niryuu/sni-each-converted huggingface dataset:
This review examines the question of whether exercise can be used as an experimental model to further our understanding of innate antimicrobial peptides and proteins (AMPs) and their role in susceptibility to infection at mucosal surfaces. There is strong evidence to suggest that AMPs, in combination with cellular and physical factors, play an important role in preventing infection. Although AMPs act directly on microorganisms, there is increasing recognition that they also exert their protective effect via immunomodulatory mechanisms, especially in noninflammatory conditions. Further studies that manipulate physiologically relevant concentrations of AMPs are required to shed light on the role they play in reducing susceptibility to infection. Evidence shows that in various form prolonged and/or exhaustive exercise is a potent modulator of the immune system, which can either sharpen or blunt the immune response to pathogens. The intensity and duration of exercise can be readily controlled in experimental settings to manipulate the degree of physical stress. This would allow for an investigation into a potential dose-response effect between exercise and AMPs. In addition, the use of controlled exercise could provide an experimental model by which to examine whether changes in the concentration of AMPs alters susceptibility to illness.
Output: Antimicrobial peptides and proteins, exercise and innate mucosal immunity
Background: Acute respiratory infections (ARIs) are one of the main causes of morbidity and mortality in children. Viruses are the main etiological agents, and their behavior tends to be seasonal and vary by geographical location. Human metapneumovirus (HMPV) has recently been described as a cause of severe acute respiratory infection and its prevalence and clinical behavior in children at moderate altitudes is unknown. Methods: A cross-sectional study was carried out on patients seen at a university hospital in Bogotá, Colombia between October 2015 and December 2017 in a city at a moderate altitude above sea level. Children with acute respiratory infections who had had a multiplex RT-PCR assay were selected. The prevalence of HMPV infection, its clinical outcomes and its relationship to rainfall were evaluated. Results: Out of a total of 14,760 discharged patients, multiplex RT-PCR was performed on 502 and a virus was detected in 420 children with acute respiratory infection (ARI). The study group had a median age of 21 months (IQR 7-60), with similar proportion of males and females (56.4 and 43.6% respectively) and 5.2% (CI 95 3.3-7.8%) prevalence of HMPV infection. The group with HMPV infection showed a greater frequency of viral coinfection (22.7% vs 14% P = 0.03) compared with ARI caused by other viruses. The rate of bacterial coinfection (P = 0.31), presence of comorbidities (p = 0.75), length of hospital stay (P = 0.42), need for mechanical ventilation (P = 0.75) and mortality (P = 0.22) were similar for HMPV and other viral infections. A moderate correlation was established between HMPV infection and rainfall peaks (Spearman's Rho 0.44 p = 0.02). Conclusions: Human metapneumovirus was the fifth most frequently isolated virus in children with ARI, had similar clinical behavior and severity to other viruses but a higher rate of viral coinfection. Its peaks seem to correlate to rainy seasons.
Output: Prevalence, clinical outcomes and rainfall association of acute respiratory infection by human metapneumovirus in children in Bogotá, Colombia
Enveloped viruses must fuse their lipid membrane to a cellular membrane to deliver their genome into the cytoplasm for replication. Viral envelope proteins catalyze this critical membrane fusion event. They fall into three distinct structural classes. In 2013, envelope proteins from a pestivirus and hepatitis C virus were found to have two distinct novel folds. This was unexpected because these viruses are in the same family as flaviviruses, which have class II fusion proteins. We propose that the membrane fusion machinery of the closely related pestiviruses and hepatitis C virus defines a new structural class. This and other recently identified structural relationships between viral fusion proteins shift the paradigm for how these proteins evolved. In many viruses, the genome is enveloped in a lipid membrane. Viral envelope proteins anchored in the membrane fulfill indispensable functions throughout the lifecycle of the virus. Envelope proteins drive virus assembly, form the protective outer shell of the virus, mediate cellular attachment and tropism, and catalyze the fusion of the viral and host cell membranes to deliver the viral genome into the cytoplasm for replication. Envelope proteins also provide a shield against the host's immune system and bear most of the neutralizing antibody epitopes against any given virus. In viruses with more than one envelope protein, the proteins responsible for cellular attachment are as varied as the host cell receptors that they recognize. In contrast, the viral envelope proteins that catalyze the essential membrane fusion step in cell entry fall into three broad yet distinct structural classes (Figure 1 ). The influenza virus hemagglutinin (HA) is the prototype of class I fusion proteins [1] , which encompass those of other orthomyxoviruses, and of paramyxoviruses [2], retroviruses [3, 4] , filoviruses [5] , and coronaviruses [6, 7] . The unifying structural features of class I fusion proteins are a proteolytically generated N-terminal fusion peptide, and a core consisting of three bundled α-helices in the prefusion conformation, which refolds into a six-helix bundle in the postfusion conformation [8] . Class II fusion proteins are a structurally unrelated class found in flaviviruses [9], alphaviruses [10], and most recently in rubella virus (sole member
Output: A novel membrane fusion protein family in Flaviviridae? NIH Public Access NIH-PA Author Manuscript A conserved overall mechanism and topology of catalysis of viral membrane fusion
for detecting the gene encoding the σB major outer-capsid protein of novel duck reovirus (NDRV). A set of primers, composed of two outer primers, two inner primers and two loop primers, was designed based on the gene of interest. The LAMP reaction was conducted in a traditional laboratory water bath at 65 °C for 50 min. We compared the performance of calcein/Mn 2+ and SYBR Green I dyes, as well as electrophoresis on agarose gel stained with GoldView nucleic acid dye to detect the RT-LAMP-amplified products and all assays could be employed to discriminate between positive and negative specimens in visible or UV light. Our data showed that there is no cross-reaction with other viruses and the RT-LAMP technique displayed high sensitivity for detecting NDRV with a minimal detection limit of 200 fg RNA input. This assay was more sensitive than conventional PCR in detecting NDRV both in natural and experimental infection. In conclusion, the RT-LAMP technique was remarkably sensitive, specific, rapid, simple and profitable for the identification of NDRV.
Output: Detection of Novel duck reovirus (NDRV) using visual reverse transcription loop-mediated isothermal amplification (RT-LAMP)
VERSION 1 -REVIEW Pedro A Piedra Baylor College of Medicine Houston, TX, USA REVIEW RETURNED 13-Aug-2018 This manuscript reports on a retrospective population-based cohort study on acute respiratory infections (ARIs) in the emergency department (ED) in Western Australia (WA) among Aboriginal and non-aboriginal children (0-17 years) residing in metropolitan, urban and rural settings from 2002 to 2012. Administrative ED datasets were linked to birth and perinatal records. The objectives were to compare overall and age-specific ED ARIs rates among Aboriginal and non-Aboriginal children in the different WA regions, monthly distribution and temporal trends, and to identify infant, maternal and socio-economic risk factors for ARI. The overall goal is to use such information to inform health service planning. Major findings. 26% of ED presentations were for ARIs. ARIs rates were highest in children <12 months for Aboriginal children (1,027.6 per 1000 child-years) and non-Aboriginal children (297.4 per 1000 child-years). Regional differences were observed, trend analysis revealed increase ARI rates for all children in rural and remote areas, and the strongest risk facts observed in Aboriginal and non-Aboriginal children were male sex, prematurity, caesarean delivery, birth in lower socio-economic areas and living in the Kimberley region. This manuscript provides strong ARI incidence rates in the ED for children residing in Western Australia, and highlights ARIs rates of 2 to 3 times higher in Aboriginal children compare to non-Aboriginal children as well as regional disparity. The root cause for these disparities were not address. Commenting on the density of physicians (per 1000 population) by metropolitan, urban and rural settings as well as by regions within WA is likely to be informative, and explain in part, the disparities observed between race and region. Areas with low density of health care providers is likely to have increased use of the ED for basic health care assessment impacting ED ARI rates.
Output: TITLE (PROVISIONAL) Geographical disparities in emergency department presentations for acute respiratory infections and risk factors for presenting: a population-based cohort study of Western Australian children AUTHORS
Purpura, particularly when accompanied by fever, is a worrisome finding in children. Acute hemorrhagic edema of infancy (AHEI) is a benign type of small-vessel leukocytoclastic vasculitis that presents with progressive purpura and has an excellent prognosis. Patients with AHEI present with large, target-like purpuric plaques affecting the face, ear lobes, and extremities. While the rapid onset of these skin findings can be dramatic, the child with AHEI is usually well appearing with reassuring laboratory testing. We describe a case of a previously healthy 8-month-old female who presented with progressive purpura in a nondependent distribution, low-grade fevers, and extremity swelling. An extensive workup was performed prior to making the diagnosis of AHEI. Coronavirus was implicated as the likely triggering pathogen, and the patient suffered a recurrence of purpuric rash and swelling several weeks after her initial presentation.
Output: Case Report Acute Hemorrhagic Edema of Infancy after Coronavirus Infection with Recurrent Rash
The inter-flat airborne cross-transmission driven by single-sided natural ventilation has been identified recently in high-rise residential buildings, where most people live now in densely populated areas, and is one of the most complex and least understood transport routes. Given potential risks of infection during the outbreak of severe infectious diseases, the need for a full understanding of its mechanism and protective measures within the field of epidemiology and engineering becomes pressing. This review paper considers progress achieved in existing studies of the concerned issue regarding different research priorities. Considerable progress in observing and modeling the inter-flat transmission and dispersion under either buoyancy-or wind-dominated conditions has been made, while fully understanding the combined buoyancy and wind effects is not yet possible. Many methods, including on-site measurements, wind tunnel tests and numerical simulations, have contributed to the research development, despite some deficiencies of each method. Although the inter-flat transmission and dispersion characteristics can be demonstrated and quantified in a time-averaged sense to some extent, there are still unanswered questions at a fundamental level about transient dispersion process and thermal boundary conditions, calling for further studies with more advanced models for simulations and more sound experiments for validations.
Output: The airborne transmission of infection between flats in high-rise residential buildings: A review
Middle East respiratory syndrome (MERS) is an acute infectious disease of the respiratory system caused by the new betacoronavirus (MERS coronavirus, MERS-CoV), which shows high mortality rates. The typical symptoms of MERS are fever, cough, and shortness of breath, and it is often accompanied by pneumonia. The MERS-CoV was introduced to Republic of Korea in May 2015 by a patient returning from Saudi Arabia. The disease spread mostly through hospital infections, and by the time the epidemic ended in August, the total number of confirmed diagnoses was 186, among which 36 patients died. Reflecting the latest evidence for antiviral drugs in the treatment of MERS-CoV infection and the experiences of treating MERS patients in Republic of Korea, these guidelines focus on antiviral drugs to achieve effective treatment of MERS-CoV infections.
Output: Infection & Chemotherapy MERS-CoV 항바이러스제 치료지침 정용필 1 , 송준영 2 , 서유빈 3 , 최재필 4 , 신형식 5 , 즉각대응팀(Rapid Response Team) * 1 울산대학교 의과대학 서울아산병원 감염내과, 2 고려대학교 의과대학 구로병원 감염내과, 3 한림대학교 의과대학 강남성심병원 감염내과, 4 서울의료원 감염내과, 5 국립의료원 감염내과
Foot-and-mouth disease virus (FMDV) represses host translation machinery, blocks protein secretion, and cleaves cellular proteins associated with signal transduction and the innate immune response to infection. Non-structural proteins (NSPs) and non-coding elements (NCEs) of FMDV play a critical role in these biological processes. The FMDV virion consists of capsid and nucleic acid. The virus genome is a positive single stranded RNA and encodes a single long open reading frame (ORF) flanked by a long structured 5ʹ-untranslated region (5ʹ-UTR) and a short 3ʹ-UTR. The ORF is translated into a polypeptide chain and processed into four structural proteins (VP1, VP2, VP3, and VP4), 10 NSPs (L pro , 2A, 2B, 2C, 3A, 3B 1-3 , 3C pro , and 3D pol ), and some cleavage intermediates. In the past decade, an increasing number of studies have begun to focus on the molecular pathogenesis of FMDV NSPs and NCEs. This review collected recent research progress on the biological functions of these NSPs and NCEs on the replication and host cellular regulation of FMDV to understand the molecular mechanism of host-FMDV interactions and provide perspectives for antiviral strategy and development of novel vaccines.
Output: Biological function of Foot-and-mouth disease virus non-structural proteins and non-coding elements
publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. factors and the gene regulatory network in Escherichia coli. Nucleic Acids Res. 31, 1234-1244 15 Richter, G. et al. (1997 Biosynthesis of riboflavin: characterization of the bifunctional deaminase-reductase of Escherichia coli and Bacillus subtilis.
Output: Biosynthesis of riboflavin. Lumazine synthase of Escherichia coli
Noroviruses have a single-stranded, positive sense 7-8 kb RNA genome, which encodes a polyprotein precursor processed by a virus-encoded 3C-like cysteine protease (3CLpro) to generate mature non-structural proteins. Because processing of the polyprotein is essential for virus replication, norovirus 3CLpro has been targeted for the discovery of anti-norovirus small molecule therapeutics. Thus, we performed functional, structural and inhibition studies of norovirus 3CLpro with fluorescence resonance energy transfer (FRET) assay, X-ray crystallography, and NMR spectroscopy with a synthetic protease inhibitor. Three 3CLpro from Norwalk virus (NV, genogroup I), MD145 (genogroup II) and murine norovirus-1 (MNV-1, genogroup V) were optimized for a FRET assay, and compared for the inhibitory activities of a synthetic protease inhibitor (GC376). The apo 3D structures of NV 3CLpro determined with X-ray crystallography and NMR spectroscopy were further analyzed. In addition, the binding mode of NV 3CLpro-GC376 was compared with X-ray crystallography and NMR spectroscopy. The results of this report provide insight into the interaction of NV 3CLpro with substrate/inhibitor for better understanding of the enzyme and antiviral drug development.
Output: Structural and Inhibitor Studies of Norovirus 3C-like Proteases
Food security in the Middle East is directly affected by a challenging combination of ongoing destructive conflicts, a global economic downturn, widespread poverty, high population growth, corruption, intolerance, and the potentially damaging consequences of climate change. Many Arab countries demonstrate nearly all the features of those countries classified as poor, less developed, or failing to achieve the eight Millennium Goals. Even the economies of the richer oil-exporting countries in the Region have been seriously damaged by the downturn in oil and gas prices as new sources come on stream elsewhere and demand falls as a result of renewable sources of energy becoming available. Climate change predictions for the Region are worrisome even if most of the environmental commitments made by countries at the UN Climate Change Conference in Paris at the end of 2015 are delivered. Large parts of the Region already suffer from periods of extreme temperatures and shortages of fresh water, so harsher conditions of higher temperatures and weather extremes pose special problems for inhabitants and policymakers, with heightened geopolitical risks and uncertainties. Agriculture is especially vulnerable. Modern agricultural technologies with improved cultivars and livestock breeds must displace poor agricultural and pastoral practices. Larger-scale, bettercapitalised production units are required with policy shifts to remove marketdistorting subsidies, tariffs, and other regulatory impedances. Agricultural "roadmaps" are needed to encourage the most appropriate crops and maintain livestock in the most appropriate places. The trading of meat, dairy products and many types of crops to water-poor regions can be regarded as an efficient way to 261 redistribute water. In unsettled times, food security requires protection of foodproducing, food-processing, and food-distribution industries are protected along with research and development facilities, and the maintenance of skilled personnel. There are doubts as to whether agencies of the United Nations, other international agencies, donor countries and charities are able to provide adequate humanitarian aid and humanitarian intervention to enable safeguarding of displaced peoples and ensuring the resumption of normal peaceful conditions essential for food security to be guaranteed. Promises of aid funds must become reality, followed by the establishment of functional supply and transport networks, and rapid transition to self-reliance thereafter. Food security and social stability are inextricably linked. The solution to the food-security problems in the Region ultimately lies in the actions of governments, businesses and individuals. Governments need embedded scientific and technological expertise, strong civil-society institutions, integrity, and a particular focus on high-quality education.
Output: Food Security in an Insecure Future
Thymic atrophy or thymus absence causes depressed thyroid-thymus axis (TTA) efficiency in old, young propyl-thiouracil (PTU) (experimental hypothyroidism) and in young-adult thymectomised (Tx) mice, respectively. Altered zinc turnover may be also involved in depressed TTA efficiency. Zinc turnover is under the control of zinc-bound metallothioneins (Zn-MTs) synthesis. Thyroid hormones, corticosterone and nutritional zinc affect Zn-MT induction. Zn-MT releases zinc in young-adult age during transient oxidative stress for prompt immune response. In constant oxidative stress (ageing and liver regeneration after partial hepatectomy), high liver Zn-MTs, low zinc ion bioavailability and depressed TTA efficiency appear. This last finding suggested that MT might not release zinc during constant oxidative stress leading to impaired TTA efficiency. The aim of this work/study is to clarify the role of Zn-MTs (I +II) in TTA efficiency during development and ageing. The main results are (1) Old and PTU mice display high corticosterone, enhanced liver MTmRNA, low zinc and depressed TTA efficiency restored by zinc supply. Increased survival and no significant increments in basal liver Zn-MTs proteins occur in old and PTU mice after zinc supply. (2) Lot of zinc ions bound with MT in the liver from old mice than young (HPLC). (3) Young-adult Tx mice, evaluated at 15 days from thymectomy, display high MTmRNA and nutritional-endocrineimmune damage restored by zinc supply or by thymus grafts from old zinc-treated mice. (4) Young-adult Tx mice, but evaluated at 40 days from thymectomy, display natural normalisation in MTmRNA and nutritional-endocrineimmune profile with survival similar to normal mice. (5) Stressed (constant dark for 10 days) mice overexpressing MT display low zinc, depressed immunity, reduced thymic cortex, high corticosterone, altered thyroid hormones turnover showing a likeness with old mice. These findings, taken altogether, show that corticosterone is pivotal in MTs induction under stress. MTs bind preferentially zinc ions in constant oxidative stress, but with no release of zinc from www.elsevier.com/locate/mechagedev : S 0 0 4 7 -6 3 7 4 ( 0 1 ) 0 0 4 1 4 -6 E. Mocchegiani et al. / Mechanisms of Ageing and De6elopment 123 (2002) 675-694 676 MT leading to impaired TTA efficiency. Zinc supply restores the defect because zinc has no interference in affecting pre-existing Zn-MTs protein concentrations in old and PTU mice. Therefore, free zinc ions are available for TTA efficiency after zinc supply. Thymus from old zinc-treated mice induces the same restoring effect when transplanted in Tx recipients. However, Tx mice display natural normalisation in MTmRNA and in nutritional -endocrine-immune profile in the long run. Therefore, Zn-MTs (I + II) are crucial in zinc homeostasis for endocrine -immune efficiency during the entire life assuming a role of potential and novel 'biological clock of ageing'.
Output: Metallothioneins (I+ II) and thyroid-thymus axis efficiency in old mice: role of corticosterone and zinc supply
Understanding viral transmission dynamics within populations of reservoir hosts can facilitate greater knowledge of the spillover of emerging infectious diseases. While bat-borne viruses are of concern to public health, investigations into their dynamics have been limited by a lack of longitudinal data from individual bats. Here, we examine capture-mark-recapture (CMR) data from a species of Australian bat (Myotis macropus) infected with a putative novel Alphacoronavirus within a Bayesian framework. Then, we developed epidemic models to estimate the effect of persistently infectious individuals (which shed viruses for extensive periods) on the probability of viral maintenance within the study population. We found that the CMR data analysis supported grouping of infectious bats into persistently and transiently infectious bats. Maintenance of coronavirus within the study population was more likely in an epidemic model that included both persistently and transiently infectious bats, compared with the epidemic model with non-grouping of bats. These findings, using rare CMR data from longitudinal samples of individual bats, increase our understanding of transmission dynamics of bat viral infectious diseases.
Output: Persistent infections support maintenance of a coronavirus in a population of Australian bats (Myotis macropus)
Emerging infectious diseases (EIDs), including West Nile virus, severe acute respiratory syndrome (SARS) and Lyme disease, have had a direct effect within Canada, while many more EIDs such as Zika, chikungunya and Ebola are a threat to Canadians while travelling. Over 75% of EIDs affecting humans are, or were originally, zoonoses (infectious diseases transmitted from animals to humans). There are two main ways by which infectious diseases can emerge: by changes in their geographical ranges and by adaptive emergence, a genetic change in a microorganism that results in it becoming capable of invading a new niche, often by jumping to a new host species such as humans. Diseases can appear to emerge simply because we become capable of detecting and diagnosing them. Management of EID events is a key role of public health globally and a considerable challenge for clinical care. Increasingly, emphasis is being placed on predicting EID occurrence to "get ahead of the curve" -that is, allowing health systems to be poised to respond to them, and public health to be ready to prevent them. Predictive models estimate where and when EIDs may occur and the levels of risk they pose. Evaluation of the internal and external drivers that trigger emergence events is increasingly considered in predicting EID events. Currently, global changes are driving increasing occurrence of EIDs, but our capacity to prevent and deal with them is also increasing. Web-based scanning and analysis methods are increasingly allowing us to detect EID outbreaks, modern genomics and bioinformatics are increasing our ability to identify their genetic and geographical origins, while developments in geomatics and earth observation will enable more real-time tracking of outbreaks. EIDs will, however, remain a key, global public health challenge in a globalized world where demographic, climatic, and other environmental changes are altering the interactions between hosts and pathogen in ways that increase spillover from animals to humans and global spread. Affiliations
Output: Emerging infectious diseases: prediction and detection
Severe Acute Respiratory Syndrome (SARS) is a newly described infectious disease caused by a coronavirus. Two outbreaks occurred in Toronto in the spring of 2003, resulting in the closure of 3 hospitals, including 2 obstetrical units. Strategies, devised using information about the coronavirus available at the time, as well as epidemiologic and infectious disease containment measures, were initiated to protect obstetrical patients and staff. In the first outbreak. the obstetrical unit of an affected Toronto hospital was kept open while other clinical services were closed. In the second outbreak, the obstetrical unit was closed along with all other clinical activities. This report details the stepwise processes used to make decisions during the SARS outbreaks and the implementation of the decisions made. It is recommended that these or similar protocols be used when an obstetrical unit is confronted with a large-scale nosocomial infectious outbreak that has a mechanism of transmission similar to that of SARS. Resume : le syndrome respiratoire aigu severe (SRAS) est une nouvelle maladie infectieuse causee par un coronavirus. Deux flam bees epidemiques se sont produites a Toronto, au printemps de 2003, et ont force la fermeture de 3 h6pitaux, y compris 2 unites d'obstetrique.
Output: MANAGING OBSTETRICAL PATIENTS DURING SEVERE ACUTE RESPIRATORY SYNDROME OUTBREAK
Virus replicate inside prokaryotic and eukaryotic cells. Outside cells, they exist as independent particles (i.e. virions) generally composed of a protein shell (sometimes covered with a lipid bilayer) that contains their genetic material made of RNA or DNA. Virus genome replication and transcription are catalyzed by virally encoded polymerases. Although all these enzymes show some homology and share structural features and their catalytic mechanism, they also have important differences that reflect diverse virus replication strategies.
Output: VIRAL POLYMERASES
Background: Low respiratory hygiene compliance among health care workers of emergency departments has become a major concern in the spread of respiratory infections. Our objective was to determine the compliance with respiratory hygiene of triage nurses at 2 university hospital centers and to identify factors influencing compliance to the respiratory hygiene principles of emergency health care workers. Methods: A 2-part, cross-sectional, descriptive study was conducted at 2 training centers. An anonymous observation of compliance with respiratory hygiene by triage emergency nurses was performed. A selfadministered, voluntary questionnaire on attitudes, perceptions, and knowledge of respiratory hygiene guidelines was distributed to the health care workers at the emergency department of the 2 hospital sites. Results: Median objective compliance with respiratory hygiene measures of triage nurses was 22% (interquartile range [IQR], 11%-33%). Median perceived compliance of the health care workers was 68% (IQR, 61%-79%). Median actual knowledge score was 75% (IQR, 75%-100%). Overall, 91.9% of respondents believed that the mask was an effective preventive measure. The main obstacles toward mask wearing by the health care worker were "tendency to forget" (37.8%) and "discomfort" (35.1%). Conclusion: The compliance rate at our institution is very low. We identified a few factors affecting adherence to respiratory hygiene measures that are of potential use in targeting groups and formulating recommendations.
Output: Respiratory hygiene in emergency departments: Compliance, beliefs, and perceptions
CCL2 is a member of the CC chemokine family that mediates the migration and recruitment of monocytes and T cells and has been identified in the central nervous system (CNS) during several neuroinflammatory diseases. In order to examine the biological effect of constitutive CCL2 expression in the CNS, the authors engineered a mouse that expressed CCL2 in the CNS under control of the human glial fibrillary acidic protein (hGFAP) promoter. The results demonstrated that transgenic expression of CCL2 in the CNS resulted in diffuse CNS monocyte infiltration and accumulation. Transgenic CCL2 expression did not alter normal development, differentiation, or function of T cells. There was no evidence of overt CNS disease or other pathologic phenotype when mice were left unchallenged with antigen or uninfected. However, when CCL2 transgenic mice were given a peripheral challenge of lipopolysaccharide (LPS), an inflammatory infiltrate with organized perivascular lesions developed. Infection of the transgenic mice with Theiler's murine encephalomyelitis virus (TMEV) resulted in accelerated onset and increased severity of clinical and histological disease. These results suggest that CCL2 expression in the CNS is a major pathogenic factor that drives macrophage accumulation in the development of CNS inflammatory disease. Journal of NeuroVirology (2003) 9, 623-636. CCL2 mediates enhanced TMEV-induced demyelination 624 JL Bennett et al CCL2 mediates enhanced TMEV-induced demyelination JL Bennett et al 625
Output: CCL2 transgene expression in the central nervous system directs diffuse infiltration of CD45 high CD11b + monocytes and enhanced Theiler's murine encephalomyelitis virus-induced demyelinating disease
In an avian flu pandemic, which drugs could be used to treat or prevent infection with influenza A (H5N1) virus? Foremost are the viral neuraminidase inhibitors oseltamivir and zanamivir, which have already been used to treat human influenza A (H1N1 and H3N2) and B virus infections. The use of the M2 ion channel blockers amantadine and rimantadine is compounded by the rapid development of drug resistance. Although formally approved for other indications (i.e. treatment of hepatitis C), ribavirin and pegylated interferon might also be useful for controlling avian flu. Combined use of the currently available drugs should be taken into account and attempts should be made to develop new strategies directed at unexplored targets such as the viral proteins hemagglutinin, the viral polymerase (and endonuclease) and the non-structural protein NS1. As has been shown for other viral infections, RNA interference could be a powerful means with which to suppress the replication of avian H5N1.
Output: Avian influenza A (H5N1) infection: targets and strategies for chemotherapeutic intervention
Analyses of viral protein-protein interactions are an important step to understand viral protein functions and their underlying molecular mechanisms. In this study, we adopted a mammalian two-hybrid system to screen the genome-wide intraviral protein-protein interactions of SARS coronavirus (SARS-CoV) and therefrom revealed a number of novel interactions which could be partly confirmed by in vitro biochemical assays. Three pairs of the interactions identified were detected in both directions: non-structural protein (nsp) 10 and nsp14, nsp10 and nsp16, and nsp7 and nsp8. The interactions between the multifunctional nsp10 and nsp14 or nsp16, which are the unique proteins found in the members of Nidovirales with large RNA genomes including coronaviruses and toroviruses, may have important implication for the mechanisms of replication/transcription complex assembly and functions of these viruses. Using a SARS-CoV replicon expressing a luciferase reporter under the control of a transcription regulating sequence, it has been shown that several viral proteins (N, X and SUD domains of nsp3, and nsp12) provided in trans stimulated the replicon reporter activity, indicating that these proteins may regulate coronavirus replication and transcription. Collectively, our findings provide a basis and platform for further characterization of the functions and mechanisms of coronavirus proteins.
Output: Genome-Wide Analysis of Protein-Protein Interactions and Involvement of Viral Proteins in SARS-CoV Replication
Over the past decade, reported incidence of human metapneumovirus (hMPV) has increased owing to the use of molecular assays for diagnosis of respiratory viral infections in cancer patients. The seasonality of these infections, differences in sampling strategies across institutions, and small sample size of published studies make it difficult to appreciate the true incidence and impact of hMPV infections. In this systematic review, we summarized the published data on hMPV infections in hematopoietic cell transplant recipients and patients with hematologic malignancy, focusing on incidence, hMPV-associated lower respiratory tract infection (LRTI), mortality, prevention, and management with ribavirin and/or intravenous immunoglobulins. Although the incidence of hMPV infections and hMPV-associated LRTI in this patient population is similar to respiratory syncytial virus or parainfluenza virus and despite lack of directed antiviral therapy, the mortality rate remains low unless patients develop LRTI. In the absence of vaccine to prevent hMPV, infection control measures are recommended to reduce its burden in cancer patients.
Output: Human Metapneumovirus Infections in Hematopoietic Cell Transplant Recipients and Hematologic Malignancy Patients: A Systematic Review
An ideal vaccine provides long lasting protection against a pathogen by eliciting a well-rounded immune response which engages both innate and adaptive immunity. However, we have a limited understanding of how components of innate immunity, antibody and cell-mediated adaptive immunity interact and function together at a systems level. With advances in high-throughput 'Omics' methodologies it has become possible to capture global changes in the host, at a cellular and molecular level, that are induced by vaccination and infection. Analysis of these datasets has shown the promise of discovering mechanisms behind vaccine mediated protection, immunological memory, adverse effects as well as development of more efficient antigens and adjuvants. In this review, we will discuss how systems vaccinology takes advantage of new technology platforms and big data analysis, to enable the rational development of better vaccines.
Output: Moving from Empirical to Rational Vaccine Design in the 'Omics' Era
Programmed −1 ribosomal frameshifting (PRF) and stop codon readthrough are two translational recoding mechanisms utilized by some RNA viruses to express their structural and enzymatic proteins at a defined ratio. Efficient recoding usually requires an RNA pseudoknot located several nucleotides downstream from the recoding site. To assess the strategic importance of the recoding pseudoknots, we have carried out a large scale genome-wide analysis in which we used an in-house developed program to detect all possible H-type pseudoknots within the genomic mRNAs of 81 animal viruses. Pseudoknots are detected downstream from ∼85% of the recoding sites, including many previously unknown pseudoknots. ∼78% of the recoding pseudoknots are the most stable pseudoknot within the viral genomes. However, they are not as strong as some designed pseudoknots that exhibit roadblocking effect on the translating ribosome. Strong roadblocking pseudoknots are not detected within the viral genomes. These results indicate that the decoding pseudoknots have evolved to possess optimal stability for efficient recoding. We also found that the sequence at the gag-pol frameshift junction of HIV1 harbors potential elaborated pseudoknots encompassing the frameshift site. A novel mechanism is proposed for possible involvement of the elaborated pseudoknots in the HIV1 PRF event.
Output: A Genome-Wide Analysis of RNA Pseudoknots That Stimulate Efficient −1 Ribosomal Frameshifting or Readthrough in Animal Viruses
The SIJR model, simplified from the SEIJR model, is adopted to analyze the important parameters of the model of SARS epidemic such as the transmission rate, basic reproductive number. And some important parameters are obtained such as the transmission rate by applying this model to analyzing the situation in Hong Kong, Singapore and Canada at the outbreak of SARS. Then forecast of the transmission of SARS is drawn out here by the adjustment of parameters (such as quarantined rate) in the model. It is obvious that inflexion lies on the crunode of the graph, which indicates the big difference in transmission characteristics between the epidemic under control and not under control. This model can also be used in the comparison of the control effectiveness among different regions. The results from this model match well with the actual data in Hong Kong, Singapore and Canada and as a by-product, the index of the effectiveness of control in the later period can be acquired. It offers some quantitative indexes, which may help the further research in epidemic diseases.
Output: SARS epidemical forecast research in mathematical model
This study examined the effect of disclosing a list of hospitals with Middle East respiratory syndrome coronavirus (MERS-CoV) patients on the number of laboratory-confirmed MERS-CoV cases in South Korea. MERS-CoV data from 20 May 2015 to 5 July 2015 were from the Korean Ministry of Health & Welfare website and analyzed using segmented linear autoregressive error models for interrupted time series. This study showed that the number of laboratory-confirmed cases was increased by 9.632 on 5 June (p < 0.001). However, this number was significantly decreased following disclosure of a list of hospitals with MERS-CoV cases (Estimate = −0.699; p < 0.001). Disclosing the list of hospitals exposed to MERS-CoV was critical to the prevention of further infection. It reduced the number of confirmed MERS-CoV cases. Thus, providing accurate and timely information is a key to critical care response.
Output: Effect of Information Disclosure Policy on Control of Infectious Disease: MERS-CoV Outbreak in South Korea
Despite the availability of an inactivated vaccine that has been licensed for >50 years, the influenza virus continues to cause morbidity and mortality worldwide. Constant evolution of circulating influenza virus strains and the emergence of new strains diminishes the effectiveness of annual vaccines that rely on a match with circulating influenza strains. Thus, there is a continued need for new, efficacious vaccines conferring cross-clade protection to avoid the need for biannual reformulation of seasonal influenza vaccines. Recombinant virus-vectored vaccines are an appealing alternative to classical inactivated vaccines because virus vectors enable native expression of influenza antigens, even from virulent influenza viruses, while expressed in the context of the vector that can improve immunogenicity. In addition, a vectored vaccine often enables delivery of the vaccine to sites of inductive immunity such as the respiratory tract enabling protection from influenza virus infection. Moreover, the ability to readily manipulate virus vectors to produce novel influenza vaccines may provide the quickest path toward a universal vaccine protecting against all influenza viruses. This review will discuss experimental virus-vectored vaccines for use in humans, comparing them to licensed vaccines and the hurdles faced for licensure of these next-generation influenza virus vaccines.
Output: Virus-Vectored Influenza Virus Vaccines
The laboratory diagnosis of infectious diseases, especially those caused by mixed infections, is challenging. Routinely, it requires submission of multiple samples to separate laboratories. Advances in next-generation sequencing (NGS) have provided the opportunity for development of a comprehensive method to identify infectious agents. This study describes the use of target-specific primers for PCRmediated amplification with the NGS technology in which pathogen genomic regions of interest are enriched and selectively sequenced from clinical samples. In the study, 198 primers were designed to target 43 common bovine and small-ruminant bacterial, fungal, viral, and parasitic pathogens, and a bioinformatics tool was specifically constructed for the detection of targeted pathogens. The primers were confirmed to detect the intended pathogens by testing reference strains and isolates. The method was then validated using 60 clinical samples (including tissues, feces, and milk) that were also tested with other routine diagnostic techniques. The detection limits of the targeted NGS method were evaluated using 10 representative pathogens that were also tested by quantitative PCR (qPCR), and the NGS method was able to detect the organisms from samples with qPCR threshold cycle (C T ) values in the 30s. The method was successful for the detection of multiple pathogens in the clinical samples, including some additional pathogens missed by the routine techniques because the specific tests needed for the particular organisms were not performed. The results demonstrate the feasibility of the approach and indicate that it is possible to incorporate NGS as a diagnostic tool in a cost-effective manner into a veterinary diagnostic laboratory.
Output: Evaluation of Targeted Next-Generation Sequencing for Detection of Bovine Pathogens in Clinical Samples
Targeted recombination was carried out to select mouse hepatitis viruses (MHVs) in a defined genetic background, containing an MHV-JHM spike gene encoding either three heptad repeat 1 (HR1) substitutions (Q1067H, Q1094H, and L1114R) or L1114R alone. The recombinant virus, which expresses spike with the three substitutions, was nonfusogenic at neutral pH. Its replication was significantly inhibited by lysosomotropic agents, and it was highly neuroattenuated in vivo. In contrast, the recombinant expressing spike with L1114R alone mediated cell-to-cell fusion at neutral pH and replicated efficiently despite the presence of lysosomotropic agents; however, it still caused only subclinical morbidity and no mortality in animals. Thus, both recombinant viruses were highly attenuated and expressed viral antigen which was restricted to the olfactory bulbs and was markedly absent from other regions of the brains at 5 days postinfection. These data demonstrate that amino acid substitutions, in particular L1114R, within HR1 of the JHM spike reduced the ability of MHV to spread in the central nervous system. Furthermore, the requirements for low pH for fusion and viral entry are not prerequisites for the highly attenuated phenotype.
Output: Amino acid substitutions within the heptad repeat domain 1 of murine coronavirus spike protein restrict viral antigen spread in the central nervous system
In-vitro metabolite and drug detection rely on designed materials-based analytical platforms, which are universally used in biomedical research and clinical practice. However, metabolic analysis in bio-samples needs tedious sample preparation, due to the sample complexity and low molecular abundance. A further challenge is to construct diagnostic tools. Herein, we developed a platform using silver nanoshells. We synthesized SiO 2 @Ag with tunable shell structures by multi-cycled silver mirror reactions. Optimized nanoshells achieved direct laser desorption/ionization mass spectrometry in 0.5 μL of bio-fluids. We applied these nanoshells for disease diagnosis and therapeutic evaluation. We identified patients with postoperative brain infection through daily monitoring and glucose quantitation in cerebrospinal fluid. We measured drug distribution in blood and cerebrospinal fluid systems and validated the function of blood-brain/cerebrospinal fluid-barriers for pharmacokinetics. Our work sheds light on the design of materials for advanced metabolic analysis and precision diagnostics.
Output: Plasmonic silver nanoshells for drug and metabolite detection
The three components of the Blueprint prioritization methodology 1. The annual review: • Convening a suitable expert group (Prioritization Committee, Table) covering: 1) microbiology of severe pathogens, including virology, bacteriology and mycology, 2) clinical management of severe infections, 3) Epidemiology, in particular during health emergencies, 4) Public health policy, including emergency response, 5) Animal health, including veterinarians and experts in zoonoses from both livestock and wildlife, 6) experts from the defense or security sectors familiar with biological weapons and 7) other experts, including anthropologists, bioethicists, and other relevant social sciences. • Identifying a long list of diseases to be fed into the annual review process. • Triaging the long list into a shorter list for more detailed analysis. • Conducting that analysis through the Analytic Hierarchy Process (AHP)/Multi-criteria Decision Analysis (MCDA) method and Delphi process. • Communicating the outcome of the review. *EURO: European region, PAHO: American region, SAERO: south-east Asian region, AFRO: African region, WIPRO: West Pacific region. Detailed country members: http://www.who.int/about/regions/en. In accordance with best practice, separate processes were used to develop the methodology and run the annual review (1-5). According to Brookes et al. 2015 , separating these processes improves transparency "by clearly separating decision-makers subjective opinions regarding the value of criteria from measurements for individual pathogens, as well as reducing opportunity for cognitive bias that can arise when directly valuing pathogens" (5). In addition to the annual exercise to update the list, the methodology itself will be reviewed every 2 years. This methodology review involves: convening a group of suitable experts; examining and revising the prioritization criteria and sub-criteria; and updating the weightings applied to the criteria. The broader prioritization process also includes a decision tree for consideration of an unknown disease or a known disease presenting with unusual characteristics. The decision instrument is intended to guide users through: considering available information, determining
Output: World Health Organization Methodology to Prioritize Emerging Infectious Diseases in Need of Research and Development