niryuu/sni-each-converted huggingface dataset:
Virus infection is a complex biological phenomenon for which in vitro experiments provide a uniquely concise view where data is often obtained from a single population of cells, under controlled environmental conditions. Nonetheless, data interpretation and real understanding of viral dynamics is still hampered by the sheer complexity of the various intertwined spatio-temporal processes. In this paper we present a tool to address these issues: a cellular automata model describing critical aspects of in vitro viral infections taking into account spatial characteristics of virus spreading within a culture well. The aim of the model is to understand the key mechanisms of SARS-CoV infection dynamics during the first 24 hours post infection. We interrogate the model using a Latin Hypercube sensitivity analysis to identify which mechanisms are critical to the observed infection of host cells and the release of measured virus particles.
Output: A Simulation Framework to Investigate in vitro Viral Infection Dynamics
A national control program against bovine respiratory syncytial virus (BRSV) and bovine coronavirus (BCV) was launched in Norway in 2016. A key strategy in the program is to test for presence of antibodies and protect testnegative herds from infection. Because these viruses are endemic, the rate of re-introduction can be high, and a disease-free status will become more uncertain as time from testing elapses. The aim of this study was to estimate the probability of freedom (PostPFree) from BRSV and BCV antibodies over time by use of bulk tank milk (BTM) antibody-testing, geographic information and animal movement data, and to validate the herd-level estimates against subsequent BTM testing. BTM samples were collected from 1148 study herds in West Norway in 2013 and 2016, and these were analyzed for BRSV and BCV antibodies. PostPFree was calculated for herds that were negative in 2013/2014, and updated periodically with new probabilities every three months. Input variables were test sensitivity, the probability of introduction through animal purchase and local transmission. Probability of introduction through animal purchase was calculated by using real animal movement data and herd prevalence in the region of the source herd. The PostPFree from the final three months in 2015 was compared to BTM test results from March 2016 using a Wilcoxon Rank Sum Test. The probability of freedom was generally high for test-negative herds immediately after testing, reflecting the high sensitivity of the tests. It did however, decrease with time since testing, and was greatly affected by purchase of livestock. When comparing the median PostPFree for the final three months to the test results in 2016, it was significantly lower (p < 0.01) for test positive herds. Furthermore, there was a large difference in the proportion of test positive herds between the first and fourth quartile of PostPFree. The results show that PostPFree provides a better estimate of herd-level BTM status for both BRSV and BCV than what can be achieved by relying solely on the previous test-result.
Output: Herd level estimation of probability of disease freedom applied on the Norwegian control program for bovine respiratory syncytial virus and bovine coronavirus
The severe acute respiratory syndrome (SARS) coronavirus (CoV) was identified as the etiological agent of an acute respiratory disease causing atypical pneumonia and diarrhea with high mortality. Different types of SARS-CoV vaccines, including nonreplicative and vectored vaccines, have been developed. Administration of these vaccines to animal model systems has shown promise for the generation of efficacious and safe vaccines. Nevertheless, the identification of side effects, preferentially in the elderly animal models, indicates the need to develop novel vaccines that should be tested in improved animal model systems. Live attenuated viruses have generally proven to be the most effective vaccines against viral infections. A limited number of SARS-CoV attenuating modifications have been described, including mutations, and partial or complete gene deletions affecting the replicase, like the nonstructural proteins (nsp1 or nsp2), or the structural genes, and drastic changes in the sequences that regulate the expression of viral subgenomic mRNAs. A promising vaccine candidate developed in our laboratory was based on deletion of the envelope E gene alone, or in combination with the removal of six additional genes nonessential for virus replication. Viruses lacking E protein were attenuated, grew in the lung, and provided homologous and heterologous protection. Improvements of this vaccine candidate have been directed toward increasing virus titers using the power of viruses with mutator phenotypes, while maintaining the attenuated phenotype. The safety of the live SARS-CoV vaccines is being increased by the insertion of complementary modifications in genes nsp1, nsp2, and 3a, by gene scrambling to prevent the rescue of a virulent phenotype by recombination or remodeling of vaccine genomes based on codon deoptimization using synthetic biology. The newly generated vaccine
Output: Recombinant Live Vaccines to Protect Against the Severe Acute Respiratory Syndrome Coronavirus
Healthcare workers accounted for a large proportion of persons with severe acute respiratory syndrome (SARS) during the worldwide epidemic of early 2003. We conducted an investigation of healthcare workers exposed to laboratory-confirmed SARS patients in the United States to evaluate infection-control practices and possible SARSassociated coronavirus (SARS-CoV) transmission. We identified 110 healthcare workers with exposure within droplet range (i.e., 3 feet) to six SARS-CoV-positive patients. Forty-five healthcare workers had exposure without any mask use, 72 had exposure without eye protection, and 40 reported direct skin-to-skin contact. Potential droplet-and aerosol-generating procedures were infrequent: 5% of healthcare workers manipulated a patient's airway, and 4% administered aerosolized medication. Despite numerous unprotected exposures, there was no serologic evidence of healthcare-related SARS-CoV transmission. Lack of transmission in the United States may be related to the relative absence of high-risk procedures or patients, factors that may place healthcare workers at higher risk for infection.
Output: Lack of SARS Transmission among Healthcare Workers, United States EMERGENCE OF SARS EMERGENCE OF SARS Search past issues of EID at www.cdc.gov/eid
A spontaneous neurological disease in cats characterized by behavioural and motor disturbances was investigated by clinical, morphological and immunological methods. Neuropathological examination showed a marked inflammatory reaction in the cerebral leptomeninges and the grey matter of the brain. In the white matter, the reaction was moderate. The changes consisted of perivascular cuffing by mononuclear cells and neuronal damage. The brain stem (thalamus, mesencephalon, caudal colliculus) was most severely affected. The spinal cord and its leptomeninges were involved to a lesser degree. The histopathological picture as well as the laboratory findings suggests a viral cause of the disease. The morphology of the disease and serological as well as immunohistochemical results indicate that this disorder is different from previously known feline viral encephalitides.
Output: Feline Non-suppurative Meningoencephalomyelitis. A Clinical and Pathological Study
A series of thiazole clubbed 1,3,4-oxadiazole derivatives (5ael) have been synthesized and characterized by IR, 1 H NMR, 13 C NMR and mass spectral analysis. Synthesized compounds were evaluated for their antimicrobial and cytotoxic activities. The results indicated that, compounds 5c and 5i exhibited the most potent antibacterial activity. Compound 5f was found to be the most potent antifungal agent. The structure activity relationship revealed that the presence of electron withdrawing groups at para position of phenyl ring remarkably enhanced the antibacterial activity of synthesized compounds. Further, the results of preliminary MTT cytotoxicity studies on HeLa cells suggested that potent antimicrobial activity of 5b, 5c, 5f, 5h and 5i is accompanied by low cytotoxicity.
Output: Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles
Ever since the discovery of SARS-CoV in the year 2003, numerous researchers around the world have been working relentlessly to understand the biology of this virus. As in other coronaviruses, nucleocapsid (N) is one of the most crucial structural components of the SARS-CoV. Hence major attention has been focused on characterization of this protein. Independent studies conducted by several laboratories have elucidated significant insight into the primary function of this protein, which is to encapsidate the viral genome. In addition, many reports also suggest that this protein interferes with different cellular pathways, thus implying it to be a key regulatory component of the virus too. In the first part of this review, we will discuss these different properties of the N-protein in a consolidated manner. Further, this protein has also been proposed to be an efficient diagnostic tool and a candidate vaccine against the SARS-CoV. Hence, towards the end of this article, we will discuss some recent progress regarding the possible clinically relevant use of the N-protein. #
Output: The SARS-CoV nucleocapsid protein: A protein with multifarious activities
Bangladesh has experienced a variety of diseases caused by natural dissemination of an array of pathogenic microorganisms into the environment. While cures for these diseases largely depend on the medication strategies of physicians, determining the reasons for disease persistence as well for the onset of reinfection is also essential. Routine diagnosis of common diseases usually means treatment with a range of appropriate medicines; however, failure of these medications because of the drug resistance of microorganisms accompanied by a lack of alertness about the etiology of diseases often leads to fatal results. The present review reports on emerging diseases in Bangladesh and focuses on associated microbiological research into ongoing diseases including enteric, urinary tract, and malarial complications. The viruses associated with acquired immunodeficiency syndrome and hepatitis are also discussed.
Output: Emerging diseases in Bangladesh: Current microbiological research perspective
Background: The cause of severe disease in some patients infected with pandemic influenza A virus is unclear. Methodology/Principal Findings: We present the cellular immunology profile in the blood, and detailed clinical (and postmortem) findings of three patients with rapidly progressive infection, including a pregnant patient who died. The striking finding is of reduction in natural killer (NK) cells but preservation of activated effector CD8 T lymphocytes; with viraemia in the patient who had no NK cells. Comparison with control groups suggests that the reduction of NK cells is unique to these severely ill patients. Conclusion/Significance: Our report shows markedly reduced NK cells in the three patients that we sampled and raises the hypothesis that NK may have a more significant role than T lymphocytes in controlling viral burden when the host is confronted with a new influenza A virus subtype.
Output: Reduction of Natural Killer but Not Effector CD8 T Lymphoyctes in Three Consecutive Cases of Severe/ Lethal H1N1/09 Influenza A Virus Infection
Diarrhea is one of the most common causes of antimicrobial use and mortality in young calves. To reduce antimicrobial use and resistance on dairy farms, research on alternative therapies for calf diarrhea is necessary. Our laboratory previously conducted a randomized clinical trial investigating the effectiveness of lactoferrin, an iron-binding protein found in colostrum, as a treatment for calf diarrhea. The trial showed significantly reduced calf mortality in diarrheic calves that were administered lactoferrin. Thus, the objective of this study was to corroborate the results of our prior clinical trial across multiple farms and to investigate the effect of lactoferrin on the morbidity and mortality of preweaned calves with naturally occurring cases of diarrhea. This randomized field trial was conducted on 5 commercial dairy farms in Ohio. In total, 485 calves (≤21 d of age) were enrolled at first diarrhea diagnosis (fecal score ≥2 defined as loose to watery) and randomly assigned to receive an oral dose of lactoferrin (3 g of lactoferrin powder dissolved in 30 mL of water) or 30 mL of water (control) once daily for 3 consecutive days. Health assessments were conducted on the day of diarrhea diagnosis (d 0) and 1, 2, 3, 7, 14, 21, 28, and 35 d following diagnosis. Producer records of disease treatment and mortality were collected 120 d following diagnosis. A Poisson regression model was used to test differences between treatments in disease frequency through 35 d post-diarrhea diagnosis and the incidence risk of treatment and mortality risk 120 d post-diarrhea diagnosis; the model controlled for calf age at enrollment, farm, and treatment. Median calf age at enrollment was 11 d and ranged from 1 to 26 d of age. At study enrollment, 51.3% (123/240) and 52.2% (128/245) of calves in the control and lactoferrin treatment groups, respectively, were diagnosed with severe diarrhea (fecal score = 3). The frequency of disease (diarrhea, dehydration, depression, signs of respiratory disease) through 35 d following diarrhea diagnosis was not significantly different for calves in the lactoferrin and control groups. Overall mortality risk for enrolled calves was 9.9%, and 10.7% (22/243) and 9.1% (26/242) of calves in the lactoferrin and control groups, respectively, died or were culled in the 120 d following diarrhea diagnosis. The relative risk of death or culling did not differ between treatment groups, however. Therefore, as performed in this study, lactoferrin as a treatment for calf diarrhea was not beneficial.
Output: A multisite, randomized field trial to evaluate the influence of lactoferrin on the morbidity and mortality of dairy calves with diarrhea
To assess the role of spatial proximity, defined as patients sharing bays, in the spread of norovirus during outbreaks in hospitals. Enhanced surveillance of norovirus outbreaks between November 2009 and November 2011. Data were gathered during 149 outbreaks of norovirus in hospital wards from five hospitals in two major cities in England serving a population of 2 million. We used the time between the first two cases of each outbreak to estimate the serial interval for norovirus in this setting. This distribution and dates of illness onset were used to calculate epidemic trees for each outbreak. We then used a permutation test to assess whether proximity, for all outbreaks, was more extreme than would be expected by chance under the null hypothesis that proximity was not associated with transmission risk. Sixty-five outbreaks contained complete data on both onset dates and ward position. We estimated the serial interval to be 1.86 days (95% confidence intervals 1.6-2.2 days), and with this value found strong evidence to reject the null hypothesis that proximity was unimportant (p < 0.001). Sensitivity analysis using different values of the serial interval showed that there was evidence to reject the null hypothesis provided the assumed serial interval was less than 2.5 days. Our results provide evidence that patients occupying the same bay as patients with symptomatic norovirus infection are at an increased risk of becoming infected by these patients compared with patients elsewhere in the same ward.
Output: Does spatial proximity drive norovirus transmission during outbreaks in hospitals? Title Does spatial proximity drive norovirus transmission during outbreaks in hospitals?
To exploit a cross passive immunotherapy for enterovirus-induced hand-foot-and-mouth disease (HFMD), the cross antiviral activity of a neutralizing antibody against enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) was investigated in vitro. White Leghorn specific-pathogen-free chickens were immunized with EV71 antigens and a specific isolated immunoglobulin (IgY) was prepared from the chicken egg yolk. IgY was further purified and characterized by SDS-PAGE, ELISA, western blotting and bidirectional immune agar diffusion testing. The antiviral activity and dose-response of the IgY were determined by assessing the cytopathic effect in rhabdomyosarcoma (RD) cells in vitro. It was indicated that the levels of IgY were increased at day 7, peaked at week 7 and were maintained at a higher level for 4 weeks following immunization when compared with the negative control. The results of western blotting and bidirectional immune agar diffusion testing revealed that the IgY had cross-binding properties in EV71 and CVA16 strains through targeting the envelope proteins (VP0, VP1 and VP3) of EV71 and CVA16. Neutralization assay results indicated that the infectivity of EV71 and CVA16 strains in RD cells was cross-blocked by IgY in a dose-dependent manner. To conclude, these findings indicate that IgY has cross antiviral activity against EV71 and CVA16 in vitro, and could potentially be developed as a passive immunotherapy for EV71-and CVA16-induced HFMD.
Output: Enterovirus type 71-immunized chicken egg yolk immunoglobulin has cross antiviral activity against coxsackievirus A16 in vitro
Since the emergence of the first cases in Wuhan, China, the novel coronavirus (2019-nCoV) infection has been quickly spreading out to other provinces and neighboring countries. Estimation of the basic reproduction number by means of mathematical modeling can be helpful for determining the potential and severity of an outbreak and providing critical information for identifying the type of disease interventions and intensity. A deterministic compartmental model was devised based on the clinical progression of the disease, epidemiological status of the individuals, and intervention measures. The estimations based on likelihood and model analysis show that the control reproduction number may be as high as 6.47 (95% CI 5.71-7.23). Sensitivity analyses show that interventions, such as intensive contact tracing followed by quarantine and isolation, can effectively reduce the control reproduction number and transmission risk, with the effect of travel restriction adopted by Wuhan on 2019-nCoV infection in Beijing being almost equivalent to increasing quarantine by a 100 thousand baseline value. It is essential to assess how the expensive, resource-intensive measures implemented by the Chinese authorities can contribute to the prevention and control of the 2019-nCoV infection, and how long they should be maintained. Under the most restrictive measures, the outbreak is expected to peak within two weeks (since 23 January 2020) with a significant low peak value. With travel restriction (no imported exposed individuals to Beijing), the number of infected individuals in seven days will decrease by 91.14% in Beijing, compared with the scenario of no travel restriction.
Output: Clinical Medicine Estimation of the Transmission Risk of the 2019-nCoV and Its Implication for Public Health Interventions
Background Globally, respiratory infections are the primary cause of illness in developing countries, specifically among children; however, an etiological agent for many of these illnesses is rarely identified. Objectives Our study aimed to estimate the frequency of human bocavirus (HBoV) infection among pediatric populations in Argentina, Nicaragua and Peru. Methods We conducted a cross-sectional study using stored samples of an influenza-like illness surveillance program. Irrespective of previous diagnosis, nasopharyngeal or nasal swab specimens were randomly selected and tested using real-time PCR from three sites during 2007 from patients younger than 6 years old. Results A total of 568 specimens from Argentina (185), Nicaragua (192) and Peru (191) were tested. The prevalence of HBoV was 10AE8% (95% CI: 6AE3; 15AE3) in Argentina, 33AE3% in Nicaragua (95% CI: 26AE6; 40AE1) and 25AE1% in Peru (95% CI: 18AE9; 31AE3). Conclusions These findings demonstrate circulation of HBoV in Argentina, Nicaragua and Peru among children with influenza-like symptoms enrolled in a sentinel surveillance program. Keywords Epidemiology, human bocavirus, respiratory illness. Please cite this paper as: Salmó n-Mulanovich et al. (2011) Frequency of human bocavirus (HBoV) infection among children with febrile respiratory symptoms in Argentina, Nicaragua and Peru. Influenza and Other Respiratory Viruses 5(1), 1-5.
Output: Frequency of human bocavirus (HBoV) infection among children with febrile respiratory symptoms in Argentina, Nicaragua and Peru
After viral infection, host cells respond by mounting an anti-viral stress response in order to create a hostile atmosphere for viral replication, leading to the shut-off of mRNA translation (protein synthesis) and the assembly of RNA granules. Two of these RNA granules have been well characterized in yeast and mammalian cells, stress granules (SGs), which are translationally silent sites of RNA triage and processing bodies (PBs), which are involved in mRNA degradation. This review discusses the role of these RNA granules in the evasion of anti-viral stress responses through virus-induced remodeling of cellular ribonucleoproteins (RNPs).
Output: viruses Who Regulates Whom? An Overview of RNA Granules and Viral Infections
Autophagy is a key innate immune response to intracellular parasites that promotes their delivery to degradative lysosomes following detection in the cytosol or within damaged vacuoles. Like Listeria and Shigella, which use specific mechanisms to avoid autophagic detection and capture, the bacterial pathogen Francisella tularensis proliferates within the cytosol of macrophages without demonstrable control by autophagy. To examine how Francisella evades autophagy, we screened a library of F. tularensis subsp. tularensis Schu S4 HimarFT transposon mutants in GFP-LC3-expressing murine macrophages by microscopy for clones localised within autophagic vacuoles after phagosomal escape. Eleven clones showed autophagic capture at six hours postinfection, whose HimarFT insertions clustered to four genetic loci involved in lipopolysaccharidic and capsular O-antigen biosynthesis. Consistent with the HimarFT mutants, in-frame deletion mutants of two representative loci, FTT1236 and FTT1448c (manC), lacking both LPS and capsular O-antigen, underwent phagosomal escape but were cleared from the host cytosol. Unlike wild type Francisella, the O-antigen deletion mutants were ubiquitinated, and recruited the autophagy adaptor p62/SQSTM1 and LC3 prior to cytosolic clearance. Autophagy-deficient macrophages partially supported replication of both mutants, indicating that O-antigen-lacking Francisella are controlled by autophagy. These data demonstrate the intracellular protective role of this bacterial surface polysaccharide against autophagy.
Output: The Francisella O-antigen mediates survival in the macrophage cytosol via autophagy avoidance NIH Public Access
To analyze the course of seasonal viral infections of respiratory tract in patients hospitalized in pediatric intensive care units (PICU) of 16 centers in Turkey. Materials and methods: It is a retrospective, observational, and multicenter study conducted in 16 tertiary PICUs in Turkey includes a total of 302 children with viral cause in the nasal swab which required PICU admission with no interventions. Results: Median age of patients was 12 months. Respiratory syncytial virus (RSV) was more common in patients over one year of age whereas influenza, human Bocavirus in patients above a year of age was more common (p <0.05). Clinical presentations influencing mortality were neurologic symptoms, tachycardia, hypoxia, hypotension, elevated lactate, and acidosis. The critical pH value related with mortality was ≤7.10, and critical PCO 2 ≥60 mm Hg. Conclusion: Our findings demonstrate that patients with neurological symptoms, tachycardia, hypoxia, hypotension, acidosis, impaired liver, and renal function at the time of admission exhibit more severe mortal progressions. Presence of acidosis and multiorgan failure was found to be predictor for mortality. Knowledge of clinical presentation and age-related variations among seasonal viruses may give a clue about severe course and prognosis. By presenting the analyzed data of 302 PICU admissions, current study reveals severity of viral respiratory tract infections and release tips for handling them.
Output: Comprehensive Analysis of Severe Viral Infections of Respiratory Tract admitted to PICUs during the Winter Season in Turkey
While the ferret is a valuable animal model for a number of human viral infections, such as influenza, Hendra and Nipah, evaluating the cellular immune response following infection has been hampered by the lack of a number of species-specific immunological reagents. Interleukin 2 (IL-2) is one such key cytokine. Ferret recombinant IL-2 incorporating a C-terminal histidine tag was expressed and purified and the three-dimensional structure solved and refined at 1.89 Å by X-ray crystallography, which represents the highest resolution and first non-human IL-2 structure. While ferret IL-2 displays the classic cytokine fold of the four-helix bundle structure, conformational flexibility was observed at the second helix and its neighbouring region in the bundle, which may result in the disruption of the spatial arrangement of residues involved in receptor binding interactions, implicating subtle differences between ferret and human IL-2 when initiating biological functions. Ferret recombinant IL-2 stimulated the proliferation of ferret lymph node cells and induced the expression of mRNA for IFN-g and Granzyme A. Crown
Output: Structural and functional characterisation of ferret interleukin-2
Background: While respiratory viral infections are recognized as a frequent cause of illness in hematopoietic stem cell transplantation (HSCT) recipients, HCoV−OC43 infections have rarely been investigated as healthcareassociated infections in this population. Objectives: In this report, HCoV−OC43 isolates collected from HSCT patients were retrospectively characterized to identify potential clusters of infection that may stand for a hospital transmission. Study design: Whole-genome and S gene sequences were obtained from nasal swabs using next-generation sequencing and phylogenetic trees were constructed. Similar identity matrix and determination of the most common ancestor were used to compare clusters of patient's sequences. Amino acids substitutions were analysed. Results: Genotypes B, E, F and G were identified. Two clusters of patients were defined from chronological data and phylogenetic trees. Analyses of amino acids substitutions of the S protein sequences identified substitutions specific for genotype F strains circulating among European people. Conclusions: HCoV−OC43 may be implicated in healthcare-associated infections.
Output: Use of whole-genome sequencing in the molecular investigation of care- associated HCoV-OC43 infections in a hematopoietic stem cell transplant unit
Duck viral enteritis (DVE) is an acute, contagious herpesvirus infection of ducks, geese, and swans of all ages and species. This disease has been responsible for significant economic losses in domestic and wild waterfowl as a result of mortality, and decreased egg production. Resveratrol is a naturally occurring phytoalexin in specific plants and exhibits inhibitory activity against many kinds of virus. In this paper, resveratrol was found to inhibit duck enteritis virus (DEV) replication in a dose-dependent manner, with a 50% inhibition concentration of 3.85 mg/mL. The inhibition in virus multiplication in the presence of resveratrol was not attributed to direct inactivation or inhibition of virus attachment to the host cells, but to the inhibition of viral multiplication in host cells. The assay of the time of addition limited the drug effect during the first 8 h of infection. This conclusion was supported by the ultrastructure images of the early stage of DEV infection, which showed that the replication of virus nucleic acid and the formation of the capsid in the cell nucleus were suppressed. In the indirect immunofluorescence assay, proteins expression in DEV infected duck embryo fibroblasts (DEFs) within 24 h post-infection (p.i.) was also effectively suppressed by resveratrol. In summary, the resveratrol has a good activity against DEV infection in vitro, which could be attributed to that fact that several essential immediate early viral proteins for virus replication were impacted by resveratrol.
Output: Inhibitory Effect of Resveratrol against Duck Enteritis Virus In Vitro
Immune responses are a double-edged sword. Effective and appropriate immune responses capable of controlling viral infection while also largely preserving tissue integrity, are critical for host survival. Too strong immune responses might result in immune pathology, while too weak immune responses might cause viral persistence. Physiologic ageing is accompanied with a decline in the normal functioning of the immune system, which is termed as "immunosenescence". We show that aged mice (16-19 months old) are more resistant to influenza A virus (IAV) infection than the young mice. Strong immune responses in the young mice after IAV infection result in faster clearance of virus, but also cause severe lung injury and higher mortality rate. While in the aged mice, the delayed and milder immune responses contribute to reduced pulmonary damage, and are still capable to clear the infection even with a slower kinetics, displaying a more resistant phenotype during IAV infection. Hence, our work demonstrates that moderate immune responses as a decline with ageing in the aged mice balance the immune pathology and viral clearance, might be beneficial for the host during certain circumstances. Our results provide important insight to our basic knowledge of immunosenescence and immune defenses to invading pathogens. Further, our results indicate that age factors should be considered when investigating the vaccination and therapeutic strategies for severe IAV infection.
Output: Aged Mice are More Resistant to Influenza Virus Infection due to Reduced Inflammation and Lung Pathology
The archaeal exosome is a phosphorolytic 3 -5 exoribonuclease complex. In a reverse reaction it synthesizes A-rich RNA tails. Its RNA-binding cap comprises the eukaryotic orthologs Rrp4 and Csl4, and an archaea-specific subunit annotated as DnaG. In Sulfolobus solfataricus DnaG and Rrp4 but not Csl4 show preference for poly(rA). Archaeal DnaG contains N-and C-terminal domains (NTD and CTD) of unknown function flanking a TOPRIM domain. We found that the NT and TOPRIM domains have comparable, high conservation in all archaea, while the CTD conservation correlates with the presence of exosome. We show that the NTD is a novel RNA-binding domain with poly(rA)-preference cooperating with the TOPRIM domain in binding of RNA. Consistently, a fusion protein containing full-length Csl4 and NTD of DnaG led to enhanced degradation of A-rich RNA by the exosome. We also found that DnaG strongly binds native and in vitro transcribed rRNA and enables its polynucleotidylation by the exosome. Furthermore, rRNA-derived transcripts with heteropolymeric tails were degraded faster by the exosome than their non-tailed variants. Based on our data, we propose that archaeal DnaG is an RNA-binding protein, which, in the context of the exosome, is involved in targeting of stable RNA for degradation.
Output: Archaeal DnaG contains a conserved N-terminal RNA-binding domain and enables tailing of rRNA by the exosome
The physiological and pharmacological role of nucleic acids structures folded into the non canonical Gquadruplex conformation have recently emerged. Their activities are targeted at vital cellular processes including telomere maintenance, regulation of transcription and processing of the pre-messenger or telomeric RNA. In addition, severe conditions like cancer, fragile X syndrome, Bloom syndrome, Werner syndrome and Fanconi anemia J are related to genomic defects that involve G-quadruplex forming sequences. In this connection G-quadruplex recognition and processing by nucleic acid directed proteins and enzymes represents a key event to activate or deactivate physiological or pathological pathways. In this review we examine protein-G-quadruplex recognition in physiologically significant conditions and discuss how to possibly exploit the interactions' selectivity for targeted therapeutic intervention.
Output: The evolving world of protein-G-quadruplex recognition: A medicinal chemist's perspective
Neonatal necrotizing enterocolitis is the most common serious gastrointestinal disorder encountered in neonatal intensive care units. It is a major cause of morbidity and mortality in the newborn, particularly in premature infants. Consistent risk factors are birth weight and prematurity. Polycythemia and hyperviscosity altering blood flow and infectious agents are also implicated. Clinical findings include abdominal distention and diarrhea, and systemic symptoms such as apnea, acidosis, and lethargy. Pneumatosis intestinalis can be demonstrated radiographically. Mucosal ulcerations, hemorrhage, and thrombosis occur early, followed by inflammatory changes. Later still necrosis develops. Ischemia, infection, and enteral feedings are suspected to be involved in the pathophysiology. Eicosanoids, especially thromboxane, platelet-activating factor, and leukotrienes are likely mediators.
Output: Neonatal Necrotizing Enterocolitis Inflammatory Bowel Disease of the Newborn
Fasting paradigms elicit a wide-range of health benefits including suppressing inflammation. Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising new therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARA directly upregulates the long non-coding RNA gene Gm15441 through binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLRP3 inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1 beta (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to metabolic and inflammatory stimuli. These findings provide evidence for a novel mechanism by which PPARA attenuates hepatic inflammasome activation in response to metabolic stress through lncRNA Gm15441 induction. Txnip expression in vivo. Gm15441 LSL mice were treated with a PPARA agonist or fasted to assess how loss of Gm15441 impacts hepatic inflammasome activation in response to both pharmacological and physiologically-induced metabolic stress. TXNIP protein, caspase-1 (CASP1) levels, and interleukin 1 beta (IL1B) cleavage were elevated in Gm15441 LSL mice and were further increased by PPARA activation, indicating that this lncRNA plays a major role in attenuating inflammasome activation. Thus, hepatic PPARA directly regulates the lncRNA Gm15441, which in turn suppresses Txnip expression, which attenuates NLRP3 inflammasome activation during periods of metabolic stress. These studies revealed a novel regulatory mechanism supporting the beneficial effects of fasting, namely, reduced inflammation. Results To assess the regulation of lncRNAs by PPARA, RNA-seq was performed using total liver RNA isolated from Ppara +/+ mice, both with and without dietary exposure to the PPARA agonist WY-14643. A lncRNA discovery pipeline was implemented that identified 15,558 liver-expressed lncRNA genes. Of these, 13,343 were intergenic, 1,966 were antisense, and 249 were intragenic lncRNAs. 44% of the 15,558 liver-expressed lncRNAs are considered novel (Melia and Waxman, 2019). Differential gene expression analysis revealed that a total of 1,735 RefSeq genes and 442 liver-expressed lncRNA genes responded to treatment with WY-14643 at an expression foldchange >2 at FDR<0.05, with 968 RefSeq genes and 245 lncRNA genes upregulated, and 767
Output: Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress
Hematological and coagulation profiles were studied in crossbred dogs experimentally infected with Angiostrongylus vasorum. Two groups of five dogs were experimentally inoculated with 50 and 100 third stage infective larvae (L 3 ) of A. vasorum per kilogram of body weight. A third group of five uninfected animals was used as control. One sample of 10 ml of blood was collected from each animal on the 10, 20, 30, and 45 days after inoculation (dai) and at 30-day intervals thereafter for the remainder of the 210-day experimental period. The blood sample was used for the complete hemogram and platelet count, as well as measurements of prothrombin time, partial thromboplastin time and factors V and VIII. Anemia was observed in infected dogs, 6 weeks after the infection. The eosinophils presented peaks in four periods after infection. Thrombocytopenia became accentuated on the 72 dai. Decreased prothrombin time activity and increased partial thromboplastin time were observed at the 6 and 9 weeks after infection and decreased of factors VIII and V activities occurred from 4 to 6 weeks after infection. It may be conclude that infection by A. vasorum in dogs may cause a discrete anemia during the acute phase which is probably regenerative. In addition, important hemostatic alterations due to the infection suggest a chronic intravascular consumption coagulopathy.
Output: Hematological and coagulation profiles in dogs experimentally infected with Angiostrongylus vasorum (Baillet, 1866)
Plants are low-cost bioreactors for the production of various biopharmaceuticals including oral vaccines. Plant-derived oral vaccines are potentially useful in combating viral infections involving mucosal immunity. Transgenic plants have been generated to successfully produce mucosal vaccines against cholera, hepatitis B, foot-and-mouth disease, and Norwalk virus. As a first step toward the generation of oral vaccines against the severe acute respiratory syndrome coronavirus (SARS-CoV), we have expressed a recombinant S1 protein of the SARS-CoV in transformed tobacco. Since plant transformation and regeneration of stable transformants require considerable time, we initially used a green fluorescent protein (GFP) to tag the antigen in transient expression. GFP was fused to the carboxy-terminus of S1 for expression of S1-GFP to show expression of recombinant S1 by agroinfiltration of tobacco leaves. The GFP tag enables a relatively quick confirmation of antigen expression in plant cells by fluorescent microscopy. Such analysis using GFP that precedes stable plant transformation will enable the rapid screening of multiple constructs to attain optimal recombinant protein expression. Furthermore, this approach determines the subcellular localization of the recombinant protein in plant cells, providing information on optimal subcellular targeting for production in plant bioreactors.
Output: Use of GFP to Investigate Expression of Plant-Derived Vaccines
Background: BCoV is identified in both healthy and diarrheic calves, complicating its assessment as a primary pathogen. Objectives: To investigate the detection rates of bovine coronavirus (BCoV) in feces of healthy and diarrheic calves and to describe the usefulness of a pancoronavirus reverse transcriptase (RT) PCR (PanCoV-RT-PCR) assay to identify BCoV in samples of diarrheic calves. Animals: Two hundred and eighty-six calves <21 days. Calves with liquid or semiliquid feces, temperature >39.5°C, and inappetence were considered as cases, and those that had pasty or firm feces and normal physical examination were designated as controls. Methods: Prospective case-control study. A specific BCoV-RT-PCR assay was used to detect BCoV in fecal samples. Association between BCoV and health status was evaluated by exact and random effect logistic regression. Fecal (n = 28) and nasal (n = 8) samples from diarrheic calves were tested for the presence of BCoV by both the PanCoV-RT-PCR and a specific BCoV-RT-PCR assays. A Kappa coefficient test was used to assess the level of agreement of both assays. Results: BCoV was detected in 55% (157/286) of calves; 46% (66/143), and 64% (91/143) of healthy and diarrheic calves, respectively. Diarrheic calves had higher odds of BCoV presence than healthy calves (OR: 2.16, 95% CI: 1.26 to 3.83, P = 0.004). A good agreement between PanCoV-RT-PCR and BCoV-RT-PCR to detect BCoV was identified (j = 0.68, 95% CI: 0.392 to 0.967; P < 0.001). Conclusions and Clinical Importance: BCoV was more likely to be detected in diarrheic than healthy calves. The PanCoV-RT-PCR assay can be a useful tool to detect CoV samples from diarrheic calves.
Output: Detection of Bovine Coronavirus in Healthy and Diarrheic Dairy Calves
Known human coronaviruses are believed to have originated in animals and made use of intermediate hosts for transmission to humans. The intermediate hosts of most of the human coronaviruses are known, but not for HCoV-NL63. This study aims to assess the possible role of some major domestic livestock species as intermediate hosts of HCoV-NL63. We developed a testing algorithm for high throughput screening of livestock sera with ELISA and confirmation with recombinant immunofluorescence assay testing for antibodies against HCoV-NL63 in livestock. Optimization of the ELISA showed a capability of the assay to significantly distinguish HCoV-NL63 from HCoV-229E (U = 27.50, p < 0.001) and HCoV-OC43 (U = 55.50, p < 0.001) in coronavirus-characterized sera. Evaluation of the assay with collected human samples showed no significant difference in mean optical density values of immunofluorescence-classified HCoV-NL63-positive and HCoV-NL63-negative samples (F (1, 215) = 0.437, p = 0.509). All the top 5% (n = 8) most reactive human samples tested by ELISA were HCoV-NL63 positive by immunofluorescence testing. In comparison, only a proportion (84%, n = 42) of the top 25% were positive by immunofluorescence testing, indicating an increased probability of the highly ELISA reactive samples testing positive by the immunofluorescence assay. None of the top 5% most ELISA reactive livestock samples were positive for HCoV-NL63-related viruses by immunofluorescence confirmation. Ghanaian domestic livestock are not likely intermediate hosts of HCoV-NL63-related coronaviruses.
Output: Development of a Whole-Virus ELISA for Serological Evaluation of Domestic Livestock as Possible Hosts of Human Coronavirus NL63
Hospital-acquired infections (HAIs) are a major concern to healthcare systems around the world. They are associated with significant morbidity and mortality, in addition to increased hospitalization costs. Recent outbreaks, including those caused by the Middle East respiratory syndrome coronavirus and Ebola virus, have highlighted the importance of infection control. Moreover, HAIs, especially those caused by multidrug-resistant Gram-negative rods, have become a top global priority. Although adequate approaches and guidelines have been in existence for many years and have often proven effective in some countries, the implementation of such approaches in low-and middle-income countries (LMICs) is often restricted due to limited resources and underdeveloped infrastructure. While evidence-based infection prevention and control (IPC) principles and practices are universal, studies are needed to evaluate simplified approaches that can be better adapted to LMIC needs, in order to guide IPC in practice. A group of experts from around the world attended a workshop held at the 17th International Congress on Infectious Diseases in Hyderabad, India in March 2016, to discuss the existing IPC practices in LMICs, and how best these can be improved within the local context.
Output: The 17th International Congress on Infectious Diseases workshop on developing infection prevention and control resources for low-and middle-income countries
Given the interconnected nature of our world today, emerging pathogens and pandemic outbreaks are an ever-growing threat to the health and economic stability of the global community. This is evident by the recent 2009 Influenza A (H1N1) pandemic, the SARS outbreak, as well as the ever-present threat of global bioterrorism. Fortunately, the biomedical community has been able to rapidly generate sequence data so these pathogens can be readily identified. To date, however, the utilization of this sequence data to rapidly produce relevant experimental results or actionable treatments is lagging in spite of obtained sequence data. Thus, a pathogenic threat that has emerged and/or developed into a pandemic can be rapidly identified; however, translating this identification into a targeted therapeutic or treatment that is rapidly available has not yet materialized. This commentary suggests that the growing technology of DNA synthesis should be fully implemented as a means to rapidly generate in vivo data and possibly actionable therapeutics soon after sequence data becomes available.
Output: Access to
Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease caused by a novel single-stranded, positive-sense RNA betacoronavirus (MERS-CoV). Dromedary camels, hosts for MERS-CoV, are implicated in direct or indirect transmission to human beings, although the exact mode of transmission is unknown. The virus was fi rst isolated from a patient who died from a severe respiratory illness in June, 2012, in Jeddah, Saudi Arabia. As of May 31, 2015, 1180 laboratory-confi rmed cases (483 deaths; 40% mortality) have been reported to WHO. Both community-acquired and hospital-acquired cases have been reported with little human-to-human transmission reported in the community. Although most cases of MERS have occurred in Saudi Arabia and the United Arab Emirates, cases have been reported in Europe, the USA, and Asia in people who travelled from the Middle East or their contacts. Clinical features of MERS range from asymptomatic or mild disease to acute respiratory distress syndrome and multiorgan failure resulting in death, especially in individuals with underlying comorbidities. No specifi c drug treatment exists for MERS and infection prevention and control measures are crucial to prevent spread in health-care facilities. MERS-CoV continues to be an endemic, low-level public health threat. However, the virus could mutate to have increased interhuman transmissibility, increasing its pandemic potential.
Output: Seminar Middle East respiratory syndrome
Alanyl aminopeptidase (APN) is a surface-bound metallopeptidase that processes the N-terminals of biologically active peptides such as enkephalins, angiotensins, neurokinins, and cytokines. It exerts profound activity on vital processes such as immune response, cellular growth, and blood pressure control. Inhibition of either APN gene expression or its enzymatic activity severely affects leukocyte growth and function. We show here that oxidoreductasemediated modulations of the cell surface thiol status affect the enzymatic activity of APN. Additional evidence for the pivotal role of extracellular cysteines in the APN molecule was obtained when substitution of any of these six cysteines caused complete loss of surface expression and enzymatic activity. In contrast, the transmembrane Cys24 appears to have no similar function. Enzymatically inactive cysteine mutants were retained in the endoplasmic reticulum as shown by high-resolution imaging and Endoglycosidase H digestion. In the absence of any crystal-structure data, the demonstration that individual extracellular cysteines contribute to APN expression and function appears to be of particular importance. The data are the first to show thiol-dependent modulation of the activity of a typical surfacebound peptidase at the cell surface, probably reflecting a general regulating mechanism. This may relate to various disease processes such as inflammation or malignant transformation.
Output: EXTRACELLULAR CYSTEINES DEFINE ECTOPEPTIDASE (APN, CD13) EXPRESSION AND FUNCTION