niryuu/sni-each-converted huggingface dataset:
The non-structural proteins (nsp or replicase proteins) of coronaviruses are relatively conserved and can be effective targets for drugs. Few studies have been conducted into the function of the severe acute respiratory syndrome coronavirus (SARS-CoV) nsp5. In this study, bioinformatics methods were employed to predict the secondary structure and construct 3-D models of the SARS-CoV GD strain nsp5. Sequencing and sequential comparison was performed to analyze the mutation trend of the polymerase nsp5 gene during the epidemic process using a nucleotide-nucleotide basic local alignment search tool (BLASTN) and a protein-protein basic local alignment search tool (BLASTP). The results indicated that the nsp5 gene was steady during the epidemic process and the protein was homologous with other coronavirus nsp5 proteins. The protein encoded by the nsp5 gene was expressed in COS-7 cells and analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This study provided the foundation for further exploration of the protein's biological function, and contributed to the search for anti-SARS-CoV drugs.
Output: Sequence Analysis and Structural Prediction of the Severe Acute Respiratory Syndrome Coronavirus nsp5
During the 2015 Korean MERS outbreak, we experienced atypical presentations of MERS-CoV infections in three immunocompromised hosts that warranted exceptional management. Case 1 showed delayed symptom development after a four-day asymptomatic period, Case 2 experienced a 20-day incubation period, and Case 3 exhibited persistent viral shedding without clinical deterioration. Recognizing these exceptions is extremely important in the management of MERS-CoV-exposed or -infected patients and for control of potential MERS outbreaks.
Output: Atypical presentations of MERS-CoV infection in immunocompromised hosts
Mythimna separata is a major agricultural pest with seasonal migrating trait in China. Formation and regulation mechanism of migration behavior has resulted in a large number of fundamental researches involving quantitative studies of gene expression in this species. Using appropriate reference gene is critical in RT-qPCR data normalization. A comprehensive study on the reference genes in M. separata is lacking. In this paper, expression stabilities of ten candidate reference genes were evaluated in M. separata under various biotic and abiotic conditions by employing four different software geNorm, NormFinder, BestKeeper, and the comparative ΔCT method. The comprehensive stabilities ranking of these genes were suggested by RefFinder. PKG as a target gene was employed to justify the number of reference genes in four larval tissues and two photoperiod treatments. Results demonstrate that the first three most stable genes were as follows: EF, CypA, and -TUB for developmental stages; EF, CypA, and RPL12 for larval tissues; EF, TBP, and -TUB for adult tissues. RPL12, -TUB, and EF for densities; EF, RPL12, and GAPDH for photoperiod treatments; -TUB, EF, and ATPase for temperature treatments. Stable reference gene combinations may reduce bias in normalization. This work provides for the first time a comprehensive list of appropriate reference genes and facilitates future studies on gene function of M. separata.
Output: Identification and Validation of Reference Genes for RT-qPCR Normalization in Mythimna separata (Lepidoptera: Noctuidae)
Object-induced three-way object concept Attribute-induced three-way attribute concept Discernibility attribute set a b s t r a c t Three-way concept analysis is a newly proposed area of formal concept analysis from which one can obtain both the inclusion decision and the exclusion decision. In general, given a context, some attributes may not be essential in three-way concept analysis, such as forming three-way concept lattice. So in this paper, we study the attribute reductions of three-way concept lattices in order to make the data easily be understood. Firstly, based on different criteria generated from object-induced three-way concept (OEconcept), four kinds of attribute reductions are proposed. The four reductions together embody different characteristics of a formal context and can be used in different occasions. Secondly, we discuss their relationships, including their advantages and disadvantages and the relationships among consistent sets and among the cores. Thirdly, based on attribute-induced three-way concept (AE-concept), we also give four attribute-induced three-way attribute reductions and discuss their relationships. Finally, the approaches to computing these attribute reductions are presented and the obtained results are demonstrated and verified by an empirical case. In this paper, we systematically investigate the attribute reductions of threeway concept lattices which enriches the study of formal concept analysis.
Output: Knowle dge-Base d Systems The attribute reductions of three-way concept lattices
Background Person-to-person transmission of respiratory pathogens, including Pseudomonas aeruginosa, is a challenge facing many cystic fibrosis (CF) centres. Viable P aeruginosa are contained in aerosols produced during coughing, raising the possibility of airborne transmission. Methods Using purpose-built equipment, we measured viable P aeruginosa in cough aerosols at 1, 2 and 4 m from the subject (distance) and after allowing aerosols to age for 5, 15 and 45 min in a slowly rotating drum to minimise gravitational settling and inertial impaction (duration). Aerosol particles were captured and sized employing an Anderson Impactor and cultured using conventional microbiology. Sputum was also cultured and lung function and respiratory muscle strength measured. Results Nineteen patients with CF, mean age 25.8 (SD 9.2) years, chronically infected with P aeruginosa, and 10 healthy controls, 26.5 (8.7) years, participated. Viable P aeruginosa were detected in cough aerosols from all patients with CF, but not from controls; travelling 4 m in 17/18 (94%) and persisting for 45 min in 14/18 (78%) of the CF group. Marked inter-subject heterogeneity of P aeruginosa aerosol colony counts was seen and correlated strongly (r=0.73-0.90) with sputum bacterial loads. Modelling decay of viable P aeruginosa in a clinic room suggested that at the recommended ventilation rate of two air changes per hour almost 50 min were required for 90% to be removed after an infected patient left the room. Conclusions Viable P aeruginosa in cough aerosols travel further and last longer than recognised previously, providing additional evidence of airborne transmission between patients with CF.
Output: Viability of Pseudomonas aeruginosa in cough aerosols generated by persons with cystic fibrosis
Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children worldwide. In the Middle East and Arab countries, the burden of RSV-associated hospitalizations is not well characterized. We sought to determine the burden and clinical/epidemiological characteristics of RSV hospitalization in young children in Amman, Jordan. We investigated risk factors for severity including vitamin D levels. Methods: We conducted viral surveillance with clinical and demographic data in children <2 years admitted with respiratory symptoms and/or fever at the Al-Bashir Government Hospital from March16, 2010 to March 31, 2013. Nasal/throat swabs were obtained and placed into lysis buffer, and frozen at −80 • C until testing by real-time RT-PCR for 11 respiratory viruses. Heel stick blood or sera samples for 25hydroxyvitamin D [25(OH)D] levels were obtained and sent to a central laboratory for mass spectrometry. Results: Of the 3168 children, >80% testing positive for one virus, with RSV the most common virus detected (44%). The RSV-associated hospitalization rate was highest in children <6 months with an annual range of 21.1-25.9 per 1000, compared to 6.0-8.0 in 6-11-month-olds and 1.6-2.5 in 12-23-month-olds. RSV-positive children compared with RSV-negative were more likely to be previously healthy without underlying medical conditions, less likely to be born prematurely, had a higher frequency of supplemental oxygen use, and had lower median vitamin D levels. Risk factors for oxygen use in RSV-positive children included underlying medical conditions, lack of breastfeeding, younger age, and higher viral load. Conclusion: RSV is a major cause of illness in hospitalized Jordanian children and is associated with increased severity compared to other respiratory viruses. Children with RSV in the Middle East would benefit from future RSV vaccines and antiviral therapy.
Output: Natural history and epidemiology of respiratory syncytial virus infection in the Middle East: Hospital surveillance for children under age two in Jordan
The Mekong Basin Disease Surveillance (MBDS) network was formally established in 2001 through a Memorandum of Understanding signed by six Ministers of Health of the countries in the Greater Mekong sub-region: Cambodia, China (Yunnan and Guangxi), Lao PDR, Myanmar, Thailand and Vietnam. The main areas of focus of the network are to: i) improve cross-border infectious disease outbreak investigation and response by sharing surveillance data and best practices in disease recognition and reporting, and by jointly responding to outbreaks; ii) develop expertise in epidemiological surveillance across the countries; and iii) enhance communication between the countries. Comprised of senior health officials, epidemiologists, health practitioners, and other professionals, the MBDS has grown and matured over the years into an entity based on mutual trust that can be sustained into the future. Other regions have started emulating the network's pioneering work. In this paper, we describe the development of MBDS, the way in which it operates today, and some of its achievements. We present key challenges the network has faced and lessons its members have learned about how to develop sufficient trust for health and other professionals to alert each other to disease threats across national borders and thereby more effectively combat these threats.
Output: Mekong Basin Disease Surveillance (MBDS): A Trust-Based Network
In this study, a pathogenic avian infectious bronchitis virus (IBV) QX-type strain YN was successfully rescued by vaccinia virus based reverse genetic technology. Ten fragments contiguously spanning the complete IBV genome were amplified and cloned into the vaccinia virus genome by homologous recombination. The full-length genomic cDNA was transcribed in vitro, and its transcript was transfected into BHK-21/N cells that could stably express IBV N protein. At 48 h post transfection, the culture medium was harvested and inoculated into 10-dayold specific-pathogen-free embryonated chicken eggs to replicate the rescued virus. This strategy was chosen to facilitate the rescue procedure and to ensure that the recombinant rYN virus will not require any cell culture adaptations. After only one in ovo passage, the recombinant YN virus (rYN) was successfully recovered and confirmed to possess the introduced silent marker mutation in its genome. Biological characteristics of rYN such as the EID 50 , TCID 50 , replication in ovo, and replication kinetcs in vitro were tested and all were similar to its parental strain YN. Our findings demonstrate the successful construction of highly-pathogenic QX-type IBV using a modified rescue procedure, allowing for future studies of the molecular biology and pathogenicity of IBV field strains.
Output: Successful establishment of a reverse genetic system for QX-type infectious bronchitis virus and technical improvement of the rescue procedure
Virus-like particles (VLPs) are formed by the self-assembly of envelope and/or capsid proteins from many viruses. In many cases such VLPs have structural characteristics and antigenicity similar to the parental virus, and some have already proven successful as vaccines against the cognate virus infection. The structural components of some VLPs have also proven amenable to the insertion or fusion of foreign antigenic sequences, allowing the production of chimeric VLPs exposing the foreign antigen on their surface. Other VLPs have been used as carriers for foreign antigens, including non-protein antigens, via chemical conjugation. This review outlines some of the advantages, disadvantages, and technical considerations for the use of a wide range of VLP systems in vaccine development.
Output: Virus-like particles: Passport to immune recognition
Under the U.S. Environmental Protection Agency's mission to protect human health and the environment, the agency seeks to conduct research on the structure and function of ecosystems and to improve our understanding of the processes that contribute to the sustained health of the nation's ecosystems and the well-being of human populations. Changes in biodiversity can profoundly impact the ability of ecosystems to provide clean water, energy, food, recreation, and other services that contribute to human well-being. In addition, changes in biodiversity can affect the transmission of infectious disease to humans, particularly vectorborne diseases such as malaria and Lyme disease. The Environmental Protection Agency's new initiative supports interdisciplinary research to characterize the mechanisms that link biodiversity and human health and to use this knowledge to develop integrative tools and approaches for quantifying and predicting these relationships. Research on these links can have an important impact on our view of biodiversity and how we manage resources to protect human and ecosystem health.
Output: Environmental Protection Agency
Cryptococcus gattii is a pathogenic environmental yeast that is considered to be emerging in different areas of the world including the Mediterranean Basin. Exposure to infection might be more likely in animals than in human beings, given their closer relationship with the natural habitat of the yeast, vegetation and soil. Thus, animals, and especially pets, can act as indicators of the presence of this yeast in a determined area. Domestic ferrets (Mustela putorius furo) have become common pets in the past 10-20 years. Their natural behavior of sniffing around and going inside narrow spaces makes them prone to contact with decaying organic matter and soil, the substrate for Cryptococcus species. This study describes two cases of cryptococcosis in ferrets in the Iberian Peninsula and Balearic Islands and documents a relationship of ferret cryptococcosis with environmental isolates in the same locations. Here, we emphasize the importance of how an adequate identification and environmental search of the yeast leads to a better understanding of the epidemiology of cryptococcosis and suggests ferrets may act as sentinels for this fungal disease.
Output: Ferrets as Sentinels of the Presence of Pathogenic Cryptococcus Species in the Mediterranean Environment
A one year active surveillance program for influenza A viruses among avian species in a live-bird market (LBM) in Bangkok, Thailand was conducted in 2009. Out of 970 samples collected, influenza A virus subtypes H4N6 (n = 2) and H4N9 (n = 1) were isolated from healthy Muscovy ducks. All three viruses were characterized by whole genome sequencing with subsequent phylogenetic analysis and genetic comparison. Phylogenetic analysis of all eight viral genes showed that the viruses clustered in the Eurasian lineage of influenza A viruses. Genetic analysis showed that H4N6 and H4N9 viruses display low pathogenic avian influenza characteristics. The HA cleavage site and receptor binding sites were conserved and resembled to LPAI viruses. This study is the first to report isolation of H4N6 and H4N9 viruses from birds in LBM in Thailand and shows the genetic diversity of the viruses circulating in the LBM. In addition, co-infection of H4N6 and H4N9 in the same Muscovy duck was observed.
Output: Genetic characterization of avian influenza subtype H4N6 and H4N9 from live bird market, Thailand
In this paper, we have proposed a two-phase procedure (combining discrete graphs and wavelets) for constructing true epidemic growth. In the first phase, a graph-theory-based approach was developed to update partial data available and in the second phase, we used this partial data to generate plausible complete data through wavelets. We have provided two numerical examples. This procedure is novel and implementable and adaptable to machine learning modeling framework. (P. Polyakov), arrao@augusta.edu (A.S.R.S. Rao). 1 Order of the authors listed is based on the alphabetical order of the last names. Here μ (infection related death rate), ν (immunization coefficient = m / n ), λ (infectivity coefficient = n / μ) and m = ν/μ are all
Output: True epidemic growth construction through harmonic analysis
Transmission between hosts is a critical part of the viral lifecycle. Recent studies of viral transmission have used genome sequence data to evaluate the number of particles transmitted between hosts, and the role of selection as it operates during the transmission process. However, the interpretation of sequence data describing transmission events is a challenging task. We here present a novel and comprehensive framework for using shortread sequence data to understand viral transmission events, designed for influenza virus, but adaptable to other viral species. Our approach solves multiple shortcomings of previous methods for this purpose; for example, we consider transmission as an event involving whole viruses, rather than sets of independent alleles. We demonstrate how selection during transmission and noisy sequence data may each affect naive inferences of the population bottleneck, accounting for these in our framework so as to achieve a correct inference. We identify circumstances in which selection for increased viral transmission may or may not be identified from data. Applying our method to experimental data in which transmission occurs in the presence of strong selection, we show that our framework grants a more quantitative insight into transmission events than previous approaches, inferring the bottleneck in a manner that accounts for selection, both for within-host virulence, and for inherent viral transmissibility. Our work provides new opportunities for studying transmission processes in influenza, and by extension, in other infectious diseases.
Output: A novel framework for inferring parameters of transmission from viral sequence data
Hepatitis C affects about 3% of the world population, yet its current treatment options are limited to interferon-ribavirin drug regimens which achieve a 50-70% cure rate depending on the hepatitis C virus (HCV) genotype. Besides extensive screening for HCV-specific compounds, some wellestablished medicinal drugs have recently demonstrated anti-HCV effect in HCV replicon cells. One of these drugs is arbidol (ARB), a Russian-made broad spectrum antiviral agent, which we have previously shown to inhibit acute and chronic HCV infection. Here we show that ARB inhibits the cell entry of HCV pseudoparticles of genotypes 1a, 1b and 2a in a dose-dependent fashion. ARB also displayed a dose-dependent inhibition of HCV membrane fusion, as assayed by using HCV pseudoparticles (HCVpp) and fluorescent liposomes. ARB inhibition of HCVpp fusion was found more effective on genotype 1a than on genotypes 1b and 2a. In vitro biochemical studies revealed ARB association with membrane-like environments such as detergents, and with lipid membranes. This association was particularly prominent at acidic pH which is optimal for HCV-mediated fusion. Our results suggest that the affinity of ARB for lipid membranes could account for its anti-HCV actions, together with a differential level of interaction with key motifs in HCV glycoproteins of different genotypes. The hepatitis C virus (HCV) infects an estimated 3% or 170 million of the world's population, and hepatitis C is now the most frequent indication for liver transplantation. Current treatment options are limited to pegylated recombinant interferon alpha (IFN-α) in combination with ribavirin. However viremia eradication is variably achieved depending on the genotype, with only 50% of virus eradication in genotype 1-infected patients. This is clearly a problem in North America, Europe and Japan, where genotype 1 is the most prevalent genotype. HCV † This work was supported by the ANRS (Agence Nationale de Recherches sur le SIDA et les hepatites virales) to E.I.P.
Output: Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol † NIH Public Access Author Manuscript
Zika virus (ZIKV) has become a global public health emergency due to its rapidly expanding range and its ability to cause severe congenital defects such as microcephaly. However, there are no FDA-approved therapies or vaccines against ZIKV infection. Through our screening of viral entry inhibitors, we found that chloroquine (CQ), a commonly used antimalarial and a FDA-approved drug that has also been repurposed against other pathogens, could significantly inhibit ZIKV infection in vitro, by blocking virus internalization. We also demonstrated that CQ attenuates ZIKV-associated morbidity and mortality in mice. Finally, we proved that CQ protects fetal mice from microcephaly caused by ZIKV infection. Our methodology of focusing on previously identified antivirals in screens for effectiveness against ZIKV proved to be a rapid and efficient means of discovering new ZIKV therapeutics. Selecting drugs that were previously FDA-approved, such as CQ, also improves the likelihood that they may more quickly reach stages of clinical testing and use by the public.
Output: Chloroquine, a FDA-approved Drug, Prevents Zika Virus Infection and its Associated Congenital Microcephaly in Mice-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/)
Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.
Output: Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures
The cattle industry is one of the most important Brazilian agribusiness sectors and is a strong contributor to the national economy. Annually about 44.6 million calves are bred, which makes the optimal management of these animals extremely important. Several diseases can affect the initial stages of the bovine production chain, being the bovine respiratory syncytial virus (BRSV) one of the most relevant pathogens. This study aimed to characterize the epidemiology of BRSV infection in dairy cattle herds of São Paulo State, Brazil, using serological and risk factors analyses. For that, 1243 blood samples were collected of animals from 26 farms and a questionnaire about possible risk factors for BRSV prevalence was performed. The obtained blood sera were analyzed using virus neutralization test (VNT). Results: VNT results showed high BRSV prevalence in dairy cattle herds, reaching 79.5% of seropositivity. The BRSV seroprevalence among studied farms ranged from 40 to 100%. The analysis of risk factors indicated that the age group and the occurrence of coinfection with bovine herpesvirus 1 (BoHV-1) and bovine viral diarrhea virus 1 (BVDV-1) should be associated with a higher prevalence of BRSV, while natural suckling was considered a protective factor. The study showed that adult animals over 1 year old are an important risk factor for the high seroprevalence of BRSV in herds. The high BRSV prevalence associated with BoHV-1 and BVDV-1 suggests that biosecurity measures should be applied in order to reduce viral dissemination. Additionally, the natural suckling may be an important management to protect calves from high BRSV seroprevalence.
Output: Bovine respiratory syncytial virus seroprevalence and risk factors in non- vaccinated dairy cattle herds in Brazil
Background: Home health emergency management plans are essential and must address infection prevention issues. Few home health planning documents exist, and many of those that have been developed do not address infection prevention issues, combine them with non-infection prevention issues, or are disease/event-specific. An all-encompassing home health infection prevention emergency management planning guide is needed. Methods: A literature review and Internet search were conducted in the summer of 2010, and data from relevant sources were extracted. A spreadsheet was created delineating home health emergency management plan components related to infection prevention. Results: Of the sources screened, 41 were deemed relevant. Ten domains were identified: (1) having a plan; (2) assessing agency readiness; (3) having infection prevention policies and procedures; (4) having occupational health policies and procedures; (5) conducting surveillance and triage; (6) reporting incidents, having a communication plan, and managing information; (7) addressing surge capacity issues; (8) having anti-infective therapy and/or vaccines; (9) providing infection prevention education; and (10) managing water and waste management issues. Conclusion: Home health disaster planners or managers should use this article as an assessment tool for evaluating their agency's emergency management plan and for developing policies and procedures that will decrease the risk of infection transmission during a mass casualty event. A home health emergency management plan is an essential component of home health agency preparedness for mass casualty events (MCEs). This plan needs to address all potential hazards, including such biological threats as bioterrorism, emerging infectious disease outbreaks, and pandemics. Studies examining home health disaster preparedness have found that the vast majority of home health agencies have a written disaster plan that covers natural disasters 1-3 ; however, studies assessing the existence of a plan that addresses biological events have reported either conflicting findings or reflect new developments in home health preparedness. 4 For example, a 2008 study of
Output: Assessing the infection prevention components of home health emergency management plans
Although preventable by vaccination, Measles still causes thousands of deaths among young children worldwide. The discovery of new antivirals is a good approach to control new outbreaks that cause such death. In this study, we tested the antiviral activity against Measles virus (MeV) of Polyphenol-rich extracts (PPs) coming from five seaweeds collected and cultivated in Mexico. An MTT assay was performed to determine cytotoxicity effect, and antiviral activity was measured by syncytia reduction assay and confirmed by qPCR. PPs from Ecklonia arborea (formerly Eisenia arborea, Phaeophyceae) and Solieria filiformis (Rhodophyta) showed the highest Selectivity Index (SI), >3750 and >576.9 respectively. Both PPs extracts were selected to the subsequent experiments owing to their high efficacy and low cytotoxicity compared with ribavirin (SI of 11.57). The combinational effect of PPs with sulphated polysaccharides (SPs) and ribavirin were calculated by using Compusyn software. Synergistic activity was observed by combining both PPs with low concentrations of Solieria filiformis SPs (0.01 µg/mL). The antiviral activity of the best combinations was confirmed by qPCR. Virucidal assay, time of addition, and viral penetration evaluations suggested that PPs act mainly by inactivating the viral particle. To our knowledge, this is the first report of the virucidal effect of Polyphenol-rich extracts of seaweeds.
Output: Virucidal and Synergistic Activity of Polyphenol-Rich Extracts of Seaweeds against Measles Virus
The success of lentiviral vectors in curing fatal genetic and acquired diseases has opened a new era in human gene therapy. However, variability in the efficacy and safety of this therapeutic approach has been reported in human patients. Consequently, lentiviral-vector-based gene therapy is limited to incurable human diseases, with little understanding of the underlying causes of adverse effects and poor efficacy. To assess the role that host genetic variation has on efficacy of gene therapy, we characterized lentiviral-vector gene therapy within a set of 12 collaborative cross mouse strains. Lentiviral vectors carrying the firefly luciferase cDNA under the control of a liver-specific promoter were administered to female mice, with total-body and hepatic luciferase expression periodically monitored through 41 weeks post-vector administration. Vector copy number per diploid genome in mouse liver and spleen was determined at the end of this study. We identified major strain-specific contributions to overall success of transduction, vector biodistribution, maximum luciferase expression, and the kinetics of luciferase expression throughout the study. Our results highlight the importance of genetic variation on gene-therapeutic efficacy; provide new models with which to more rigorously assess gene therapy approaches; and suggest that redesigning preclinical studies of gene-therapy methodologies might be appropriate.
Output: Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery
Traditionally, most of the proposed probabilistic models of decision under uncertainty rely on numerical measures and representations. Alternative proposals call for qualitative (non-numerical) treatment of uncertainty, based on preference relations and belief orders. The automation of both numerical and non-numerical frameworks surely represents a preliminary step in the development of inference engines of intelligent agents, expert systems, and decision-support tools. In this paper we exploit Answer Set Programming to formalize and reason about uncertainty expressed as belief orders. The availability of ASP-solvers supports the design of automated tools to handle such formalizations. Our proposal reveals particularly suitable whenever the domain of discernment is partial. We first illustrate how to automatically "classify ^^, according to the most well-known uncertainty frameworks, any given qualitative uncertainty assessment. Then, we show how to compute an enlargement of the assessment, to any other new inference target.
Output: Management of uncertainty orderings through ASP
Background. Community-acquired pneumonia (CAP) in young children is most commonly associated with viral infections; however, the role of viruses in CAP of school-age children is still inconclusive. Methods. Seventy-five school-age children hospitalized with CAP were prospectively evaluated for the presence of viral and bacterial pathogens. Nasopharyngeal washes were examined by polymerase chain reaction for viruses and atypical bacteria. Antibody assays to detect bacterial pathogens in acute-phase and convalescent-phase serum samples were also performed. Results. A viral infection was identified in 65% of cases. Rhinovirus RNA was detected in 45% of patients; infection with another virus occurred in 31%. The most common bacterial pathogen was Mycoplasma pneumoniae, which was diagnosed in 35% of cases. Chlamydia pneumoniae DNA was not detected in any patient; results of serological tests were positive in only 2 patients (3%). Mixed infections were documented in 35% of patients, and the majority were a viral-bacterial combination. Conclusions. The high prevalence of viral and mixed viral-bacterial infections supports the notion that the presence of a virus, acting either as a direct or an indirect pathogen, may be the rule rather than the exception in the development of CAP in school-age children requiring hospitalization. Community-acquired pneumonia (CAP) is a serious cause of morbidity among children in developed countries and has a considerable effect on the health care system. In the developing world, the incidence of pneumonia is higher, and this infection is one of the primary causes of death among young children [1] . Detailed information on the etiology of CAP is required for the formulation of treatment recommendations and the introduction of preventive measures. Evaluation of mixed infections and the relative importance of each potential pathogen may also contribute to improved understanding of the etiopathogenesis of
Output: Etiology of Community-Acquired Pneumonia in Hospitalized School-Age Children: Evidence for High Prevalence of Viral Infections
The unmet need for effective antivirals against potential agents of bioterrorism and emerging infections is obvious; however, the challenges to developing such drugs are daunting. Even with the passage of Project BioShield and more recently the BARDA legislation, there is still not a clear market for these types of drugs and limited federal funding available to support expensive drug development studies. SIGA Technologies, Inc. is a small biotech company committed to developing novel products for the prevention and treatment of severe infectious diseases, with an emphasis on products for diseases that could result from bioterrorism. Through trials and error SIGA has developed an approach to this problem in order to establish the infrastructure necessary to successfully advance new antiviral drugs from the discovery stage on through to licensure. The approach that we have taken to drug development is biology driven and dependent on a dispersive development model utilizing essential collaborations with academic, federal, and private sector partners. This consortium approach requires success in acquiring grants and contracts as well as iterative communication with the government and regulatory agencies. However, it can work as evidenced by the rapid progress of our lead antiviral against smallpox, ST-246, and should serve as the template for development of new antivirals against important biological pathogens.
Output: Discovery and Development of Antiviral Drugs for Biodefense: Experience of a Small Biotechnology Company
Severe acute respiratory syndrome (SARS) is caused by the SARS coronavirus (CoV). The spike protein of SARS-CoV consists of S1 and S2 domains, which are responsible for virus binding and fusion, respectively. The receptor-binding domain (RBD) positioned in S1 can specifically bind to angiotensin-converting enzyme 2 (ACE2) on target cells, and ACE2 regulates the balance between vasoconstrictors and vasodilators within the heart and kidneys. Here, a recombinant fusion protein containing 193-amino acid RBD (residues 318-510) and glutathione S-transferase were prepared for binding to target cells. Additionally, monoclonal RBD antibodies were prepared to confirm RBD binding to target cells through ACE2. We first confirmed that ACE2 was expressed in various mouse cells such as heart, lungs, spleen, liver, intestine, and kidneys using a commercial ACE2 polyclonal antibody. We also confirmed that the mouse fibroblast (NIH3T3) and human embryonic kidney cell lines (HEK293) expressed ACE2. We finally demonstrated that recombinant RBD bound to ACE2 on these cells using a cellular enzymelinked immunosorbent assay and immunoassay. These results can be applied for future research to treat ACE2related diseases and SARS.
Output: Functional analysis of the receptor binding domain of SARS coronavirus S1 region and its monoclonal antibody
Lectins are proteins with a high degree of stereospecificity to recognize various sugar structures and form reversible linkages upon interaction with glyco-conjugate complexes. These are abundantly found in plants, animals and many other species and are known to agglutinate various blood groups of erythrocytes. Further, due to the unique carbohydrate recognition property, lectins have been extensively used in many biological functions that make use of protein-carbohydrate recognition like detection, isolation and characterization of glycoconjugates, histochemistry of cells and tissues, tumor cell recognition and many more. In this review, we have summarized the immunomodulatory effects of plant lectins and their effects against diseases, including antimicrobial action. We found that many plant lectins mediate its microbicidal activity by triggering host immune responses that result in the release of several cytokines followed by activation of effector mechanism. Moreover, certain lectins also enhance the phagocytic activity of macrophages during microbial infections. Lectins along with heat killed microbes can act as vaccine to provide long term protection from deadly microbes. Hence, lectin based therapy can be used as a better substitute to fight microbial diseases efficiently in future.
Output: Structure-function and application of plant lectins in disease biology and immunity
Introduction Significant teratogenic effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin is prescribed for chronic hepatitis C and is contraindicated in women who are pregnant and in the male sexual partners of women who are pregnant. Both sexes are advised to avoid pregnancy for 6 months after exposure. The Ribavirin Pregnancy Registry was established in 2003 to monitor pregnancy exposures to ribavirin for signals of possible human teratogenicity. Methods This voluntary registry enrolls pregnant women with prenatal exposure to ribavirin. Exposure is classified as direct-women taking ribavirin during pregnancy or the 6 months prior to conception-or indirect-women exposed through sexual contact, 6 months prior to or during pregnancy, with a man who is taking or has taken ribavirin in the past 6 months. Women are followed until delivery and infants for 1 year. When enrollment is complete, birth defect rates will be compared with the Metropolitan Atlanta Congenital Defects Program's
Output: The Ribavirin Pregnancy Registry: An Interim Analysis of Potential Teratogenicity at the Mid-Point of Enrollment
A novel series of (3-diethoxyphosphoryl)isoxazolidines substituted at C5 with various quinazolinones have been synthesized by the 1,3-dipolar cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N3-substitued 2-vinyl-3H-quinazolin-4-ones. All isoxazolidines were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-11f/cis-11f (90:10), trans-11h and trans-11i/cis-11i (97:3) showed weak activity (EC 50 = 6.84, 15.29 and 9.44 µM) toward VZV (TK + strain) which was only one order of magnitude lower than that of acyclovir used as a reference drug. Phosphonates trans-11b/cis-11b (90:10), trans-11c, trans-11e/cis-11e (90:10) and trans-11g appeared slightly active toward cytomegalovirus (EC 50 = 27-45 µM). Compounds containing benzyl substituents at N3 in the quinazolinone skeleton exhibited slight antiproliferative activity towards the tested immortalized cells with IC 50 in the 21-102 µM range.
Output: molecules New Isoxazolidine-Conjugates of Quinazolinones-Synthesis, Antiviral and Cytostatic Activity
Influenza virus infection has a significant impact on public health, since it is a major cause of morbidity and mortality. It is not well-known whether influenza virus infection affects cell death and human immunodeficiency virus (HIV)-1 replication in HIV-1-infected patients. Using a lymphoma cell line, Jurkat, we examined the in vitro effects of pandemic influenza A (H1N1) virus (pH1N1) infection on cell death and HIV-1 RNA production in infected cells. We found that pH1N1 infection increased apoptotic cell death through Fas and Bax-mediated pathways in HIV-1-infected Jurkat cells. Infection with pH1N1 virus could promote HIV-1 RNA production by activating host transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), nuclear factor of activated T-cells (NFAT) and activator protein 1 (AP-1) through mitogen-activated protein kinases (MAPK) pathways and T-cell antigen receptor (TCR)-related pathways. The replication of HIV-1 latent infection could be reactivated by pH1N1 infection through TCR and apoptotic pathways. These data indicate that HIV-1 replication can be activated by pH1N1 virus in HIV-1-infected cells resulting in induction of cell death through apoptotic pathways.
Output: Pandemic Influenza A (H1N1) Virus Infection Increases Apoptosis and HIV-1 Replication in HIV-1 Infected Jurkat Cells
The endoplasmic reticulum (ER) is an architecturally diverse organelle that serves as a membrane source for the replication of multiple viruses. Flaviviruses, including yellow fever virus, West Nile virus, dengue virus, and Zika virus, induce unique single-membrane ER invaginations that house the viral replication machinery 1 . Whether this virus-induced ER remodeling is vulnerable to antiviral pathways is unknown. Here, we show that flavivirus replication at the ER is targeted by the interferon (IFN) response. Through genome-scale CRISPR screening, we uncovered an antiviral mechanism mediated by a functional gene pairing between IFI6, an interferon-stimulated gene (ISG) cloned over 30 years ago 2 , and HSPA5, which encodes the ER-resident HSP70 chaperone BiP. We reveal that IFI6 is an ERlocalized integral membrane effector that is stabilized through interactions with BiP. Mechanistically, IFI6 prophylactically protects uninfected cells by preventing formation of virus-induced ER membrane invaginations. Notably, IFI6 has little effect on other mammalian RNA viruses, including the related Flaviviridae member hepatitis C virus, which replicates in double-membrane vesicles that protrude outward from the ER. These findings support a model in which the IFN response is armed with a membrane-targeted effector that discriminately blocks the establishment of virus-specific ER microenvironments required for replication. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Output: A CRISPR screen identifies IFI6 as an ER-resident interferon effector that blocks flavivirus replication HHS Public Access Author manuscript
We review the basic concepts of intervention analysis in the context of structural time series models and we apply this methodology to investigate the possible reduction in monthly crime rates reported from January 1984 up to and including December 2010 after Virginia abolished parole and reformed sentencing in January 1995. We find that the change in legislation has significantly reduced the burglary rates and to a lesser extent the murder rates in Virginia. The robustness of our results is investigated with an automatic detection of breaks procedure as well as with analyses of quarterly rather than monthly data.
Output: Intervention time series analysis of crime rates: The case of sentence reform in Virginia
Background: Porcine parvovirus (PPV) infection primarily causes reproductive failure of pregnant swine and results in host cell death. Boars, as an important disseminator, shed PPV to sows via semen. PPV infects and numerously replicates in boar testicle, which results in damage of swine testicle in vivo. Reactive oxygen species (ROS), a mediator of cell apoptosis, play a crucial role in the mitochondria apoptotic pathway. However, whether PPV infection induces ST cells apoptosis and ROS accumulation is still unclear. Methods: To determine the effects of PPV infection on the apoptosis, we detected morphological changes, DNA ladder, activities of caspases, and expression of PARP in PPV-infected ST cells. Moreover, aiming to investigate the effect of PPV infection on the mitochondrial apoptotic pathway and ROS accumulation, we detected the Δψm, apoptosis-related genes, and ROS. To investigate the role of ROS in the process of PPV-induced apoptosis, the ST cells were infected with PPV and treated with the ROS antioxidants. The ROS level was measured using Reactive Oxygen Species Assay Kit and the Δψm, expression level of Bcl-2, translocation of Bax, and redistribution of mitochondria cytochrome c were tested. In this study, we demonstrated that PPV infection could induce apoptosis that was characterized by morphological changes, DNA fragmentation and activation of caspases. Moreover, PPV infection suppressed Bcl-2 expression, enhanced Bax expression and translocation to mitochondria, decreased the mitochondrial transmembrane potential, and triggered the release of cytochrome c, which caused the subsequent activation of caspase-9 and caspase-3 and initiation of apoptosis. However, during the process of PPV-induced apoptosis, the protein levels of Fas and FasL were not affected. Further studies showed that PPV infection caused ROS accumulation. Inhibition of ROS could reduce mitochondrial transmembrane potential and could significantly block ST cells apoptosis via suppressing Bax translocation, cytochrome c and caspase-3 activation. Conclusions: All these results suggest that PPV-induced ROS accumulation mediates apoptosis in ST cells, which provided theoretical basis for the molecular pathogenesis of PPV infection.
Output: Porcine parvovirus infection activates mitochondria-mediated apoptotic signaling pathway by inducing ROS accumulation
Coronavirus disease broke out in Wuhan, Hubei province, China, in December 2019 and soon after Chinese health authorities took unprecedented prevention and control measures to curb the spreading of the novel coronavirus-related pneumonia. We develop a mathematical model based on daily updates of reported cases to study the evolution of the epidemic. With the model, on 95% confidence level, we estimate the basic reproduction number, R 0 = 2.82 ± 0.11, time between March 19 and March 21 when the effective reproduction number becoming less than one, the epidemic ending after April 2 and the total number of confirmed cases approaching 14408 ± 429 on the Chinese mainland excluding Hubei province.
Output: A deterministic epidemic model for the emergence of COVID-19 in China
Zika virus is an emergent pathogen that gained significant importance during the epidemic in South and Central America as unusual and alarming complications of infection were recognized. Although initially considered a self-limited benign infection, a panoply of neurologic complications were recognized including a Guillain-Barré-like syndrome and in-utero fetal infection causing microcephaly, blindness, and other congenital neurologic complications. Numerous Zika virus vaccines were developed, with nine different vaccines representing five different platforms entered into clinical trials, one progressing to Phase II. Here we review the current landscape and challenges confronting Zika virus vaccine development.
Output: Tropical Medicine and Infectious Disease Zika Vaccine Development-Current Progress and Challenges for the Future