it is also well suited to laboratories in remote areas of resource-poor countries, because a simple magnet is the only device required to perform the procedure manually. Performance characteristics and clinical application of the MagaZorb technology are briefly described here.
Output: MagaZorb: A Simple Tool for Rapid Isolation of Viral Nucleic Acids
In many systems transfer between the endoplasmic reticulum and the Golgi apparatus is blocked at temperatures below 16°C. In virus-infected cells in culture, a special membrane compartment is seen to accumulate. Our studies with rat liver show a similar response to temperature both in situ with slices and in vitro with isolated transitional endoplasmie reticulum fractions. With isolated transitional endoplasmic reticulum fractions, when incubated in the presence of nucleoside tripbosphate and a cytosol fraction, temperature dependent formation of vesicles occurred with a Ql0 of "2 but was apparent only at temperatures greater than 12°C. A similar response was seen in situ at 12°C and 16°C where fusion of transition vesicles with cis Golgi apparatus, but not their formation, was blocked and transition vesicles accumulated in large numbers. At 18°C and below and especially at 8°C and 12°C, the cells responded by accumulating smooth tubular transitional membranes near the cis Golgi apparatus face. With cells and tissue slices at 20°C neither transition vesicles nor the smooth tubular elements accumulated. Those transition vesicles which formed at 3"/°C were of a greater diameter than those formed at 4°C both in situ and in vitro. The findings show parallel responses between the temperature dependency of transition vesicle formation in vitro and in situ and suggest that a subP0Pulation of the transitional endoplasmic reticulum may be morphologically and functionally homologous to the 16°C compartment observed in vitally-infected cell lines grown at low temperatures. transition vesicle --endoplasmie reticulum --temperature --rat liver
Output: Identification of the 16°C compartment of the endoplasmic reticulum in rat liver and cultured hamster kidney cells
A major obstacle to anticipating the cross-species transmission of zoonotic diseases and developing novel strategies for their control is the scarcity of data informing how these pathogens circulate within natural reservoir populations. Vampire bats are the primary reservoir of rabies in Latin America, where the disease remains among the most important viral zoonoses affecting humans and livestock. Unpredictable spatiotemporal dynamics of rabies within bat populations have precluded anticipation of outbreaks and undermined widespread bat culling programs. By analysing 1146 vampire bat-transmitted rabies (VBR) outbreaks in livestock across 12 years in Peru, we demonstrate that viral expansions into historically uninfected zones have doubled the recent burden of VBR. Viral expansions are geographically widespread, but severely constrained by high elevation peaks in the Andes mountains. Within Andean valleys, invasions form wavefronts that are advancing towards large, unvaccinated livestock populations that are heavily bitten by bats, which together will fuel high transmission and mortality. Using spatial models, we forecast the pathways of ongoing VBR epizootics across heterogeneous landscapes. These results directly inform vaccination strategies to mitigate impending viral emergence, reveal VBR as an emerging rather than an enzootic disease and create opportunities to test novel interventions to manage viruses in bat reservoirs.
Output: Spatial expansions and travelling waves of rabies in vampire bats
Background: The four types of human parainfluenza viruses (PIV) are important causes of community-acquired pneumonia, particularly in children; however, limited information exists about the incidence of PIV in critically ill patients. The aim of this study is to describe the spectrum, incidence and clinical features of PIV-associated infections diagnosed during the hospital stay of patients admitted to pediatric intensive care unit (PICU) and intensive care unit (ICU) of 5 medical centers across Kuwait. Methods: This was a population-based, retrospective study from 2013 to 2015. Specimens were analyzed by molecular methods. This analysis was performed using the database of Virology Unit, Mubarak Al-Kabeer Hospital. Data from 1510 admitted patients with suspected respiratory viral infections was extracted. Results: The database contained a total of 39 (2.6%) patients infected with PIV (53.8% male and 46.2% females) and 20 (51.3%) were under 1 year of age. The most frequently isolated type was type 3 (28, 71.8%) followed by type 1 (9, 23.1%). At admission the most common clinical diagnosis was pneumonia in 12 patients (30.8%, p < 0.05) followed by bronchiolitis in 10 patients (25.6%). Conclusion: PIV plays an important yet unrecognized role in the outcomes of PIUC and ICU patients. Our results contribute to the limited epidemiologic data of PIV in PIUC and ICU in this region.
Output: The potential influence of human parainfluenza viruses detected during hospitalization among critically ill patients in Kuwait, 2013-2015
Several arenaviruses can cause viral hemorrhagic fever, a severe disease with case-fatality rates in hospitalized individuals ranging from 15-30%. Because of limited prophylaxis and treatment options, new medical countermeasures are needed for these viruses classified by the National Institutes of Allergy and Infectious Diseases (NIAID) as top priority biodefense Category A pathogens. Recombinant consensus interferon alpha (cIFN-a) is a licensed protein with broad clinical appeal. However, while cIFN-a has great therapeutic value, its utility for biodefense applications is hindered by its short in vivo half-life, mode and frequency of administration, and costly production. To address these limitations, we describe the use of DEF201, a replicationdeficient adenovirus vector that drives the expression of cIFN-a, for pre-and post-exposure prophylaxis of acute arenaviral infection modeled in hamsters. Intranasal administration of DEF201 24 h prior to challenge with Pichindé virus (PICV) was highly effective at protecting animals from mortality and preventing viral replication and liver-associated disease. A significant protective effect was still observed with a single dosing of DEF201 given two weeks prior to PICV challenge. DEF201 was also efficacious when administered as a treatment 24 to 48 h post-virus exposure. The protective effect of DEF201 was largely attributed to the expression of cIFN-a, as dosing with a control empty vector adenovirus did not protect hamsters from lethal PICV challenge. Effective countermeasures that are highly stable, easily administered, and elicit long lasting protective immunity are much needed for arena and other viral infections. The DEF201 technology has the potential to address all of these issues and may serve as a broad-spectrum antiviral to enhance host defense against a number of viral pathogens. Citation: Gowen BB, Ennis J, Russell A, Sefing EJ, Wong M-H, et al. (2011) Use of Recombinant Adenovirus Vectored Consensus IFN-a to Avert Severe Arenavirus Infection. PLoS ONE 6(10): e26072.
Output: Use of Recombinant Adenovirus Vectored Consensus IFN-a to Avert Severe Arenavirus Infection
Apolipoprotein D (ApoD) gene expression is increased in several neurological disorders such as Alzheimer's disease (AD) and multiple sclerosis. We previously showed that transgenic mice that overexpress human ApoD show a better resistance against paraquat or OC43 coronavirusinduced neurodegeneration. Here, we identified several nuclear factors from the cortex of control and OC43-infected mice which bind a fragment of the proximal ApoD promoter in vitro. Of interest, we detected apolipoprotein E (ApoE). Human ApoE consists of three isoforms (E2, E3, and E4) with the E4 and E2 alleles representing a greater and a lower risk for developping AD, respectively. Our results show that ApoE is located in the nucleus and on the ApoD promoter in human hepatic and glioblastoma cells lines. Furthermore, overexpression of ApoE3 and ApoE4 isoforms but not ApoE2 significantly inhibited the ApoD promoter activity in U87 cells (E3/E3 genotype) cultured under normal or different stress conditions while ApoE knock-down by siRNA had a converse effect. Consistent with these results, we also demonstrated by ChIP assay that E3 and E4 isoforms, but not E2, bind the ApoD promoter. Moreover, using the Allen Brain Atlas in situ hybridization database, we observed an inverse correlation between ApoD and ApoE mRNA expression during development and in several regions of the mouse brain, notably in the cortex, hippocampus, plexus choroid, and cerebellum. This negative correlation was also observed for cortex layers IV-VI based on a new Transcriptomic Atlas of the Mouse Neocortical Layers. These findings reveal a new function for ApoE by regulating ApoD gene expression.
Output: Binding and Repressive Activities of Apolipoprotein E3 and E4 Isoforms on the Human ApoD Promoter
Middle East respiratory syndrome coronavirus (MERS-CoV) shedding and antibody responses are not fully understood, particularly in relation to underlying medical conditions, clinical manifestations, and mortality. We enrolled MERS-CoVpositive patients at a hospital in Saudi Arabia and periodically collected specimens from multiple sites for real-time reverse transcription PCR and serologic testing. We conducted interviews and chart abstractions to collect clinical, epidemiologic, and laboratory information. We found that diabetes mellitus among survivors was associated with prolonged MERS-CoV RNA detection in the respiratory tract. Among case-patients who died, development of robust neutralizing serum antibody responses during the second and third weeks of illness was not sufficient for patient recovery or virus clearance. Fever and cough among mildly ill patients typically aligned with RNA detection in the upper respiratory tract; RNA levels peaked during the first week of illness. These findings should be considered in the development of infection control policies, vaccines, and antibody therapeutics.
Output: Middle East Respiratory Syndrome Coronavirus Infection Dynamics and Antibody Responses among Clinically Diverse Patients, Saudi Arabia
Viral diseases such as influenza, which are easily transferable from person to person or even country to country, pose one of the biggest threats to health today. Viruses such as avian influenza viruses (N1H5 and H9N1) have been reported to spread in the present decade and, very recently, the novel coronavirus that has caused many life-threatening illnesses and deaths all around the world has received much attention. To prevent these highly contagious viral infections, we have proposed the combination of IMODä and Arbidol to increase their immunomodulatory effects as a novel medicine to prevent and cure influenza and some other infectious diseases such as hepatitis B and C. On the one hand, IMODä within the last few years has been proven to safely and effectively increase the life expectancy for human immunodeficiency virus (HIV)-infected individuals by increasing CD4 lymphocytes. On the other hand, Arbidol, an antiviral agent has been used safely and effectively in the past two decades to prevent and cure all types of influenza and flu. Therefore, the combination of both in a single dosage to further increase CD4 lymphocytes and interferon gamma (IFN-c) could be a better choice for treatment of viral infections. This proposal tries to provide enough support and background for approval of a randomized clinical trial by a relevant team of investigators. ª 2014 Published
Output: Combination of IMODä and Arbidol to increase their immunomodulatory effects as a novel medicine to prevent and cure influenza and some other infectious diseases Journal of Medical Hypotheses and Ideas
Although the influenza vaccine is relatively safe and effective, serious complications can develop in rare cases. We encountered two cases of interstitial pneumonia that developed after vaccination during the 2014-2015 influenza season. Overall, nine cases, including the two presented here, have been recorded in PubMed and the Cochrane library; eight patients were treated with corticosteroids, and all nine survived, suggesting a good prognosis. Interstitial pneumonia is rare; however, we found an increase in its incidence after 2009. Therefore, clinicians must be aware of the possibility of this complication and duly educate all patients in advance.
Output: CASE REPORT Interstitial Pneumonia Associated with the Influenza Vaccine: A Report of Two Cases
Ethnopharmacological relevance: Yu Ping Feng San (YPFS, in Chinese: Jade Windscreen Powder), a wellknown traditional Chinese medicine, is commonly used to cure the diseases of respiratory systems and immune systems. Aim of the study: A selective and sensitive high-performance liquid chromatography coupled with mass spectrometry method (HPLC-MS) was developed and validated for simultaneous quantification of cycloastragenol, formononetin, calycosin, 4 0 -O-b-glucopyranosyl-5-O-methylvisamminol (GMV) and cimifugin in rat plasma after oral administration of Yu Ping Feng San decoction. Materials and methods: Plasma samples were extracted via solid-phase extraction (SPE), separated on a Zorbax SB-C18 column, detected by single quadruple mass spectrometry with an electrospray ionization interface, and quantified using selected ion monitoring mode. The current SPE-HPLC-MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability. The method was applied to a comparative pharmacokinetic study after administration of Yu Ping Feng San to rats at different doses (10, 20 and 40 g/kg). Results: The calibration curves were linear over the ranges 0.50-50 ng/mL and 17.36-1736 ng/mL. Intra-and inter-day precisions (relative standard deviations) were from 0.45% to 10.95%, and accuracy (relative recovery) from 95% to 115%. The extraction recoveries were greater than 88.42% for all analytes. Dose-dependence was shown for some constituents in the drug concentration-time profiles. Among all the active ingredients detected, cimifugin had the highest blood concentration (881-1510 ng/mL), and cycloastragenol had the longest retention time in the rat body (15.06-20.44 h). Conclusion: This analytical method is a selective, sensitive, precise, accurate, and reliable assay for simultaneous determination of cycloastragenol, calycosin, formononetin, GMV, and cimifugin in rat plasma.
Output: Development of an SPE-HPLC-MS method for simultaneous determination and pharmacokinetic study of bioactive constituents of Yu Ping Feng San in rat plasma after oral administration
Some pathogens utilize unique routes to enter cells that may evade the intracellular barriers encountered by the typical clathrin-mediated endocytic pathway. Retrograde transport and caveolar uptake are among the better characterized pathways, as alternatives to clathrin-mediated endocytosis, that are known to facilitate entry of pathogens and potential delivery agents. Recent characterization of the trafficking mechanisms of prion proteins and certain bacteria may present new paradigms for strategizing improvements in therapeutic spread and retention of therapy. This review will provide an overview of such endocytic pathways, and discuss current and future possibilities in using these routes as a means to improve therapeutic delivery. *
Output: "Alternative" Endocytic Mechanisms Exploited by Pathogens: New Avenues for Therapeutic Delivery?
Background. Middle East respiratory syndrome coronavirus (MERS-CoV) causes pneumonia with a relatively high case fatality rate in humans. Smokers and chronic obstructive pulmonary disease (COPD) patients have been reported to be more susceptible to MERS-CoV infection. Here, we determined the expression of MERS-CoV receptor, dipeptidyl peptidase IV (DPP4), in lung tissues of smokers without airflow limitation and COPD patients in comparison to nonsmoking individuals (never-smokers). Methods. DPP4 expression was measured in lung tissue of lung resection specimens of never-smokers, smokers without airflow limitation, COPD GOLD stage II patients and in lung explants of end-stage COPD patients. Both control subjects and COPD patients were well phenotyped and age-matched. The mRNA expression was determined using qRT-PCR and protein expression was quantified using immunohistochemistry. Results. In smokers and subjects with COPD, both DPP4 mRNA and protein expression were significantly higher compared to never-smokers. Additionally, we found that both DPP4 mRNA and protein expression were inversely correlated with lung function and diffusing capacity parameters. Conclusions. We provide evidence that DPP4 is upregulated in the lungs of smokers and COPD patients, which could partially explain why these individuals are more susceptible to MERS-CoV infection. These data also highlight a possible role of DPP4 in COPD pathogenesis. Keywords. Middle East respiratory syndrome coronavirus (MERS-CoV); dipeptidyl peptidase 4 (DPP4); smoking; chronic obstructive pulmonary disease (COPD).
Output: DPP4, the Middle East Respiratory Syndrome Coronavirus Receptor, is Upregulated in Lungs of Smokers and Chronic Obstructive Pulmonary Disease Patients
Diseases likely affect large carnivore demography and can hinder conservation efforts. We considered three highly contagious viruses that infect a wide range of domestic and wild mammals: canine parvovirus type 2 (CPV-2), canine distemper virus (CDV) and canine enteric coronaviruses (CECoV). Infection by either one of these viruses can affect populations through increased mortality and/or decreased general health. We investigated infection in the wolf populations of Abruzzo, Lazio e Molise National Park (PNALM), Italy, and of Mercantour National Park (PNM), France. Faecal samples were collected during one winter, from October to March, from four packs in PNALM (n=79) and from four packs in PNM (n=66). We screened samples for specific sequences of viral nucleic acids. To our knowledge, our study is the first documented report of CECoV infection in wolves outside Alaska, and of the large-scale occurrence of CPV-2 in European wolf populations. The results suggest that CPV-2 is enzootic in the population of PNALM, but not in PNM and that CECoV is episodic in both areas. We did not detect CDV. Our findings suggest that density and spatial distribution of susceptible hosts, in particular free-ranging dogs, can be important factors influencing infections in wolves. This comparative study is an important step in evaluating the nature of possible disease threats in the studied wolf populations. Recent emergence of new viral strains in Europe additionally strengthens the need for proactive monitoring of wolves and other susceptible sympatric species for viral threats and other impairing infections.
Output: Comparative survey of canine parvovirus, canine distemper virus and canine enteric coronavirus infection in free-ranging wolves of central Italy and south-eastern France
Recently, a novel verocytotoxin named VT2y was described which belongs to the STx family and is produced by Escherichia coli isolated from domestic poultry with swollen head syndrome (SHS). The VT2y toxin induced apoptosis in Vero, HeLa, CHO, CEF (primary chicken embryo fibroblast) and PCK (primary chicken kidney) cell lines. Morphological evidence (nuclear shrinkage, chromatin condensation and blebbing of the plasma membrane) of apoptosis could be distinguished in 15 min and was maximal at 1 h after treatment with VT2y. This was confirmed by the terminal dUTP nick-end-labeling (TUNEL) method. ß
Output: Morphological and intracellular alterations induced by cytotoxin VT2y produced by Escherichia coli isolated from chickens with swollen head syndrome
Topography-induced twisted wind flows are frequently observed in Hong Kong due to the abundance existence of mountains. Observed twisted wind profiles are with larger wind twist angles and are confined to the lower 500 m of the atmosphere, thus may impose significant effects on both structures and near-ground wind conditions. In order to investigate the influences of twisted wind flows on the pedestrian-level wind environment, two twisted wind profiles were simulated in a boundary layer wind tunnel by using 1.5 m tall wooden vanes. The maximum guide angles of vanes were 15°and 30°at the ground level to represent two nominal yaw angles of 'high' and 'extreme' twisted wind flows. Simulated twisted wind profiles followed the power-law profile and have acceptable longitudinal and lateral turbulence power spectra similar to conventional wind flows. The yaw angle profiles were exponentially decayed with the height but had smaller maximum yaw angles than of the guide vanes. The evaluation of wind conditions near an isolated building and a row of buildings in twisted wind flows has displayed substantially modified flow features such as asymmetric wind speed distributions about the building centre line and reduced wind speeds in the passages between buildings.
Output: Simulation of twisted wind flows in a boundary layer wind tunnel for pedestrian-level wind tunnel tests
Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) is a central mediator important for inducing type I interferon (IFN) production in response to intracellular double-stranded RNA (dsRNA). Here, we report the identification of Sec16A and p115, two proteins of the ER-to-Golgi vesicular transport system, as novel components of the TRAF3 interactome network. Notably, in non-infected cells, TRAF3 was found associated with markers of the ER-Exit-Sites (ERES), ER-to-Golgi intermediate compartment (ERGIC) and the cis-Golgi apparatus. Upon dsRNA and dsDNA sensing however, the Golgi apparatus fragmented into cytoplasmic punctated structures containing TRAF3 allowing its colocalization and interaction with Mitochondrial AntiViral Signaling (MAVS), the essential mitochondria-bound RIG-I-like Helicase (RLH) adaptor. In contrast, retention of TRAF3 at the ER-to-Golgi vesicular transport system blunted the ability of TRAF3 to interact with MAVS upon viral infection and consequently decreased type I IFN response. Moreover, depletion of Sec16A and p115 led to a drastic disorganization of the Golgi paralleled by the relocalization of TRAF3, which under these conditions was unable to associate with MAVS. Consequently, upon dsRNA and dsDNA sensing, ablation of Sec16A and p115 was found to inhibit IRF3 activation and anti-viral gene expression. Reciprocally, mild overexpression of Sec16A or p115 in Hec1B cells increased the activation of IFNb, ISG56 and NF-kB -dependent promoters following viral infection and ectopic expression of MAVS and Tank-binding kinase-1 (TBK1). In line with these results, TRAF3 was found enriched in immunocomplexes composed of p115, Sec16A and TBK1 upon infection. Hence, we propose a model where dsDNA and dsRNA sensing induces the formation of membrane-bound compartments originating from the Golgi, which mediate the dynamic association of TRAF3 with MAVS leading to an optimal induction of innate immune responses.
Output: Proteomic Profiling of the TRAF3 Interactome Network Reveals a New Role for the ER-to-Golgi Transport Compartments in Innate Immunity
Hemodialysis (HD) patients had a high rate of infection transmission and mortality during the middle east respiratory syndrome coronavirus (MERS-CoV) outbreak in Saudi Arabia. A standardized guideline on isolation technique for exposed HD patients is not available. Thus, this study aimed to evaluate the effect of different isolation strategies on the prevention of secondary viral transmission and clinical outcomes among exposed HD patients. During the 2015 MERS-CoV outbreak in Korea, 116 patients in 3 HD units were incidentally exposed to individuals with confirmed MERS-CoV infection and underwent different types of isolation, which were as follows: single-room isolation (n = 54, 47%), cohort isolation (n = 46, 40%), and self-imposed quarantine (n = 16, 13%). The primary outcome was rate of secondary viral transmission. The secondary outcome measures were changes in clinical and biochemical markers during the isolation period, difference in clinical and biochemical markers according to the types of isolation practice, and effect of isolation practice on patient survival. During a mean isolation period of 15 days, no further cases of secondary transmission were detected among HD patients. Plasma hemoglobin, serum calcium, and serum albumin levels and single-pool Kt/V decreased during the isolation period but normalized thereafter. Patients who were subjected to self-imposed quarantine had higher systolic and diastolic blood pressure, lower total cholesterol level, and lower Kt/V than those who underwent single-room or cohort isolation. During the 24-month follow-up period, 12 patients died. However, none of the deaths occurred during the isolation period, and no differences were observed in patient survival rate according to different isolation strategies. Although 116 participants in 3 HD units were incidentally exposed to MERS-CoV during the 2015 outbreak in Korea, strict patient surveillance and proper isolation practice prevented secondary transmission of the virus. Thus, a renal disaster protocol, which includes proper contact surveillance and isolation practice, must be established in the future to accommodate the needs of HD patients during disasters or outbreaks. Abbreviations: BP = blood pressure, ELISA = enzyme-linked immunosorbent assay, Hb = hemoglobin, HD = hemodialysis, IFA = immunofluorescence assay, MERS-CoV = middle east respiratory syndrome coronavirus, ppNT = pseudoparticle neutralization assay.
Output: Effect of isolation practice on the transmission of middle east respiratory syndrome coronavirus among hemodialysis patients A 2-year prospective cohort study
Simply by repetition, medical facts can become enshrined as truth even when there is little empirical evidence supporting them. We present an intuitive and clear visual design for tracking the citation history of a particular scientific fact over time. We apply this method to data from a previously published literature review on the incubation period of nine respiratory viral infections. The resulting citation networks reveal that the conventional wisdom about the incubation period for these diseases was based on a small fraction of available data and in one case, on no retrievable empirical evidence. Overall, 50% of all incubation period statements did not provide a source for their estimate and 65% of original sources for incubation period data were not incorporated into subsequent publications. More standardized and widely available methods for visualizing these histories of medical evidence are needed to ensure that conventional wisdom cannot stray too far from empirically supported knowledge.
Output: Visualizing Clinical Evidence: Citation Networks for the Incubation Periods of Respiratory Viral Infections
Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus that was originally identified from human prostate cancer patients and subsequently linked to chronic fatigue syndrome. Recent studies showed that XMRV is a recombinant mouse retrovirus; hence, its association with human diseases has become questionable. Here, we demonstrated that XMRV envelope (Env)-mediated pseudoviral infection is not blocked by lysosomotropic agents and cellular protease inhibitors, suggesting that XMRV entry is not pH-dependent. The full length XMRV Env was unable to induce syncytia formation and cell-cell fusion, even in cells overexpressing the viral receptor, XPR1. However, truncation of the C-terminal 21 or 33 amino acid residues in the cytoplasmic tail (CT) of XMRV Env induced substantial membrane fusion, not only in the permissive 293 cells but also in the nonpermissive CHO cells that lack a functional XPR1 receptor. The increased fusion activities of these truncations correlated with their enhanced SU shedding into culture media, suggesting conformational changes in the ectodomain of XMRV Env. Noticeably, further truncation of the CT of XMRV Env proximal to the membrane-spanning domain severely impaired the Env fusogenicity, as well as dramatically decreased the Env incorporations into MoMLV oncoretroviral and HIV-1 lentiviral vectors resulting in greatly reduced viral transductions. Collectively, our studies reveal that XMRV entry does not require a low pH or low pH-dependent host proteases, and that the cytoplasmic tail of XMRV Env critically modulates membrane fusion and cell entry. Our data also imply that additional cellular factors besides XPR1 are likely to be involved in XMRV entry. Citation: Cô té M, Zheng Y-M, Liu S-L (2012) Membrane Fusion and Cell Entry of XMRV Are pH-Independent and Modulated by the Envelope Glycoprotein's Cytoplasmic Tail. PLoS ONE 7(3): e33734.
Output: Membrane Fusion and Cell Entry of XMRV Are pH- Independent and Modulated by the Envelope Glycoprotein's Cytoplasmic Tail
Background: Concerns have been raised regarding the safety of Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) in patients with COVID-19, based on the hypothesis that such medications may raise expression of ACE2, the receptor for SARS-CoV-2. We conducted a literature review of studies (n=12) in experimental animals and human subjects (n=11) and evaluated the evidence regarding the impact of administration of ACEIs and ARBs on ACE2 expression. We prioritized studies that assessed ACE2 protein expression data, measured directly or inferred from ACE2 activity assays. The findings in animals are inconsistent with respect to an increase in ACE2 expression in response to treatment with ACEIs or ARBs. Control/sham animals show little to no effect in the plurality of studies. Those studies that report increases in ACE2 expression tend to involve acute injury models and/or higher doses than typically administered to patients. Data from human studies overwhelmingly imply that administration of ACEIs/ARBs does not increase ACE2 expression. Conclusion: Available evidence, in particular, data from human studies, does not support the hypothesis that ACEI/ARB use increases ACE2 expression and the risk of complications from COVID-19. We conclude that patients being treated with ACEIs and ARBs should continue their use for approved indications.
Output: Dangers of ACE inhibitor and ARB usage in COVID-19: evaluating the evidence
M36 is the first member of a novel class of potent HIV-1 entry inhibitors based on human engineered antibody domains (eAds). It exhibits broad inhibitory activity suggesting that its CD4-induced epitope is highly conserved. Here, we describe fine mapping of its epitope by using several approaches. First, a panel of mimotopes was affinity-selected from a random peptide library and potential m36-binding residues were computationally predicted. Second, homology modeling of m36 and molecular docking of m36 onto gp120 revealed potentially important residues in gp120-m36 interactions. Third, the predicted contact residues were verified by site-directed mutagenesis. Taken together, m36 epitope comprising three discontinuous sites including six key gp120 residues (Site C1: Thr123 and Pro124; Site C3: Glu370 and Ile371; Site C4: Met426 and Trp427) were identified. In the 3D structure of gp120, the sites C1 and C4 are located in the bridging sheet and the site C3 is within the b15-a3 excursion, which play essential roles for the receptor-and coreceptor-binding and are major targets of neutralizing antibodies. Based on these results we propose a precise localization of the m36 epitope and suggest a mechanism of its broad inhibitory activity which could help in the development of novel HIV-1 therapeutics based on eAds.
Output: Epitope Mapping of M36, a Human Antibody Domain with Potent and Broad HIV-1 Inhibitory Activity
A review of some methods for analysis of space-time disease surveillance data is presented. Increasingly, surveillance systems are capturing spatial and temporal data on disease and health outcomes in a variety of public health contexts. A vast and growing suite of methods exists for detection of outbreaks and trends in surveillance data and the selection of appropriate methods in a given surveillance context is not always clear. While most reviews of methods focus on algorithm performance, in practice, a variety of factors determine what methods are appropriate for surveillance. In this review, we focus on the role of contextual factors such as scale, scope, surveillance objective, disease characteristics, and technical issues in relation to commonly used approaches to surveillance. Methods are classified as testing-based or model-based approaches. Reviewing methods in the context of factors other than algorithm performance highlights important aspects of implementing and selecting appropriate disease surveillance methods.
Output: Review of methods for space-time disease surveillance