niryuu/sni-each-converted huggingface dataset:
In simple infection models, the susceptible proportion s * in endemic equilibrium is related to the basic reproduction number R 0 by s * = 1/R 0 . We investigate the extent to which this relationship remains valid under more realistic modelling assumptions. In particular, we relax the biologically implausible assumptions that individuals' lifetimes and infectious periods follow exponential distributions; allow a general recruitment process; allow for multiple stages of infection; and consider extension to a multigroup model in which the groups may represent, for instance, spatial heterogeneity, or the existence of super-spreaders. For a homogeneous population, we find that: (i) the susceptible proportion is s * = 1/R e 0 , where R e 0 is a modified reproduction number, equal to R 0 only in certain circumstances; (ii) the proportions of the population in each stage of infection are proportional to the expected time spent by an infected individual in that stage before recovery or death. We demonstrate robustness of the formula s * = 1/R 0 for many human infections by noting conditions under which R e 0 is approximately equal to R 0 , while pointing out other circumstances under which this approximation fails. For heterogeneous populations, the formula s * = 1/R 0 does not hold in general, but we are able to exhibit symmetry conditions under which it is valid.
Output: Generality of endemic prevalence formulae
Human rhinoviruses (HRV) are known to cause common cold as well as more complicated respiratory infections. HRV species -A, -B and -C have all been associated with lower respiratory infections and exacerbations of asthma. However, the type distribution of strains connected to different kinds of lower respiratory conditions is not clearly known. We have analysed the presence of HRV in sputum specimens derived from military recruits with and without pre-diagnosed asthma at times of acute respiratory infection (CIAS Study, 2004. The analysis was performed with HRV and HEV real-time RT-PCR assays. Viruses 2009, 1 1179 Subsequently we studied type distribution of HRV strains by genetic typing in the VP4/VP2 genomic region. In total 146 (38.8%) specimens were HRV-positive and 36 (9.3%) HEVpositive. No difference was found in HRV detection between the asthmatic vs. nonasthmatic patients. Most of the genetically typed strains, 18 (62.1%), belonged to HRV-A, while HRV-B strains constituted five (17.2%) of the HRV-positive strains. HRV-C strain was typed four times from the HRV-positive cases and a HEV-D strain twice. We further typed six HEV positive strains in the partial VP1 region. Three of these belonged to HRV-A and three to HEV-D. HRV-A strains were discovered throughout the study period, while HRV-C strains originated from winter and spring specimens. Interestingly, four out of five typed HRV-B strains originated from the summer season specimens.
Output: All Known Human Rhinovirus Species Are Present in Sputum Specimens of Military Recruits During Respiratory Infection
Background: Glycyrrhizin (GA) and primary metabolite 18β-glycyrrhetinic acid (GRA) are pharmacologically active components of the medicinal licorice root, and both have been shown to have antiviral and immunomodulatory properties. Although these properties are well established, the mechanisms of action are not completely understood. In this study, GA and GRA were tested for the ability to inhibit rotavirus replication in cell culture, toward a long term goal of discovering natural compounds that may complement existing vaccines. Methods: Epithelial cells were treated with GA or GRA various times pre-or post-infection and virus yields were measured by immunofluorescent focus assay. Levels of viral proteins VP2, VP6, and NSP2 in GRA treated cells were measured by immunoblot to determine if there was an effect of GRA treatment on the accumulation of viral protein. Results: GRA treatment reduced rotavirus yields by 99% when added to infected cultures post-virus adsorption, whereas virus yields in GA treated cultures were similar to mock treated controls. Time of addition experiments indicated that GRA-mediated replication inhibition likely occurs at a step or steps subsequent to virus entry. The amounts of VP2, VP6 and NSP2 were substantially reduced when GRA was added to cultures up to two hours postentry. Conclusions: GRA, but not GA, has significant antiviral activity against rotavirus replication in vitro, and studies to determine whether GRA attenuates rotavirus replication in vivo are underway.
Output: 8β-glycyrrhetinic acid inhibits rotavirus replication in culture
Intestinal infection with enterotoxigenic Escherichia coli (ETEC) is an important disease in swine resulting in significant economic losses. Knowledge about the epidemiology, the diagnostic approach and methods of control are of fundamental importance to tackle the disease. The ETEC causing neonatal colibacillosis mostly carry the fimbriae F4 (k88), F5 (k99), F6 (987P) or F41, while the ETEC of post-weaning diarrhoea carry the fimbriae F4 (k88) and F18. These fimbriae adhere to specific receptors on porcine intestinal brush border epithelial cells (enterocytes), starting the process of enteric infection. After this colonization, the bacteria produce one or more enterotoxins inducing diarrhoea, such as the heat stable toxin a (STa), the heat stable toxin b (STb), and the heat labile toxin (LT). A role in the pathogenesis of the disease was demonstrated for these toxins. The diagnosis of enteric colibacillosis is based on the isolation and quantification of the pathogenic E.coli coupled with the demonstration by PCR of the genes encoding for virulence factors (fimbriae and toxins). The diagnostic approach to enteric colibacillosis must consider the differential diagnosis and the potential different causes that can be involved in the outbreak. Among the different methods of control of colibacillosis, the use of antimicrobials is widely practiced and antibiotics are used in two main ways: as prophylactic or metaphylactic treatment to prevent disease and for therapeutic purposes to treat diseased pigs. An accurate diagnosis of enteric colibacillosis needs an appropriate sampling for the isolation and quantification of the ETEC responsible for the outbreak by using semi-quantitative bacteriology. Definitive diagnosis is based on the presence of characteristic lesions and results of bacteriology along with confirmation of appropriate virulence factors to identify the isolated E.coli. It is important to confirm the diagnosis and to perform antimicrobial sensitivity tests because antimicrobial sensitivity varies greatly among E. coli isolates. Growing concern on the increase of antimicrobial resistance force a more rational use of antibiotics and this can be achieved through a correct understanding of the issues related to antibiotic therapy and to the use of antibiotics by both practitioners and farmers.
Output: Swine enteric colibacillosis: diagnosis, therapy and antimicrobial resistance
Background: Neuroinflammation plays a critical role in the onset and development of neurodegeneration disorders such as Parkinson's disease. The immune activities of the central nervous system are profoundly affected by peripheral immune activities. Immune tolerance refers to the unresponsiveness of the immune system to continuous or repeated stimulation to avoid excessive inflammation and unnecessary by-stander injury in the face of continuous antigen threat. It has been proved that the immune tolerance could suppress the development of various peripheral inflammation-related diseases. However, the role of immune tolerance in neuroinflammation and neurodegenerative diseases was not clear. Methods: Rats were injected with repeated low-dose lipopolysaccharide (LPS, 0.3 mg/kg) intraperitoneally for 4 days to induce peripheral immune tolerance. Neuroinflammation was produced using intracranial LPS (15 μg) injection. Inflammation cytokines were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Microglial activation were measured using immunostaining of Iba-1 and ED-1. Dopaminergic neuronal damage was evaluated using immunochemistry staining and stereological counting of TH-positive neurons. Behavioral impairment was evaluated using amphetamine-induced rotational behavioral assessment. Results: Compared with the non-immune tolerated animals, pre-treatment of peripheral immune tolerance significantly decreased the production of inflammatory cytokines, suppressed the microglial activation, and increased the number of dopaminergic neuronal survival in the substantia nigra. Conclusions: Our results indicated that peripheral immune tolerance attenuated neuroinflammation and inhibited neuroinflammation-induced dopaminergic neuronal death.
Output: Peripheral immune tolerance alleviates the intracranial lipopolysaccharide injection- induced neuroinflammation and protects the dopaminergic neurons from neuroinflammation-related neurotoxicity
Background: Recurrent respiratory infections are one of the most important causes of morbidity in childhood. When immune functions are still largely immature, the airway epithelium plays a primary defensive role since, besides providing a physical barrier, it is also involved in the innate and the adaptive immune responses. A study was therefore designed to evaluate in vitro whether pidotimod, a synthetic dipeptide able to stimulate the inflammatory and immune effector cells, could activate bronchial epithelial cell functions involved in response to infections. Methods: BEAS-2B cell line (human bronchial epithelial cells infected with a replication-defective Adenovirus 12-SV40 virus hybrid) were cultured in the presence of pidotimod, with or without tumor necrosis factor (TNF)-α or zymosan to assess: a) intercellular adhesion molecule (ICAM)-1 expression, by flow cytometry; b) toll-like receptor (TLR)-2 expression and production, by immunofluorescence flow cytometry and western blotting; d) interleukin (IL)-8 release, by enzyme-linked immunosorbent assay (ELISA); e) activated extracellular-signal-regulated kinase (ERK1/2) phosphorylation and nuclear factor-kappa B (NF-kB) activation, by western blotting. The constitutive expression of ICAM-1 and IL-8 release were significant up-regulated by TNF-α (ICAM-1) and by TNF-α and zymosan (IL-8), but not by pidotimod. In contrast, an increased TLR-2 expression was found after exposure to pidotimod 10 and 100 μg/ml (p < 0.05) and to the association pidotimod 100 μg/ml + TNF-α (p < 0.05). Western blot analysis substantiated that the constitutive TLR-2 expression was significantly increased after exposure to all the stimuli. Finally, while a remarkable inhibition of TNF-α -induced ERK1/2 phosphorylation was observed in the presence of pidotimod, both TNF-α and pidotimod were effective in inducing NF-kB protein expression in the cytoplasm and its nuclear translocation. Conclusion: Through different effects on ERK1/2 and NF-kB, pidotimod was able to increase the expression of TLR-2 proteins, surface molecules involved in the initiation of the innate response to infectious stimuli. The lack of effect on ICAM-1 expression, the receptor for rhinovirus, and on IL-8 release, the potent chemotactic factor for neutrophils (that are already present in sites of infection), may represent protective functions. If confirmed in vivo, these activities may, at least in part, clarify the mechanism of action of this molecule at airway level.
Output: Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression
Purpose of the review-Pathogens of different taxa, from prions to protozoa, target cellular cholesterol metabolism to advance own development and to impair host immune responses, but also causing metabolic complications, e.g. atherosclerosis. This review describes recent findings of how pathogens do it. Recent findings-A common theme in interaction between pathogens and host cholesterol metabolism is pathogens targeting lipid rafts of the host plasma membrane. Many intracellular pathogens use rafts as an entry gate, taking advantage of the endocytic machinery and high abundance of outward looking molecules that can be used as receptors. At the same time, disruption of the rafts' functional capacity, achieved by the pathogens through a number of various means, impairs the ability of the host to generate immune response, thus helping pathogen to thrive. Pathogens cannot synthesise cholesterol, and salvaging host cholesterol helps pathogens build advanced cholesterol-containing membranes and assembly platforms. Impact on cholesterol metabolism is not limited to the infected cells; proteins and miRNAs secreted by infected cells affect lipid metabolism systemically. Summary-Given an essential role that host cholesterol metabolism plays in pathogen development, targeting this interaction may be a viable strategy to fight infections as well as metabolic complications of the infections.
Output: Interaction of pathogens with host cholesterol metabolism
Graphical Abstract Highlights d Combined measurements of host-viral scRNA-seq during in vivo influenza infection d High prevalence of infection in a variety of immune and nonimmune cell types d Extensive cellular heterogeneity exists within infected and bystander cells d Generic and cell-type-specific differences between infected and bystander cells SUMMARY The influenza virus is a major cause of morbidity and mortality worldwide. Yet, both the impact of intracellular viral replication and the variation in host response across different cell types remain uncharacterized. Here we used single-cell RNA sequencing to investigate the heterogeneity in the response of lung tissue cells to in vivo influenza infection. Analysis of viral and host transcriptomes in the same single cell enabled us to resolve the cellular heterogeneity of bystander (exposed but uninfected) as compared with infected cells. We reveal that all major immune and non-immune cell types manifest substantial fractions of infected cells, albeit at low viral transcriptome loads relative to epithelial cells. We show that all cell types respond primarily with a robust generic transcriptional response, and we demonstrate novel markers specific for influenza-infected as opposed to bystander cells. These findings open new avenues for targeted therapy aimed exclusively at infected cells.
Output: Dissection of Influenza Infection In Vivo by Single- Cell RNA Sequencing
To begin to understand why IFN is produced in infected macrophages, we infected bone marrow-derived macrophages (BMM) and as a control, bone marrowderived DC (BMDC) with the coronavirus mouse hepatitis virus (MHV). As expected, BMM but not BMDC expressed type I IFN. IFN production in infected BMM was nearly completely dependent on signaling through the alpha/beta interferon (IFN-␣/␤) receptor (IFNAR). Several IFN-dependent cytokines and chemokines showed the same expression pattern, with enhanced production in BMM compared to BMDC and dependence upon signaling through the IFNAR. Exogenous IFN enhanced IFN-dependent gene expression in BMM at early times after infection and in BMDC at all times after infection but did not stimulate expression of molecules that signal through myeloid differentiation factor 88 (MyD88), such as tumor necrosis factor (TNF). Collectively, our results show that IFN is produced at early times postinfection (p.i.) in MHV-infected BMM, but not in BMDC, and primes expression of IFN and IFN-responsive genes. Further, our results also show that BMM are generally more responsive to MHV infection, since MyD88-dependent pathways are also activated to a greater extent in these cells than in BMDC. This pathway of cellular activation may be a useful target for modulating macrophage function in order to selectively enhance the antivirus immune response and diminish the pathogenic role of these cells in SARS and other coronavirus infections. . 2010. Autocrine interferon priming in macrophages but not dendritic cells results in enhanced cytokine and chemokine production after coronavirus infection. mBio 1(4):
Output: Autocrine Interferon Priming in Macrophages but Not Dendritic Cells Results in Enhanced Cytokine and Chemokine Production after Coronavirus Infection
Influenza is often complicated by bacterial pathogens that colonize the nasopharynx and invade the middle ear and/or lung epithelium. Incidence and pathogenicity of influenza-bacterial coinfections are multifactorial processes that involve various pathogenic virulence factors and host responses with distinct site-and strain-specific differences. Animal models and kinetic models have improved our understanding of how influenza viruses interact with their bacterial co-pathogens and the accompanying immune responses. Data from these models indicate that considerable alterations in epithelial surfaces and aberrant immune responses lead to severe inflammation, a key driver of bacterial acquisition and infection severity following influenza. However, further experimental and analytical studies are essential to determining the full mechanistic spectrum of different viral and bacterial strains and species and to finding new ways to prevent and treat influenza-associated bacterial coinfections. Here, we review recent advances regarding transmission and disease potential of influenza-associated bacterial infections and discuss the current gaps in knowledge.
Output: Secondary Bacterial Infections in Influenza Virus Infection Pathogenesis
The development of high-throughput molecular technologies and associated bioinformatics has dramatically changed the capacities of scientists to produce, handle, and analyze large amounts of genomic, transcriptomic, and proteomic data. A clear example of this step-change is represented by the amount of DNA sequence data that can be now produced using next-generation sequencing (NGS) platforms. Similarly, recent improvements in protein and peptide separation effi ciencies and highly accurate mass spectrometry have promoted the identifi cation and quantifi cation of proteins in a given sample. These advancements in biotechnology have increasingly been applied to the study of animal infectious diseases and are beginning to revolutionize the way that biological and evolutionary processes can be studied at the molecular level. Studies have demonstrated the value of NGS technologies for molecular characterization, ranging from metagenomic characterization of unknown pathogens or microbial communities to molecular epidemiology and evolution of viral quasispecies. Moreover, high-throughput technologies now allow detailed studies of hostpathogen interactions at the level of their genomes (genomics), transcriptomes (transcriptomics), or proteomes (proteomics). Ultimately, the interaction between pathogen and host biological networks can be questioned by analytically integrating these levels (integrative OMICS and systems biology). The application of high-throughput biotechnology platforms in these fi elds and their typical low-cost per information content has revolutionized the resolution with which these processes can now be studied. The aim of this chapter is to provide a current and prospective view on the opportunities and challenges associated with the application of massive parallel sequencing technologies to veterinary medicine, with particular focus on applications that have a potential impact on disease control and management.
Output: Chapter 30 Next-Generation Sequencing in Veterinary Medicine: How Can the Massive Amount of Information Arising from High- Throughput Technologies Improve Diagnosis, Control, and Management of Infectious Diseases?
The emergence of highly pathogenic human coronaviruses (hCoVs) in the last two decades has illuminated their potential to cause high morbidity and mortality in human populations and disrupt global economies. Global pandemic concerns stem from their high mortality rates, capacity for human-to-human spread by respiratory transmission, and complete lack of approved therapeutic countermeasures. Limiting disease may require the development of virus-directed and host-directed therapeutic strategies due to the acute etiology of hCoV infections. Therefore, understanding how hCoV-host interactions cause pathogenic outcomes relies upon mammalian models that closely recapitulate the pathogenesis of hCoVs in humans. Pragmatism has largely been the driving force underpinning mice as highly effective mammalian models for elucidating hCoV-host interactions that govern pathogenesis. Notably, tractable mouse genetics combined with hCoV reverse genetic systems has afforded the concomitant manipulation of virus and host genetics to evaluate virus-host interaction networks in disease. In addition to assessing etiologies of known hCoVs, mouse models have clinically predictive value as tools to appraise potential disease phenotypes associated with pre-emergent CoVs. Knowledge of CoV pathogenic potential before it crosses the species barrier into the human population provides a highly desirable preclinical platform for addressing global pathogen preparedness, an overarching directive of the World Health Organization. Although we recognize that results obtained in robust mouse models require evaluation in non-human primates, we focus this review on the current state of hCoV mouse models, their use as tractable complex genetic organisms for untangling complex hCoV-host interactions, and as pathogenesis models for preclinical evaluation of novel therapeutic interventions.
Output: Modeling pathogenesis of emergent and pre-emergent human coronaviruses in mice
In the present study, anti-IBV (infectious bronchitis virus) activities of (-)pinenes were studied by MTT assay, as well as docking and molecular dynamic (MD) simulations. The CC 50 values of (-)-α-pinene and (-)-β-pinene were above 10 mM. And the maximum noncytotoxic concentrations (TD 0 ) of (-)-α-pinene and (-)-β-pinene were determined as 7.88 ± 0.06 and 6.09 ± 0.31 mM, respectively. The two compounds were found to inhibit IBV with an IC 50 of 0.98 ± 0.25 and 1.32 ± 0.11 mM. The MTT assay showed that the inhibitions of (-)-pinenes against IBV appear to occur moderately before entering the cell but are much stronger occur after penetration of the virus into the cell. Molecular simulations indicated that (-)-α-pinene and (-)-β-pinene specifically interact with the active site which is located at the N terminus of phosphorylated nucleocapsid (N) protein, with the former being more potent than the latter. The binding energies of them are −36.83 and −35.59 kcal mol −1 , respectively. Results presented here may suggest that (-)-αpinene and (-)-β-pinene possess anti-IBV properties, and therefore are a potential source of anti-IBV ingredients for the pharmaceutical industry.
Output: molecules Comparative Anti-Infectious Bronchitis Virus (IBV) Activity of (-)-Pinene: Effect on Nucleocapsid (N) Protein
Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A-BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) β pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFα, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances.
Output: Management of Kawasaki disease
Inflammatory responses to an infection from a zoonotic pathogen, such as avian influenza viruses, hantaviruses and some coronaviruses, are distinctly different in their natural reservoir versus human host. While not as well studied in the natural reservoirs, the pro-inflammatory response and viral replication appear controlled and show no obvious pathology. In contrast, infection in humans results in an initial high viral load marked by an aggressive pro-inflammatory response known as a cytokine storm. The key difference in the course of the infection between the reservoir and human host is the inflammatory response. In this investigation, we apply a simple two-component differential equation model for proinflammatory and anti-inflammatory responses and a detailed mathematical analysis to identify specific regions in parameter space for single stable endemic equilibrium, bistability or periodic solutions. The extensions of the deterministic model to two stochastic models account for variability in responses seen at the cell (local) or tissue (global) levels. Numerical solutions of the stochastic models exhibit outcomes that are typical of a chronic infection in the natural reservoir or a cytokine storm in human infection. In the chronic infection, occasional flare-ups between high and low responses occur when model parameters are in a region of bistability or periodic solutions. The cytokine storm with a vigorous pro-inflammatory response and less vigorous anti-inflammatory response occurs in the parameter region for a single stable endemic equilibrium with a strong pro-inflammatory response. The results of the model analyses and the simulations are interpreted in terms of the functional role of the cytokines and the inflammatory responses seen in infection of the natural reservoir or of the human host.
Output: Models of cytokine dynamics in the inflammatory response of viral zoonotic infectious diseases
Animal antimicrobial use and husbandry practices increase risk of emerging zoonotic disease and antibiotic resistance. We surveyed 700 households to elicit information on human and animal medicine use and husbandry practices. Households that owned livestock (n=265/459, 57.7%) reported using animal treatments 630 times during the previous 6 months; 57.6% obtained medicines, including antibiotics, from drug-sellers. Government animal health care providers were rarely visited (9.7 %), respondents more often sought animal health care from pharmacies and village doctors (70.6% and 11.9% respectively), citing the latter two as less costly and more successful based on past performance. Animal husbandry practices that could promote the transmission of microbes from animals to humans included: the proximity of chickens to humans (50.1% of households reported that the chickens slept in the bedroom); the shared use of natural bodies of water for human and animal bathing (78.3%); the use of livestock waste as fertilizer (60.9%); and gender roles that dictate that females are the primary care takers of poultry and children (62.8%). In the absence of an effective animal health care system, villagers must depend on local animal health care practitioners for treatment of their animals. Suboptimal use of antimicrobials coupled with unhygienic animal husbandry practices are important risk factors for emerging zoonotic disease and resistant pathogens.
Output: Household animal and human medicine use and animal husbandry practices in rural Bangladesh: risk factors for emerging zoonotic disease and antibiotic resistance HHS Public Access
The current study aims to investigate the pharmacokinetic study of five phenolic acids (neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, 3,5-dicaffeoylquinic acid and 3,4-dicaffeoylquinic acid) following oral administration of Flos Lonicerae preparations in rats. A rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to simultaneously determine the five phenolic acids in rat plasma. After mixing with the internal standard (IS) tinidazole, plasma samples were pretreated by liquid-liquid extraction with ethyl acetate/n-hexane (9:1, v/v). The separation was performed on an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 m) at a flow rate of 0.4 ml min −1 , and acetonitrile/methanol (4:1, v/v)-0.4% formic acid was used as mobile phase. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) via electrospray ionization (ESI) source with positive ionization mode. All calibration curves had good linearity (r > 0.991) over the concentration ranges of 0.74-378 ng ml −1 for neochlorogenic acid, 0.50-1030 ng ml −1 for chlorogenic acid, 1.9-250 ng ml −1 for cryptochlorogenic acid, 0.74-380 ng ml −1 for 3,5-dicaffeoylquinic acid, and 5.1-328 ng ml −1 for 3,4-dicaffeoylquinic acid. The intra-and inter-day precision were within 15% and the accuracy ranged from 86.2% to 114.1%.
Output: Simultaneous determination of phenolic acids by UPLC-MS/MS in rat plasma and its application in pharmacokinetic study after oral administration of Flos Lonicerae preparations
To identify protein split sites quickly, a selection procedure by using chloramphenicol acetyl transferase (CAT) as reporter was introduced to search for folded protein fragments from libraries generated by random digestion and reassembly of the target gene, which yielded an abundant amount of DNA fragments with controllable lengths. Experimental results of tryptophan synthase alpha subunit (TSa) and TEM-1 b-lactamase agreed well with what the literature has reported. The solubility of these fragments correlated roughly with the minimum inhibitory concentrations of the CAT fusions. The application of this dissection protocol to protein fragment complementation assay (PCA) was evaluated using aminoglycoside-3 0 -phosphotransferase I (APH(3 0 )-I) as a model protein. Three nearly bisectional sites and a number of possible split points were identified, and guided by this result, four novel pairs of fragments were tested for complementation. Three out of four pairs partially restored the APH activity with the help of leucine zippers, and a truncated but active APH(3 0 )-I (D1-25) was also found. Finally, the weakly active APH(3 0 )-I-(1-253)NZ/CZ (254-271) containing a short 18 residue tag was further improved by errorprone PCR, and a best mutant was obtained showing a fourfold improvement after just one round of evolution. These results demonstrate that protein random dissection based on the CAT selection can provide an efficient search for protein breakage points and guide the design of fragments for protein complementation assay. Furthermore, more active fragment pairs can be achieved with the classical directed evolution approach.
Output: Random dissection to select for protein split sites and its application in protein fragment complementation
Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver operator characteristic curves (AUC) to quantify our ability to predict therapeutic resistance in individual patients where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4,601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in MRC/NCRI, HOVON, SWOG, and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk, and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ("primary refractoriness"). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:defined as primary refractoriness or short relapse-free survival (RFS), was even more difficult. Our ability to forecast resistance based on routinely available pre-treatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and post-treatment data to optimize resistance prediction in AML. Acute myeloid leukemia; area under the receiver operator characteristic curve; prediction; therapeutic resistance Walter et al. [x10 3 /μL], median (range) 15 (0-559) 19 (1-510) 14 (0-370) 8 (1-340) 15 (0-559) Platelets 1 [x10 3 /μL], median (range) 56 (2-983) 66 (3-998) 54 (2-9,300) 41 (3-1,069) 58 (2-9,300) Bone marrow blasts 1 , median% (range) 70 (0-100) 60 (0-98) 67 (3-100) 47 (6-96) 65 (0-100) Performance status 1 , n (%) 0-1 2,081 (80) 1,051 (93) 368 (83) 374 (91) 3,874 (84) 
Output: Resistance Prediction in AML: Analysis of 4,601 Patients from MRC/NCRI, HOVON/SAKK, SWOG, and MD Anderson Cancer Center HHS Public Access
DNA microarrays represent a powerful technology that enables whole-scale comparison of bacterial genomes. This, coupled with new methods to model DNA microarray data, is facilitating the development of robust comparative phylogenomics analyses. Such studies have dramatically increased our ability to differentiate between bacteria, highlighting previously undetected genetic differences and population structures and providing new insight into virulence and evolution of bacterial pathogens. Recent results from such studies have generated insights into the evolution of bacterial pathogens, the levels of diversity and plasticity in the genome of a species, as well as the differences in virulence amongst pathogenic bacteria. Comparative phylogenomics of pathogenic bacteria by microarray analysis Dorrell, Hinchliffe and Wren 621 Figure 1 Principles of comparative phylogenomics using DNA microarrays. For further details, see main body of text. www.sciencedirect.com Current Opinion in Microbiology 2005, 8:620-626 Comparative phylogenomics of pathogenic bacteria by microarray analysis Dorrell, Hinchliffe and Wren 625 www.sciencedirect.com Current Opinion in Microbiology 2005, 8:620-626
Output: Comparative phylogenomics of pathogenic bacteria by microarray analysis
Background-As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective-Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion-Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics.
Output: Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites
Ecological niche modeling (ENM) is widely employed in ecology to predict species' potential geographic distributions in relation to their environmental constraints and is rapidly becoming the gold-standard method for disease risk mapping. However, given the biological complexity of disease systems, the traditional ENM framework requires reevaluation. We provide an overview of the application of ENM to disease systems and propose a theoretical framework based on the biological properties of both hosts and parasites to produce reliable outputs resembling disease system distributions. Additionally, we discuss the differences between biological considerations when implementing ENM for distributional ecology and epidemiology. This new framework will help the field of disease ecology and applications of biogeography in the epidemiology of infectious diseases. The recent rise of emerging infectious diseases (EIDs) (see Glossary) [1] has increased the burden of infectious diseases and negatively impacted the global economy [2][3][4] [5] . Approximately 60% of emerging human diseases are caused by pathogenic parasites of animal origin (zoonoses), particularly wildlife [6] . As human activities intensify, contact with wildlife and exposure to novel parasites increase, potentially driving zoonotic disease emergence [1, 7] . Given the threat that EIDs pose to human populations, understanding the underlying drivers of parasite geographic distribution and their spillover to humans is particularly relevant for epidemiologists, public-health practitioners, and policy makers [9] . Ecological niche modeling (ENM) has proven useful to forecast the distribution of a vast number of organisms [10-13] and is increasingly employed to predict parasite distributions locally and globally [14] [15] [16] [17] . Despite great strides made in the implementation of ENM to forecast complex biological phenomena such as disease systems [18], traditional frameworks may render biologically unrealistic predictions and thus must be revised, as we show in this review. We provide an overview of the current state of disease ENM and propose a framework based on the biological properties of both parasites and hosts to produce reliable outputs resembling disease systems distributions. Specifically, our theoretical framework: (i) addresses the selection of an appropriate modeling approach and highlights the importance of including biologically sound predictor variables; (ii) proposes the concept of a microscale parasitic niche defined by host traits to identify relevant parasite-host associations; and (iii) integrates traditional parasite ENM with the proposed microscale niche to better understand geographic distributions and improve fine-scale predictions of disease transmission risk. ENM estimates the distributions of species by linking their geographic occurrence with their environmental constraints, often utilizing correlative approaches (detailed explanations in [18] ). Highlights
Output: An Ecological Framework for Modeling the Geography of Disease Transmission
Type I interferons (IFNs) are well-known cytokines that, among their main functions, are key components of the host immune response against viral infections. Due to its immune modulation properties, they are commonly used in the therapeutic approach of various retroviral infections, namely human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV). In HIV infection, it has been shown that IFN therapy limits early viral replication, particularly useful on post-exposure prophylaxis. In veterinary medicine, recombinant feline interferon omega (rFeIFN-ω) was the first interferon licensed for use in cats. Several studies have recently shown that this compound seems to stimulate the innate immunity, decreasing clinical signs and co-infections in naturally FIV-infected cats. More than summarizing the main conclusions about rFeIFN-ω in cats, this review emphasizes the immune-modulation properties of IFN therapy, opening new perspectives for its use in retroviral infections. Either in FIV-infected cats or in HIV individuals, type I IFNs seem to induce an innate immune-modulation and should not be overlooked as a therapeutic option in retroviral infections.
Output: The Use of Recombinant Feline Interferon Omega Therapy as an Immune-Modulator in Cats Naturally Infected with Feline Immunodeficiency Virus: New Perspectives
Human herpesvirus 6 (HHV-6) is a ubiquitous β-herpesvirus associated with a number of clinical disorders. Two closely but biologically distinct variants have been described. HHV-6 variant B causes the common childhood disease exhanthem subitum, and although the pathologic characteristics for HHV-6 variant A are less well defined, HHV-6A has been suggested to be more neurotropic. We studied the effect of both HHV-6 variants in an oligodendrocyte cell line (MO3.13). Infection of M03.13 was monitored by cytopathic effect (CPE), quantitative TaqMan PCR for viral DNA in cells and supernatant, reverse transcriptase-polymerase chain reaction (RT-PCR) to detect viral RNA, and indirect immunofluorescence (IFA) to detect viral protein expression. HHV-6A infection induced significantly more CPE than infection with HHV-6B. HHV-6B induced an abortive infection associated with a decrease of the initial viral DNA load over time, early RNA expression, and no expression of viral antigen. In contrast, infection with HHV-6A DNA persisted in cells for at least 62 days. During the acute phase of infection with HHV-6A, intracellular and extracellular viral load increased and cells expressed the viral protein IE-2 and gp116/54/64. No HHV-6A RNA or protein was expressed after 30 days post infection, suggesting that HHV-6A formed a latent infection. These studies provide in vitro support to the hypothesis that HHV-6 can actively infect oligodendrocytes. Our results suggest that HHV-6A and HHV-6B have different tropism in MO3.13 cells and that an initially active HHV-6A infection can develop latency. Differences between HHV-6A and -6B infection in different neural cell types may be associated with different neurological diseases. Journal of NeuroVirology (2005) 11, 384-394. HHV-6 tropism and latency in MO3.13 cells J Ahlqvist et al 385
Output: Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes
In 2002, lower respiratory tract infections accounted for approximately 4 million deaths worldwide and 7% of all deaths that year." Scope of the problem Acute respiratory tract infection is the leading cause of hospitalization for infants and young children in developed countries, and a major determinant of death in developing countries. In 2002, lower respiratory tract infections accounted for approximately 4 million deaths worldwide and 7% of all deaths that year [1]. Therefore, there is a huge need for new diagnostic tools that enable the detection of a broad range of respiratory pathogens, especially those that are difficult or impossible to obtain by conventional culture methods.
Output: Multiplex PCR theranostics of severe respiratory infections
Background: Exhaled breath condensate (EBC) sampling has been considered an inventive and novel method for the isolation of respiratory viruses. Methods: In our study, 102 volunteers experiencing upper airway infection were recruited over the winter and early spring of 2008/2009 and the first half of the winter of 2009/2010. Ninety-nine EBCs were successfully obtained and screened for 14 commonly circulating respiratory viruses. To investigate the efficiency of virus isolation from EBC, a nasal swab was taken in parallel from a subset of volunteers. The combined use of the ECoVent device with the RTube™ allowed the registration of the exhaled volume and breathing frequency during collection. In this way, the number of exhaled viral particles per liter air or per minute can theoretically be estimated. Results: Viral screening resulted in the detection of 4 different viruses in EBC and/or nasal swabs: Rhinovirus, Human Respiratory Syncytial Virus B, Influenza A and Influenza B. Rhinovirus was detected in 6 EBCs and 1 EBC was Influenza B positive. We report a viral detection rate of 7% for the EBCs, which is much lower than the detection rate of 46.8% observed using nasal swabs. Conclusion: Although very promising, EBC collection using the RTube™ is not reliable for diagnosis of respiratory infections.
Output: Exhaled breath condensate sampling is not a new method for detection of respiratory viruses
Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferatoractivated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful ''core hopping'' and ''glide docking'' techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPARgamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the ''core hopping'' technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.
Output: Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach
Human rhinovirus (HRV)-A and -B is a common cause of upper respiratory tract infections. Recently, a third species, HRV-C, was categorized based on molecular typing studies. The results showed that the HRV-C genome had diverged from that of HRV-A and -B. Despite its late identification, increasing evidence suggests that HRV-C causes more severe pathogenic infections than HRV-A or -B; however, a large amount of epidemiological data is required to confirm this association in different clinical settings. Consequently, a simple and rapid method for identifying HRV-C is required to expedite such epidemiological studies. Here, two degenerate primer sets (HEV and HRVC) were designed based on bioinformatic analyses. The HEV set targeting the fifth IRES domain sequence within the 5 -UTR, which is highly conserved among enteroviruses, was designed to detect all enteroviruses, whereas the HRVC set, which targeted the VP2 coding region, was designed to detect HRV-C alone. Both primer sets were tested against a panel of standard enteroviruses and clinical lavage samples. HEV detected all enteroviruses tested whereas HRVC was specific for HRV-C. Although the primer design strategy was confirmed with a limited number of samples, extensive tests are required to be applied in clinical settings.
Output: Degenerate PCR primer design for the specific identification of rhinovirus C