niryuu/sni-each-converted huggingface dataset:
The early systemic production of interferon (IFN)-ab is an essential component of the antiviral host defense mechanisms, but is also thought to contribute to the toxic side effects accompanying gene therapy with adenoviral vectors. Here we investigated the IFN-ab response to human adenoviruses (Ads) in mice. By comparing the responses of normal, myeloid (m)DC-and plasmacytoid (p)DC-depleted mice and by measuring IFN-ab mRNA expression in different organs and cells types, we show that in vivo, Ads elicit strong and rapid IFN-ab production, almost exclusively in splenic mDCs. Using knockout mice, various strains of Ads (wild type, mutant and UV-inactivated) and MAP kinase inhibitors, we demonstrate that the Ad-induced IFN-ab response does not require Toll-like receptors (TLR), known cytosolic sensors of RNA (RIG-I/MDA-5) and DNA (DAI) recognition and interferon regulatory factor (IRF)-3, but is dependent on viral endosomal escape, signaling via the MAP kinase SAPK/JNK and IRF-7. Furthermore, we show that Ads induce IFN-ab and IL-6 in vivo by distinct pathways and confirm that IFN-ab positively regulates the IL-6 response. Finally, by measuring TNF-a responses to LPS in Ad-infected wild type and IFN-abR 2/2 mice, we show that IFN-ab is the key mediator of Ad-induced hypersensitivity to LPS. These findings indicate that, like endosomal TLR signaling in pDCs, TLR-independent virus recognition in splenic mDCs can also produce a robust early IFN-ab response, which is responsible for the bulk of IFN-ab production induced by adenovirus in vivo. The signaling requirements are different from known TLR-dependent or cytosolic IFN-ab induction mechanisms and suggest a novel cytosolic viral induction pathway. The hypersensitivity to components of the microbial flora and invading pathogens may in part explain the toxic side effects of adenoviral gene therapy and contribute to the pathogenesis of adenoviral disease.
Output: Key Role of Splenic Myeloid DCs in the IFN-ab Response to Adenoviruses In Vivo
Background: Protease-activated receptor 2 (PAR-2) is activated by proteases involved in allergy and triggers airway epithelial secretion and inflammation. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. Objective: We tested if epithelial remodeling during diseases characterized by loss of cilia and squamous metaplasia may alter PAR-2 polarization. Methods: Endogenous PAR-2 responses were measured by live cell calcium and cilia imaging, measurement of fluid secretion, and quantification of cytokines. We utilized airway squamous cell lines, primary differentiated air-liquid interface cultures, and tissue explants. Cells were exposed to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency. We used concentrations and exposure times that altered epithelial morphology without causing breakdown of the epithelial barrier, likely reflecting early disease states.
Output: Altered polarization of PAR-2 signaling during airway epithelial remodeling
Structured RNA elements within messenger RNA often direct or modulate the cellular production of active proteins. As reviewed here, RNA structures have been discovered that govern nearly every step in protein production: mRNA production and stability; translation initiation, elongation, and termination; protein folding; and cellular localization. Regulatory RNA elements are common within RNAs from every domain of life. This growing body of RNA-mediated mechanisms continues to reveal new ways in which mRNA structure regulates translation. We integrate examples from several different classes of RNA structure-mediated regulation to present a global perspective that suggests that the secondary and tertiary structure of RNA ultimately constitutes an additional level of the genetic code that both guides and regulates protein biosynthesis.
Output: The genetic code as expressed through relationships between mRNA structure and protein function
Mathematical models when applied to infectious disease data can provide extremely useful insights into the possible future impacts of potential emerging epidemics and how they might be best controlled or mitigated. Modelling, which is like any other hypothesis-driven approach, aims to develop a better understanding of biological phenomena. However, diseases processes generally, and particularly those related to transmission, will in many cases be imperfectly understood or too complex to systematically describe, so models will necessarily be simplifications of the overall system. It is essential, therefore, that models are designed carefully and used appropriately. Key to this is identifying what specific questions a model might be expected to answer and what data is available to inform the model. A particular type of model might be fine for one particular situation but highly inappropriate for another. It is also important to appreciate and communicate what simplifications and assumptions have had to be made and how this might affect the robustness of the modelling results. It is also particularly important to understand that models frequently make what can be hidden assumptions about underlying processes because of the way they have been constructed and these assumptions also need to be carefully considered and made explicit, particularly for non-expert audiences. This chapter, therefore, provides a brief introduction to some of these aspects of epidemic modelling for those that might be less familiar with them.
Output: Chapter 23 Modelling Emerging Viral Epidemics for Public Health Protection
Drug-resistant tuberculosis (TB) is an occupational hazard for health care workers (HCWs) in South Africa. We undertook this qualitative study to contextualize epidemiological findings suggesting that HCWs elevated risk of drug-resistant TB is related to workplace exposure. 55 HCWs and 7 hospital managers participated in focus groups and interviews about infection control (IC). Participants discussed caring for patients with drug-resistant TB, IC measures, occupational health programs, and stigma and support in the workplace. Key themes included: 1) lack of resources that hinders IC, 2) distrust of IC efforts among HCWs, and 3) disproportionate focus on individual level personal protections, particularly N95 masks. IC programs should be evaluated, and the impact of new policies to rapidly diagnose drug-resistant TB and decentralize treatment should be assessed as part of the effort to control drug-resistant TB and create a safe workplace.
Output: Health Care Worker Perspectives on Workplace Safety, Infection Control and Drug-Resistant Tuberculosis in a High Burden HIV setting
Nipah virus (NiV) is a member of the genus Henipavirus of the family Paramyxoviridae, characterized by high pathogenicity and endemic in South Asia. It is classified as a Biosafety Level-4 (BSL-4) agent. The case-fatality varies from 40% to 70% depending on the severity of the disease and on the availability of adequate healthcare facilities. At present no antiviral drugs are available for NiV disease and the treatment is just supportive. Phylogenetic and evolutionary analyses can be used to help in understanding the epidemiology and the temporal origin of this virus. This review provides an overview of evolutionary studies performed on Nipah viruses circulating in different countries. Thirty phylogenetic studies have been published from 2000 to 2015 years, searching on pubmed using the key words 'Nipah virus AND phylogeny' and twenty-eight molecular epidemiological studies from 2006 to 2015 have been performed, typing the key words 'Nipah virus AND molecular epidemiology'. Overall data from the published study demonstrated as phylogenetic and evolutionary analysis represent promising tools to evidence NiV epidemics, to study their origin and evolution and finally to act with effective preventive measure.
Output: Molecular epidemiology and phylogeny of Nipah virus infection: A mini review
Severe fever with thrombocytopenia syndrome (SFTS) is a novel emerging virus infection that was first found and reported in Peoples' Republic of China in 2009 and 2011, respectively. SFTS was later reported in Japan and South Korea, suggesting that SFTS is endemic to East Asian countries. Among these countries, the most SFTS cases have been reported in China. Geographically, SFTS cases have been mainly reported in rural and mountainous areas of the Eastern, Central, and North-Eastern China. So far, the number of SFTS cases has increased and the geographical distribution has expanded in China. From epidemiological studies, it was suggested that various factors including occupation, habit, tick bites, animal contact, environment, meteorological factor, demographic data, clinical symptoms, or laboratory data were associated with SFTS infection or fatal outcome. In this article, epidemiology of SFTS in China is described in detail to assess distributions over time, place, and person.
Output: Epidemiology of SFTS in China
We introduce a new approach to investigate the dual nucleotides compositions of 11 Gram-positive and 12 Gram-negative eubacteria recently studied by Sorimachi and Okayasu. The approach firstly obtains a 16-dimension vector set of dual nucleotides by PN-curve from the complete genome of organism. Each vector of the set corresponds to a single gene of genome. Then we reduce the 16-dimension vector set to 2-dimension by principal components analysis (PCA). The reduction avoids possible loss of information averaging all 16-dimension vectors. Then we suggest a 2D graphical representation based on the 2-dimension vector to investigate the classification patters among different organisms. Crown
Output: Classification analysis of dual nucleotides using dimension reduction
Using 11 overlapping synthetic peptides covering more than 95% of the amino acid sequence of capsid protein of rubella virus, 7 CD4+ T cell clones (Rl 0, Rl 1, R18, A2, Al 0, Al 1, and Al 2) isolated from 2 rubella seropositive donors reacted strongly to rubella capsid peptides C6 (residues 119-l 521, C9 (residues 205-233), or Cl 1 (residues 255-280), respectively, in both proliferation and cytotoxicity assay. Truncated peptides C6E (residues 125-l 39), C9B (residues 205-216), and Cl 1 E (residues 260-272) were shown to be involved directly to the T cell determinants of C6, C9, and Cl 1, respectively. Genetic restriction of these T cell clones was analyzed by using human cell lines with various HLA-DR phenotypes as targets and/or antigen-presenting cells in cytotoxicity assay and/or proliferation assays. The results indicated that the recognition of peptide C6 byT cell clones (Rl 1 and R18) was associated with DRw9 molecule, while the HLA restriction element of the responses of other T cell clones (A2 and Al 1, Al 0, and Al 2) that reacted with peptide C9 or Cl 1 was DR4 molecule. However, there may be a cross-recognition by the T cell clone (Al 2) between DRl and DR4 subtypes.
Output: Characterization of the Specificity and Genetic Restriction of Human CD4+ Cytotoxic T Cell Clones Reactive to Capsid Antigen of Rubella Virus
Invertebrates are hosts to diverse RNA viruses that have all possible types of encapsidated genomes (positive, negative and ambisense single stranded RNA genomes, or a double stranded RNA genome). These viruses also differ markedly in virion morphology and genome structure. Invertebrate RNA viruses are present in three out of four currently recognized orders of RNA viruses: Mononegavirales, Nidovirales, and Picornavirales, and 10 out of 37 RNA virus families that have yet to be assigned to an order. This mini-review describes general properties of the taxonomic groups, which include invertebrate RNA viruses on the basis of their current classification by the International Committee on Taxonomy of Viruses (ICTV).
Output: Invertebrate RNA virus diversity from a taxonomic point of view
Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the role of CSF1 in steady-state control of monocyte production and differentiation and tissue repair, we previously developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with the Fc region of pig IgG1a. CSF1-Fc administration to pigs expanded progenitor pools in the marrow and selectively increased monocyte numbers and their expression of the maturation marker CD163. There was a rapid increase in the size of the liver, and extensive proliferation of hepatocytes associated with increased macrophage infiltration. Despite the large influx of macrophages, there was no evidence of liver injury and no increase in circulating liver enzymes. Microarray expression profiling of livers identified increased expression of macrophage markers, i.e., cytokines such as TNF, IL1, and IL6 known to influence hepatocyte proliferation, alongside cell cycle genes. The analysis also revealed selective enrichment of genes associated with portal, as opposed to centrilobular regions, as seen in hepatic regeneration. Combined with earlier data from the mouse, this study supports the existence of a CSF1-dependent feedback loop, linking macrophages of the liver with bone marrow and blood monocytes, to mediate homeostatic control of the size of the liver. The results also provide evidence of safety and efficacy for possible clinical applications of CSF1-Fc. hepatosplenomegaly; CD163; macrophages; hepatostat; M-CSF This study is based on extensive studies in the mouse of the role of CSF1 in monocyte-macrophage production and differentiation and the function of macrophages in the control of hepatocyte proliferation. We use a novel form of CSF1, an Fc fusion protein, to demonstrate that the findings in mice can be extended to large animals. We discuss the possible role for CSF1 in homeostatic control of the size of the liver. MACROPHAGE COLONY-STIMULATING FACTOR (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage (23). Subsequent to the original isolation of human CSF1 cDNA in the 1980s and demonstration that injection of the recombinant CSF1 protein can expand macrophage popu-* K. A. Sauter and L. A. Waddell contributed equally to this work.
Output: Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs Licensed under Creative Commons Attribution CC-BY 3.0
In terms of its highly pathogenic nature, there remains a significant need to further define the immune pathology of SARScoronavirus (SARS-CoV) infection, as well as identify correlates of immunity to help develop vaccines for severe coronaviral infections. Here we use a SARS-CoV infection-reinfection ferret model and a functional genomics approach to gain insight into SARS immunopathogenesis and to identify correlates of immune protection during SARS-CoV-challenge in ferrets previously infected with SARS-CoV or immunized with a SARS virus vaccine. We identified gene expression signatures in the lungs of ferrets associated with primary immune responses to SARS-CoV infection and in ferrets that received an identical second inoculum. Acute SARS-CoV infection prompted coordinated innate immune responses that were dominated by antiviral IFN response gene (IRG) expression. Reinfected ferrets, however, lacked the integrated expression of IRGs that was prevalent during acute infection. The expression of specific IRGs was also absent upon challenge in ferrets immunized with an inactivated, Al(OH) 3 -adjuvanted whole virus SARS vaccine candidate that protected them against SARS-CoV infection in the lungs. Lack of IFN-mediated immune enhancement in infected ferrets that were previously inoculated with, or vaccinated against, SARS-CoV revealed 9 IRG correlates of protective immunity. This data provides insight into the molecular pathogenesis of SARS-CoV and SARS-like-CoV infections and is an important resource for the development of CoV antiviral therapeutics and vaccines. Citation: Cameron MJ, Kelvin AA, Leon AJ, Cameron CM, Ran L, et al. (2012) Lack of Innate Interferon Responses during SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model. PLoS ONE 7(9): e45842.
Output: Lack of Innate Interferon Responses during SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model
Background. Severity of human metapneumovirus (hMPV) lower respiratory illness (LRTI) is considered similar to that observed for respiratory syncytial virus (RSV). However, differences in severity between these pathogens have been noted, suggesting the degree of illness may vary in different populations. Moreover, a potential association between hMPV and asthma also suggests that hMPV may preferentially affect asthmatic subjects. Methods. In a population-based surveillance study in children aged <2 years admitted for severe LRTI in Argentina, nasopharyngeal aspirates were tested by RT-PCR for hMPV, RSV, influenza A, and human rhinovirus. Results. Of 3947 children, 383 (10%) were infected with hMPV. The hospitalization rate for hMPV LRTI was 2.26 per 1000 children (95% confidence interval [CI], 2.04-2.49). Thirty-nine (10.2%) patients infected with hMPV experienced life-threatening disease (LTD; 0.23 per 1000 children; 95% CI, .16-.31/1000), and 2 died (mortality rate 0.024 per 1000; 95% CI, .003-.086). In hMPV-infected children birth to an asthmatic mother was an increased risk for LTD (odds ratio, 4.72; 95% CI, 1.39-16.01). We observed a specific interaction between maternal asthma and hMPV infection affecting risk for LTD. Conclusions. Maternal asthma increases the risk for LTD in children <2 years old hospitalized for severe hMPV LRTI.
Output: The Journal of Infectious Diseases Role for Maternal Asthma in Severe Human Metapneumovirus Lung Disease Susceptibility in Children
The development of safe and effective vaccines for the prevention and control of emerging and neglected infectious diseases is an international priority, as is the development of similar control measures for bioterrorist threats. International standards have been established to ensure the protection of human subjects and the scientific integrity of clinical trial study design and data collection. A general overview of the history of the regulatory guidelines and ethical principles underpinning the vaccine development process is provided, with an emphasis on clinical trials conducted in the United States. 157 The contemporary vaccine development process involves sequential assessment of safety, immunogenicity, and efficacy in phase1, 2, and 3 clinical trials. The process is not always linear or straightforward, and adaptive flexible clinical trial designs can increase the likelihood of a successful outcome. Because the efficacy of vaccines for a number of the diseases discussed in this volume cannot be tested directly in humans, alternative approaches have been developed to address this challenge. The major elements of typical clinical trial protocol are discussed, and a checklist of essential documents supporting the trial is provided. As novel vaccine approaches and technologies emerge, the regulatory and ethical considerations will need to be revisited and adapted to respond to the everchanging landscape.
Output: Clinical Trials of Vaccines for Biodefense and Emerging and Neglected Diseases 12 12 Introduction Historical Considerations Regulatory issues Ethical issues Stages of Vaccine Development Overview Pre-IND stage IND stage Phase 1 clinical trials Phase 2 clinical trials Phase 3 clinical trials Phase 4 clinical trials Clinical Trial Protocol Development Background and rationale Objectives and purpose Study design Study population Study agent/interventions Study procedures and evaluations Study schedule Assessment of safety Clinical monitoring Statistical considerations Quality management Ethics/protection of human subjects Data management and record keeping Other considerations II. FUNDAMENTAL ASPECTS OF VACCINOLOGY CLINICAL TRIALS OF VACCINES FOR BIODEFENSE AND EMERGING AND NEGLECTED DISEASES 158
Faeces samples from 218, 1 to 30-day-old, diarrheic dairy calves in 65 dairy herds were screened for the presence of Cryptosporidium and concurrent infections with rotavirus, coronavirus, F5 Escherichia coli and Salmonella spp. Calves were grouped according to their age as follows: 1±7, 8±14, 15±21 and 22±30 days. Cryptosporidium infection was detected in 43.8%, 71.9%, 63.2% and 6.9% of the calves in the respective age groups. Significant differences in the detection rate of Cryptosporidium were found between the age group 22±30 days and all other age groups, and between the age group 1±7 days and the age groups 8±14 days and 15±21 days. Cryptosporidium was the only enteropathogen detected in 60 of the 114 (52.6%) diarrheic calves. Concurrent infections with other enteropathogen(s) were detected in 64.3%, 46.3%, 39.5% and 0% of the Cryptosporidium-infected calves in the age groups 1±7, 8±14, 15±21 and 22±30 days, respectively. A significant age-associated decrease in the detection rate of mixed infections (p < 0.05) was found. The detection rates of the other enteropathogens considered in calves with Cryptosporidium infection were 87% for rotavirus, 11.1% for coronavirus, 27.8% for F5 E. coli and 1.8% for Salmonella. #
Output: Cryptosporidium and concurrent infections with other major enterophatogens in 1 to 30-day-old diarrheic dairy calves in central Spain
Beijing has been severely affected by SARS, and SARS-associated coronavirus has been confirmed as its cause. However, clinical and experimental evidence implicates the possibility of co-infection. In this report, reovirus was isolated from throat swabs of SARS patients, including the first case in Beijing and her mother. Identification with the electron microscopy revealed the characteristic features of reovirus. 24 of 38 samples from other SARS cases were found to have serologic responses to the reovirus. Primers designed for reovirus have amplified several fragments of DNA, one of which was sequenced (S2 gene fragment), which indicates it as a unique reovirus (orthoreovirus). Preliminary animal experiment showed that inoculation of the reovirus in mice caused death with atypical pneumonia. Nevertheless, the association of reovirus with SARS outbreak requires to be further investigated.
Output: Reovirus, isolated from SARS patients
Objectives: The rapid emergence of drug-resistant Shigella sonnei is a serious public health problem. This study aimed to characterise the antimicrobial resistance patterns, molecular subtypes, and integron types and resistance gene cassettes in S. sonnei from Jiangsu Province, China. Methods: In total, 340 S. sonnei were collected in 2002-2011 throughout Jiangsu Province. Antimicrobial susceptibility testing, pulsed-field gel electrophoresis (PFGE), PCR amplification of integrons, restriction fragment length polymorphism (RFLP) and DNA sequencing of cassette regions were performed. Results: Resistance rates to ampicillin (67.7%), nalidixic acid (75.2%), tetracycline (73.7%) and trimethoprim/sulfamethoxazole (68.7%) remained high. Strains from Centre and South Jiangsu showed higher resistance and multiresistance rates compared with the North. PFGE analysis indicated that largescale clonal transmission among different cities occurred several times during 10 years. Among all strains, 55.9% (190/340) harboured class 1 integrons, 80.3% (273/340) harboured class 2 integrons and 49.4% (168/340) harboured an atypical class 1 integron. Resistance rates to nine antimicrobials in the class 1 integron-positive group were significantly higher than in the negative group (P < 0.05). Seven different gene cassettes were detected in class 1 integrons. The most prevalent type was aacA4-cmlA1 (114/286). Class 2 integrons carried the gene cassette array dfrA1-sat1-aadA1, and the atypical class 1 integron carried bla OXA-30 -aadA1. Conclusions: The increasing antimicrobial resistance and significant clonal transmission of S. sonnei circulating in Jiangsu were closely related to the high prevalence of integrons and gene cassettes. Longterm cross-regional monitoring of antimicrobial resistance is urgently required for S. sonnei.
Output: A 10-year surveillance of antimicrobial susceptibility patterns in Shigella sonnei isolates circulating in Jiangsu Province, China
Single cell suspensions obtained from day 7 human embryoid bodies (d7EBs) injected i.v. 1 hour after cecal ligation and puncture significantly reduced lung inflammation and edema as well as production of tumor necrosis factor-␣ and interferon-␥ in lungs compared with controls, whereas interleukin-10 production remained elevated. d7EB cell transplantation also reduced mortality to 50% from 90% in the control group. The protection was ascribed to d7EB cell interaction with lung resident CD11b؉ cells, and was correlated with the ability of d7EB cells to reduce it also reduced production of proinflammatory cytokines by CD11؉ cells, and to endothelial NO synthase-derived NO by d7EB cells, leading to inhibition of inducible macrophage-type NO synthase activation in CD11b؉ cells. The protective progenitor cells were positive for the endothelial and hematopoietic lineage marker angiotensin converting enzyme (ACE). Only the ACE؉ fraction modulated the proinflammatory profile of CD11b؉ cells and reduced mortality in septic mice. In contrast to the nonprotective ACE-cell fraction, the ACE؉ cell fraction also produced NO. These findings suggest that an ACE؉ subset of human embryonic stem cell-derived progenitor cells has a highly specialized anti-inflammatory function that ameliorates sepsis-induced lung inflammation and reduces mortality.
Output: Interaction of a Specific Population of Human Embryonic Stem Cell-Derived Progenitor Cells with CD11bϩ Cells Ameliorates Sepsis-Induced Lung Inflammatory Injury
Diabetes mellitus is a growing problem in all parts of the world. Both clinical trials and animal models of type I and type II diabetes have shown that hyperactivity of angiotensin-II (Ang-II) signaling pathways contribute to the development of diabetes and diabetic complications. Of clinical relevance, blockade of the renin-angiotensin system prevents new-onset diabetes and reduces the risk of diabetic complications. Angiotensin-converting enzyme (ACE) 2 is a recently discovered monocarboxypeptidase and the first homolog of ACE. It is thought to inhibit Ang-II signaling cascades mostly by cleaving Ang-II to generate Ang-(1−7), which effects oppose Ang-II and are mediated by the Mas receptor. The enzyme is present in the kidney, liver, adipose tissue and pancreas. Its expression is elevated in the endocrine pancreas in diabetes and in the early phase during diabetic nephropathy. ACE2 is hypothesized to act in a compensatory manner in both diabetes and diabetic nephropathy. Recently, we have shown the presence of the Mas receptor in the mouse pancreas and observed a reduction in Mas receptor immuno-reactivity as well as higher fasting blood glucose levels in ACE2 knockout mice, indicating that these mice may be a new model to study the role of ACE2 in diabetes. In this review we will examine the role of the renin-angiotensin system in the physiopathology and treatment of diabetes and highlight the potential benefits of the ACE2/Ang-(1 −7)/Mas receptor axis, focusing on recent data about ACE2.
Output: The sweeter side of ACE2: Physiological evidence for a role in diabetes
Preterm birth is a major obstetric problem. An exploration of the season of conception in relation to preterm birth may provide direction in the search for risk factors. We conducted a retrospective cohort study of 82 213 singleton livebirths (20-45 weeks' gestation) to 61 630 women at Magee-Womens Hospital, Pittsburgh, PA, from 1995 to 2005. Conception was estimated based on gestational age determined by best obstetric estimate. Fourier series analysis was used to model seasonal trends. Spontaneous preterm birth at <37 weeks was associated with conception season (P < 0.05). The peak prevalence occurred among conceptions in winter and spring (peaking February 23 at 6.9%), with an average trough among late summer/early autumn conceptions (August 25 at 6.2%). The pattern for spontaneous preterm birth <32 weeks was similar (P < 0.05), with the peak on March 13 (1.7%), and nadir on September 12 (1.4%). Results were similar when indicated preterm births were included. These seasonal changes may increase our insight into the role of exposures with seasonal periodicity in the pathophysiology of preterm birth.
Output: The prevalence of preterm birth and season of conception
We previously reported the crystal structure of an acetyl esterase (TcAE206) belonging to carbohydrate esterase family 3 from Talaromyces cellulolyticus. In this study, we solved the crystal structure of an S10A mutant of TcAE206 complexed with an acetate ion. The acetate ion was stabilized by three hydrogen bonds in the oxyanion hole instead of a water molecule as in the structure of wild-type TcAE206. Furthermore, the catalytic triad residue His182 moved 0.8 Å toward the acetate ion upon substrate entering the active site, suggesting that this movement is necessary for completion of the catalytic reaction.
Output: Crystal structure of an acetyl esterase complexed with acetate ion provides insights into the catalytic mechanism
FIG 3 Investigation of CSFV-infected pDC-derived cytokines on the MHC class II expression of NK and ␥␦ T cells. (A) pDCs or mDCs were exposed to CSFV C-strain, Brescia strain, or a mock virus-infected cryolysate supernatant, and after 24 h in culture, the levels of TNF-␣ and type I IFN in the supernatants were analyzed using a porcine cytokine multiplex ELISA and Mx/CAT reporter gene assay, respectively. (B) Enriched NK and ␥␦ T cells were then cultured in cRPMI medium alone or in the presence of porcine recombinant IFN-␣ and/or TNF-␣, at concentrations comparable to those detected in infected pDC cocultures, and the expression of MHC-II was assessed by flow cytometry after 24 h. The mean Ϯ SEM data from three independent experiments utilizing different animals are shown. The values for each group were compared to the corresponding unstimulated control (mock stimulation in panel A and no cytokine treatment in panel B) using a one-way ANOVA, followed by Dunnett's multiple comparison test: ***, P Ͻ 0.001; **, P Ͻ 0.01; *, P Ͻ 0.05. Franzoni et al. 1416 cvi.asm.org Clinical and Vaccine Immunology
Output: Partial Activation of Natural Killer and ␥␦ T Cells by Classical Swine Fever Viruses Is Associated with Type I Interferon Elicited from Plasmacytoid Dendritic Cells
Viral infections are commonplace and often innocuous. Nevertheless, within the population of patients with primary immunodeficiencies (PIDDs), viral infections can be the feature that drives a diagnostic evaluation or can be the most significant morbidity for the patient. This review is focused on the viral complications of PIDDs. It will focus on respiratory viruses, the most common type of viral infection in the general population. Children and adults with an increased frequency or severity of respiratory viral infections are often referred for an immunologic evaluation. The classic teaching is to investigate humoral function in people with recurrent sinopulmonary infections, but this is often interpreted to mean recurrent bacterial infections. Recurrent or very severe viral infections may also be a harbinger of a primary immunodeficiency as well. This review will also cover persistent cutaneous viral infections, systemic infections, central nervous system infections, and gastrointestinal infections. In each case, the specific viral infections may drive a diagnostic evaluation that is specific for that type of virus. This review also discusses the management of these infections, which can become problematic in patients with PIDDs.
Output: Recurrent and Sustained Viral Infections in Primary Immunodeficiencies
A Chinese isolate of avian infectious bronchitis virus (IBV) designated HH06 was isolated from the kidney tissues of a chicken flock experiencing an outbreak of nephritis. In vivo pathogenicity of the IBV isolate HH06 was determined by inoculating specific pathogen-free (SPF) chickens. The clinical signs and related gross lesions of HH06 infected chickens were similar with those of the field-infected chickens. SPF embryonated eggs were inoculated with virus suspension for serial passage and their genomic RNA was extracted. RT-PCR technique was utilized to amplify the M gene sequence encoding membrane protein of IBV. Recombinant plasmid named T-vector-M was constructed via inserting the M gene into the TA cloning vector, pMD 18-T. The sequenced M gene and its deduced amino acid (aa) sequences were compared with the published sequences of reference strains. The M gene is of 687 bp in length encoding the M protein of 228 amino acids with a predicted molecular weight of 25.4 kDa. The sequences of the M gene and M protein share 83.9-97.9% and 83.6-96.5% homologous identities, respectively, compared with 29 IBV reference strains derived from different regions or countries, which revealed that there are still significant variations between strains. Furthermore, a phylogenetic tree based on these M DNA sequences was generated, and the tree topology suggests that some Chinese IBV strains may have a common ancestor; however, HH06 is a new local IBV isolate that is responsible for the field outbreak of nephritis.
Output: Characterization and membrane gene-based phylogenetic analysis of avian infectious bronchitis virus Chinese strain HH06
Infection with Middle East respiratory syndrome coronavirus (MERS-CoV) could be asymptomatic or cause mild influenza-like illness. Therefore, the prevalence of MERS-CoV infections in the general population could be underestimated, which necessitates active surveillance to determine the epidemiological importance of asymptomatic cases. The aim of this study is to evaluate the performance of various serological assays and to estimate the seroprevalence of anti-MERS-CoV antibodies in high-and low-risk groups in Qatar. A total of 4858 samples were screened, including 4719 samples collected from healthy blood donors (BD) over a period of five years (2012-2016), 135 samples from baseline case contacts (CC) collected from individuals in close contact with three positive PCR-confirmed patients (CP), and four samples from MERS-CoV CP. Initial screening using anti-MERS-CoV IgG (IgG rS1-ELISA kit) revealed ten reactive samples from BD (10/4719, 0.21%), one from CC (1/135, 0.74%), and three from CP (3/4, 75%). Samples from CP but not from BD were also reactive by whole-virus anti-MERS-CoV IgG (n = 3/4) and IgM (n = 1/4) indirect immunefluorescent tests (IIFT) and pseudoparticle neutralization test (ppNT). The reactive sample from CC was also confirmed by ppNT. Surprisingly, one out of thirteen (7.7%) randomly selected IgG rS1-ELISA-negative BD samples from the initial screening was reactive by the IgM-IIFT (but not by the IgG-IIFT) and was subsequently confirmed by ppNT. All IgG rS1-ELISA-reactive samples from BD exhibited considerable reactivity to the four circulating human coronaviruses (HKU1, OC43, 229E, and NL63). Cross-reactivity with SARS was only reported for samples from CP using IgG and IgM-IIFT. In conclusion, we report a low prevalence of anti-MERS antibodies in the general population, which coincides with the low number of all reported cases by the time of our study (2017) in Qatar (n = 21). The false-positive results and the observed cross-reactivity between MERS-CoV and other circulating human coronavirus necessitate more detailed evaluation of available serological assays.
Output: Comparative Serological Study for the Prevalence of Anti-MERS Coronavirus Antibodies in High-and Low-Risk Groups in Qatar
Maternally-derived antibody to enterotropic mouse hepatitis virus (MHV) strain Y was transferred to pups by both intrauterine (IgG) and lactogenic (IgA and IgG) routes. Antibody present in the gastric whey of pups suckling immune dams dropped to undetectable levels by weaning age (21 days post partum). MHV-specific IgG was found in the serum of passively immune pups up to 10 weeks of age. Immune dams transferred equal levels of antibody to 3 consecutive litters of pups, without evidence of decline. Immunoblots showed that IgA and IgG in whey and serum were directed against nucleoprotein N and glycoprotein S. MHV-specific IgM was not detected in any sample.
Output: Maternally-derived passive immunity to enterotropic mouse hepatitis virus
The novel coronavirus, COVID-19, has sparked an outflow of scientific research seeking to understand the virus, its spread, and best practices in prevention and treatment. If this international research effort is going to be as swift and effective as possible, it will need to rely on a principle of open science. When researchers share data, code, and software and generally make their work as transparent as possible, it allows other researchers to verify and expand upon their work. Furthermore, it allows public officials to make informed decisions. In this study, we analyzed 535 preprint articles related to COVID-19 for eight transparency criteria and recorded study location and funding information. We found that individual researchers have lined up to help during this crisis, quickly tackling important public health questions, often without funding or support from outside organizations. However, most authors could improve their data sharing and scientific reporting practices. The contrast between researchers' commitment to doing important research and their reporting practices reveals underlying weaknesses in the research community's reporting habits, but not necessarily their science.
Output: Reproducibility and reporting practices in COVID-19 preprint manuscripts
Inspired by bioactive biaryl-containing natural products found in plants and the marine 19 environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family 20 was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs in a single-21 round infectivity assay resulted in the identification of three promising antiviral compounds, 22 including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOL B#24), which exhibited low-23 micromolar activity. The active compounds and several close structural analogues were further 24 tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus 25 replication system (EASY-HIT). Mode-of-action studies using a time-of-addition assay indicated 26 that azaBINOL B#24 acts after viral entry but before viral assembly and budding. HIV-1 reverse 27 transcriptase (RT) assays that individually test for polymerase and RNase H activity were used to 28 demonstrate that B#24 inhibits RNase H activity, most likely allosterically. Further binding 29 analysis using bio-layer interferometry (BLI) showed that B#24 interacts with HIV-1 RT in a 30 highly specific manner. These results indicate that azaBINOL B#24 is a potentially viable, novel 31
Output: Biological Evaluation of Molecules of the azaBINOL Class as Antiviral Agents: 1 Specific Inhibition of HIV-1 RNase H Activity by 7-Isopropoxy-8-(naphth-1-yl)quinoline 2 3 4 5
A case-control study was performed to identify clinical predictors for Middle East respiratory syndrome coronavirus (MERS-CoV) infection among patients with acute febrile illness during the nosocomial outbreak. Patients with MERS-CoV were more likely to have monocytosis with normal white blood cell (WBC) count and lower C-reactive protein (CRP) level. Simple laboratory data such as complete blood counts (CBC) with differential count could be a useful marker for the prediction of MERS and triage at the initial presentation of acute febrile patients in outbreak setting.
Output: Differential Cell Count and CRP Level in Blood as Predictors for Middle East Respiratory Syndrome Coronavirus Infection in Acute Febrile Patients during Nosocomial Outbreak
Treatment with first-generation antihistamines reduces sneezing, rhinorrhea, nasal mucus weight, and, in some instances, cough in subjects with experimental or natural colds; however, treatment with second-generation antihistamines has not been effective for these complaints in trials in subjects with natural colds. This article reports the negative results of a clinical trial with loratadine, a second-generation antihistamine, in adults in the rhinovirus challenge model. This finding in the highly controlled setting of the challenge model confirms the earlier negative studies with second-generation antihistamines in natural colds. First-generation antihistamines block both histaminic and muscarinic receptors as well as passing the blood-brain barrier. Secondgeneration antihistamines mainly block histaminic receptors and do not pass the blood-brain barrier. The effectiveness of first-generation antihistamines in blocking sneezing in colds may be due primarily to neuropharmacological manipulation of histaminic and muscarinic receptors in the medulla. The individual symptoms of a common cold are due to multiple and somewhat specific pathways of inflammation [1]. Sneezing has been generally thought to result from the release of histamine from nasal mast cells and basophils, which are activated by a cold virus infection. Supporting this belief is the finding that intranasal challenge with histamine in normal volunteers elicited sneezing whereas intranasal exposure to other
Output: Variant Effect of First-and Second-Generation Antihistamines as Clues to Their Mechanism of Action on the Sneeze Reflex in the Common Cold
A recent outbreak of novel coronavirus (SARS-CoV-2), the causative agent of COVID-19, has spread rapidly all over the world. Human immunodeficiency virus (HIV) is another deadly virus and causes acquired immunodeficiency syndrome (AIDS). Rapid and early detection of these viruses will facilitate early intervention and reduce disease transmission risk. Here, we present an All-In-One Dual CRISPR-Cas12a (termed "AIOD-CRISPR") assay method for simple, rapid, ultrasensitive, one-pot, and visual detection of coronavirus SARS-CoV-2 and HIV virus. In our AIOD CRISPR assay, a pair of crRNAs was introduced to initiate dual CRISPR-Cas12a detection and improve detection sensitivity. The AIOD-CRISPR assay system was successfully utilized to detect nucleic acids (DNA and RNA) of SARS-CoV-2 and HIV with a sensitivity of few copies. Also, it was evaluated by detecting HIV-1 RNA extracted from human plasma samples, achieving a comparable sensitivity with real-time RT-PCR method. Thus, our method has a great potential for developing next-generation point-of-care molecular diagnostics.
Output: All-in-One Dual CRISPR-Cas12a (AIOD-CRISPR) Assay: A Case for Rapid, Ultrasensitive and Visual Detection of Novel Coronavirus SARS-CoV-2 and HIV virus
The development and use of topical microbicides potentially offers an additional strategy to reduce the spread of the Human Immunodeficiency Virus (HIV). Carbohydrate-binding agents (CBAs) that show specificity for high mannose carbohydrates on the surface of the heavily glycosylated envelope of HIV are endowed with potent anti-HIV activity. In fact, a number of algal lectins such as cyanovirin-N, microvirin, microcystis viridis lectin, scytovirin, Oscillatoria agardhii agglutinin and griffithsin are considered as potential microbicide candidates to prevent the sexual transmission of HIV through topical applications. They not only inhibit infection of cells by cell-free virus but they can also efficiently prevent virus transmission from virus-infected cells to uninfected CD4 + target T-lymphocytes and DC-SIGN-directed capture of HIV-1 and transmission to CD4 + T lymphocytes. This review focuses on the structural properties and carbohydrate specificity of these algal lectins, their antiviral activity against HIV and several other enveloped viruses, their safety profile and viral resistance patterns.
Output: Algal Lectins as Potential HIV Microbicide Candidates
Research Facility at Fort Detrick, Frederick, Maryland, coordinate and facilitate preclinical research on infectious diseases to develop medical countermeasures for high-consequence pathogens. This facility is unique in that it is the only maximum containment laboratory in the world where conventional and molecular medical imaging equipments are incorporated into the design of the facility. This capability provides investigators with unique tools to dissect disease pathogenesis, evaluate the ability of animal models to recapitulate human disease, and test candidate countermeasures. Importantly, advanced molecular imaging has the potential to provide alternative endpoints to lethality. Using these alternative endpoints, investigators can reduce the number of animals used in experiments and evaluate countermeasures in sublethal models. With the incorporation of medical imaging modalities, a clinical laboratory modeled after those existing in hospitals, and a highly trained veterinary medicine team, IRF-Frederick is uniquely suited to advance our understanding of emerging infectious diseases and to facilitate the development of medical countermeasures and clinical care paradigms previously considered impossible.
Output: The NIAID Integrated Research Facility at Frederick, Maryland: a unique international resource to facilitate medical countermeasure development for BSL-4 pathogens
RNA pseudoknots are structural elements that participate in a variety of biological processes. At À1 ribosomal frameshifting sites, several types of pseudoknot have been identi®ed which differ in their organisation and functionality. The pseudoknot found in infectious bronchitis virus (IBV) is typical of those that possess a long stem 1 of 11-12 bp and a long loop 2 (30-164 nt). A second group of pseudoknots are distinguishable that contain stems of only 5 to 7 bp and shorter loops. The NMR structure of one such pseudoknot, that of mouse mammary tumor virus (MMTV), has revealed that it is kinked at the stem 1-stem 2 junction, and that this kinked conformation is essential for ef®cient frameshifting. We recently investigated the effect on frameshifting of modulating stem 1 length and stability in IBV-based pseudoknots, and found that a stem 1 with at least 11 bp was needed for ef®cient frameshifting. Here, we describe the sequence manipulations that are necessary to bypass the requirement for an 11 bp stem 1 and to convert a short non-functional IBV-derived pseudoknot into a highly ef®cient, kinked frameshifter pseudoknot. Simple insertion of an adenine residue at the stem 1-stem 2 junction (an essential feature of a kinked pseudoknot) was not suf®cient to create a functional pseudoknot. An additional change was needed: ef®cient frameshifting was recovered only when the last nucleotide of loop 2 was changed from a G to an A. The requirement for an A at the end of loop 2 is consistent with a loop-helix contact similar to those described in other RNA tertiary structures. A mutational analysis of both partners of the proposed interaction, the loop 2 terminal adenine residue and two G ÁC pairs near the top of stem 1, revealed that the interaction was essential for ef®cient frameshifting. The speci®c requirement for a 3 H -terminal A residue was lost when loop 2 was increased from 8 to 14 nt, suggesting that the loop-helix contact may be required only in those pseudoknots with a short loop 2.
Output: Evidence for an RNA Pseudoknot Loop-Helix Interaction Essential for Efficient À1 Ribosomal Frameshifting