niryuu/sni-each-converted huggingface dataset:
The lung is a major entry point for many of the most detrimental pathogens to human health. The onslaught of pathogens encountered by the lung is counteracted by protective immune responses that are generated locally, which can be stimulated through vaccine strategies to prevent pathogen infections. Here, we discuss the use of virus-like particles (VLPs), nonpathogen derivatives of viruses or protein cage structures, to construct new vaccines exploiting the lung as a site for immunostimulation. VLPs are unique in their ability to be engineered with near molecular level detail and knowledge of their composition and structure. A summary of research in developing VLP-based vaccines for the lung is presented that suggests promising results for future vaccine development. Nanoparticles present ideal sized scaffolds for attaching and presenting antigens to the immune system to induce responses in a multivalent presentation and that can also be taken up by cells. While there are many synthetic platforms that have been utilized, such as polymeric nanoparticles, dendrimers, and membranous structures (i.e., liposomes, polymerosomes and micelles) [1], in this review we will focus on the utilization of protein cages and/or virus-like particles (VLPs) as a class of nanoscaffolds that have great demonstrated potential. Several good reviews have been written on the topic of utilizing VLPs for development of vaccines and immunogenic nanomaterials [2] [3] [4] , and in this review we want to provide a greater discussion on what makes VLPs so unique from a materials point of view. In addition, we will focus on utilizing VLPs for targeting protective immune
Output: Virus-like particles as antigenic nanomaterials for inducing protective immune responses in the lung HHS Public Access
Experimental infection studies with bluetongue virus (BTV) in the mammalian host have a history that stretches back to the late 18th century. Studies in a wide range of ruminant and camelid species as well as mice have been instrumental in understanding BTV transmission, bluetongue (BT) pathogenicity/pathogenesis, viral virulence, the induced immune response, as well as reproductive failures associated with BTV infection. These studies have in many cases been complemented by in vitro studies with BTV in different cell types in tissue culture. Together these studies have formed the basis for the understanding of BTV-host interaction and have contributed to the design of successful control strategies, including the development of effective vaccines. This review describes some of the fundamental and contemporary infection studies that have been conducted with BTV in the mammalian host and provides an overview of the principal animal welfare issues that should be considered when designing experimental infection studies with BTV in in vivo infection models. Examples are provided from the authors' own laboratory where the three Rs (replacement, reduction and refinement) have been implemented in the design of experimental infection studies with BTV in mice and goats. The use of the ARRIVE guidelines for the reporting of data from animal infection studies is emphasized.
Output: A review of experimental infections with bluetongue virus in the mammalian host
Aims: The chronic consumption of alcohol is known to result in neurodegeneration and impairment of cognitive function. Pathological and neuroimaging studies have confirmed that brain atrophy in alcoholics is mainly due to widespread white matter (WM) loss with neuronal loss restricted to specific regions, such as the prefrontal cortex. Neuroimaging studies of cigarette smokers also suggest that chronic inhalation of tobacco smoke leads to brain atrophy, although the neurotoxic component is unknown. As a high proportion of chronic alcoholics also smoke cigarettes it has been hypothesized that at least some alcohol-related brain damage is due to tobacco smoke exposure. Methods: 39 Long Evans rats were subjected to 8 weeks exposure to alcohol and/or 5 weeks coexposure to nicotine-specific nitrosamine ketone (NNK), a proxy for tobacco smoke. Their frontal WM was then assayed with transmission electron microscopy. Results: NNK and ethanol co-exposure had a synergistic effect in decreasing myelinated fibre density. Furthermore, NNK treatment led to a greater reduction in myelin sheath thickness than ethanol whereas only the ethanol-treated animals showed a decrease in unmyelinated fibre density. Conclusion: These data suggest that NNK causes WM degeneration, an effect that is exacerbated by alcohol, but unlike alcohol, it has little impact on the neuronal components of the brain.
Output: The Differential Effects of Alcohol and Nicotine- Specific Nitrosamine Ketone on White Matter Ultrastructure
This review paper presents an overview of individual monitoring, as well as the national dose register and dose record management of radiation workers in China. Progress has recently been made on the individual monitoring of radiation workers. A critical analysis of current status and problems in individual monitoring is also presented and necessary future research on individual monitoring, such as the monitoring technology in the form of the ring dosimeters and eye lens dosimeters, is suggested.
Output: Individual Monitoring and Occupational Dose Record Management in China: History, Current Status and Perspectives
| Antibodies have been used for more than 100 years in the therapy of infectious diseases, but a new generation of highly potent and/or broadly cross-reactive human monoclonal antibodies (sometimes referred to as 'super-antibodies') offers new opportunities for intervention. The isolation of these antibodies, most of which are rarely induced in human infections, has primarily been achieved by large-scale screening for suitable donors and new single B cell approaches to human monoclonal antibody generation. Engineering the antibodies to improve half-life and effector functions has further augmented their in vivo activity in some cases. Super-antibodies offer promise for the prophylaxis and therapy of infections with a range of viruses, including those that are highly antigenically variable and those that are newly emerging or that have pandemic potential. The next few years will be decisive in the realization of the promise of super-antibodies. NATURE REVIEWS | IMMUNOLOGY VOLUME 18 | MAY 2018 | 297 REVIEWS © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . Genetically engineered mouse antibodies in which the protein sequence has been modified to increase its similarity to human antibodies, thereby decreasing its potential immunogenicity.
Output: Passive immunotherapy of viral infections: 'super-antibodies' enter the fray
Human immunodeficiency virus (HIV) is a global health concern affecting millions of individuals with a wide variety of currently circulating subtypes affecting various regions of the globe. HIV relies on multiple regulatory proteins to modify the host cell to promote replication in infected T cells, and these regulatory proteins can have subtle phenotypic differences between subtypes. One of these proteins, HIV-1 Trans-Activator of Transcription (Tat), is capable of RNA interference (RNAi) Silencing Suppressor (RSS) activity and induction of cell death in T cells. However, the subtype-specific RSS activity and induction of cell death have not been explored. We investigated the ability of Tat subtypes and variants to induce RSS activity and cell death. TatB, from HIV-1 subtype B, was found to be a potent RSS activator by 40% whereas TatC, from HIV-1 subtype C, showed 15% RSS activity while subtype TatC variants exhibited varying levels. A high level of cell death (50-53%) was induced by subtype TatB when compared to subtype TatC (25-28%) and varying levels were observed with subtype TatC variants. These differential activities could be due to variations in the functional domains of Tat. These observations further our understanding of subtype-specific augmentation of Tat in HIV-1 replication and pathogenesis.
Output: In-Vitro Subtype-Specific Modulation of HIV-1 Trans-Activator of Transcription (Tat) on RNAi Silencing Suppressor Activity and Cell Death
The frequency of reported outbreaks of infectious diseases has increased over the past 3 decades, with predictions that this rise will continue. Outbreak response continues to follow nine basic principles: establish the presence of an outbreak, verify the diagnosis, make a case definition, find cases and contacts, conduct basic epidemiology, test hypotheses, institute control measures, communicate the situation and establish ongoing surveillance. Within each of these areas, significant advances have been made over the past 5 years using progress in digital, laboratory, epidemiology and anthropological equipment or techniques. Irrespective of these, future outbreaks of highconsequence are inevitable, and vigilance and preparation must continue in order to prevent significant mortality, morbidity and socio-economic crisis.
Output: Outbreak science: recent progress in the detection and response to outbreaks of infectious diseases
Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that theTLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endo-somalTLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.
Output: TargetingToll-like receptors: promising therapeutic strategies for the management of sepsis-associated pathology and infectious diseases
There is an urgent need for rapid methods to develop vaccines in response to emerging viral pathogens. Whole inactivated virus (WIV) vaccines represent an ideal strategy for this purpose; however, a universal method for producing safe and immunogenic inactivated vaccines is lacking. Conventional pathogen inactivation methods such as formalin, heat, ultraviolet light, and gamma rays cause structural alterations in vaccines that lead to reduced neutralizing antibody specificity, and in some cases, disastrous T helper type 2-mediated immune pathology. We have evaluated the potential of a visible ultrashort pulsed (USP) laser method to generate safe and immunogenic WIV vaccines without adjuvants. Specifically, we demonstrate that vaccination of mice with laser-inactivated H1N1 influenza virus at about a 10-fold lower dose than that required using conventional formalin-inactivated influenza vaccines results in protection against lethal H1N1 challenge in mice. The virus, inactivated by the USP laser irradiation, has been shown to retain its surface protein structure through hemagglutination assay. Unlike conventional inactivation methods, laser treatment did not generate carbonyl groups in protein, thereby reducing the risk of adverse vaccine-elicited T helper type 2 responses. Therefore, USP laser treatment is an attractive potential strategy to generate WIV vaccines with greater potency and safety than vaccines produced by current inactivation techniques.
Output: Chemical-free inactivated whole influenza virus vaccine prepared by ultrashort pulsed laser treatment Chemical-free inactivated whole influenza virus vaccine prepared by ultrashort pulsed laser treatment
The genome sequences of new viruses often contain many "orphan" or "taxon-specific" proteins apparently lacking homologs. However, because viral proteins evolve very fast, commonly used sequence similarity detection methods such as BLAST may overlook homologs. We analyzed a data set of proteins from RNA viruses characterized as "genus specific" by BLAST. More powerful methods developed recently, such as HHblits or HHpred (available through web-based, user-friendly interfaces), could detect distant homologs of a quarter of these proteins, suggesting that these methods should be used to annotate viral genomes. In-depth manual analyses of a subset of the remaining sequences, guided by contextual information such as taxonomy, gene order, or domain cooccurrence, identified distant homologs of another third. Thus, a combination of powerful automated methods and manual analyses can uncover distant homologs of many proteins thought to be orphans. We expect these methodological results to be also applicable to cellular organisms, since they generally evolve much more slowly than RNA viruses. As an application, we reanalyzed the genome of a bee pathogen, Chronic bee paralysis virus (CBPV). We could identify homologs of most of its proteins thought to be orphans; in each case, identifying homologs provided functional clues. We discovered that CBPV encodes a domain homologous to the Alphavirus methyltransferase-guanylyltransferase; a putative membrane protein, SP24, with homologs in unrelated insect viruses and insect-transmitted plant viruses having different morphologies (cileviruses, higreviruses, blunerviruses, negeviruses); and a putative virion glycoprotein, ORF2, also found in negeviruses. SP24 and ORF2 are probably major structural components of the virions.
Output: Powerful Sequence Similarity Search Methods and In-Depth Manual Analyses Can Identify Remote Homologs in Many Apparently "Orphan" Viral Proteins
Inclusion body disease (IBD) is an infectious fatal disease of snakes typified by behavioral abnormalities, wasting, and secondary infections. At a histopathological level, the disease is identified by the presence of large eosinophilic cytoplasmic inclusions in multiple tissues. To date, no virus or other pathogen has been definitively characterized or associated with the disease. Using a metagenomic approach to search for candidate etiologic agents in snakes with confirmed IBD, we identified and de novo assembled the complete genomic sequences of two viruses related to arenaviruses, and a third arenavirus-like sequence was discovered by screening an additional set of samples. A continuous boa constrictor cell line was established and used to propagate and isolate one of the viruses in culture. Viral nucleoprotein was localized and concentrated within large cytoplasmic inclusions in infected cells in culture and tissues from diseased snakes. In total, viral RNA was detected in 6/8 confirmed IBD cases and 0/18 controls. These viruses have a typical arenavirus genome organization but are highly divergent, belonging to a lineage separate from that of the Old and New World arenaviruses. Furthermore, these viruses encode envelope glycoproteins that are more similar to those of filoviruses than to those of other arenaviruses. These findings implicate these viruses as candidate etiologic agents of IBD. The presence of arenaviruses outside mammals reveals that these viruses infect an unexpectedly broad range of species and represent a new reservoir of potential human pathogens. The cause of the disease has remained elusive, and no treatment exists. In addition to being important to pet owners, veterinarians, breeders, zoological parks, and aquariums, the study of animal disease is significant since animals are the source of virtually every emerging infectious human disease. We searched for candidate causative agents in snakes diagnosed with IBD and found a group of novel viruses distantly related mainly to arenaviruses but also to filoviruses, both of which can cause fatal hemorrhagic fevers when transmitted from animals to humans. In addition to providing evidence that strongly suggests that these viruses cause snake IBD, this discovery reveals a new and unanticipated domain of virus biology and evolution. Citation Stenglein MD, et al. 2012. Identification, characterization, and in vitro culture of highly divergent arenaviruses from boa constrictors and annulated tree boas: candidate etiological agents for snake inclusion body disease. mBio 3(4):e00180-12.
Output: Identification, Characterization, and In Vitro Culture of Highly Divergent Arenaviruses from Boa Constrictors and Annulated Tree Boas: Candidate Etiological Agents for Snake Inclusion Body Disease
From 2002 to 2003, a global pandemic of severe acute respiratory syndrome (SARS) spread to 5 continents and caused 8000 respiratory infections and 800 deaths. To ameliorate the effects of future outbreaks as well as to prepare for biodefense, a process for the production of a recombinant protein vaccine candidate is under development. Previously, we reported the 5 L scale expression and purification of a promising recombinant SARS vaccine candidate, RBD219-N1, the 218eamino acid residue receptorbinding domain (RBD) of SARS coronavirus expressed in yeastePichia pastoris X-33. When adjuvanted with aluminum hydroxide, this protein elicited high neutralizing antibody titers and high RBD-specific antibody titers. However, the yield of RBD219-N1 (60 mg RBD219-N1 per liter of fermentation supernatant; 60 mg/L FS) still required improvement to reach our target of >100 mg/L FS. In this study, we optimized the 10 L scale production process and increased the fermentation yield 6-to 7-fold to 400 mg/ L FS with purification recovery >50%. A panel of characterization tests indicated that the process is reproducible and that the purified, tag-free RBD219-N1 protein has high purity and a well-defined structure and is therefore a suitable candidate for production under current Good Manufacturing Practice and future phase-1 clinical trials.
Output: Optimization of the Production Process and Characterization of the Yeast-Expressed SARS-CoV Recombinant Receptor-Binding Domain (RBD219-N1), a SARS Vaccine Candidate
Emerging and re-emerging infectious diseases are an expanding global threat to public health, security, and economies. Increasing populations, urbanization, deforestation, climate change, anti-vaccination movements, war, and international travel are some of the contributing factors to this trend. The recent Ebola, MERS-CoV, and Zika outbreaks demonstrated we are insufficiently prepared to respond with proven safe and effective countermeasures (i.e., vaccines and therapeutics). The State University of New York Upstate Medical University and the Trudeau Institute convened a summit of key opinion and thought leaders in the life sciences and biomedical research and development enterprises to explore global biopreparedness challenges, take an inventory of existing capabilities and capacities related to preparation and response, assess current ''gaps," and prospect what could be done to improve our position. Herein we describe the summit proceedings, ''Translational Immunology Supporting Biomedical Countermeasure Development for Emerging Vector-borne Viral Diseases," held October 2-3, 2018, at the Trudeau Institute in Saranac Lake, NY.
Output: Summit proceedings: Biomedical countermeasure development for emerging vector-borne viral diseases
RT-PCR targeting the conserved regions. The infection rates for mammarenavirus, hantaviruses, and HEV in rodents and shrews were 3.56%, 6.89%, and 1.66%, respectively. Partial genome fragment analysis indicated that mammarenavirus and hantavirus strains had more than 90% and 99% nucleic acid identity with Cardamones virus and Seoul virus, respectively, which cause diseases in humans. Although the present HEV strains identified are typically found worldwide, phylogenetic analysis demonstrated a divergence of 16%. To our knowledge, the present work is the first report of the prevalence of mammarenavirus, hantaviruses, and rat HEV strains in rodents and shrews from Shenzhen city, China. Our findings highlight the zoonotic potential of rodent-and shrew-borne mammarenavirus and hantavirus, and the biodiversity of rat HEV isolates in Shenzhen city. The present work suggests that utilization of good hygiene habits is important to minimize the risk of zoonosis.
Output: Detection and characterization of three zoonotic viruses in wild rodents and shrews from Shenzhen city, China
Cutaneous leishmaniasis is a neglected tropical disease caused by the parasite Leishmania and transmitted by sandflies. It has become a major health problem in many tropical and subtropical countries, especially in regions of conflict and political instability. Currently, there are only limited drug treatments and no available licensed vaccine; thus, the need for more therapeutic interventions remains urgent. Previously, a DNA vaccine encoding a 15 kDa sandfly (Phlebotomus papatasi) salivary protein (PpSP15) and recombinant nonpathogenic Leishmania tarentolae secreting PpSP15 have been shown to induce protective immunity against Leishmania major in mice, demonstrating that PpSP15 is a promising vaccine candidate. In this study, we developed a fermentation process in yeast with a yield of~1g PpSP15/L and a scalable purification process consisting of only 2 chromatographic purification steps with high binding capacity for PpSP15, suggesting that PpSP15 can be produced economically. The biophysical/biochemical analysis of the purified PpSP15 indicated that the protein was of high purity (>97%) and conformationally stable between pH 4.4 and 9.0. More importantly, the recombinant protein had a defined structure similar to that of the related PdSP15 from Phlebotomus duboscqi, implying the suitability of the yeast expression system for producing a correctly folded PpSP15. Abbreviations used: CL, cutaneous leishmaniasis; PpSP15, 15 kDa sandfly (P. papatasi) salivary protein; PdSP15, 15 kDa sandfly (P. duboscqi) salivary protein; OD, optical density; DO, dissolved oxygen; BH, bed height; ID, internal diameter; CV, column volume.
Output: Process Characterization and Biophysical Analysis for a Yeast-Expressed Phlebotomus papatasi Salivary Protein (PpSP15) as a Leishmania Vaccine Candidate
The sequence of the S gene of a field canine coronavirus (CCoV), strain Elmo/02, revealed low nucleotide (61%) and amino acid (54%) identity to reference CCoV strains. The highest correlation (77% nt and 81.7% aa) was found with feline coronavirus type I. A PCR assay for the S gene of strain Elmo/02 detected analogous CCoVs of different geographic origin, all which exhibited at least 92 Á/96% nucleotide identity to each other and to strain Elmo/02. The evident genetic divergence between the reference CCoV strains and the newly identified Elmo/02-like CCoVs strongly suggests that a novel genotype of CCoV is widespread in the dog population. #
Output: Genetic diversity of a canine coronavirus detected in pups with diarrhoea in Italy
Chemical compounds studied in this article: Celastrol (PubChem CID: 122,724) triptocalline A (PubChem CID: 44,559,634) polpunonic acid (PubChem CID: 343,427) demethylzeylasteral (PubChem CID: 10,322,911) wilforol A (PubChem CID: 10,096,097) regelin D (PubChem CID: 129,520) triptotriterpenic acid B (PubChem CID: 195,563) wilforlide A (PubChem CID: 158,477) wilforlide B (PubChem CID: 174,362) triptocallic acid A (PubChem CID: 44,575,704) regelinol (PubChem CID: 163,809) regelin (PubChem CID: 163,808) dulcioic acid (PubChem CID: 101,051,955) tripterygic acid A (PubChem CID: 21,672,627) demethylregelin (PubChem CID: 44,559,663) Three new triterpenoids, triregelolides A, B (1, 2), and triregeloic acid (3), were isolated from the stems of Tripterygium regelii along with twenty known triterpene analogues (4-23). The structures of three new compounds were identified by analyzing their NMR spectroscopic and HRESIMS data. Compounds 4, 7, 8, 10, 13, 14, 17, [21] [22] [23] were isolated from T. regelii for the first time. Compounds 3, 5, 6, 8, 9, 10, 14 and 16 showed inhibitory effects on the proliferation of human breast cancer cells MCF-7 by 24.1%, 69.6%, 72.8%, 21.6%, 23.1%, 43.3%, 25.5% and 23.5% (p b 0.05) at a concentration of 10 μM, respectively.
Output: Triterpenoids from the stems of Tripterygium regelii
Zika virus (ZIKV) has been associated with serious health conditions, and an intense search to discover different ways to prevent and treat ZIKV infection is underway. Berberine and emodin possess several pharmacological properties and have been shown to be particularly effective against the entry and replication of several viruses. We show that emodin and berberine trigger a virucidal effect on ZIKV. When the virus was exposed to 160 µM of berberine, a reduction of 77.6% in the infectivity was observed; when emodin was used (40 µM), this reduction was approximately 83.3%. Dynamic light scattering data showed that both compounds significantly reduce the hydrodynamic radius of virus particle in solution. We report here that berberine and emodin, two natural compounds, have strong virucidal effect in Zika virus.
Output: Natural Products Isolated from Oriental Medicinal Herbs Inactivate Zika Virus
Background: We aimed to investigate the frequency of standard precautions (SPs) compliance and the factors affecting the compliance among nursing students (NSs). Methods: A cross-sectional survey study guided by the health belief model was conducted in 2009. The study questionnaire is valid (content validity index, 0.81) and reliable (Cronbach a range, 0.65-0.94). Results: There were 678 questionnaires analyzed, with a response rate of 68.9%. The mean frequency score of SPs compliance was 4.38 AE 0.40 out of 5. Tukey honest significant difference post hoc test indicated that year 2 and year 4 students had better SPs compliance than year 3 students. Further analysis using a univariate general linear model identified an interaction effect of perceived influence of nursing staff and year of study (F 1,593 ¼ 3.72; P < .05). The 5 following predictors for SPs compliance were identified: knowledge of SPs, perceived barriers, adequacy of training, management support, and influence of nursing staff. Conclusion: Although the SPs compliance among NSs was high, the compliance varied by year of study and was affected by the nursing staff. Furthermore, SPs compliance among NSs can be enhanced by increasing SPs knowledge, providing more SPs training, promoting management support, reducing identified SPs barriers, and improving nursing staff compliance to SPs.
Output: Predictors for compliance of standard precautions among nursing students
We report in this work that a cellular and humoral autoreactive response can be induced against liver-speci®c self-determinants by repeated immunization with a chimeric tissue-speci®c selfantigen carrying a heterologous T h epitope. Epitope spreading rendering the autoimmune reaction independent of the presence of the cognate heterologous help is also demonstrated. Although neutrophil in®ltrates can be demonstrated in the livers of treated mice, no clinical sign of organ damage is observed. These ®ndings suggest that breakage of tolerance by this means leads the process only up to the next checkpoint in the progression of autoimmune disease and that further events are required to precipitate functional organ impairment.
Output: Lack of patent liver autoimmunity after breakage of tolerance in a mouse model
A six-week feeding trial was conducted to evaluate the use of a yeast-based, certified organic protein source as a replacement for fish meal in diets for cobia. Five experimental diets were formulated to provide 40% crude protein and 11% dietary lipid (dry matter basis) with the yeast-based protein source replacing Special Select® menhaden fish meal at 25%, 50%, 75% and 100% of dietary protein. Ten juvenile cobia (initial weight 11.5 g/fish) were randomly stocked in triplicate 300 l circular fiberglass tanks (n = 30 treatment − 1 ) and hand-fed the diets based upon total tank biomass two times daily at 0900 and 1400 h. Fish were group weighed weekly to monitor performance and adjust feeding rations. Water temperature and salinity were maintained at 27°C and 15‰, respectively. At the end of the feeding trial, weight gain, ranging from 86% to 512%, and feed conversion ratio values, ranging from 1.9 to 5.8, were significantly affected by the inclusion of the yeast-based protein source, with decreasing values as inclusion levels of the yeast-based protein source rose above 25% of dietary protein. Cobia fed the diet containing 25% of dietary protein from the yeastbased protein source had equal weight gain and feed conversion ratio values as fish fed the control diet composed of 100% fish meal (503 vs. 512 and 1.9 vs. 1.9, respectively). Biological indices including hepatosomatic index, visceral somatic index and muscle ratio were all similarly affected by inclusion of the yeast-based protein source, with significant impacts when inclusion levels rose above 25% of dietary protein. As with the weight gain and feed efficiency ratio values, fish fed the diet containing 25% of protein from the yeast-based source had similar values as those observed in the control animals. This study represents the first attempt to utilize an organically certified protein source as a replacement for fish meal in diets for juvenile cobia. Although levels of inclusion of the yeast-based protein source above 50% of dietary protein resulted in detrimental effects on production characteristics, the data clearly suggest that, at a minimum, 25% of dietary protein can be provided by this yeast-based protein in diets for cobia.
Output: Replacement of fish meal in cobia (Rachycentron canadum) diets using an organically certified protein
2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.
Output: Structure analysis of the receptor binding of 2019-nCoV
Background. Hematopoietic cell transplant (HCT) recipients are frequently infected with respiratory viruses (RVs) in the upper respiratory tract (URT), but the concordance between URT and lower respiratory tract (LRT) RV detection is not well characterized. Methods. Hematopoietic cell transplant candidates and recipients with respiratory symptoms and LRT and URT RV testing via multiplex PCR from 2009 to 2016 were included. Logistic regression models were used to analyze risk factors for LRT RV detection. Results. Two-hundred thirty-five HCT candidates or recipients had URT and LRT RV testing within 3 days. Among 115 subjects (49%) positive for a RV, 37% (42 of 115) had discordant sample pairs. Forty percent (17 of 42) of discordant pairs were positive in the LRT but negative in the URT. Discordance was common for adenovirus (100%), metapneumovirus (44%), rhinovirus (34%), and parainfluenza virus type 3 (28%); respiratory syncytial virus was highly concordant (92%). Likelihood of LRT detection was increased with URT detection (oods ratio [OR] = 73.7; 95% confidence interval [CI], and in cytomegalovirus-positive recipients (OR = 3.70; 95% CI, 1.30-10.0). Conclusions. High rates of discordance were observed for certain RVs. Bronchoalveolar lavage sampling may provide useful diagnostic information to guide management in symptomatic HCT candidates and recipients.
Output: The Journal of Infectious Diseases Predictive Value of Respiratory Viral Detection in the Upper Respiratory Tract for Infection of the Lower Respiratory Tract With Hematopoietic Stem Cell Transplantation
Virus-like particle (VLP) formation by the coronavirus E and M proteins suggests that interactions between these proteins play a critical role in coronavirus assembly. We studied interactions between the infectious bronchitis virus (IBV) E and M proteins using in vivo crosslinking and VLP assembly assays. We show that IBV E and M can be crosslinked to each other in IBV-infected and transfected cells, indicating that they interact. The cytoplasmic tails of both proteins are important for this interaction. We also examined the ability of the mutant and chimeric E and M proteins to form VLPs. IBV M proteins that are missing portions of their cytoplasmic tails or transmembrane regions were not able to support VLP formation, regardless of their ability to be crosslinked to IBV E. Interactions between the E and M proteins and the membrane bilayer are likely to play an important role in VLP formation and virus budding.
Output: The cytoplasmic tails of infectious bronchitis virus E and M proteins mediate their interaction
Human respiratory syncytial virus (HRSV) is a major cause of pediatric lower respiratory tract disease to which there is no vaccine or efficacious chemotherapeutic strategy. Although RNA synthesis and virus assembly occur in the cytoplasm, HRSV is known to induce nuclear responses in the host cell as replication alters global gene expression. Quantitative proteomics was used to take an unbiased overview of the protein changes in transformed human alveolar basal epithelial cells infected with HRSV. Underpinning this was the use of stable isotope labeling with amino acids in cell culture coupled to LC-MS/MS, which allowed the direct and simultaneous identification and quantification of both cellular and viral proteins. To reduce sample complexity and increase data return on potential protein localization, cells were fractionated into nuclear and cytoplasmic extracts. This resulted in the identification of 1,140 cellular proteins and six viral proteins. The proteomics data were analyzed using Ingenuity Pathways Analysis to identify defined canonical pathways and functional groupings. Selected data were validated using Western blot, direct and indirect immunofluorescence confocal microscopy, and functional assays. The study served to validate and expand upon known HRSVhost cell interactions, including those associated with the antiviral response and alterations in subnuclear structures such as the nucleolus and ND10 (promyelocytic leukemia bodies). In addition, novel changes were observed in mitochondrial proteins and functions, cell cycle regulatory molecules, nuclear pore complex proteins and nucleocytoplasmic trafficking proteins. These data shed light into how the cell is potentially altered to create conditions more favorable for infection. Addition-ally, the study highlights the application and advantage of stable isotope labeling with amino acids in cell culture coupled to LC-MS/MS for the analysis of virus-host interactions.
Output: Quantitative Proteomic Analysis of A549 Cells Infected with Human Respiratory Syncytial Virus* □ S
The 2 0 ,5 0 -oligoadenylate synthetase 1 (OAS1) is one of the major interferon-inducible proteins and a critical component of the host defense system against viral infection. A single nucleotide polymorphism (SNP), rs10774671, presumably responsible for alternate splicing of this gene, has frequently been associated with a variety of viral diseases, including emerging respiratory infections. We investigated the SNP-dependent expression of OAS1 variants in primary cultured human bronchial epithelial cells. Total RNA was subjected to real-time RT-PCR with specific primer sets designed to amplify each transcript variant. We found that the p46 transcript was mainly expressed in cells with the GG genotype, whereas the p42 transcript was highly expressed, and the p44a (alternate exon in intron 5), p48, and p52 transcripts were expressed to a lesser extent, in cells with the AA genotype. Immunoblot analysis revealed that the p46 isoform and a smaller amount of the p42 isoform were present in cells with the GG genotype, whereas only the p42 isoform was clearly observed in cells with the AA genotype. Cellular DNA fragmentation induced by neutrophil elastase was more preferentially found in cells with the AA genotype. Thus, our findings provide insights into the potential role of OAS1 polymorphisms in respiratory infection. Ó
Output: Differential effects of a common splice site polymorphism on the generation of OAS1 variants in human bronchial epithelial cells
Numerous studies have shown that viral epitopes and subunits of bacterial toxins can be expressed and correctly processed in transgenic plants. The recombinant proteins induce immune responses and have several benefits over current vaccine technologies, including increased safety, economy, stability, versatility and efficacy. Antigens expressed in corn are particularly advantageous since the seed can be produced in vast quantities and shipped over long distances at ambient temperature, potentially allowing global vaccination. We have expressed the B-subunit of Escherichia coli heat-labile enterotoxin and the spike protein of swine transmissible gastroenteritis virus at high levels in corn, and demonstrate that these antigens delivered in the seed elicit protective immune responses.
Output: Plant-based vaccines: unique advantages
The paramyxovirus family includes important human pathogens such as measles, mumps, respiratory syncytial virus and the recently emerged, highly pathogenic Hendra and Nipah viruses. The viral fusion (F) protein plays critical roles in infection, promoting both the viral-cell membrane fusion events needed for viral entry as well as cell-cell fusion events leading to syncytia formation. We describe the surprising finding that addition of the short epitope HA tag to the cytoplasmic tail (CT) of the Hendra virus F protein leads to a significant increase in cell-cell membrane fusion. This increase was not due to alterations in surface expression, cleavage state, or association with lipid microdomains. Addition of a Myc tag of similar length did not alter Hendra F fusion activity, indicating that the observed stimulation was not solely a result of lengthening the CT. Three tyrosine residues within the HA tag were critical for the increase in fusion, suggesting C-terminal tyrosines may modulate Hendra fusion activity. The effects of HA tag addition varied with other fusion proteins, as parainfluenza virus 5 F-HA showed decreased surface expression and no stimulation in fusion. These results indicate that additions to the C-terminal end of the F protein CT can modulate protein function in a sequence specific manner, reinforcing the need for careful analysis of epitope tagged glycoproteins. In addition, our results implicate C-terminal tyrosine residues in modulation of the membrane fusion reaction promoted by these viral glycoproteins.
Output: C-terminal tyrosine residues modulate the fusion activity of the Hendra virus fusion protein
In recent years, many studies have drawn attention to the important role of collective awareness and human behaviour during epidemic outbreaks. A number of modelling efforts have investigated the interaction between the disease transmission dynamics and human behaviour change mediated by news coverage and by information spreading in the population. Yet, given the scarcity of data on public awareness during an epidemic, few studies have relied on empirical data. Here, we use fine-grained, geo-referenced data from three online sources -Wikipedia, the GDELT Project and the Internet Archive -to quantify population-scale information seeking about the 2016 Zika virus epidemic in the U.S., explicitly linking such behavioural signal to epidemiological data. Geolocalized Wikipedia pageview data reveal that visiting patterns of Zika-related pages in Wikipedia were highly synchronized across the United States and largely explained by exposure to national television broadcast. Contrary to the assumption of some theoretical models, news volume and Wikipedia visiting patterns were not significantly correlated with the magnitude or the extent of the epidemic. Attention to Zika, in terms of Zika-related Wikipedia pageviews, was high at the beginning of the outbreak, when public health agencies raised an international alert and triggered 1 All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/346411 doi: bioRxiv preprint media coverage, but subsequently exhibited an activity profile that suggests nonlinear dependencies and memory effects in the relation between information seeking, media pressure, and disease dynamics. This calls for a new and more general modelling framework to describe the interaction between media exposure, public awareness and disease dynamics during epidemic outbreaks.
Output: The impact of news exposure on collective attention in the United States during the 2016 Zika epidemic
Antibody therapeutics are one of the fastest growing classes of pharmaceuticals, with an annual US market over $20 billion, developed to treat a variety of diseases including cancer, autoimmune and infectious diseases. Most are currently administered as a single molecule to treat a single disease, however there is mounting evidence that cocktails of multiple antibodies, each with a unique binding specificity and protective mechanism, may improve clinical efficacy. Here, we review progress in the development of oligoclonal combinations of antibodies to treat disease, focusing on identification of synergistic antibodies. We then discuss the application of modern antibody engineering technologies to produce highly potent antibody preparations, including oligoclonal antibody cocktails and truly recombinant polyclonal antibodies. Specific examples illustrating the synergy conferred by multiple antibodies will be provided for diseases caused by botulinum toxin, cancer and immune thrombocytopenia. The bioprocessing and regulatory options for these preparations will be discussed.
Output: Back to the future: recombinant polyclonal antibody therapeutics
In the era of the "sickest first" policy, patients with very high model for end-stage liver disease (MELD) scores have been increasingly admitted to the intensive care unit with the expectation that they will receive a liver transplant (LT) in the absence of improvement on supportive therapies. Such patients are often admitted in a context of acute-on-chronic liver failure with extrahepatic failures. Sequential assessment of scores or classification based on organ failures within the first days after admission help to stratify the risk of mortality in this population. Although the prognosis of severely ill cirrhotic patients has recently improved, transplant-free mortality remains high. LT is still the only curative treatment in this population. Yet, the increased relative scarcity of graft resource must be considered alongside the increased risk of losing a graft in the initial postoperative period when performing LT in "too sick to transplant" patients. Variables associated with poor immediate post-LT outcomes have been identified in large studies. Despite this, the performance of scores based on these variables is still insufficient. Consideration of a patient's comorbidities and frailty is an appealing predictive approach in this population that has proven of great value in many other diseases. So far, local expertise remains the last safeguard to LT. Using this expertise, data are accumulating on favourable post-LT outcomes in very high MELD populations, particularly when LT is performed in a situation of stabilization/improvement of organ failures in selected candidates. The absence of "definitive" contraindications and the control of "dynamic" contraindications allow a "transplantation window" to be defined. This window must be identified swiftly after admission given the poor short-term survival of patients with very high MELD scores. In the absence of any prospect of LT, withdrawal of care could be discussed to ensure respect of patient life, dignity and wishes.
Output: Approaches for patients with very high MELD scores
The COP9 signalosome (CSN), an evolutionally highly conserved protein complex composed of 8 unique subunits (CSN1 through CSN8) in higher eukaryotes, is purported to modulate protein degradation mediated by the ubiquitinproteasome system (UPS) but this has not been demonstrated in a critical mitotic parenchymal organ of vertebrates. Hepatocyte-specific knockout of the Cops8 gene (HS-Csn8KO) was shown to cause massive hepatocyte apoptosis and liver malfunction but the underlying mechanism remains unclear. Here, we report that Csn8/CSN exerts profound impacts on hepatic UPS function and is critical to the stability of the pro-apoptotic protein Bim. Significant decreases in CIS (cytokine-inducible Src homology 2 domain-containing protein), a Bim receptor of a cullin2-based ubiquitin ligase, were found to co-exist with a marked increase of Bim proteins. Csn8 deficiency also significantly decreased 19S proteasome subunit Rpt5 and markedly increased high molecular weight neddylated and ubiquitinated proteins. The use of a surrogate UPS substrate further reveals severe impairment of UPS-mediated proteolysis in HS-Csn8KO livers. Inclusion body-like materials were accumulated in Csn8 deficient hepatocytes. In addition to Bim, massive hepatocyte apoptosis in HS-Csn8KO livers is also associated with elevated expression of other members of the Bcl2 family, including pro-apoptotic Bax as well as anti-apoptotic Bcl2 and Bcl-XL. Increased interaction between Bcl2 and Bim, but not between Bcl2 and Bax, was detected. Hence, it is concluded that hepatic CSN8 deficiency impairs the UPS in the liver and the resultant Bim upregulation likely plays an important role in triggering hepatocyte apoptosis via sequestering Bcl2 away from Bax.
Output: Hepatic Deficiency of COP9 Signalosome Subunit 8 Induces Ubiquitin-Proteasome System Impairment and Bim-Mediated Apoptosis in Murine Livers
Acute viral bronchiolitis is a major cause of morbidity and mortality in infants. 1,2 Bronchiolitis, which literally means inflammation of the bronchioles, was first described more than 150 years ago as 'congestive catarrhal fever' to illustrate the clinical pattern of fever, rhinorrhoea, wheezing, crepitations, dyspnoea and difficulty feeding. It was not until 1957 that the epidemiology and viral aetiology were first described. 3 Respiratory syncytial virus (RSV) is the main virus to cause bronchiolitis and is associated with over 75% of cases where a pathogen has been isolated. 4 Other viruses, including
Output: Innate immune response and bronchiolitis and preschool recurrent wheeze