niryuu/sni-each-converted huggingface dataset:
China, respiratory manifestations of the disease have been observed. However, as a fatal comorbidity, acute myocardial injury (AMI) in COVID-19 patients has not been previously investigated in detail. We investigated the clinical characteristics of COVID-19 patients with AMI and determined the risk factors for AMI in them. We analyzed data from 53 consecutive laboratory-confirmed and hospitalized COVID-19 patients (28 men, 25 women; age, 19-81 years). We collected information on epidemiological and demographic characteristics, clinical features, routine laboratory tests (including cardiac injury biomarkers), echocardiography, electrocardiography, imaging findings, management methods, and clinical outcomes. Results: Cardiac complications were found in 42 of the 53 (79.25%) patients: tachycardia (n=15), electrocardiography abnormities (n=11), diastolic dysfunction (n=20), elevated myocardial enzymes (n=30), and AMI (n=6). All the six AMI patients were aged >60 years; five of them had two or more underlying comorbidities (hypertension, diabetes, cardiovascular diseases, and chronic obstructive pulmonary disease). Novel coronavirus pneumonia (NCP) severity was higher in the AMI patients than in patients with non-definite AMI (p<0.001). All the AMI patients required care in intensive care unit; of them, three died, two remain hospitalized. Multivariate analyses showed that C-reactive protein (CRP) levels, NCP severity, and underlying comorbidities were the risk factors for cardiac abnormalities in COVID-19 patients. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Output: Acute Myocardial Injury of Patients with Coronavirus Disease 2019
The World Health Organization (WHO) has recommended that a severe acute respiratory syndrome (SARS) alert should be raised when two or more healthcare workers (HCW) in the same health care unit fulfil the SARS clinical criteria, with onset of illness in the same 10-day period. However, in a number of European countries (including Italy) data on reasons for sickness absence are not routinely collected within current HCW worker sickness reporting systems, because of concerns about privacy. To help plan for the implementation of the proposed alert system in Italy, we aimed to determine the minimum number of alert cases defining a cluster. Patients and Methods: Sickness absences longer than 7 days in HCW employed in three hospitals in 2003, were identified by checking the hospitals' administrative databases. HCW with onset of illness in the same 10-day period were contacted and asked whether they have been diagnosed with pneumonia. Results: Overall, 273 absences > 7 days were recorded and 36 clusters of at least two absences > 7 days were identified; a total of 94 HCW were involved in these clusters. Only two HCW involved in different clusters, reported pneumonia. Conclusion: The occurrence of clusters of two or more cases of pneumonia in HCW in the same hospital unit appears to be an uncommon event, and thus the alert system proposed is not likely to result in large numbers of false positive alerts. However, it may be difficult to implement this alert system in countries where clinical data on sickness absences are not routinely collected, and alternative mechanisms should be considered.
Output: Clustered Cases of Pneumonia among Healthcare Workers over a 1-year Period in Three Italian Hospitals: Applying the WHO SARS Alert
G-quadruplexes (G4s) have become one of the most exciting nucleic acid secondary structures. A noncanonical, four-stranded structure formed in guanine-rich DNA and RNA sequences, G-quadruplexes can readily form under physiologically relevant conditions and are globularly folded structures. DNA is widely recognized as a double-helical structure essential in genetic information storage. However, only~3% of the human genome is expressed in protein; RNA and DNA may form noncanonical secondary structures that are functionally important. G-quadruplexes are one such example which have gained considerable attention for their formation and regulatory roles in biologically significant regions, such as human telomeres, oncogene-promoter regions, replication initiation sites, and 5 0 -and 3 0 -untranslated region (UTR) of mRNA. They are shown to be a regulatory motif in a number of critical cellular processes including gene transcription, translation, replication, and genomic stability. G-quadruplexes are also found in nonhuman genomes, particularly those of human pathogens. Therefore, G-quadruplexes have emerged as a new class of molecular targets for drug development. In addition, there is considerable interest in the use of G-quadruplexes for biomaterials, biosensors, and biocatalysts. The First International Meeting on Quadruplex DNA was held in 2007, and the G-quadruplex field has been growing dramatically over the last decade. The methods used to study G-quadruplexes have been essential to the rapid progress in our understanding of this exciting nucleic acid secondary structure.
Output: Chapter 1 G-Quadruplex DNA and RNA
The basic reproduction number R 0 is one of the most important concepts in modern infectious disease epidemiology. However, for more realistic and more complex models than those assuming homogeneous mixing in the population, other threshold quantities can be defined that are sometimes more useful and easily derived in terms of model parameters. In this paper, we present a model for the spread of a permanently immunizing infection in a population socially structured into households and workplaces/schools, and we propose and discuss a new household-to-household reproduction number R H for it. We show how R H overcomes some of the limitations of a previously proposed threshold parameter, and we highlight its relationship with the effort required to control an epidemic when interventions are targeted at randomly selected households.
Output: Threshold parameters for a model of epidemic spread among households and workplaces
Findings PLANET relies on real-time information from three levels of participants in large-scale programs: funders, managers and recipients. At each level, information is solicited to assess five key risks that are most relevant to each level of operations. The risks at the level of funders involve systematic neglect of certain areas, focus on donor' s interests over that of program recipients, ineffective co-ordination between donors, questionable mechanisms of delivery and excessive loss of funding to "middle men". At the level of managers, the risks are corruption, lack of capacity and/or competence, lack of information and /or communication, undue avoidance of governmental structures / preference to non-governmental organizations and exclusion of local expertise. At the level of primary recipients, the risks are corruption, parallel operations / "verticalization", misalignment with local priorities and lack of community involvement, issues with ethics, equity and/or acceptability, and low likelihood of sustainability beyond the end of the program' s implementation. Interpretation PLANET is intended as an additional tool available to policy-makers to prioritize, monitor and evaluate large-scale development programs. In this, it should complement tools such as LiST (for health care/interventions), EQUIST (for health care/interventions) and CHNRI (for health research), which also rely on information from local experts and on local context to set priorities in a transparent, userfriendly, replicable, quantifiable and specific, algorithmic-like manner.
Output: VIEWPOINTS PaPErS journal of health global Improving health aid for a better planet: The planning, monitoring and evaluation tool (PLaNET)
Background: Despite the seriousness of dengue-related disease, with an estimated 50-100 million cases of dengue fever and 250,000-500,000 cases of dengue hemorrhagic fever/dengue shock syndrome each year, a clear understanding of dengue pathogenesis remains elusive. Because of the lack of a disease model in animals and the complex immune interaction in dengue infection, the study of host response and immunopathogenesis is difficult. The development of genomics technology, microarray and high throughput quantitative PCR have allowed researchers to study gene expression changes on a much broader scale. We therefore used this approach to investigate the host response in dengue virusinfected cell lines and in patients developing dengue fever. Methodology/Principal Findings: Using microarray and high throughput quantitative PCR method to monitor the host response to dengue viral replication in cell line infection models and in dengue patient blood samples, we identified differentially expressed genes along three major pathways; NF-kB initiated immune responses, type I interferon (IFN) and the ubiquitin proteasome pathway. Among the most highly upregulated genes were the chemokines IP-10 and I-TAC, both ligands of the CXCR3 receptor. Increased expression of IP-10 and I-TAC in the peripheral blood of ten patients at the early onset of fever was confirmed by ELISA. A highly upregulated gene in the IFN pathway, viperin, was overexpressed in A549 cells resulting in a significant reduction in viral replication. The upregulation of genes in the ubiquitin-proteasome pathway prompted the testing of proteasome inhibitors MG-132 and ALLN, both of which reduced viral replication. Conclusion/Significance: Unbiased gene expression analysis has identified new host genes associated with dengue infection, which we have validated in functional studies. We showed that some parts of the host response can be used as potential biomarkers for the disease while others can be used to control dengue viral replication, thus representing viable targets for drug therapy.
Output: Host Gene Expression Profiling of Dengue Virus Infection in Cell Lines and Patients
A recombinant vaccinia virus producing the bacteriophage T7 RNA polymerase was used to express foreign genes in eukaryotic cells. Translation efficiency in this expression system was enhanced significantly by employing the encephalomyocarditis virus (EMCV) 5'-untranslated region (UTR) which confers cap-independent translation by directing internal initiation of translation. The enhancement was accomplished by fusing open reading frames (ORFs) to the N terminus of the EMCV polyprotein coding region, thus utilizing its highly efficient translation initiation site. Expression vectors were constructed to allow cloning in all three reading frames. As reporter genes, we used the IucZ gene and a number of genes encoding coronavirus structural proteins: among others the genes encoding glycoproteins with N-terminal signal sequences. The signal sequences of these glycoproteins are located internally in the primary translation product. We demonstrated that this did not interfere with translocation and glycosylation and yields biologically active proteins. The usefulness of sequences that direct internal initiation was extended by using EMCV UTR s to express two and three ORFs from polycistronic mRNAs.
Output: Enhancement of the vaccinia virus/phage T7 RNA polymerase expression system using encephalomyocarditis virus 5'-untranslated region sequences
has rapidly spread to almost all parts of world. In coronaviruses, the receptor binding domain (RBD) in the distal part of S1 subunit of SARS-CoV-2 spike protein can directly bind to angiotensin converting enzyme 2 (ACE2). RBD promote viral entry into the host cells and is an important therapeutic target. In this study, we discovered that theaflavin showed the lower idock score (idock score: −7.95 kcal/mol). To confirm the result, we discovered that theaflavin showed FullFitness score of -991.21 kcal/mol and estimated ΔG of -8.53 kcal/mol for the most favorable interaction with contact area of SARS-CoV-2 RBD by SwissDock service. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were formed between theaflavin and Arg454, Phe456, Asn460, Cys480, Gln493, Asn501 and Val503 of SARS-CoV-2 RBD, near the direct contact area with ACE2. Our results suggest that theaflavin could be the candidate of SARS-CoV-2 entry inhibitor for further study.
Output: The potential SARS-CoV-2 entry inhibitor
We used a regression model to examine the impact of influenza on death rates in tropical Singapore for the period 1996-2003. Influenza A (H3N2) was the predominant circulating influenza virus subtype, with consistently significant and robust effect on mortality rates. Influenza was associated with an annual death rate from all causes, from underlying pneumonia and influenza, and from underlying circulatory and respiratory conditions of 14.8 (95% confidence interval 9.8-19.8), 2.9 (1.0-5.0), and 11.9 (8.3-15.7) per 100,000 person-years, respectively. These results are comparable with observations in the United States and subtropical Hong Kong. An estimated 6.5% of underlying pneumonia and influenza deaths were attributable to influenza. The proportion of influenza-associated deaths was 11.3 times higher in persons age >65 years than in the general population. Our findings support the need for influenza surveillance and annual influenza vaccination for at-risk populations in tropical countries.
Output: Influenza-associated Deaths in Tropical Singapore Influenza-associated Deaths in Tropical Singapore
Many viruses cause disease within an infected host after spread from an initial portal of entry to secondary sites of replication. Viruses can disseminate via the bloodstream or through nerves. Mammalian orthoreoviruses (reoviruses) are neurotropic viruses that use both bloodborne and neural pathways to spread systemically within their hosts to cause disease. Using a robust mouse model and a dynamic reverse genetics system, we have identified a viral receptor and a viral nonstructural protein that are essential for hematogenous reovirus dissemination. Junctional adhesion molecule-A (JAM-A) is a member of the immunoglobulin superfamily expressed in tight junctions and on hematopoietic cells that serves as a receptor for all reovirus serotypes. Expression of JAM-A is required for infection of endothelial cells and development of viremia in mice, suggesting that release of virus into the bloodstream from infected endothelial cells requires JAM-A. Nonstructural protein σ1s is implicated in cell cycle arrest and apoptosis in reovirus-infected cells but is completely dispensable for reovirus replication in cultured cells. Surprisingly, a recombinant σ1s-null reovirus strain fails to spread hematogenously in infected mice, suggesting that σ1s facilitates apoptosis of reovirus-infected intestinal epithelial cells. It is possible that apoptotic bodies formed as a consequence of σ1s expression lead to reovirus uptake by dendritic cells for subsequent delivery to the mesenteric lymph node and the blood. Thus, both host and viral factors are required for efficient hematogenous dissemination of reovirus. Understanding mechanisms of reovirus bloodborne spread may shed light on how microbial pathogens invade the bloodstream to disseminate and cause disease in infected hosts.
Output: Mechanisms of Reovirus Bloodstream Dissemination
Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidencebased guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline.
Output: Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations
Hepatitis B virus (HBV) infection is considered a major public health problem worldwide, and a significant number of reports on nosocomial and occupational outbreaks have been reported. This systematic investigation of HBV stability and susceptibility to different antiseptics revealed that HBV infectivity was very stable, with a half-life of >22 days at 37°C. At 4°C, infectivity was barely reduced for up to 9 months. Different alcohols and commercially available hand antiseptics had a virucidal effect against HBV. We propose that very strict compliance with established hygienic guidelines should be mandatory to avoid and prevent HBV infections.
Output: The Journal of Infectious Diseases High Environmental Stability of Hepatitis B Virus and Inactivation Requirements for Chemical Biocides
Chronic diseases are the dominant issues for global public health in terms of mortality, morbidity, and cost, and they have been identified as such for >40 years. Despite their predominance, however, these diseasescardiovascular disease (CVD), diabetes, cancer, pulmonary disease, mental health, and dementia-attract little attention in the public health curriculum and even less from the funding community. We explore the rationales that have perpetuated this inability or unwillingness to match need with effort. We examine 3 concepts that impede changing this relationship: 1) the traditional contextual view of public health that emerged, to be sure with great success, in the posteWorld War II era; 2) the failure of public health to transition to economic development as the goal of health assistance; and 3) the unwillingness of public health to confront social, political, and economic policies as the foci of upstream drivers of the public's health. We conclude with a discussion of the need for public health to expand its horizon and tear down the walls of the silos that inhibit the emergence of relevant global public health.
Output: And Why So Great a "No?" The Donor and Academic Communities' Failure to Confront Global Chronic Disease
Background: Bovine coronavirus (BCoV) is a widely distributed pathogen, causing disease and economic losses in the cattle industry worldwide. Prevention of virus spread is impeded by a lack of basic knowledge concerning viral shedding and transmission potential in individual animals. The aims of the study were to investigate the duration and quantity of BCoV shedding in feces and nasal secretions related to clinical signs, the presence of virus in blood and tissues and to test the hypothesis that seropositive calves are not infectious to naïve in-contact calves three weeks after BCoV infection. Methods: A live animal experiment was conducted, with direct contact between animal groups for 24 h as challenge procedure. Four naïve calves were commingled with a group of six naturally infected calves and sequentially euthanized. Two naïve sentinel calves were commingled with the experimentally exposed group three weeks after exposure. Nasal swabs, feces, blood and tissue samples were analyzed for viral RNA by RT-qPCR, and virus isolation was performed on nasal swabs. Serum was analyzed for BCoV antibodies. Results: The calves showed mild general signs, and the most prominent signs were from the respiratory system. The overall clinical score corresponded well with the shedding of viral RNA the first three weeks after challenge. General depression and cough were the signs that correlated best with shedding of BCoV RNA, while peak respiratory rate and peak rectal temperature appeared more than a week later than the peak shedding. Nasal shedding preceded fecal shedding, and the calves had detectable amounts of viral RNA intermittently in feces through day 35 and in nasal secretions through day 28, however virus isolation was unsuccessful from day six and day 18 from the two calves investigated. Viral RNA was not detected in blood, but was found in lymphatic tissue through day 42 after challenge. Although the calves were shedding BCoV RNA 21 days after infection the sentinel animals were not infected. Conclusions: Prolonged shedding of BCoV RNA can occur, but detection of viral RNA does not necessarily indicate a transmission potential. The study provides valuable information with regard to producing scientifically based biosecurity advices.
Output: Bovine coronavirus in naturally and experimentally exposed calves; viral shedding and the potential for transmission
Hepatitis B virus (HBV) is a unique, tiny, partially doublestranded, reverse-transcribing DNA virus with proteins encoded by multiple overlapping reading frames. The substitution rate is surprisingly high for a DNA virus, but lower than that of other reverse transcribing organisms. More than 260 million people worldwide have chronic HBV infection, which causes 0.8 million deaths a year. Because of the high burden of disease, international health agencies have set the goal of eliminating HBV infection by 2030. Nonetheless, the intriguing HBV genome has not been well characterized. We summarize data on the HBV genome structure and replication cycle, explain and quantify diversity within and among infected individuals, and discuss advances that can be offered by application of next-generation sequencing technology. Indepth HBV genome analyses could increase our understanding of disease pathogenesis and allow us to better predict patient outcomes, optimize treatment, and develop new therapeutics.
Output: Insights From Deep Sequencing of the HBV Genome-Unique, Tiny, and Misunderstood Abbreviations used in the
The interferon (IFN) system is one of the most important defensive responses of mammals against viruses, and is rapidly evoked when the pathogen-associated molecular patterns (PAMPs) of viruses are sensed. Non-self, virus-derived RNA species have been identified as the PAMPs of RNA viruses. In the present study, we compared different types of IFN-β-inducing and -non-inducing viruses in the context of Sendai virus infection. We found that some types of unusual viral RNA species were produced by infections with IFN-β-inducing viruses and accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner. One of these structures was similar to the so-called antiviral stress granules (avSGs) formed by an infection with IFN-inducing viruses whose C proteins were knocked-out or mutated. Non-encapsidated, unusual viral RNA harboring the 5 -terminal region of the viral genome as well as RIG-I and typical SG markers accumulated in these granules. Another was a non-SG-like inclusion formed by an infection with the Cantell strain; a copyback-type DI genome, but not an authentic viral genome, specifically accumulated in the inclusion, whereas RIG-I and SG markers did not. The induction of IFN-β was closely associated with the production of these unusual RNAs as well as the formation of the cytoplasmic structures.
Output: a section of the journal Frontiers in Microbiology IFN-β-inducing, unusual viral RNA species produced by paramyxovirus infection accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner
Background: c-Jun NH 2 -terminal kinase/stress-activated kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase (p38 MAPK) are important components of cellular signal transduction pathways, which have been reported to be involved in viral replication. However, little is known about JNK1/2 and p38 MAPK signaling pathways in enterovirus 71 (EV71)-infected immature dendritic cells (iDCs). Thus, iDCs were induced from peripheral blood mononuclear cells (PBMC) and performed to explore the expressions and phosphorylation of molecules in the two signaling pathways as well as secretions of inflammatory cytokines and interferons during EV71 replication. Results: We showed that EV71 infection could activate both JNK1/2 and p38 MAPK in iDCs and phosphorylate their downstream transcription factors c-Fos and c-Jun, which further promoted the production of IL-2, IL-6, IL-10, and TNF-α. Moreover, EV71 infection also increased the release of IFN-β and IL-12 p40. Pretreatment of iDCs with SP600125 and SB203580 (20 μM) could severely impair viral replication and its induced phosphorylation of JNK1/2, p38 MAPK, c-Fos and c-Jun. In addition, treatment of EV71-infected iDCs with SP600125 and SB203580 could inhibit secretions of IL-6, IL-10 and TNF-α. Conclusion: JNK1/2 and p38 MAPK signaling pathways are beneficial to EV71 infection and positively regulate secretions of inflammatory cytokines in iDCs.
Output: Activation of JNK1/2 and p38 MAPK signaling pathways promotes enterovirus 71 infection in immature dendritic cells
The objective of this study was to obtain insight into the adverse health effects of airborne particulate matter (PM) collected from live bird markets and to determine whether biological material in PM accounts for immune-related inflammatory response. Mice were exposed to a single or repeated dose of PM, after which the expression of toll-like receptors (TLRs), cytokines, and chemokines in the lungs of infected mice were examined by enzyme-linked immunosorbent assay and histopathological analysis. Results after single and repeated PM stimulation with PM + + 2.5 , PM − 2.5 , PM 10 , and PM − 10 indicated that TLR2 and TLR4 played a dominant role in the inflammatory responses of the lung. Further analysis demonstrated that the expression levels of IL-1β, TNF-α, IFN-γ, IL-8, IP-10, and MCP-1 increased significantly, which could eventually contribute to lung injury. Moreover, biological components in PM were critical in mediating immune-related inflammatory responses and should therefore not be overlooked.
Output: Immunity-Related Protein Expression and Pathological Lung Damage in Mice Poststimulation with Ambient Particulate Matter from Live Bird Markets
As the deployment of electronic medical records (EMR) expands, so is the availability of long-term datasets that could serve to enhance public health surveillance. We hypothesized that EMR-based surveillance systems that incorporate seasonality and other long-term trends would discover outbreaks of acute respiratory infections (ARI) sooner than systems that only consider the recent past. conditions, SARIMA could reduce detection delay by 5-16 days. It also was more sensitive at detecting the summer wave of the 2009 influenza pandemic. Time series modeling of long-term historical EMR data can reduce the time it takes to discover epidemics of ARI. Realistic surveillance simulations may prove invaluable to optimize system design and tuning.
Output: Can long-term historical data from electronic medical records improve surveillance for epidemics of acute respiratory infections? A systematic evaluation
Human intestinal maltase (HMA) is an αglucosidase responsible for the hydrolysis of α-1,4-linkages from the non-reducing end of malto-oligosaccharides. HMA has become an important target in the treatment of type-2 diabetes. In this study, epigallocatechin gallate (EGCG) and EGCG glucoside (EGCG-G1) were identified as inhibitors of HMA by an in vitro assay with IC 50 of 20 ± 1.0 and 31.5 ± 1.0 µM, respectively. A Lineweaver-Burk plot confirmed that EGCG and EGCG-G1 were competitive inhibitors of maltose substrate against HMA and inhibition kinetic constants (K i ) calculated from a Dixon plot were 5.93 ± 0.26 and 7.88 ± 0.57 µM, respectively. Both EGCG and EGCG-G1 bound to the active site of HMA with numerous hydrophobic and hydrogen bond interactions.
Output: Inhibitory Effects of Epigallocatechin Gallate and Its Glucoside on the Human Intestinal Maltase Inhibition
The human respiratory coronavirus OC43 was grown on a human rectal tumor cell line and was isotopically labeled with amino acids, glucosamine, and orthophosphate to analyze virion structural proteins. Four major protein species were resolved by electrophoresis and many of their properties were deduced from digestion studies using proteolytic enzymes. The four proteins are: (1) A 190 kDa protein, the presumed peplomeric protein, that was glycosylated and proteolytically cleavable by trypsin into subunits of 110 and 90 kDa. The subunits each represent a different amino acid sequence on the basis of peptide mapping; (2) a 130 kDa protein that was glycosylated and behaved as a disulfide-linked dimer of 65 kDa molecules. It is the apparent virion hemagglutinin on the basis of digestion studies with trypsin, bromelain and pronase; (3) a 55 kDa nucleocapsid protein that was phosphorylated; (4) a 26 kDa matrix protein that was glycosylated. The 190, 130, 55 and 26 kDa species can therefore be designated P, H, N and M, respectively. They exist in molar ratios of 4 : 1 : 33 : 33, and are calculated to be present at the rate of 88, 22, 726, and 726 molecules per virion, respectively. human respiratory coronovirus 0C43, structural proteins 0168-1702/86/$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)
Output: Structural proteins of human respiratory coronavirus 0C43
A human microsatellite DNA-mimicking ODN (MS ODN) composed of CCT repeats, designated as SAT05f, has been studied for its capacity of negatively regulating innate immunity induced by TLR7/TLR9 agonists in vitro and in mice. The result showed that SAT05f could downregulate TLR7/9-dependent IFN-α production in cultured human PBMC stimulated by inactivated Flu virus PR8 or HSV-1 or CpG ODN or imiquimod, protect D-GalN-treated mice from lethal shock induced by TLR9 agonist, not by TLR3/4 agonist. In addition, SAT05f significantly inhibit IFN-α production from purified human plasmacytoid cells (pDCs) stimulated by CpG ODN. Interestingly, SAT05f could up-regulate CD80, CD86, and HLA-DR on the pDCs in vitro, implying that SAT05fmediated inhibition on IFN-α production could be related to the activation of pDCs. The data suggest that SAT05f could be developed as a candidate medicament for the treatment of TLR7/9 activation-associated diseases by inhibiting TLR7/9 signaling pathways.
Output: A human microsatellite DNA-mimicking oligodeoxynucleotide with CCT repeats negatively regulates TLR7/9-mediated innate immune responses via selected TLR pathways
Transchromosomic bovines (Tc-bovines) adaptively produce fully human polyclonal immunoglobulin (Ig)G antibodies after exposure to immunogenic antigen(s). The National Interagency Confederation for Biological Research and collaborators rapidly produced and then evaluated anti-Ebola virus IgG immunoglobulins (collectively termed SAB-139) purified from Tc-bovine plasma after sequential hyperimmunization with an Ebola virus Makona isolate glycoprotein nanoparticle vaccine. SAB-139 was characterized by several in vitro production, research, and clinical level assays using wild-type Makona-C05 or recombinant virus/antigens from different Ebola virus variants. SAB-139 potently activates natural killer cells, monocytes, and peripheral blood mononuclear cells and has high-binding avidity demonstrated by surface plasmon resonance. SAB-139 has similar concentrations of galactose-α-1,3-galactose carbohydrates compared with human-derived intravenous Ig, and the IgG1 subclass antibody is predominant. All rhesus macaques infected with Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 and treated with sufficient SAB-139 at 1 day (n = 6) or 3 days (n = 6) postinfection survived versus 0% of controls. This study demonstrates that Tc-bovines can produce pathogen-specific human Ig to prevent and/or treat patients when an emerging infectious disease either threatens to or becomes an epidemic.
Output: The Journal of Infectious Diseases Fully Human Immunoglobulin G From Transchromosomic Bovines Treats Nonhuman Primates Infected With Ebola Virus Makona Isolate
This study investigates property securities bubbles and crashes by using a dynamic mathematical methodology developed from the previous research (Watanabe et al. 2007a, b [31,32]). The improved model is used to detect the bubble and crash periods in five international countries/cities (namely, . By this model definition, we are able to detect the beginning of each bubble period even before it bursts. Meanwhile, the empirical results show that most of property securities markets experienced bubble periods between 2003 and 2007, and crashes happened in Apr 2008 triggered by the Subprime Mortgage Crisis of US. In contrast, Japan suffered the shortest bubble period and no evidence has documented the existence of crash there.
Output: Physica A A dynamic mathematical test of international property securities bubbles and crashes
Monocytes are a heterogeneous population of bone marrow-derived cells that are recruited to sites of infection and inflammation in many models of human diseases, including those of the central nervous system (CNS). Ly6C hi / CCR2 hi inflammatory monocytes have been identified as the circulating precursors of brain macrophages, dendritic cells and arguably microglia in experimental autoimmune encephalomyelitis; Alzheimer's disease; stroke; and more recently in CNS infection caused by Herpes simplex virus, murine hepatitis virus, Theiler's murine encephalomyelitis virus, Japanese encephalitis virus and West Nile virus. The precise differentiation pathways and functions of inflammatory monocyte-derived populations in the inflamed CNS remains a contentious issue, especially in regard to the existence of monocyte-derived microglia. Furthermore, the contributions of monocyte-derived subsets to viral clearance and immunopathology are not well-defined. Thus, understanding the pathways through which inflammatory monocytes migrate to the brain and their functional capacity within the CNS is critical to inform future therapeutic strategies. This review discusses some of the key aspects of inflammatory monocyte trafficking to the brain and addresses the role of these cells in viral encephalitis.
Output: Inflammatory monocytes and the pathogenesis of viral encephalitis
The etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology supports a relationship of KD to an infectious disease. Several pathological mechanisms are being considered, including a superantigen response, direct invasion by an infectious etiology or an autoimmune phenomenon. Treating affected patients with intravenous immunoglobulin is effective at reducing the rates of coronary aneurysms. However, the role of B cells and antibodies in KD pathogenesis remains unclear. Murine models are not clear on the role for B cells and antibodies in pathogenesis. Studies on rare aneurysm specimens reveal plasma cell infiltrates. Antibodies generated from these aneurysmal plasma cell infiltrates showed cross-reaction to intracellular inclusions in the bronchial epithelium of a number of pathologic specimens from children with KD. These antibodies have not defined an etiology. Notably, a number of autoantibody responses have been reported in children with KD. Recent studies show acute B cell responses are similar in children with KD compared to children with infections, lending further support of an infectious disease cause of KD. Here, we will review and discuss the inconsistencies in the literature in relation to B cell responses, specific antibodies, and a potential role for humoral immunity in KD pathogenesis or diagnosis.
Output: Molecular Sciences Review B Cells and Antibodies in Kawasaki Disease
In 2012, a novel coronavirus (CoV) associated with severe respiratory disease, Middle East respiratory syndrome (MERS-CoV; previously known as human coronavirus-Erasmus Medical Center or hCoV-EMC), emerged in the Arabian Peninsula. To date, 114 human cases of MERS-CoV have been reported, with 54 fatalities. Animal models for MERS-CoV infection of humans are needed to elucidate MERS pathogenesis and to develop vaccines and antivirals. In this study, we developed rhesus macaques as a model for MERS-CoV using intratracheal inoculation. The infected monkeys showed clinical signs of disease, virus replication, histological lesions, and neutralizing antibody production, indicating that this monkey model is suitable for studies of MERS-CoV infection.
Output: An Animal Model of MERS Produced by Infection of Rhesus Macaques With MERS Coronavirus
The outcome of viral infection depends on the interplay between host factors and the environment. Host factors, like the expression of viral receptors, convey permissiveness to infection, define tropism, regulate antiviral immune responses, determine viral clearance, and spread. The host microbiota, the constellation of microbes inhabiting an organism, also plays a key role in the outcome of infection. Microbes and microbial products can directly interact with viral particles. Our understanding of how the microbiota impacts virus infection is largely limited to the bacterial component of the microbiota. Although bacteria do not support eukaryotic virus infection, they can promote viral fitness by enhancing virion stability, promoting infection of eukaryotic cells, and increasing coinfection rates. Virus binding of bacteria can also impact bacterial biology, including bacterial adherence to eukaryotic cells. These interactions can also indirectly affect the host response to viral infection. In this Pearl, we focus on how direct and indirect interactions between viruses and bacteria impact viral biology and touch on recent findings that illustrate how bacterial biology can also be impacted by interactions with eukaryotic viruses (Fig 1) .
Output: Virus interactions with bacteria: Partners in the infectious dance
Despite intensive ongoing research, key aspects of the spatial-temporal evolution of the 2001 foot and mouth disease (FMD) epidemic in Great Britain (GB) remain unexplained. Here we develop a Markov Chain Monte Carlo (MCMC) method for estimating epidemiological parameters of the 2001 outbreak for a range of simple transmission models. We make the simplifying assumption that infectious farms were completely observed in 2001, equivalent to assuming that farms that were proactively culled but not diagnosed with FMD were not infectious, even if some were infected. We estimate how transmission parameters varied through time, highlighting the impact of the control measures on the progression of the epidemic. We demonstrate statistically significant evidence for assortative contact patterns between animals of the same species. Predictive risk maps of the transmission potential in different geographic areas of GB are presented for the fitted models.
Output: Transmission Parameters of the 2001 Foot and Mouth Epidemic in Great Britain
Two sequences of major histocompatibility complex (MHC) regions in the domestic cat, 2.976 and 0.362 Mbps, which were separated by an ancient chromosome break (55-80 MYA) and followed by a chromosomal inversion were annotated in detail. Gene annotation of this MHC was completed and identified 183 possible coding regions, 147 human homologues, possible functional genes and 36 pseudo/unidentified genes) by GENSCAN and BLASTN, BLASTP RepeatMasker programs. The first region spans 2.976 Mbp sequence, which encodes six classical class II antigens (three DRA and three DRB antigens) lacking the functional DP, DQ regions, nine antigen processing molecules (DOA/DOB, DMA/DMB, TAPASIN, and LMP2/ LMP7,TAP1/TAP2), 52 class III genes, nineteen class I genes/gene fragments (FLAI-A to FLAI-S). Three class I genes (FLAI-H, I-K, I-E) may encode functional classical class I antigens based on deduced amino acid sequence and promoter structure. The second region spans 0.362 Mbp sequence encoding no class I genes and 18 cross-species conserved genes, excluding class I, II and their functionally related/associated genes, namely framework genes, including three olfactory receptor genes. One previously identified feline endogenous retrovirus, a baboon retrovirus derived sequence (ECE1) and two new endogenous retrovirus sequences, similar to brown bat endogenous retrovirus (FERVmlu1, FERVmlu2) were found within a 140 Kbp interval in the middle of class I region. MHC SNPs were examined based on comparisons of this BAC sequence and MHC homozygous 1.96WGS sequences and found that 11,654 SNPs in 2.84 Mbp (0.00411 SNP per bp), which is 2.4 times higher rate than average heterozygous region in the WGS (0.0017 SNP per bp genome), and slightly higher than the SNP rate observed in human MHC (0.00337 SNP per bp).
Output: Sequences, Annotation and Single Nucleotide Polymorphism of the Major Histocompatibility Complex in the Domestic Cat
Coronavirus infectious bronchitis virus (IBV) encodes a trypsin-like proteinase (3C-like proteinase) by ORF 1a, which has been demonstrated to play a pivotal role in proteolytic processing of gene 1-encoded polyproteins. In our previous studies, the proteinase was identified as a 33-kDa protein in IBV-infected cells, and its catalytic center was shown to consist of H 2820 and C 2922 residues. It is released from the 1a and 1a/1b polyproteins by autoprocessing at two Q-S dipeptide bonds (Q 2779 -S 2780 and Q 3086 -S 3087 ). In this report, further characterization of the two cleavage sites demonstrates that the N-terminal Q 2779 -S 2780 site is tolerant to mutations at the P1 position. Deletion of the C-terminal region of the proteinase shows that a significant amount of the enzymatic activity is maintained upon deletion of up to 67 amino acids, suggesting that the extreme C-terminal region may be dispensable for the proteolytic activity of the proteinase. Analysis of the autoprocessing kinetics in vitro reveals that proteolysis at the Q 2779 -S 2780 site is the first cleavage event mediated by this proteinase. This is followed by cleavage at the Q 3086 -S 3087 site. The occurrence of both cleavage events in intact cells is potentially rapid and efficient, as no intermediate cleavage products covering the proteinase were detected in either IBV-infected or transfected cells. Immunofluorescence microscopy and subcellular fractionation studies further show differential subcellular localization of the proteinase in IBV-infected cells and in cells expressing the 3C-like proteinase alone, indicating that additional roles in viral replication might be played by this protein. Finally, a Q-A (Q 3379 -A 3380 ) dipeptide bond encoded by nucleotides 10,663 to 10,668 was demonstrated to be a cleavage site of the proteinase.
Output: Further Characterization of the Coronavirus Infectious Bronchitis Virus 3C-like Proteinase and Determination of a New Cleavage Site
Human immunodeficiency virus type 1 (HIV-1) Tat plays an important role in HIV-associated neuropathogenesis; the underlying mechanisms are still evolving. We have recently shown that HIV-1 Tat induces expression of glial fibrillary acidic protein (GFAP), a characteristic of HIV-1 infection of the central nervous system (CNS). We have also shown that the Tat-induced GFAP expression in astrocytes is regulated by p300, and that deletion of the early growth response 1 (Egr-1) cis-transacting element within the p300 promoter abolishes Tat-induced GFAP expression. In this study, we further examined the relationship between Tat and Egr-1 in astrocytes. We found increased Egr-1 protein expression in Tat-expressing human astrocytoma cells and mouse primary astrocytes. Using the Egr-1 promoter-driven firefly luciferase reporter gene assay and the sitedirected mutagenesis, we demonstrated that Tat increased Egr-1 expression by transactivating the Egr-1 promoter and involving specific serum response elements (SRE) within the promoter. Consistent with these data, we showed that Tat transactivation of the Egr-1 promoter was abrogated when astrocytes were cultured in serum-reduced media. Taken together, these results reveal that Tat directly transactivates Egr-1 expression and suggest that Tat interaction with Egr-1 is probably one of the very upstream molecular events that initiate Tat-induced astrocyte dysfunction and subsequent Tat neurotoxicity.
Output: Activation of Egr-1 expression in astrocytes by HIV-1 Tat: new insights into astrocyte-mediated Tat neurotoxicity
Background: Equine coronavirus (ECoV) is considered to be a diarrheic pathogen in foals. In central Kentucky in the United States, it has been shown that approximately 30 % of thoroughbred foals are infected with ECoV and thus it is considered widely prevalent. In contrast, the epidemiology of ECoV and its relationship to diarrhea in foals are poorly understood in Japan. We investigated ECoV in rectal swabs collected from thoroughbred foals in Japan. We collected 337 rectal swabs from 307 diarrheic foals in the Hidaka district of Hokkaido, the largest thoroughbred horse breeding region in Japan, between 2012 and 2014. In addition, 120 rectal swabs were collected from 120 healthy foals in 2012. These samples were tested by reverse transcription loop-mediated isothermal amplification and a real-time reverse transcription-polymerase chain reaction. All samples collected from diarrheic foals were negative, and only three samples (2.5 %) collected from healthy foals were positive for ECoV. Compared with central Kentucky, ECoV is not prevalent among thoroughbred foals in the Hidaka district of Hokkaido.
Output: Low prevalence of equine coronavirus in foals in the largest thoroughbred horse breeding region of Japan, 2012-2014
The aim of the present study was to analyze the clinical significance of the dynamic monitoring of blood lactic acid levels, the oxygenation index and C-reactive protein (CRP) levels in patients with severe pneumonia. The clinical data of 34 cases with severe pneumonia were collected. According to the clinical outcome, the patients were divided into a survival group (n=26) and a fatality group (n=8). Various factors, including the blood lactic acid level, oxygenation index, CRP level and acute physiology and chronic health evaluation II (APACHE II) score, were retrospectively analyzed in order to investigate whether these values had clinical significance for the prognosis of the patients. No statistically significant differences with regard to age, gender, initial concentrations of blood lactic acid and CRP, and APACHE II scores were observed between the two groups at admission to the Intensive Care Unit. However, the blood lactic acid levels were found to decrease to a normal level within 12-24 h after treatment in the survival group, while the levels were maintained at a higher concentration in the fatality group, even at 72 h after treatment (P<0.05). Furthermore, the oxygenation index in the survival group was significantly higher when compared with that in the fatality group. The oxygenation index was maintained at a normal level in the survival group, while the oxygenation index levels were below normal and continued to decline in the fatality group. A positive correlation was observed between the blood lactic acid level and the APACHE II scores (r=0.656, P<0.05). Therefore, the present study demonstrated that dynamic monitoring of blood lactic acid, oxygenation index and CRP levels in patients with severe pneumonia can be used to evaluate the therapeutic efficiency, in addition to serving as a prognosis indicator, for patients with severe pneumonia.
Output: Clinical significance of dynamic monitoring of blood lactic acid, oxygenation index and C-reactive protein levels in patients with severe pneumonia