Unnamed: 0
int64 0
160k
| title
stringlengths 3
1.06k
⌀ | abstract
stringlengths 3
122k
⌀ |
|---|---|---|
2,900 | Extremely low risk for acquisition of a respiratory viral infection in the emergency room of a large pediatric hospital during the winter season | Please cite this paper as: Maltezou et al. (2012). Extremely low risk for acquisition of a respiratory viral infection in the emergency room of a large pediatric hospital during the winter season. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2012.00355.x. The aim of this study was to investigate the rate of transmission of respiratory viral infections to children visiting the emergency room of a large pediatric hospital during winter. A total of 615 children were prospectively studied. Twenty‐two (3·6%) children developed at least one symptom compatible with a respiratory viral infection within 1–7 days after the visit, including cough (12 children), fever (8), rhinorrhea (7), and/or respiratory distress (1). Three children (0·49%) developed an influenza‐like illness. These findings indicate that transmission of respiratory viral infections to children visiting an emergency room during the winter season is extremely low. |
2,901 | Detection of influenza A virus in live bird markets in Kenya, 2009–2011 | Please cite this paper as: Munyua et al. (2013) Detection of influenza A virus in live bird markets in Kenya, 2009–2011. Influenza and Other Respiratory Viruses 7(2), 113–119. Background Surveillance for influenza viruses within live bird markets (LBMs) has been recognized as an effective tool for detecting circulating avian influenza viruses (AIVs). In Sub‐Saharan Africa, limited data exist on AIVs in animal hosts, and in Kenya the presence of influenza virus in animal hosts has not been described. Objectives This surveillance project aimed to detect influenza A virus in poultry traded in five LBMs in Kenya. Methods We visited each market monthly and collected oropharyngeal and cloacal specimens from poultry and environmental specimens for virological testing for influenza A by real time RT‐PCR. On each visit, we collected information on the number and types of birds in each market, health status of the birds, and market practices. Results During March 24, 2009–February 28, 2011, we collected 5221 cloacal and oropharyngeal swabs. Of the 5199 (99·6%) specimens tested, influenza A virus was detected in 42 (0·8%), including 35/4166 (0·8%) specimens from chickens, 3/381 (0·8%) from turkeys, and 4/335 (1·2%) from geese. None of the 317 duck specimens were positive. Influenza was more commonly detected in oropharyngeal [33 (1·3%)] than in cloacal [9 (0·4%)] specimens. None of the 485 environmental specimens were positive. Virus was detected in all five markets during most (14/22) of the months. Ducks and geese were kept longer at the market (median 30 days) than chickens (median 2 days). Conclusions Influenza A was detected in a small percentage of poultry traded in LBMs in Kenya. Efforts should be made to promote practices that could limit the maintenance and transmission of AIVs in LBMs. |
2,902 | Case report: a fatal case of disseminated adenovirus infection in a non-transplant adult haematology patient | BACKGROUND: We report a fatal case of disseminated adenovirus infection in a non-transplant haematology adult patient with chronic lymphocytic leukaemia who had completed combination chemoimmunotherapy a few months before developing respiratory symptoms. In such non-transplant patients, monitoring for adenovirus in the blood is not routine. However, with adenoviruses, when there is a more peripheral (i.e. non-blood) site of infection such as the chest, serial adenovirus monitoring in blood for the duration of that illness may be warranted. CASE PRESENTATION: This case started with an initial bacterial chest infection that responded to treatment, followed by an adenovirus pneumonitis that disseminated to his blood a week later with levels of up to 92 million adenovirus DNA copies/ml. Despite prompt treatment with cidofovir, his respiratory function continued to deteriorate over the next two weeks and he was moved to intensive care. Intravenous immunoglobulin and ribavirin were subsequently added to his treatment. However, he died soon after this with a final adenovirus load of 20 million copies/ml in his blood. CONCLUSIONS: We recommend that even in non-transplant haematology patients, where such patients present with an acute respiratory adenovirus infection, teams should consider checking the blood for adenovirus to check for signs of disseminated infection. The earlier this can be tested, the earlier treatment can be initiated (if adenovirus positive), which may produce more successful clinical outcomes. |
2,903 | Mortality, morbidity and health in developed societies: a review of data sources | The purpose of this paper is to review the major sources of data on mortality, morbidity and health in Europe and in other developed regions in order to examine their potential for analysing mortality and morbidity levels and trends. The review is primarily focused on routinely collected information covering a whole country. No attempt is made to draw up an inventory of sources by country; the paper deals instead with the pros and cons of each source for mortality and morbidity studies in demography. While each source considered separately can already yield useful, though partial, results, record linkage among data sources can significantly improve the analysis. Record linkage can also lead to the detection of possible causal associations that could eventually be confirmed. More generally, Big Data can reveal changing mortality and morbidity trends and patterns that could lead to preventive measures being taken rather than more costly curative ones. |
2,904 | Politics of Ebola and the critical role of global health diplomacy for the CARICOM | The 2014 Ebola epidemic was the largest in history, affecting Guinea, Liberia, Sierra Leone, Nigeria, and Mali in West Africa. The International Health Regulations are legally binding in 194 countries including all the member states of WHO “to prevent, protect against, control, and provide a public health response to the international spread of disease.” Since the Caribbean Community region heavily depends on tourism, a single case of the disease anywhere in the region could have serious negative consequences for the rest of the region's tourism industry. Global health diplomacy brings together the disciplines of public health, international affairs, management, law, and economics and focuses on negotiations that shape and manage the global policy environment for health. The regional institutes such as Caribbean Public Health Agency should play a more proactive and pivotal role in the creation of regional response teams in all the island nations collaborating with the departments of public health and epidemiology at the regional campuses of The University of the West Indies. The role of global health diplomacy and its practice should be encouraged to reach a consensus among the stakeholders considering the threat to the health security in the region. There is a need for the cadre of global health diplomats who has a critical understanding of health and also the practice of diplomacy since such serious health issues have implications at the global level in this globalized world. |
2,905 | Global ubiquitination analysis reveals extensive modification and proteasomal degradation of cowpox virus proteins, but preservation of viral cores | The emergence of Variola virus-like viruses by natural evolution of zoonotic Orthopoxviruses, like Cowpox virus (CPXV), is a global health threat. The proteasome is essential for poxvirus replication, making the viral components interacting with the ubiquitin-proteasome system attractive antiviral targets. We show that proteasome inhibition impairs CPXV replication by prevention of uncoating, suggesting that uncoating is mediated by proteasomal degradation of viral core proteins. Although Orthopoxvirus particles contain considerable amounts of ubiquitin, distinct modification sites are largely unknown. Therefore, for the first time, we analyzed globally ubiquitination sites in CPXV mature virion proteins using LC-MS/MS. Identification of 137 conserved sites in 54 viral proteins among five CPXV strains revealed extensive ubiquitination of structural core proteins. Moreover, since virions contained primarily K48-linked polyubiquitin, we hypothesized that core proteins are modified accordingly. However, quantitative analysis of ubiquitinated CPXV proteins early in infection showed no proteasomal degradation of core proteins. Instead, our data indicate that the recently suggested proteasomal regulation of the uncoating factor E5 is a prerequisite for uncoating. Expanding our understanding of poxvirus uncoating and elucidating a multitude of novel ubiquitination sites in poxvirus proteins, the present study verifies the major biological significance of ubiquitin in poxvirus infection. |
2,906 | A Low-Cost Palmtop High-Speed Capillary Electrophoresis Bioanalyzer with Laser Induced Fluorescence Detection | In this work, we developed a miniaturized palmtop high-speed capillary electrophoresis (CE) system integrating whole modules, including picoliter-scale sample injection, short capillary-based fast CE, high-voltage power supply, orthogonal laser induced fluorescence (LIF) detection, battery, system control, on-line data acquisition, processing, storage, and display modules. A strategy of minimalist miniaturization combining minimal system design and low-cost system construction was adopted to achieve the instrument miniaturization with extremely low cost, which is differing from the current microfabrication strategy used in most reported miniaturized CE systems. With such a strategy, the total size of the bioanalyzer was minimized to 90 × 75 × 77 mm (length × width × height) and the instrument cost was reduced to ca. $500, which demonstrated the smallest and lowest-cost CE instrument with LIF detection in so far reported systems. The present bioanalyzer also exhibited comparable analytical performances to previously-reported high-speed CE systems. A limit of detection of 1.02 nM sodium fluorescein was obtained. Fast separations were achieved for multiple types of samples as amino acids, amino acid enantiomers, DNA fragments, and proteins with high efficiency. We applied this instrument in colorectal cancer diagnosis for detecting KRAS mutation status by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. |
2,907 | Bismuth antimicrobial drugs serve as broad-spectrum metallo-β-lactamase inhibitors | Drug-resistant superbugs pose a huge threat to human health. Infections by Enterobacteriaceae producing metallo-β-lactamases (MBLs), e.g., New Delhi metallo-β-lactamase 1 (NDM-1) are very difficult to treat. Development of effective MBL inhibitors to revive the efficacy of existing antibiotics is highly desirable. However, such inhibitors are not clinically available till now. Here we show that an anti-Helicobacter pylori drug, colloidal bismuth subcitrate (CBS), and related Bi(III) compounds irreversibly inhibit different types of MBLs via the mechanism, with one Bi(III) displacing two Zn(II) ions as revealed by X-ray crystallography, leading to the release of Zn(II) cofactors. CBS restores meropenem (MER) efficacy against MBL-positive bacteria in vitro, and in mice infection model, importantly, also slows down the development of higher-level resistance in NDM-1-positive bacteria. This study demonstrates a high potential of Bi(III) compounds as the first broad-spectrum B1 MBL inhibitors to treat MBL-positive bacterial infection in conjunction with existing carbapenems. |
2,908 | Antibody-mediated enhancement aggravates chikungunya virus infection and disease severity | The arthropod-transmitted chikungunya virus (CHIKV) causes a flu-like disease that is characterized by incapacitating arthralgia. The re-emergence of CHIKV and the continual risk of new epidemics have reignited research in CHIKV pathogenesis. Virus-specific antibodies have been shown to control virus clearance, but antibodies present at sub-neutralizing concentrations can also augment virus infection that exacerbates disease severity. To explore this occurrence, CHIKV infection was investigated in the presence of CHIKV-specific antibodies in both primary human cells and a murine macrophage cell line, RAW264.7. Enhanced attachment of CHIKV to the primary human monocytes and B cells was observed while increased viral replication was detected in RAW264.7 cells. Blocking of specific Fc receptors (FcγRs) led to the abrogation of these observations. Furthermore, experimental infection in adult mice showed that animals had higher viral RNA loads and endured more severe joint inflammation in the presence of sub-neutralizing concentrations of CHIKV-specific antibodies. In addition, CHIKV infection in 11 days old mice under enhancing condition resulted in higher muscles viral RNA load detected and death. These observations provide the first evidence of antibody-mediated enhancement in CHIKV infection and pathogenesis and could also be relevant for other important arboviruses such as Zika virus. |
2,909 | Characterization of Influenza Virus Pseudotyped with Ebolavirus Glycoprotein | We have produced a new Ebola virus pseudotype, E-S-FLU, that can be handled in biosafety level 1/2 containment for laboratory analysis. The E-S-FLU virus is a single-cycle influenza virus coated with Ebolavirus glycoprotein, and it encodes enhanced green fluorescence protein as a reporter that replaces the influenza virus hemagglutinin. MDCK-SIAT1 cells were transduced to express Ebolavirus glycoprotein as a stable transmembrane protein for E-S-FLU virus production. Infection of cells with the E-S-FLU virus was dependent on the Niemann-Pick C1 protein, which is the well-characterized receptor for Ebola virus entry at the late endosome/lysosome membrane. The E-S-FLU virus was neutralized specifically by an anti-Ebolavirus glycoprotein antibody and a variety of small drug molecules that are known to inhibit the entry of wild-type Ebola virus. To demonstrate the application of this new Ebola virus pseudotype, we show that a single laboratory batch was sufficient to screen a library (LOPAC(1280); Sigma) of 1,280 pharmacologically active compounds for inhibition of virus entry. A total of 215 compounds inhibited E-S-FLU virus infection, while only 22 inhibited the control H5-S-FLU virus coated in H5 hemagglutinin. These inhibitory compounds have very dispersed targets and mechanisms of action, e.g., calcium channel blockers, estrogen receptor antagonists, antihistamines, serotonin uptake inhibitors, etc., and this correlates with inhibitor screening results obtained with other pseudotypes or wild-type Ebola virus in the literature. The E-S-FLU virus is a new tool for Ebola virus cell entry studies and is easily applied to high-throughput screening assays for small-molecule inhibitors or antibodies. IMPORTANCE Ebola virus is in the Filoviridae family and is a biosafety level 4 pathogen. There are no FDA-approved therapeutics for Ebola virus. These characteristics warrant the development of surrogates for Ebola virus that can be handled in more convenient laboratory containment to study the biology of the virus and screen for inhibitors. Here we characterized a new surrogate, named E-S-FLU virus, that is based on a disabled influenza virus core coated with the Ebola virus surface protein but does not contain any genetic information from the Ebola virus itself. We show that E-S-FLU virus uses the same cell entry pathway as wild-type Ebola virus. As an example of the ease of use of E-S-FLU virus in biosafety level 1/2 containment, we showed that a single production batch could provide enough surrogate virus to screen a standard small-molecule library of 1,280 candidates for inhibitors of viral entry. |
2,910 | Estimates of global research productivity in using nicotine replacement therapy for tobacco cessation: a bibliometric study | BACKGROUND: Tobacco use is a major healthcare problem worldwide. Tobacco smoking remains the most important risk factor for both cancer and heart diseases. This study was initiated due to the lack of published data concerning the real progress in research output in the use of nicotine replacement therapy (NRT) for tobacco cessation. This study was aimed to use bibliometric analysis to estimate the NRT literature indexed in Scopus database at global level. METHODS: Core of the search strategy was the documents that contained specific words or phrases regarding NRT as keywords in the title. Publication output of most prolific countries was adjusted to the gross domestic product and population size. All citations analysis were accomplished on December 22, 2017. RESULTS: A total of 2138 references were retrieved and published from 56 countries, which were published between 1970 and 2016. The USA has the most number of published articles accounted to 986, followed by the UK (312 publications) and then Australia (102 publications), and Sweden (102 publications). No data related to NRT were published from 156 countries. No significant correlation was found between the country population size or 2016 gross domestic product values and the number of publications of the top-10 most prolific countries in the field of NRT (r = − 0.156, P = 0.664; and r = − 0.173, P = 0.632, respectively). Furthermore, there is no correlation between prevalence of tobacco smoking and number of publications of the top-10 most prolific countries in the field of NRT (r = − 0.235, P = 0.514). CONCLUSIONS: The present data reveal a solid mass of research activity on NRT. The USA was by far the predominant country in the amount of NRT-based research activity. NRT-based research activities were low or not available in most countries. The results of this study delineate a framework for better understanding the situations of current NRT research and prospective directions of the research in this field which could be applied for managing and prioritizing future research efforts in NRT research. |
2,911 | Economic burden of pneumococcal infections in children under 5 years of age | The present study aimed to determine the cost of childhood pneumococcal infections under 5 years of age and to provide further data for future health economy studies. Electronic medical records of children diagnosed with meningitis caused by S. pneumoniae and all-cause pneumonia, and acute otitis media (AOM) between January 2013-April 2014 were retrospectively evaluated. Direct costs for the treatments of hospitalized patients (pneumonia and pneumococcal meningitis) including costs of healthcare services consisted of costs of hospital bed, examination, laboratory analyses, scanning methods, consultation, vascular access procedures, and infusion and intravenous treatments. Direct costs for patients (AOM) treated in outpatient setting included constant price paid for the examination and cost of prescribed antibiotics. Indirect costs included cost of work loss of parents and their transportation expenses. Data of 130 children with pneumococcal meningitis (n = 10), pneumonia (n = 53), and AOM (n = 67) were analyzed. The total median cost was €4,060.38 (direct cost: €3,346.38 and indirect cost: €829.18) for meningitis, €835.91 (direct cost: €480.66 and indirect cost: €330.09) for pneumonia, and €117.32 (direct cost: €17.59 and indirect cost: €99.73) for AOM. The medication cost (p = 0.047), indirect cost (p = 0.032), and total cost (p = 0.011) were significantly higher in pneumonia patients aged ≥36 months than those aged <36 months; however, direct cost of AOM were significantly higher in the patients aged <36 months (p = 0.049). Results of the present study revealed that the treatment cost was significantly enhanced for hospitalization and for advanced disease. Thus, preventive actions, mainly vaccination, should be conducted regularly. |
2,912 | Revision of clinical case definitions: influenza-like illness and severe acute respiratory infection | The formulation of accurate clinical case definitions is an integral part of an effective process of public health surveillance. Although such definitions should, ideally, be based on a standardized and fixed collection of defining criteria, they often require revision to reflect new knowledge of the condition involved and improvements in diagnostic testing. Optimal case definitions also need to have a balance of sensitivity and specificity that reflects their intended use. After the 2009–2010 H1N1 influenza pandemic, the World Health Organization (WHO) initiated a technical consultation on global influenza surveillance. This prompted improvements in the sensitivity and specificity of the case definition for influenza – i.e. a respiratory disease that lacks uniquely defining symptomology. The revision process not only modified the definition of influenza-like illness, to include a simplified list of the criteria shown to be most predictive of influenza infection, but also clarified the language used for the definition, to enhance interpretability. To capture severe cases of influenza that required hospitalization, a new case definition was also developed for severe acute respiratory infection in all age groups. The new definitions have been found to capture more cases without compromising specificity. Despite the challenge still posed in the clinical separation of influenza from other respiratory infections, the global use of the new WHO case definitions should help determine global trends in the characteristics and transmission of influenza viruses and the associated disease burden. |
2,913 | Marion Koopmans: greater regional capacity to fight disease outbreaks | Marion Koopmans tells Fiona Fleck why the world needs a publicly-funded network of hubs in all regions with local experts able to respond to infectious disease threats as they emerge. |
2,914 | SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses | The human interferon (IFN)-induced MxA protein is a key antiviral host restriction factor exhibiting broad antiviral activity against many RNA viruses, including highly pathogenic avian influenza A viruses (IAV) of the H5N1 and H7N7 subtype. To date the mechanism for how MxA exerts its antiviral activity is unclear, however, additional cellular factors are believed to be essential for this activity. To identify MxA cofactors we performed a genome-wide siRNA-based screen in human airway epithelial cells (A549) constitutively expressing MxA using an H5N1 reporter virus. These data were complemented with a proteomic screen to identify MxA-interacting proteins. The combined data identified SMARCA2, the ATPase subunit of the BAF chromatin remodeling complex, as a crucial factor required for the antiviral activity of MxA against IAV. Intriguingly, our data demonstrate that although SMARCA2 is essential for expression of some IFN-stimulated genes (ISGs), and the establishment of an antiviral state, it is not required for expression of MxA, suggesting an indirect effect on MxA activity. Transcriptome analysis of SMARCA2-depleted A549-MxA cells identified a small set of SMARCA2-regulated factors required for activity of MxA, in particular IFITM2 and IGFBP3. These findings reveal that several virus-inducible factors work in concert to enable MxA restriction of IAV. |
2,915 | Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions | Activation and regulation of the cascade systems of the blood (the complement system, the coagulation/contact activation/kallikrein system, and the fibrinolytic system) occurs via activation of zymogen molecules to specific active proteolytic enzymes. Despite the fact that the generated proteases are all present together in the blood, under physiological conditions, the activity of the generated proteases is controlled by endogenous protease inhibitors. Consequently, there is remarkable little crosstalk between the different systems in the fluid phase. This concept review article aims at identifying and describing conditions where the strict system-related control is circumvented. These include clinical settings where massive amounts of proteolytic enzymes are released from tissues, e.g., during pancreatitis or post-traumatic tissue damage, resulting in consumption of the natural substrates of the specific proteases and the available protease inhibitor. Another example of cascade system dysregulation is disseminated intravascular coagulation, with canonical activation of all cascade systems of the blood, also leading to specific substrate and protease inhibitor elimination. The present review explains basic concepts in protease biochemistry of importance to understand clinical conditions with extensive protease activation. |
2,916 | Whole-Genome Sequence of Human Rhinovirus C47, Isolated from an Adult Respiratory Illness Outbreak in Butte County, California, 2017 | Here, we report the full coding sequence of rhinovirus C47 (RV-C47), obtained from a patient respiratory sample collected during an acute respiratory illness investigation in Butte County, California, in January 2017. This is the first whole-genome sequence of RV-C47 to be reported. |
2,917 | Quantitative Analysis of Hepatitis C NS5A Viral Protein Dynamics on the ER Surface | Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles. |
2,918 | Improving the Hospital Quality of Care during Winter Periods by Optimizing Budget Allocation Between Rotavirus Vaccination and Bed Expansion | BACKGROUND: During each winter the hospital quality of care (QoC) in pediatric wards decreases due to a surge in pediatric infectious diseases leading to overcrowded units. Bed occupancy rates often surpass the good hospital bed management threshold of 85%, which can result in poor conditions in the workplace. This study explores how QoC-scores could be improved by investing in additional beds and/or better vaccination programs against vaccine-preventable infectious diseases. METHODS: The Cobb–Douglas model was selected to define the improvement in QoC (%) as a function of two strategies (rotavirus vaccination coverage [%] and addition of extra hospital beds [% of existing beds]), allowing improvement-isocurves to be produced. Subsequently, budget minimization was applied to determine the combination of the two strategies needed to reach a given QoC improvement at the lowest cost. Data from Jessa Hospital (Hasselt, Belgium) were chosen as an example. The annual population in the catchment area to be vaccinated was 7000 children; the winter period was 90 days with 34 pediatric beds available. Rotavirus vaccination cost per course was €118.26 and the daily cost of a pediatric bed was €436.53. The target QoC increase was fixed at 50%. The model was first built with baseline parameter values. RESULTS: The model predicted that a combination of 64% vaccine coverage and 39% extra hospital beds (≈ 13 extra beds) in winter would improve QoC-scores by 50% for the minimum budget allocation. CONCLUSION: The model allows determination of the most efficient allocation of the healthcare budget between rotavirus vaccination and bed expansion for improving QoC-scores during the annual epidemic winter seasons. |
2,919 | Non-specific Effect of Vaccines: Immediate Protection against Respiratory Syncytial Virus Infection by a Live Attenuated Influenza Vaccine | The non-specific effects (NSEs) of vaccines have been discussed for their potential long-term beneficial effects beyond direct protection against a specific pathogen. Cold-adapted, live attenuated influenza vaccine (CAIV) induces local innate immune responses that provide a broad range of antiviral immunity. Herein, we examined whether X-31ca, a donor virus for CAIVs, provides non-specific cross-protection against respiratory syncytial virus (RSV). The degree of RSV replication was significantly reduced when X-31ca was administered before RSV infection without any RSV-specific antibody responses. The vaccination induced an immediate release of cytokines and infiltration of leukocytes into the respiratory tract, moderating the immune perturbation caused by RSV infection. The potency of protection against RSV challenge was significantly reduced in TLR3(-/-) TLR7(-/-) mice, confirming that the TLR3/7 signaling pathways are necessary for the observed immediate and short-term protection. The results suggest that CAIVs provide short-term, non-specific protection against genetically unrelated respiratory pathogens. The additional benefits of CAIVs in mitigating acute respiratory infections for which vaccines are not yet available need to be assessed in future studies. |
2,920 | Functional role of the type 1 pilus rod structure in mediating host-pathogen interactions | Uropathogenic E. coli (UPEC), which cause urinary tract infections (UTI), utilize type 1 pili, a chaperone usher pathway (CUP) pilus, to cause UTI and colonize the gut. The pilus rod, comprised of repeating FimA subunits, provides a structural scaffold for displaying the tip adhesin, FimH. We solved the 4.2 Å resolution structure of the type 1 pilus rod using cryo-electron microscopy. Residues forming the interactive surfaces that determine the mechanical properties of the rod were maintained by selection based on a global alignment of fimA sequences. We identified mutations that did not alter pilus production in vitro but reduced the force required to unwind the rod. UPEC expressing these mutant pili were significantly attenuated in bladder infection and intestinal colonization in mice. This study elucidates an unappreciated functional role for the molecular spring-like property of type 1 pilus rods in host-pathogen interactions and carries important implications for other pilus-mediated diseases. |
2,921 | Crisis Communication in Public Health Emergencies: The Limits of ‘Legal Control’ and the Risks for Harmful Outcomes in a Digital Age | Communication by public authorities during a crisis situation is an essential and indispensable part of any response to a situation that may threaten both life and property. In the online connected world possibilities for such communication have grown further, in particular with the opportunity that social media presents. As a consequence, communication strategies have become a key plank of responses to crises ranging from epidemics to terrorism to natural disaster. Such strategies involve a range of innovative practices on social media. Whilst being able to bring about positive effects, they can also bring about a range of harmful unintended side effects. This include economic harms produced by incorrect information and a range of social harms that can be fuelled by myths and rumours, worsening negative phenomena such as stigmatisation and discrimination. Given the potential for such harms, one might expect that affected or potentially affected individuals would be able to challenge such measures before courts or administrative tribunals. As this paper demonstrates however this is not the case. More often than not seemingly applicable legal approaches are unlikely to be able to engage such methods. This is often because such measures represent activities that are purely expressive in nature and therefore not capable of imposing any binding legal or corporeal changes on individuals. Whilst some forms of soft law may pose requirements for public officials involved in such activities (e.g. codes of conduct or of professional ethics), they are not likely to offer potentially harmed individuals the chance to to challenge particular communication strategies before courts or legal tribunals. The result is that public authorities largely have a free reign to communicate how they wish and do not have to have to comply with a range of requirements (e.g. relating to form and substantive) content) that would in general apply to most forms of official administrative act. |
2,922 | H5N1 influenza virus-specific miRNA-like small RNA increases cytokine production and mouse mortality via targeting poly(rC)-binding protein 2 | Infection of H5N1 influenza virus causes the highest mortality among all influenza viruses. The mechanisms underlying such high viral pathogenicity are incompletely understood. Here, we report that the H5N1 influenza virus encodes a microRNA-like small RNA, miR-HA-3p, which is processed from a stem loop-containing viral RNA precursor by Argonaute 2, and plays a role in enhancing cytokine production during H5N1 infection. Mechanistic study shows that miR-HA-3p targets poly(rC)-binding protein 2 (PCBP2) and suppresses its expression. Consistent with PCBP2 being an important negative regulator of RIG-I/MAVS-mediated antiviral innate immunity, suppression of PCBP2 expression by miR-HA-3p promotes cytokine production in human macrophages and mice infected with H5N1 virus. We conclude that miR-HA-3p is the first identified influenza virus-encoded microRNA-like functional RNA fragment and a novel virulence factor contributing to H5N1-induced 'cytokine storm' and mortality. |
2,923 | Far-UVC light: A new tool to control the spread of airborne-mediated microbial diseases | Airborne-mediated microbial diseases such as influenza and tuberculosis represent major public health challenges. A direct approach to prevent airborne transmission is inactivation of airborne pathogens, and the airborne antimicrobial potential of UVC ultraviolet light has long been established; however, its widespread use in public settings is limited because conventional UVC light sources are both carcinogenic and cataractogenic. By contrast, we have previously shown that far-UVC light (207–222 nm) efficiently inactivates bacteria without harm to exposed mammalian skin. This is because, due to its strong absorbance in biological materials, far-UVC light cannot penetrate even the outer (non living) layers of human skin or eye; however, because bacteria and viruses are of micrometer or smaller dimensions, far-UVC can penetrate and inactivate them. We show for the first time that far-UVC efficiently inactivates airborne aerosolized viruses, with a very low dose of 2 mJ/cm(2) of 222-nm light inactivating >95% of aerosolized H1N1 influenza virus. Continuous very low dose-rate far-UVC light in indoor public locations is a promising, safe and inexpensive tool to reduce the spread of airborne-mediated microbial diseases. |
2,924 | TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing | Intracellular nucleic acid sensors often undergo sophisticated modifications that are critical for the regulation of antimicrobial responses. Upon recognition of DNA, the cytosolic sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the second messenger cGAMP, which subsequently initiates downstream signaling to induce interferon-αβ (IFNαβ) production. Here we report that TRIM56 E3 ligase-induced monoubiquitination of cGAS is important for cytosolic DNA sensing and IFNαβ production to induce anti-DNA viral immunity. TRIM56 induces the Lys335 monoubiquitination of cGAS, resulting in a marked increase of its dimerization, DNA-binding activity, and cGAMP production. Consequently, TRIM56-deficient cells are defective in cGAS-mediated IFNαβ production upon herpes simplex virus-1 (HSV-1) infection. Furthermore, TRIM56-deficient mice show impaired IFNαβ production and high susceptibility to lethal HSV-1 infection but not to influenza A virus infection. This adds TRIM56 as a crucial component of the cytosolic DNA sensing pathway that induces anti-DNA viral innate immunity. |
2,925 | Function of aquaporins in sepsis: a systematic review | BACKGROUND: Sepsis is a common cause of death in intensive care units worldwide. Due to the high complexity of this immunological syndrome development of novel therapeutic strategies is urgent. Promising drug targets or biomarkers may depict aquaporins (AQPs) as they regulate crucial key mechanisms of sepsis. MAIN BODY: Here we report on base of the current literature that several AQPs are involved in different physiological processes of sepsis. In immune system mainly AQPs 3, 5 and 9 seem to be important, as they regulate the migration of different immune cells. Several studies showed that AQP3 is essential for T cell function and macrophage migration and that AQP5 and AQP9 regulate neutrophil cell migration and impact sepsis survival. Additionally, to the function in immune system AQPs 1 and 5 play a role in sepsis induced lung injury and their downregulation after inflammatory stimuli impair lung injury. By contrast, AQP4 expression is up-regulated during brain inflammation and aggravates brain edema in sepsis. In kidney AQP2 expression is downregulated during sepsis and can cause renal failure. Some studies also suggest a role of AQP1 in cardiac function. CONCLUSION: In conclusion, AQPs are involved in many physiological dysfunctions in sepsis and their expressions are differently regulated. Additional research on the regulatory mechanisms of aquaporins may identify potential therapeutic targets. |
2,926 | Surfactant Protein D in Respiratory and Non-Respiratory Diseases | Surfactant protein D (SP-D) is a multimeric collectin that is involved in innate immune defense and expressed in pulmonary, as well as non-pulmonary, epithelia. SP-D exerts antimicrobial effects and dampens inflammation through direct microbial interactions and modulation of host cell responses via a series of cellular receptors. However, low protein concentrations, genetic variation, biochemical modification, and proteolytic breakdown can induce decomposition of multimeric SP-D into low-molecular weight forms, which may induce pro-inflammatory SP-D signaling. Multimeric SP-D can decompose into trimeric SP-D, and this process, and total SP-D levels, are partly determined by variation within the SP-D gene, SFTPD. SP-D has been implicated in the development of respiratory diseases including respiratory distress syndrome, bronchopulmonary dysplasia, allergic asthma, and chronic obstructive pulmonary disease. Disease-induced breakdown or modifications of SP-D facilitate its systemic leakage from the lung, and circulatory SP-D is a promising biomarker for lung injury. Moreover, studies in preclinical animal models have demonstrated that local pulmonary treatment with recombinant SP-D is beneficial in these diseases. In recent years, SP-D has been shown to exert antimicrobial and anti-inflammatory effects in various non-pulmonary organs and to have effects on lipid metabolism and pro-inflammatory effects in vessel walls, which enhance the risk of atherosclerosis. A common SFTPD polymorphism is associated with atherosclerosis and diabetes, and SP-D has been associated with metabolic disorders because of its effects in the endothelium and adipocytes and its obesity-dampening properties. This review summarizes and discusses the reported genetic associations of SP-D with disease and the clinical utility of circulating SP-D for respiratory disease prognosis. Moreover, basic research on the mechanistic links between SP-D and respiratory, cardiovascular, and metabolic diseases is summarized. Perspectives on the development of SP-D therapy are addressed. |
2,927 | A cold-inducible RNA-binding protein (CIRP)-derived peptide attenuates inflammation and organ injury in septic mice | Cold-inducible RNA-binding protein (CIRP) is a novel sepsis inflammatory mediator and C23 is a putative CIRP competitive inhibitor. Therefore, we hypothesized that C23 can ameliorate sepsis-associated injury to the lungs and kidneys. First, we confirmed that C23 dose-dependently inhibited TNF-α release, IκBα degradation, and NF-κB nuclear translocation in macrophages stimulated with CIRP. Next, we observed that male C57BL/6 mice treated with C23 (8 mg/kg BW) at 2 h after cecal ligation and puncture (CLP) had lower serum levels of LDH, ALT, IL-6, TNF-α, and IL-1β (reduced by ≥39%) at 20 h after CLP compared with mice treated with vehicle. C23-treated mice also had improved lung histology, less TUNEL-positive cells, lower serum levels of creatinine (34%) and BUN (26%), and lower kidney expression of NGAL (50%) and KIM-1 (86%). C23-treated mice also had reduced lung and kidney levels of IL-6, TNF-α, and IL-1β. E-selectin and ICAM-1 mRNA was significantly lower in C23-treated mice. The 10-day survival after CLP of vehicle-treated mice was 55%, while that of C23-treated mice was 85%. In summary, C23 decreased systemic, lung, and kidney injury and inflammation, and improved the survival rate after CLP, suggesting that it may be developed as a new treatment for sepsis. |
2,928 | Comparison of viral infection in healthcare-associated pneumonia (HCAP) and community-acquired pneumonia (CAP) | BACKGROUND: Although viruses are known to be the second most common etiological factor in community-acquired pneumonia (CAP), the respiratory viral profile of the patients with healthcare-associated pneumonia (HCAP) has not yet been elucidated. We investigated the prevalence and the clinical impact of respiratory virus infection in adult patients with HCAP. METHODS: Patients admitted with HCAP or CAP, between January and December 2016, to a tertiary referral hospital in Korea, were prospectively enrolled, and virus identification was performed using reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: Among 452 enrolled patients (224 with HCAP, 228 with CAP), samples for respiratory viruses were collected from sputum or endotracheal aspirate in 430 (95.1%) patients and from nasopharyngeal specimens in 22 (4.9%) patients. Eighty-seven (19.2%) patients had a viral infection, and the proportion of those with viral infection was significantly lower in the HCAP than in the CAP group (13.8% vs 24.6%, p = 0.004). In both the HCAP and CAP groups, influenza A was the most common respiratory virus, followed by entero-rhinovirus. The seasonal distributions of respiratory viruses were also similar in both groups. In the HCAP group, the viral infection resulted in a similar length of hospital stay and in-hospital mortality as viral–bacterial coinfection and bacterial infection, and the CAP group showed similar results. CONCLUSIONS: The prevalence of viral infection in patients with HCAP was lower than that in patients with CAP, and resulted in a similar prognosis as viral–bacterial coinfection or bacterial infection. |
2,929 | Differences in the intestinal microbiota between uninfected piglets and piglets infected with porcine epidemic diarrhea virus | Porcine epidemic diarrhea, a disastrous gastrointestinal disease, causes great financial losses due to its high infectivity, morbidity and mortality in suckling piglets despite the development and application of various vaccines. In this study, high-throughput sequencing was used to explore differences in the intestinal microbiota between uninfected piglets and piglets infected with porcine epidemic diarrhea virus (PEDV). The results revealed that the small intestinal microbiota of suckling piglets infected with PEDV showed low diversity and was dominated by Proteobacteria (49.1%). Additionally, the composition of the small intestinal microbiota of sucking piglets infected with PEDV showed marked differences from that of the uninfected piglets. Some of the taxa showing differences in abundance between uninfected piglets and piglets infected with PEDV were associated with cellular transport and catabolism, energy metabolism, the biosynthesis of other secondary metabolites, and amino acid metabolism as determined through the prediction of microbial function based on the bacterial 16S rRNA gene. Therefore, adjusting the intestinal microbiota might be a promising method for the prevention or treatment of PEDV. |
2,930 | Nuclear targeting of the betanodavirus B1 protein via two arginine-rich domains induces G1/S cell cycle arrest mediated by upregulation of p53/p21 | The molecular functions of betanodavirus non-structural protein B and its role in host cell survival remain unclear. In the present study, we examined the roles of specific nuclear targeting domains in B1 localization as well as the effect of B1 nuclear localization on the cell cycle and host cell survival. The B1 protein of the Red spotted grouper nervous necrosis virus (RGNNV) was detected in GF-1 grouper cells as early as 24 hours post-infection (hpi). Using an EYFP-B1 fusion construct, we observed nuclear localization of the B1 protein (up to 99%) in GF-1 cells at 48 hpi. The nuclear localization of B1 was mediated by two arginine-rich nuclear targeting domains (B domain: (46)RRSRR(51); C domain: (63)RDKRPRR(70)) and domain C was more important than domain B in this process. B1 nuclear localization correlated with upregulation of p53 and p21((wef1/cip1)); downregulation of Cyclin D1, CDK4 and Mdm2; and G1/S cell cycle arrest in GF-1 cells. In conclusion, nuclear targeting of the RGNNV B1 protein via two targeting domains causes cell cycle arrest by up-regulating p53/p21 and down-regulating Mdm2, thereby regulating host cell survival. |
2,931 | Peste des Petits Ruminants Virus Enters Caprine Endometrial Epithelial Cells via the Caveolae-Mediated Endocytosis Pathway | Peste des petits ruminants virus (PPRV) causes an acute and highly contagious disease of sheep and goats and has spread with alarming speed around the world. The pathology of Peste des petits ruminants is linked to retrogressive changes and necrotic lesions in lymphoid tissues and epithelial cells. However, the process of PPRV entry into host epithelial cells remains largely unknown. Here, we performed a comprehensive study of the entry mechanism of PPRV into caprine endometrial epithelial cells (EECs). We clearly demonstrated that PPRV internalization was inhibited by chloroquine and ammonium chloride, which elevate the pH of various organelles. However, PPRV entry was not affected by chlorpromazine and knockdown of the clathrin heavy chain in EECs. In addition, we found that the internalization of PPRV was dependent on dynamin and membrane cholesterol and was suppressed by silencing of caveolin-1. Macropinocytosis did not play a role, but phosphatidylinositol 3-kinase (PI3K) was required for PPRV internalization. Cell type and receptor-dependent differences indicated that PPRV entry into caprine fetal fibroblast cells (FFCs) occurred via a different route. Taken together, our findings demonstrate that PPRV enters EECs through a cholesterol-dependent caveolae-mediated uptake mechanism that is pH-dependent and requires dynamin and PI3K but is independent of clathrin. This potentially provides insight into the entry mechanisms of other morbilliviruses. |
2,932 | Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study | BACKGROUND: Respiratory tract infections (RTIs) are a major morbidity factor contributing largely to health care costs and individual quality of life. The aim of the study was to test whether obesity (BMI ≥ 30 kg/m(2)) is one of the risk factors underlying frequent RTIs in the German adult population. METHODS: We recruited 1455 individuals between 18 to 70 years from a cross-sectional survey on airway infections in Germany and invited them to self-report in diaries incident RTIs experienced during three consecutive winter/spring seasons. RTIs reported in these 18 months and summary measures adding-up individual RTIs were the outcomes of interest. RESULTS: Compared to individuals with normal weight, obese individuals reported a consistently higher frequency of upper and lower RTIs and predominantly fell in the upper 10% group of a diary sumscore adding-up 10 different RTI symptoms over time. Obesity was associated both with lower RTIs ((adjusted)OR = 2.02, 95%CI = 1.36–3.00) and upper RTIs ((adjusted)OR = 1.55, 95%CI = 1.22–1.96). Adjusting for demographic and lifestyle variables did only marginally affect ORs. Stratified analyses suggested a stronger association for women and effect modifications by sports activity and dietary habits. CONCLUSIONS: We confirm the association of obesity with infection burden and present evidence for putative interaction with sports activity and dietary patterns. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12889-018-5172-8) contains supplementary material, which is available to authorized users. |
2,933 | Incorporating health workers’ perspectives into a WHO guideline on personal protective equipment developed during an Ebola virus disease outbreak | Background: Ebola virus disease (EVD) health facility transmission can result in infection and death of health workers. The World Health Organization (WHO) supports countries in preparing for and responding to public health emergencies, which often require developing new guidance in short timelines with scarce evidence. The objective of this study was to understand frontline physicians’ and nurses’ perspectives about personal protective equipment (PPE) use during the 2014-2016 EVD outbreak in West Africa and to incorporate these findings into the development process of a WHO rapid advice guideline. Methods : We surveyed frontline physicians and nurses deployed to West Africa between March and September of 2014. Results: We developed the protocol, obtained ethics approval, delivered the survey, analysed the data and presented the findings as part of the evidence-to-decision tables at the expert panel meeting where the recommendations were formulated within eight weeks. Forty-four physicians and nurses responded to the survey. They generally felt at low or extremely low risk of virus transmission with all types of PPE used. Eye protection reduced the ability to provide care, mainly due to impaired visibility because of fogging. Heat and dehydration were a major issue for 76% of the participants using goggles and for 64% using a hood. Both gowns and coveralls were associated with significant heat stress and dehydration. Most participants (59%) were very confident that they were using PPE correctly. Conclusion : Our study demonstrated that it was possible to incorporate primary data on end-users’ preferences into a rapid advice guideline for a public health emergency in difficult field conditions. Health workers perceived a balance between transmission protection and ability to care for patients effectively while wearing PPE. These findings were used by the guideline development expert panel to formulate WHO recommendations on PPE for frontline providers caring for EVD patients in outbreak conditions. |
2,934 | Protective effects and immunomodulation on piglets infected with rotavirus following resveratrol supplementation | Rotavirus (RV), belonging to Reoviridae family, is the leading cause of acute severe viral diarrhea in children (under 5 years old) and infant animals worldwide. Although vaccines are commonly used to prevent infection, episodes of diarrhea caused by RV frequently occur. Thus, this study was conducted to determine whether resveratrol had protective effects against RV infection in piglets. Following pretreatment with resveratrol dry suspension through adding into the basal diet for 3 weeks, the piglets were orally challenged with RV. We found that resveratrol could alleviate diarrhea induced by RV infection. Resveratrol-treatment inhibited the TNF-α production, indicating that the anti-RV activity of resveratrol may be achieved by reducing the inflammatory response. The IFN-γ level was elevated in 10mg/kg/d resveratrol-treated group and 30mg/kg/d resveratrol-treated group after RV infection. The ratios of CD4+/CD8+ in resveratrol-treated groups were the same as that in mock infected group, suggesting that resveratrol could maintain the immune function in RV-infected piglets. It was found that resveratrol could alleviate diarrhea induced by RV infection. These results revealed that resveratrol dry suspension could be a new control measure for RV infection. |
2,935 | Identification of a novel compound targeting the nuclear export of influenza A virus nucleoprotein | Although antiviral drugs are available for the treatment of influenza infection, it is an urgent requirement to develop new antiviral drugs regarding the emergence of drug‐resistant viruses. The nucleoprotein (NP) is conserved among all influenza A viruses (IAVs) and has no cellular equivalent. Therefore, NP is an ideal target for the development of new IAV inhibitors. In this study, we identified a novel anti‐influenza compound, ZBMD‐1, from a library of 20,000 compounds using cell‐based influenza A infection assays. We found that ZBMD‐1 inhibited the replication of H1N1 and H3N2 influenza A virus strains in vitro, with an IC (50) ranging from 0.41–1.14 μM. Furthermore, ZBMD‐1 inhibited the polymerase activity and specifically impaired the nuclear export of NP. Further investigation indicated that ZBMD‐1 binds to the nuclear export signal 3 (NES3) domain and the dimer interface of the NP pocket. ZBMD‐1 also protected mice that were challenged with lethal doses of A/PR/8/1934 (H1N1) virus, effectively relieving lung histopathology changes, as well as strongly inhibiting the expression of pro‐inflammatory cytokines/chemokines, without inducing toxicity effects in mice. These results suggest that ZBMD‐1 is a promising anti‐influenza compound which can be further investigated as a useful strategy against IAVs in the future. |
2,936 | Vps3 and Vps8 control integrin trafficking from early to recycling endosomes and regulate integrin-dependent functions | Recycling endosomes maintain plasma membrane homeostasis and are important for cell polarity, migration, and cytokinesis. Yet, the molecular machineries that drive endocytic recycling remain largely unclear. The CORVET complex is a multi-subunit tether required for fusion between early endosomes. Here we show that the CORVET-specific subunits Vps3 and Vps8 also regulate vesicular transport from early to recycling endosomes. Vps3 and Vps8 localise to Rab4-positive recycling vesicles and co-localise with the CHEVI complex on Rab11-positive recycling endosomes. Depletion of Vps3 or Vps8 does not affect transferrin recycling, but delays the delivery of internalised integrins to recycling endosomes and their subsequent return to the plasma membrane. Consequently, Vps3/8 depletion results in defects in integrin-dependent cell adhesion and spreading, focal adhesion formation, and cell migration. These data reveal a role for Vps3 and Vps8 in a specialised recycling pathway important for integrin trafficking. |
2,937 | Development of improved therapeutic mesothelin-based vaccines for pancreatic cancer | Pancreatic cancer is the 5(th) leading cause of cancer deaths, and there are no effective treatments. We developed a poxvirus platform vaccine with improved immunogenicity and inserted the mesothelin gene to create an anti-mesothelin cancer vaccine. Mesothelin expression is mostly restricted to tumors in adult mammals and thus may be a good target for cancer treatment. We show here that the modified vaccinia virus Ankara (MVA) virus expressing mesothelin and the enhanced MVA virus missing the immunosuppressive A35 gene and expressing mesothelin were both safe in mice and were able to induce IFN-gamma secreting T cells in response to mesothelin expressing tumor cells. In addition, the MVA virus has oncolytic properties in vitro as it can replicate in and kill Panc02 pancreatic adenocarcinoma cell line tumor cells, even though it is unable to replicate in most mammalian cells. Deletion of the A35 gene in MVA improved T cell responses as expected. However, we were unable to demonstrate inhibition of Panc02 tumor growth in immunocompetent mice with pre-vaccination of mice, boosts, or even intratumoral injections of the recombinant viruses. Vaccine efficacy may be limited by shedding of mesothelin from tumor cells thus creating a protective screen from the immune system. |
2,938 | Lipidomic analysis of immune activation in equine leptospirosis and Leptospira-vaccinated horses | Currently available diagnostic assays for leptospirosis cannot differentiate vaccine from infection serum antibody. Several leptospiral proteins that are upregulated during infection have been described, but their utility as a diagnostic marker is still unclear. In this study, we undertook a lipidomics approach to determine if there are any differences in the serum lipid profiles of horses naturally infected with pathogenic Leptospira spp. and horses vaccinated against a commercially available bacterin. Utilizing a high-resolution mass spectrometry serum lipidomics analytical platform, we demonstrate that cyclic phosphatidic acids, diacylglycerols, and hydroperoxide oxidation products of choline plasmalogens are elevated in the serum of naturally infected as well as vaccinated horses. Other lipids of interest were triacylglycerols that were only elevated in the serum of infected horses and sphingomyelins that were increased only in the serum of vaccinated horses. This is the first report looking at the equine serum lipidome during leptospiral infection and vaccination. |
2,939 | TBC2target: A Resource of Predicted Target Genes of Tea Bioactive Compounds | Tea is one of the most popular non-alcoholic beverages consumed worldwide. Numerous bioactive constituents of tea were confirmed to possess healthy benefits via the mechanisms of regulating gene expressions or protein activities. However, a complete interacting profile between tea bioactive compounds (TBCs) and their target genes is lacking, which put an obstacle in the study of healthy function of tea. To fill this gap, we developed a database of target genes of TBCs (TBC2target, http://camellia.ahau.edu.cn/TBC2target) based on a pharmacophore mapping approach. In TBC2target, 6,226 interactions between 240 TBCs and 673 target genes were documented. TBC2target contains detailed information about each interacting entry, such as TBC, CAS number, PubChem CID, source of compound (e.g., green, black), compound type, target gene(s) of TBC, gene symbol, gene ID, ENSEMBL ID, PDB ID, TBC bioactivity and the reference. Using the TBC-target associations, we constructed a bipartite network and provided users the global network and local sub-network visualization and topological analyses. The entire database is free for online browsing, searching and downloading. In addition, TBC2target provides a BLAST search function to facilitate use of the database. The particular strengths of TBC2target are the inclusion of the comprehensive TBC-target interactions, and the capacity to visualize and analyze the interacting networks, which may help uncovering the beneficial effects of tea on human health as a central resource in tea health community. |
2,940 | Private collection: high correlation of sample collection and patient admission date in clinical microbiological testing complicates sharing of phylodynamic metadata | Infectious pathogens are known for their rapid evolutionary rates with new mutations arising over days to weeks. The ability to rapidly recover whole genome sequences and analyze the spread and evolution of pathogens using genetic information and pathogen collection dates has lead to interest in real-time tracking of infectious transmission and outbreaks. However, the level of temporal resolution afforded by these analyses may conflict with definitions of what constitutes protected health information (PHI) and privacy requirements for de-identification for publication and public sharing of research data and metadata. In the United States, dates and locations associated with patient care that provide greater resolution than year or the first three digits of the zip code are generally considered patient identifiers. Admission and discharge dates are specifically named as identifiers in Department of Health and Human Services guidance. To understand the degree to which one can impute admission dates from specimen collection dates, we examined sample collection dates and patient admission dates associated with more than 270,000 unique microbiological results from the University of Washington Laboratory Medicine Department between 2010 and 2017. Across all positive microbiological tests, the sample collection date exactly matched the patient admission date in 68.8% of tests. Collection dates and admission dates were identical from emergency department and outpatient testing 86.7% and 96.5% of the time, respectively, with >99% of tests collected within 1 day from the patient admission date. Samples from female patients were significantly more likely to be collected closer to admission date that those from male patients. We show that PHI-associated dates such as admission date can confidently be imputed from deposited collection date. We suggest that publicly depositing microbiological collection dates at greater resolution than the year may not meet routine Safe Harbor-based requirements for patient de-identification. We recommend the use of Expert Determination to determine PHI for a given study and/or direct patient consent if clinical laboratories or phylodynamic practitioners desire to make these data available. |
2,941 | A paralogous pair of mammalian host restriction factors form a critical host barrier against poxvirus infection | Host restriction factors constitute a formidable barrier for viral replication to which many viruses have evolved counter-measures. Human SAMD9, a tumor suppressor and a restriction factor for poxviruses in cell lines, is antagonized by two classes of poxvirus proteins, represented by vaccinia virus (VACV) K1 and C7. A paralog of SAMD9, SAMD9L, is also encoded by some mammals, while only one of two paralogs is retained by others. Here, we show that SAMD9L functions similarly to SAMD9 as a restriction factor and that the two paralogs form a critical host barrier that poxviruses must overcome to establish infection. In mice, which naturally lack SAMD9, overcoming SAMD9L restriction with viral inhibitors is essential for poxvirus replication and pathogenesis. While a VACV deleted of both K1 and C7 (vK1L(-)C7L(-)) was restricted by mouse cells and highly attenuated in mice, its replication and virulence were completely restored in SAMD9L(-/-) mice. In humans, both SAMD9 and SAMD9L are poxvirus restriction factors, although the latter requires interferon induction in many cell types. While knockout of SAMD9 with Crispr-Cas9 was sufficient for abolishing the restriction for vK1L(-)C7L(-) in many human cells, knockout of both paralogs was required for abolishing the restriction in interferon-treated cells. Both paralogs are antagonized by VACV K1, C7 and C7 homologs from diverse mammalian poxviruses, but mouse SAMD9L is resistant to the C7 homolog encoded by a group of poxviruses with a narrow host range in ruminants, indicating that host species-specific difference in SAMD9/SAMD9L genes serves as a barrier for cross-species poxvirus transmission. |
2,942 | Study on expression of plasma sCD138 in patients with hemorrhagic fever with renal syndrome | BACKGROUND: Until now, there is non-specific treatment, and exploring early and novel biomarkers to determine the disease severity and prognosis of hemorrhagic fever with renal syndrome (HFRS) would be of importance for clinician to take systematic and timely intervention. This study observed the expression of plasma sCD138, a soluble component shedding from the glycocalyx (GCX) to the circulating blood, and evaluated its predictive value on disease severity and prognosis of HFRS. METHODS: One hundred and seventy-six patients with HFRS who were treated at our center between January 2011 and December 2013 were randomly enrolled in this study. The patients were divided into a mild-type group, a moderate-type group, a severe-type group and a critical-type group according to the HFRS criteria for clinical classification. Thirty-five blood samples from healthy subjects were obtained as the controls. The concentrations of sCD138 were detected using enzyme linked immunosorbent assay (ELISA). The levels of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cells (WBC), platelets (PLT), glucose (GLU), blood urea nitrogen (BUN) and serum creatinine (Scr) in the samples were routinely tested. The levels of sCD138 among the different types were compared; the correlation among sCD138 and the laboratory parameters mentioned above were analyzed. The predictive effectiveness for prognosis of sCD138 was evaluated using the receiver operating characteristic (ROC) curve analysis. RESULTS: Except for the mild-type, the levels of sCD138 in the moderate-, severe- and critical-type patients during the acute stage were significantly higher than that of the convalescent stage and the control (P<0.05). With the aggravation of the disease, the levels of sCD138 during the acute stage had an increasing tendency, while demonstrated no significant difference among the moderate-, severe- and critical-type patients (P>0.05). sCD138 was negatively correlated with Fib, PLT and ALB, and was positively correlated with WBC and AST (P<0.05). sCD138 demonstrated predictive effectiveness for prognosis with the area under the curve (AUC) of 0.778 (P<0.001). CONCLUSION: Dynamic detection of plasma sCD138 might be benefit to evaluating the disease severity and prognosis of the patients with HFRS. |
2,943 | Transcriptional Innate Immune Response of the Developing Chicken Embryo to Newcastle Disease Virus Infection | Traditional approaches to assess the immune response of chickens to infection are through animal trials, which are expensive, require enhanced biosecurity, compromise welfare, and are frequently influenced by confounding variables. Since the chicken embryo becomes immunocompetent prior to hatch, we here characterized the transcriptional response of selected innate immune genes to Newcastle disease virus (NDV) infection in chicken embryos at days 10, 14, and 18 of embryonic development. The results suggest that the innate immune response 72 h after challenge of 18-day chicken embryo is both consistent and robust. The expression of CCL5, Mx1, and TLR3 in lung tissues of NDV challenged chicken embryos from the outbred Kuroiler and Tanzanian local ecotype lines showed that their expression was several orders of magnitude higher in the Kuroiler than in the local ecotypes. Next, the expression patterns of three additional innate-immunity related genes, IL-8, IRF-1, and STAT1, were examined in the highly congenic Fayoumi (M5.1 and M15.2) and Leghorn (Ghs6 and Ghs13) sublines that differ only at the microchromosome bearing the major histocompatibility locus. The results show that the Ghs13 Leghorn subline had a consistently higher expression of all genes except IL-8 and expression seemed to be subline-dependent rather than breed-dependent, suggesting that the innate immune response of chicken embryos to NDV infection may be genetically controlled by the MHC-locus. Taken together, the results suggest that the chicken embryo may represent a promising model to studying the patterns and sources of variation of the avian innate immune response to infection with NDV and related pathogens. |
2,944 | Punica granatum L. Leaf Extract Attenuates Lung Inflammation in Mice with Acute Lung Injury | The hydroalcoholic extract of Punica granatum (pomegranate) leaves was previously demonstrated to be anti-inflammatory in a rat model of lipopolysaccharide- (LPS-) induced acute peritonitis. Here, we investigated the anti-inflammatory effects of the ethyl acetate fraction obtained from the pomegranate leaf hydroalcoholic extract (EAFPg) on the LPS-induced acute lung injury (ALI) mouse model. Male Swiss mice received either EAFPg at different doses or dexamethasone (per os) prior to LPS intranasal instillation. Vehicle-treated mice were used as controls. Animals were culled at 4 h after LPS challenge, and the bronchoalveolar lavage fluid (BALF) and lung samples were collected for analysis. EAFPg and kaempferol effects on NO and cytokine production by LPS-stimulated RAW 264.7 macrophages were also investigated. Pretreatment with EAFPg (100–300 mg/kg) markedly reduced cell accumulation (specially neutrophils) and collagen deposition in the lungs of ALI mice. The same animals presented with reduced lung and BALF TNF-α and IL-1β expression in comparison with vehicle controls (p < 0.05). Additionally, incubation with either EAFPg or kaempferol (100 μg/ml) reduced NO production and cytokine gene expression in cultured LPS-treated RAW 264.7 macrophages. Overall, these results demonstrate that the prophylactic treatment with EAFPg attenuates acute lung inflammation. We suggest this fraction may be useful in treating ALI. |
2,945 | Selection of suitable reference genes for normalization of quantitative RT-PCR (RT-qPCR) expression data across twelve tissues of riverine buffaloes (Bubalus bubalis) | Selection of reference genes has become an integral step in any real time quantitative PCR (RT-qPCR) based expression studies. The importance of this study stems from the fact that riverine buffaloes are major dairy species of Indian sub-continent and the information generated here will be of great interest to the investigators engaged in functional genomic studies of this important livestock species. In this study, an effort was made to evaluate a panel of 10 candidate reference genes (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), beta- actin (ACTB), ubiquitously expressed transcript (UXT), ribosomal protein S15 (RPS15), ribosomal protein L-4 (RPL4), ribosomal protein S9 (RPS9), ribosomal protein S23 (RPS23), hydroxymethylbilane synthase (HMBS), β2 Microglobulin (β2M) and eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) across 12 tissues (mammary gland, kidney, spleen, liver, heart, intestine, ovary, lung, muscle, brain, subcutaneous fat and testis) of riverine buffaloes. In addition to overall analysis, tissue wise evaluation of expression stability of individual RG was also performed. Three different algorithms provided in geNorm, NormFinder and BestKeeper softwares were used to evaluate the stability of 10 potential reference genes from different functional classes. The M-value given by geNorm ranged from 0.9797 (RPS9 and UXT) to 1.7362 (RPS15). From the most stable to the least stable, genes were ranked as: UXT/RPS9> RPL4> RPS23> EEF1A1> ACTB> HMBS> GAPDH> B2M> RPS15. While NormFinder analysis ranked the genes as: UXT> RPS23> RPL4> RPS9> EEF1A1> HMBS> ACTB> β2M> GAPDH> RPS15. Based on the crossing point SD value and range of fold change expression, BestKeeper analysis ranked the genes as: RPS9> RPS23/UXT> RPL4> GAPDH> EEF1A1> ACTB> HMBS> β2M> RPS15. Overall the study has identified RPS23, RPS9, RPL4 and UXT genes to be the most stable and appropriate RGs that could be utilized for normalization of transcriptional data in various tissues of buffaloes. This manuscript thus provide useful information on panel of reference genes that could be helpful for researchers conducting functional genomic studies in riverine buffaloes. |
2,946 | Challenges and Solution of Invasive Aspergillosis in Non-neutropenic Patients: A Review | Invasive aspergillosis (IA) is a serious opportunistic infection, which has increasingly been recognized as an emerging disease of non-neutropenic patients. In this group of patients, the diagnosis of IA can be challenging owing to the lack of specificity of symptoms, the difficulty in discriminating colonization from infection, and the lower sensitivity of microbiological and radiological tests compared with immunocompromised patients. The aim of this article is to present to clinicians a critical review on the management of IA in non-neutropenic patients. |
2,947 | Comparative Evaluation of Three Preprocessing Methods for Extraction and Detection of Influenza A Virus Nucleic Acids from Sputum | Viscous sputum specimens usually cannot undergo automated extraction, and thus, a pre-homogenization process is desirable before isolating nucleic acids for real-time reverse transcription PCR. In this study, we compared three preprocessing methods [preprocessing with normal saline (NS), dithiothreitol (DTT), and proteinase K (PK)] of sputum specimens on the extraction and detection of influenza A virus (IAV) nucleic acids. Based on the experimental results of 217 specimens, we found that DTT and PK could be used to improve the homogenization effects of sputum and increase the positive rates by 5.53–6.91% higher than that of the NS group. Comparison of 49 positive specimens in all of the three groups demonstrated that the threshold cycle values of the DTT group and PK group were significantly lower and their nucleic acid concentration and A(260)/A(280) ratio within 1.8–2.0 were higher than those of the NS group. Thus, sputum homogenization before nucleic acid extraction is essential for the accurate diagnosis of IAV infection. |
2,948 | The temporal distribution of new H7N9 avian influenza infections based on laboratory-confirmed cases in Mainland China, 2013–2017 | In this study, estimates of the growth rate of new infections, based on the growth rate of new laboratory-confirmed cases, were used to provide a statistical basis for in-depth research into the epidemiological patterns of H7N9 epidemics. The incubation period, interval from onset to laboratory confirmation, and confirmation time for all laboratory-confirmed cases of H7N9 avian influenza in Mainland China, occurring between January 2013 and June 2017, were used as the statistical data. Stochastic processes theory and maximum likelihood were used to calculate the growth rate of new infections. Time-series analysis was then performed to assess correlations between the time series of new infections and new laboratory-confirmed cases. The rate of new infections showed significant seasonal fluctuation. Laboratory confirmation was delayed by a period of time longer than that of the infection (average delay, 13 days; standard deviation, 6.8 days). At the lags of −7.5 and −15 days, respectively, the time-series of new infections and new confirmed cases were significantly correlated; the cross correlation coefficients (CCFs) were 0.61 and 0.16, respectively. The temporal distribution characteristics of new infections and new laboratory-confirmed cases were similar and strongly correlated. |
2,949 | Acral melanoma detection using a convolutional neural network for dermoscopy images | BACKGROUND/PURPOSE: Acral melanoma is the most common type of melanoma in Asians, and usually results in a poor prognosis due to late diagnosis. We applied a convolutional neural network to dermoscopy images of acral melanoma and benign nevi on the hands and feet and evaluated its usefulness for the early diagnosis of these conditions. METHODS: A total of 724 dermoscopy images comprising acral melanoma (350 images from 81 patients) and benign nevi (374 images from 194 patients), and confirmed by histopathological examination, were analyzed in this study. To perform the 2-fold cross validation, we split them into two mutually exclusive subsets: half of the total image dataset was selected for training and the rest for testing, and we calculated the accuracy of diagnosis comparing it with the dermatologist’s and non-expert’s evaluation. RESULTS: The accuracy (percentage of true positive and true negative from all images) of the convolutional neural network was 83.51% and 80.23%, which was higher than the non-expert’s evaluation (67.84%, 62.71%) and close to that of the expert (81.08%, 81.64%). Moreover, the convolutional neural network showed area-under-the-curve values like 0.8, 0.84 and Youden’s index like 0.6795, 0.6073, which were similar score with the expert. CONCLUSION: Although further data analysis is necessary to improve their accuracy, convolutional neural networks would be helpful to detect acral melanoma from dermoscopy images of the hands and feet. |
2,950 | Species-specific vulnerability of RanBP2 shaped the evolution of SIV as it transmitted in African apes | HIV-1 arose as the result of spillover of simian immunodeficiency viruses (SIVs) from great apes in Africa, namely from chimpanzees and gorillas. Chimpanzees and gorillas were, themselves, infected with SIV after virus spillover from African monkeys. During spillover events, SIV is thought to require adaptation to the new host species. The host barriers that drive viral adaptation have predominantly been attributed to restriction factors, rather than cofactors (host proteins exploited to promote viral replication). Here, we consider the role of one cofactor, RanBP2, in providing a barrier that drove viral genome evolution during SIV spillover events. RanBP2 (also known as Nup358) is a component of the nuclear pore complex known to facilitate nuclear entry of HIV-1. Our data suggest that transmission of SIV from monkeys to chimpanzees, and then from chimpanzees to gorillas, both coincided with changes in the viral capsid that allowed interaction with RanBP2 of the new host species. However, human RanBP2 subsequently provided no barrier to the zoonotic transmission of SIV from chimpanzees or gorillas, indicating that chimpanzee- and gorilla-adapted SIVs are pre-adapted to humans in this regard. Our observations are in agreement with RanBP2 driving virus evolution during cross-species transmissions of SIV, particularly in the transmissions to and between great ape species. |
2,951 | Interferon-β deficiency at asthma exacerbation promotes MLKL mediated necroptosis | Defective production of antiviral interferon (IFN)-β is thought to contribute to rhinovirus-induced asthma exacerbations. These exacerbations are associated with elevated lung levels of lactate dehydrogenase (LDH), indicating occurrence of cell necrosis. We thus hypothesized that reduced lung IFN-β could contribute to necrotic cell death in a model of asthma exacerbations. Wild-type and IFN-β(−/−) mice were given saline or house dust mite (HDM) intranasally for 3 weeks to induce inflammation. Double-stranded RNA (dsRNA) was then given for additional 3 days to induce exacerbation. HDM induced an eosinophilic inflammation, which was not associated with increased expression of cleaved caspase-3, cleaved PARP or elevated bronchoalveolar lavage fluid (BALF) LDH levels in wild-type. However, exacerbation evoked by HDM + dsRNA challenges increased BALF levels of LDH, apoptotic markers and the necroptotic markers receptor-interacting protein (RIP)-3 and phosphorylation of mixed linage kinase domain-like protein (pMLKL), compared to HDM + saline. Absence of IFN-β at exacerbation further increased BALF LDH and protein expression of pMLKL compared to wild-type. We demonstrate that cell death markers are increased at viral stimulus-induced exacerbation in mouse lungs, and that absence of IFN-β augments markers of necroptotic cell death at exacerbation. Our data thus suggest a novel role of deficient IFN-β production at viral-induced exacerbation. |
2,952 | TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity | The pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is driven by genetic predisposition and environmental triggers that lead to dysregulated immune responses. These include the generation of pathogenic autoantibodies and aberrant production of inflammatory cytokines. Current therapies for RA and other autoimmune diseases reduce inflammation by targeting inflammatory mediators, most of which are innate response cytokines, resulting in generalized immunosuppression. Overall, this strategy has been very successful, but not all patients respond, responses can diminish over time and numerous side effects can occur. Therapies that target the germinal center (GC) reaction and/or antibody-secreting plasma cells (PC) potentially provide a novel approach. TANK-binding kinase 1 (TBK1) is an IKK-related serine/threonine kinase best characterized for its involvement in innate antiviral responses through the induction of type I interferons. TBK1 is also gaining attention for its roles in humoral immune responses. In this review, we discuss the role of TBK1 in immunological pathways involved in the development and maintenance of antibody responses, with particular emphasis on its potential relevance in the pathogenesis of humoral autoimmunity. First, we review the role of TBK1 in the induction of type I IFNs. Second, we highlight how TBK1 mediates inducible T cell co-stimulator signaling to the GC T follicular B helper population. Third, we discuss emerging evidence on the contribution of TBK1 to autophagic pathways and the potential implications for immune cell function. Finally, we discuss the therapeutic potential of TBK1 inhibition in autoimmunity. |
2,953 | Lipid-Based Particles: Versatile Delivery Systems for Mucosal Vaccination against Infection | Vaccination is the process of administering immunogenic formulations in order to induce or harness antigen (Ag)-specific antibody and T cell responses in order to protect against infections. Important successes have been obtained in protecting individuals against many deleterious pathological situations after parenteral vaccination. However, one of the major limitations of the current vaccination strategies is the administration route that may not be optimal for the induction of immunity at the site of pathogen entry, i.e., mucosal surfaces. It is now well documented that immune responses along the genital, respiratory, or gastrointestinal tracts have to be elicited locally to ensure efficient trafficking of effector and memory B and T cells to mucosal tissues. Moreover, needle-free mucosal delivery of vaccines is advantageous in terms of safety, compliance, and ease of administration. However, the quest for mucosal vaccines is challenging due to (1) the fact that Ag sampling has to be performed across the epithelium through a relatively limited number of portals of entry; (2) the deleterious acidic and proteolytic environment of the mucosae that affect the stability, integrity, and retention time of the applied Ags; and (3) the tolerogenic environment of mucosae, which requires the addition of adjuvants to elicit efficient effector immune responses. Until now, only few mucosally applicable vaccine formulations have been developed and successfully tested. In animal models and clinical trials, the use of lipidic structures such as liposomes, virosomes, immune stimulating complexes, gas-filled microbubbles and emulsions has proven efficient for the mucosal delivery of associated Ags and the induction of local and systemic immune reponses. Such particles are suitable for mucosal delivery because they protect the associated payload from degradation and deliver concentrated amounts of Ags via specialized sampling cells (microfold cells) within the mucosal epithelium to underlying antigen-presenting cells. The review aims at summarizing recent development in the field of mucosal vaccination using lipid-based particles. The modularity ensured by tailoring the lipidic design and content of particles, and their known safety as already established in humans, make the continuing appraisal of these vaccine candidates a promising development in the field of targeted mucosal vaccination. |
2,954 | Health-seeking behavior and transmission dynamics in the control of influenza infection among different age groups | BACKGROUND: It has been found that health-seeking behavior has a certain impact on influenza infection. However, behaviors with/without risk perception on the control of influenza transmission among age groups have not been well quantified. OBJECTIVES: The purpose of this study was to assess to what extent, under scenarios of with/without control and preventive/protective behaviors, the age-specific network-driven risk perception influences influenza infection. MATERIALS AND METHODS: A behavior-influenza model was used to estimate the spread rate of age-specific risk perception in response to an influenza outbreak. A network-based information model was used to assess the effect of network-driven risk perception information transmission on influenza infection. A probabilistic risk model was used to assess the infection risk effect of risk perception with a health behavior change. RESULTS: The age-specific overlapping percentage was estimated to be 40%–43%, 55%–60%, and 19%–35% for child, teenage and adult, and elderly age groups, respectively. Individuals perceive the preventive behavior to improve risk perception information transmission among teenage and adult and elderly age groups, but not in the child age group. The population with perceived health behaviors could not effectively decrease the percentage of infection risk in the child age group, whereas for the elderly age group, the percentage of decrease in infection risk was more significant, with a 97.5th percentile estimate of 97%. CONCLUSION: The present integrated behavior-infection model can help health authorities in communicating health messages for an intertwined belief network in which health-seeking behavior plays a key role in controlling influenza infection. |
2,955 | The Gut, Its Microbiome, and Hypertension | PURPOSE OF THE REVIEW: Evidence is rapidly accumulating implicating gut dysbiosis in hypertension (HTN). However, we are far from understanding whether this is a cause or consequence of HTN, and how to best translate this fundamental knowledge to advance the management of HTN. This review aims to summarize recent advances in the field, illustrate the connections between the gut and hypertension, and establish that the gut microbiota (GM)-gut interaction is centrally positioned for consideration as an innovative approach for HTN therapeutics. RECENT FINDINGS: Animal models of HTN have shown that gut pathology occurs in HTN, and provides some clues to mechanisms linking the dysbiosis, gut pathology, and HTN. SUMMARY: Circumstantial evidence links gut dysbiosis and HTN. Gut pathology, apparent in animal HTN models, has not been fully investigated in hypertensive patients. Objective evidence and an understanding of mechanisms could have a major impact for new antihypertensive therapies and/or improved applications of current ones. |
2,956 | Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy | Although the genetic basis of Duchenne muscular dystrophy has been known for almost thirty years, the cellular and molecular mechanisms characterizing the disease are not completely understood and an efficacious treatment remains to be developed. In this study we analyzed proteomics data obtained with the SomaLogic technology from blood serum of a cohort of patients and matched healthy subjects. We developed a workflow based on biomarker identification and network-based pathway analysis that allowed us to describe different deregulated pathways. In addition to muscle-related functions, we identified other biological processes such as apoptosis, signaling in the immune system and neurotrophin signaling as significantly modulated in patients compared with controls. Moreover, our network-based analysis identified the involvement of FoxO transcription factors as putative regulators of different pathways. On the whole, this study provided a global view of the molecular processes involved in Duchenne muscular dystrophy that are decipherable from serum proteome. |
2,957 | Evolution of Synonymous Codon Usage Bias in West African and Central African Strains of Monkeypox Virus | The evolution of bias in synonymous codon usage in chosen monkeypox viral genomes and the factors influencing its diversification have not been reported so far. In this study, various trends associated with synonymous codon usage in chosen monkeypox viral genomes were investigated, and the results are reported. Identification of factors that influence codon usage in chosen monkeypox viral genomes was done using various codon usage indices, such as the relative synonymous codon usage, the effective number of codons, and the codon adaptation index. The Spearman rank correlation analysis and a correspondence analysis were used for correlating various factors with codon usage. The results revealed that mutational pressure due to compositional constraints, gene expression level, and selection at the codon level for utilization of putative optimal codons are major factors influencing synonymous codon usage bias in monkeypox viral genomes. A cluster analysis of relative synonymous codon usage values revealed a grouping of more virulent strains as one major cluster (Central African strains) and a grouping of less virulent strains (West African strains) as another major cluster, indicating a relationship between virulence and synonymous codon usage bias. This study concluded that a balance between the mutational pressure acting at the base composition level and the selection pressure acting at the amino acid level frames synonymous codon usage bias in the chosen monkeypox viruses. The natural selection from the host does not seem to have influenced the synonymous codon usage bias in the analyzed monkeypox viral genomes. |
2,958 | Prolonging herd immunity to cholera via vaccination: Accounting for human mobility and waning vaccine effects | BACKGROUND: Oral cholera vaccination is an approach to preventing outbreaks in at-risk settings and controlling cholera in endemic settings. However, vaccine-derived herd immunity may be short-lived due to interactions between human mobility and imperfect or waning vaccine efficacy. As the supply and utilization of oral cholera vaccines grows, critical questions related to herd immunity are emerging, including: who should be targeted; when should revaccination be performed; and why have cholera outbreaks occurred in recently vaccinated populations? METHODS AND FINDINGS: We use mathematical models to simulate routine and mass oral cholera vaccination in populations with varying degrees of migration, transmission intensity, and vaccine coverage. We show that migration and waning vaccine efficacy strongly influence the duration of herd immunity while birth and death rates have relatively minimal impacts. As compared to either periodic mass vaccination or routine vaccination alone, a community could be protected longer by a blended “Mass and Maintain” strategy. We show that vaccination may be best targeted at populations with intermediate degrees of mobility as compared to communities with very high or very low population turnover. Using a case study of an internally displaced person camp in South Sudan which underwent high-coverage mass vaccination in 2014 and 2015, we show that waning vaccine direct effects and high population turnover rendered the camp over 80% susceptible at the time of the cholera outbreak beginning in October 2016. CONCLUSIONS: Oral cholera vaccines can be powerful tools for quickly protecting a population for a period of time that depends critically on vaccine coverage, vaccine efficacy over time, and the rate of population turnover through human mobility. Due to waning herd immunity, epidemics in vaccinated communities are possible but become less likely through complementary interventions or data-driven revaccination strategies. |
2,959 | Building the atomic model of a boreal lake virus of unknown fold in a 3.9 Å cryo-EM map | We report here the protocol adopted to build the atomic model of the newly discovered virus FLiP (Flavobacterium infecting, lipid-containing phage) into 3.9 Å cryo-electron microscopy (cryo-EM) maps. In particular, this report discusses the combination of density modification procedures, automatic model building and bioinformatics tools applied to guide the tracing of the major capsid protein (MCP) of this virus. The protocol outlined here may serve as a reference for future structural determination by cryo-EM of viruses lacking detectable structural homologues. |
2,960 | General Prediction of Peptide-MHC Binding Modes Using Incremental Docking: A Proof of Concept | The class I major histocompatibility complex (MHC) is capable of binding peptides derived from intracellular proteins and displaying them at the cell surface. The recognition of these peptide-MHC (pMHC) complexes by T-cells is the cornerstone of cellular immunity, enabling the elimination of infected or tumoral cells. T-cell-based immunotherapies against cancer, which leverage this mechanism, can greatly benefit from structural analyses of pMHC complexes. Several attempts have been made to use molecular docking for such analyses, but pMHC structure remains too challenging for even state-of-the-art docking tools. To overcome these limitations, we describe the use of an incremental meta-docking approach for structural prediction of pMHC complexes. Previous methods applied in this context used specific constraints to reduce the complexity of this prediction problem, at the expense of generality. Our strategy makes no assumption and can potentially be used to predict binding modes for any pMHC complex. Our method has been tested in a re-docking experiment, reproducing the binding modes of 25 pMHC complexes whose crystal structures are available. This study is a proof of concept that incremental docking strategies can lead to general geometry prediction of pMHC complexes, with potential applications for immunotherapy against cancer or infectious diseases. |
2,961 | Asymmetric expression level of clock genes in left vs. right nasal mucosa in humans with and without allergies and in rats: Circadian characteristics and possible contribution to nasal cycle | Numerous peripheral tissues possess self-sustaining daily biologic rhythms that are regulated at the molecular level by clock genes such as PER1, PER2, CLOCK, and BMAL1. Physiological function of nasal mucosa exhibits rhythmic variability to a day-night environmental cycle. Nevertheless, little is known of the expression and distribution pattern of clock genes in nasal mucosa. The present study investigates the expression level and distribution pattern of PER1, PER2, CLOCK, and BMAL1 genes in nasal mucosa of healthy controls, allergic rhinitis patients, and normal rats. In human and rat nasal mucosa, the levels of these genes are asymmetrically expressed in nasal mucosa derived from right and left cavities in normal controls, allergic patients, and rat. In human nasal mucosa, the expression levels of these genes were higher in the decongested side than the congested mucosa. In rat nasal mucosa, these clock genes are expressed in a rhythmic circadian manner under the regular light/dark cycles. The expression levels of MUC5AC, a key mucin genes produced in superficial epithelium, are higher in decongested side than that congested side in human nasal mucosa. In rat nasal mucosa, MUC5AC levels showed a circadian rhythm which was associated with different expression levels in nasal mucosa derived from the right and left nasal cavities. Taken together with these results, the present study shows that the clock genes such as PER1, PER2, CLOCK, and BMAL1 are present in human and rat nasal mucosa, and suggest that these clock genes may control the pathophysiological function of nasal mucosa as circadian oscillators and affect the maintenance of the nasal cycle. |
2,962 | Translating Lung Microbiome Profiles into the Next-Generation Diagnostic Gold Standard for Pneumonia: a Clinical Investigator’s Perspective | Severe bacterial pneumonia is a major global cause of morbidity and mortality, yet current diagnostic approaches rely on identification of causative pathogens by cultures, which require extended incubation periods and often fail to detect relevant pathogens. Consequently, patients are prescribed broad-spectrum antibiotics in a “one-size-fits-all” manner, which may be inappropriate for their individual needs and promote antibiotic resistance. My research focuses on leveraging next-generation sequencing of microbial DNA directly from patient samples for the development of new, culture-independent definitions of pneumonia. In this perspective article, I discuss the current state of the field and focus on the conceptual and research design challenges for clinical translation. With ongoing technological advancements and application of computational biology methods for assessing clinical validity and utility, I anticipate that sequencing-based diagnostics will soon be able to positively disrupt the way we think about, diagnose, and treat pulmonary infections. |
2,963 | Adenine Enrichment at the Fourth CDS Residue in Bacterial Genes Is Consistent with Error Proofing for +1 Frameshifts | Beyond selection for optimal protein functioning, coding sequences (CDSs) are under selection at the RNA and DNA levels. Here, we identify a possible signature of “dual-coding,” namely extensive adenine (A) enrichment at bacterial CDS fourth sites. In 99.07% of studied bacterial genomes, fourth site A use is greater than expected given genomic A-starting codon use. Arguing for nucleotide level selection, A-starting serine and arginine second codons are heavily utilized when compared with their non-A starting synonyms. Several models have the ability to explain some of this trend. In part, A-enrichment likely reduces 5′ mRNA stability, promoting translation initiation. However T/U, which may also reduce stability, is avoided. Further, +1 frameshifts on the initiating ATG encode a stop codon (TGA) provided A is the fourth residue, acting either as a frameshift “catch and destroy” or a frameshift stop and adjust mechanism and hence implicated in translation initiation. Consistent with both, genomes lacking TGA stop codons exhibit weaker fourth site A-enrichment. Sequences lacking a Shine–Dalgarno sequence and those without upstream leader genes, that may be more error prone during initiation, have greater utilization of A, again suggesting a role in initiation. The frameshift correction model is consistent with the notion that many genomic features are error-mitigation factors and provides the first evidence for site-specific out of frame stop codon selection. We conjecture that the NTG universal start codon may have evolved as a consequence of TGA being a stop codon and the ability of NTGA to rapidly terminate or adjust a ribosome. |
2,964 | Mammarenaviral Infection Is Dependent on Directional Exposure to and Release from Polarized Intestinal Epithelia | Mammarenavirusesare single-stranded RNA viruses with a bisegmented ambisense genome. Ingestion has been shown as a natural route of transmission for both Lassa virus (LASV) and Lymphocytic choriomeningitis virus (LCMV). Due to the mechanism of transmission, epithelial tissues are among the first host cells to come in contact with the viruses, and as such they potentially play a role in spread of virus to naïve hosts. The role of the intestinal epithelia during arenavirus infection remains to be uncharacterized. We have utilized a well-established cell culture model, Caco-2, to investigate the role of intestinal epithelia during intragastric infection. We found that LCMV-Armstrong, LCMV-WE, and Mopeia (MOPV) release infectious progeny via similar patterns. However, the reassortant virus, ML-29, containing the L segment of MOPV and S segment of LASV, exhibits a unique pattern of viral release relative to LCMV and MOPV. Furthermore, we have determined attachment efficacy to Caco-2 cells is potentially responsible for observed replication kinetics of these viruses in a polarized Caco-2 cell model. Collectively, our data shows that viral dissemination and interaction with intestinal epithelia may be host, tissue, and viral specific. |
2,965 | Role of Fly Cleaning Behavior on Carriage of Escherichia coli and Pseudomonas aeruginosa | Flies are known to be mechanical vectors of bacterial, viral, and parasitic diseases. Although flies are known to transmit disease, the effects of cleaning behavior have not been well studied. This study quantified the cleaning effectiveness and behavior of three fly species: Sarcophaga bullata, Musca domestica L., and Drosophila virilis. Flies were transferred to plates of Escherichia coli or Pseudomonas aeruginosa and allowed to walk on the bacteria for a total of 5 min. After the flies were contaminated, they were either immediately collected to quantify bacteria or were placed onto sterile plates to clean for 5 or 10 min. After cleaning, flies were placed into tubes with 1 ml of sterile 0.85% saline and were gently shaken for 1 min to remove bacteria. A serial dilution was made and 50-µl spot titers were plated. Cleaning behavior was also monitored and scored for a period of 5 min. Results demonstrate a bacterial reduction for both bacteria on all three fly species. Sarcophaga bullata and D. virilis both showed a significant reduction of both bacteria within 10 min, whereas M. domestica only showed a significant reduction in P. aeruginosa. Cleaning behavior increased significantly in flies that were exposed to bacteria compared to flies that were not exposed to bacteria. This study is important, as it demonstrates that fly cleaning could affect mechanical transmission of disease, and additional studies should look at flies’ abilities to remove other types of microorganisms. |
2,966 | Chinese research into severe ulcerative colitis has increased in quantity and complexity | AIM: To investigate the current state of research output from Chinese studies into severe ulcerative colitis (SUC) using a bibliometric analysis of publications. METHODS: The contents of the Chinese periodical databases WANFANG, VIP, and China National Knowledge Infrastructure were searched for all papers regarding UC or SUC published in last the 15 years (from 2001 to 2015). The number of publications in each year was recorded to assess the temporal trends of research output. All SUC related publications were downloaded and the complexity of this research was evaluated with methods described previously. The number of patients with SUC reported each year was recorded and their clinical characteristics were analyzed using information available in the relevant papers. RESULTS: There were 13499 publications regarding UC published in Chinese medical journals between 2001 and 2015, of which 201 focused on SUC. The number of publications increased rapidly with more than half of all papers being published in the most recent 5-year period. There was a significant increase in analytical studies and clinical trials over the study period (P < 0.01), with research into the management of SUC, included pharmacotherapy, nutrition support as well as surgery, predominating. Almost half (46.2%) of the observational analytical studies and clinical trials focused on Traditional Chinese Medicine, with little research on the efficacy of cyclosporin and infliximab in disease management. About 6222 patients with SUC were reported in the 201 SUC relevant papers, with a ratio of male/female of 1.38. The number of patients reported in each 5-year period significantly increased. The colectomy rate and short-term mortality rate were 7.7% and 0.8% respectively. The most commonly employed operation was total proctocolectomy with ileal pouch-anal anastomosis. CONCLUSION: The output and complexity of research related to SUC in China increased significantly over the previous 15 years, however few of these studies focused on salvage therapy. |
2,967 | Clinical characteristics from co-infection with avian influenza A H7N9 and Mycoplasma pneumoniae: a case report | BACKGROUND: More and more cases of human infections with avian influenza A H7N9 have been reported since it was first mentioned in 2013 in China, but concurrence of influenza A H7N9 with Mycoplasma pneumoniae, however, has never been described. Here, we reported the case of a woman co-infected by influenza A H7N9 and Mycoplasma pneumoniae, whose treatment process was a little bit longer and a little bit complicated as well. CASE PRESENTATION: Our patient was an 80-year-old Chinese woman who presented with fever, cough, chest tightness, and shortness of breath. A computed tomography scan showed obvious infiltrations at lower parts of both lungs. Arterial blood gas analysis confirmed a severe respiratory failure (type I). Her sputum and throat swabs were checked for nucleic acid of influenza A and the result was positive for influenza A H7N9. She was diagnosed as having severe influenza A H7N9 and acute respiratory distress syndrome, and was admitted to an intensive care unit. She was given comprehensive treatment, including oseltamivir, methylprednisolone, immunoglobulin, gastric protection, and noninvasive mechanical ventilation. Her condition improved 4 days later. However, some symptoms exacerbated again 2 days later with ground-glass changes appearing in upper area of right lung and the titer of antibody to Mycoplasma pneumoniae rising from 1:80 to 1:640. She was reasonably considered to be infected with Mycoplasma pneumoniae as well, and azithromycin and moxifloxacin were added to her treatment. Oseltamivir was discontinued because of three consecutive negative results of nucleic acid for influenza A H7N9, but anti-Mycoplasma treatment was continued. Although her symptoms and abnormal changes on computed tomography scan slowly went away, she finally recovered from the mixed infection after a total of 33 days of management. CONCLUSION: In patients with confirmed influenza A H7N9 infection whose condition worsens again, especially with new infiltration or lung ground-glass infiltration, one should suspect infection by other pathogens such as Mycoplasma pneumoniae. |
2,968 | Prenatal dexamethasone and postnatal high-fat diet have a synergistic effect of elevating blood pressure through a distinct programming mechanism of systemic and adipose renin–angiotensin systems | BACKGROUND: Hypertension may result from high-fat (HF) diet induced-obesity and overexposure to glucocorticoids in utero. Recent studies demonstrated the potent contribution of adipose tissue’s renin-angiotensin system (RAS) to systemic RAS, which plays a key role in regulating blood pressure (BP). In this study, we investigated the effects of prenatal dexamethasone (DEX) exposure and postnatal HF diet on RAS of adipose tissue. METHODS: RAS and BP of 6-month old rats exposed to prenatal DEX and/or postnatal HF diet were examined. RESULTS: Prenatal DEX plus postnatal HF exerted a synergistic effect on systolic BP. Prenatal DEX exposure suppressed plasma angiotensin (ANG) I and ANG II, whereas postnatal HF suppressed plasma ANG-(1–7) level. Prenatal DEX increased prorenin receptor and renin levels, but suppressed angiotensinogen (AGT) and angiotensin-converting-enzyme 1 (ACE1) mRNA expressions in adipose tissue. Postnatal HF increased AGT mRNA expression, but suppressed prorenin receptor, renin, ACE2, ANG II type 2 receptor (AT2R), and Mas receptor (MasR) mRNA expression levels. CONCLUSIONS: Prenatal GC exposure altered the ACE1/ANG II/ANG II type 1 receptor (AT1R) axis, whereas postnatal HF negatively impacted the ACE2/ANG-(1–7)/MasR axis. Prenatal DEX exposure and postnatal HF synergistically elevated BP through a distinct programming mechanism of systemic and adipose RAS. Adipose RAS might be a target for precise hypertension treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12944-018-0701-0) contains supplementary material, which is available to authorized users. |
2,969 | The Hemagglutinin A Stem Antibody MEDI8852 Prevents and Controls Disease and Limits Transmission of Pandemic Influenza Viruses | BACKGROUND: MEDI8852 is a novel monoclonal antibody (mAb) that neutralizes both group I and group II influenza A viruses (IAVs) in vitro. We evaluated whether MEDI8852 was effective for prophylaxis and therapy against representative group I (H5N1) and group II (H7N9) pandemic IAVs in mice and ferrets and could be used to block transmission of influenza H1N1pdm09 in ferrets, compared to an irrelevant control mAb R347 and oseltamivir. METHODS: MEDI8852 was administered to mice and ferrets by intraperitoneal injection at varying doses, 24 hours prior to intranasal infection with H5N1 and H7N9 viruses for prophylaxis, and 24, 48, and 72 hours post-infection for treatment. A comparison with oseltamivir alone and combination of MEDI8852 and oseltamivir was included in some studies. Survival, weight loss, and viral titers were assessed over a 14-day study period. For the transmission study, naive respiratory contact ferrets received MEDI8852 or R347 prior to exposure to ferrets infected with an H1N1pdm09 virus. RESULTS: MEDI8852 was effective for prophylaxis and treatment of H7N9 and H5N1 infection in mice, with a clear dose-dependent response and treatment with MEDI8852 24, 48, or 72 hours postinfection was superior to oseltamivir for H5N1. MEDI8852 alone was effective treatment for lethal H5N1 infection in ferrets compared to oseltamivir and R347, and MEDI8852 plus oseltamivir was better than oseltamivir alone. MEDI8852 or oseltamivir alone early in infection was equally effective for H7N9 infection in ferrets while the combination yielded similar protection when treatment was delayed. MEDI8852 was able to protect naive ferrets from airborne transmission of H1N1pdm09. CONCLUSIONS: MEDI8852, alone or with oseltamivir, shows promise for prophylaxis or therapy of group I and II IAVs with pandemic potential. Additionally, MEDI8852 blocked influenza transmission in ferrets, a unique finding among influenza-specific mAbs. |
2,970 | Supplemental Oxygen–Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus | BACKGROUND: Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection. METHODS: Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen–free days were defined as any day while alive after diagnosis of RSV infection during which ≤2 L of supplemental oxygen per minute was received. RESULTS: Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 [16%]). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 [27%]) than in those with proven/probable LRTI (29 of 42 [69%]). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen–free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 [26%]). CONCLUSIONS: Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen–free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals. |
2,971 | Cross-Reactive Antibody Responses to Novel H5Nx Influenza Viruses Following Homologous and Heterologous Prime-Boost Vaccination with a Prepandemic Stockpiled A(H5N1) Vaccine in Humans | Recently, novel highly pathogenic avian influenza H5Nx viruses (clade 2.3.4.4) caused outbreaks in US poultry. We evaluated the potential of a stockpiled A(H5N1) A/Anhui/1/2005 (clade 2.3.4) vaccine to elicit cross-reactive antibody responses to these emerging viruses. Sera from subjects who received 2 doses of MF59-adjuvanted A/Anhui/1/2005, or 1 dose of MF59-adjuvanted A/Anhui/1/2005 following priming with a clade 1 vaccine were characterized by microneutralization assays and modified hemagglutination inhibition (HI) assays. Only heterologous prime-boost vaccination induced modest cross-reactive HI antibody responses to H5Nx viruses. Heterologous prime-boost may provide a more effective vaccination strategy to broaden the antibody responses to emerging viruses. |
2,972 | Ebola Virus Neutralizing Antibodies Detectable in Survivors of theYambuku, Zaire Outbreak 40 Years after Infection | The first reported outbreak of Ebola virus disease occurred in 1976 in Yambuku, Democratic Republic of Congo. Antibody responses in survivors 11 years after infection have been documented. However, this report is the first characterization of anti-Ebola virus antibody persistence and neutralization capacity 40 years after infection. Using ELISAs we measured survivor’s immunological response to Ebola virus Zaire (EBOV) glycoprotein and nucleoprotein, and assessed VP40 reactivity. Neutralization of EBOV was measured using a pseudovirus approach and plaque reduction neutralization test with live EBOV. Some survivors from the original EBOV outbreak still harbor antibodies against all 3 measures. Interestingly, a subset of these survivors’ serum antibodies could still neutralize live virus 40 years postinitial infection. These data provide the longest documentation of both anti-Ebola serological response and neutralization capacity within any survivor cohort, extending the known duration of response from 11 years postinfection to at least 40 years after symptomatic infection. |
2,973 | Dysregulated T-Helper Type 1 (Th1):Th2 Cytokine Profile and Poor Immune Response in Pregnant Ferrets Infected With 2009 Pandemic Influenza A(H1N1) Virus | Pregnancy has been associated with severe influenza, an association highlighted during the 2009 pandemic of influenza A(H1N1) virus (A[H1N1]pdm09) infection. To assess the underlying mechanism, we infected pregnant and non-pregnant ferrets with A(H1N1) pdm09 virus. A(H1N1)pdm09-infected pregnant ferrets also had higher levels of inflammatory cytokines in their pulmonary tracts. Systemically, total CD8(+) T cell counts and A(H1N1)pdm09-specific B-cell responses in blood were significantly lower in pregnant ferrets. This model predicts that the poorer outcome for pregnant women during the A(H1N1)pdm09 pandemic was due to an elevated level of viral replication and to a cytokine imbalance that led to a less effective immune response. |
2,974 | Chromogenic detection of yam mosaic virus by closed-tube reverse transcription loop-mediated isothermal amplification (CT-RT-LAMP) | A closed-tube reverse transcription loop-mediated isothermal amplification (CT-RT-LAMP) assay was developed for the detection of yam mosaic virus (YMV, genus Potyvirus) infecting yam (Dioscorea spp.). The assay uses a set of six oligonucleotide primers targeting the YMV coat protein region, and the amplification products in YMV-positive samples are visualized by chromogenic detection with SYBR Green I dye. The CT-RT-LAMP assay detected YMV in leaf and tuber tissues of infected plants. The assay is 100 times more sensitive in detecting YMV than standard RT-PCR, while maintaining the same specificity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00705-018-3706-0) contains supplementary material, which is available to authorized users. |
2,975 | Spread of different rhinovirus B genotypes in hospitalized children in Spain | Please cite this paper as: Cuevas et al. (2013) Spread of different rhinovirus B genotypes in hospitalized children in Spain. Influenza and Other Respiratory Viruses 7(5), 623–628. Human Rhinovirus (HRV) classification is an evolving process. New genotypes have been described within HRV‐A and HRV‐C species, but only one has been accepted related to HRV‐B. From 2003 to 2010, a total of 3987 nasopharyngeal aspirate samples were taken from pediatric patients admitted to the Severo Ochoa Hospital in Madrid (Spain). After viral analysis, 949 (23·8%) tested positive to HRV. A random selection of 397 (42%) positive samples showed that 39 (9·8%) were HRV‐B. The sequencing of partial VP4/VP2 coding region revealed the spread of 13 of 25 defined HRV‐B serotypes and three putative new genotypes. Such results remark the high diversity of HRV‐B. |
2,976 | Mapping road network communities for guiding disease surveillance and control strategies | Human mobility is increasing in its volume, speed and reach, leading to the movement and introduction of pathogens through infected travelers. An understanding of how areas are connected, the strength of these connections and how this translates into disease spread is valuable for planning surveillance and designing control and elimination strategies. While analyses have been undertaken to identify and map connectivity in global air, shipping and migration networks, such analyses have yet to be undertaken on the road networks that carry the vast majority of travellers in low and middle income settings. Here we present methods for identifying road connectivity communities, as well as mapping bridge areas between communities and key linkage routes. We apply these to Africa, and show how many highly-connected communities straddle national borders and when integrating malaria prevalence and population data as an example, the communities change, highlighting regions most strongly connected to areas of high burden. The approaches and results presented provide a flexible tool for supporting the design of disease surveillance and control strategies through mapping areas of high connectivity that form coherent units of intervention and key link routes between communities for targeting surveillance. |
2,977 | Near-Patient Sampling to Assist Infection Control—A Case Report and Discussion | Air sampling as an aid to infection control is still in an experimental stage, as there is no consensus about which air samplers and pathogen detection methods should be used, and what thresholds of specific pathogens in specific exposed populations (staff, patients, or visitors) constitutes a true clinical risk. This case report used a button sampler, worn or held by staff or left free-standing in a fixed location, for environmental sampling around a child who was chronically infected by a respiratory adenovirus, to determine whether there was any risk of secondary adenovirus infection to the staff managing the patient. Despite multiple air samples taken on difference days, coinciding with high levels of adenovirus detectable in the child’s nasopharyngeal aspirates (NPAs), none of the air samples contained any detectable adenovirus DNA using a clinically validated diagnostic polymerase chain reaction (PCR) assay. Although highly sensitive, in-house PCR assays have been developed to detect airborne pathogen RNA/DNA, it is still unclear what level of specific pathogen RNA/DNA constitutes a true clinical risk. In this case, the absence of detectable airborne adenovirus DNA using a conventional diagnostic assay removed the requirement for staff to wear surgical masks and face visors when they entered the child’s room. No subsequent staff infections or outbreaks of adenovirus have so far been identified. |
2,978 | Development of a Rapid Diagnostic Test Kit to Detect IgG/IgM Antibody against Zika Virus Using Monoclonal Antibodies to the Envelope and Non-structural Protein 1 of the Virus | We developed a Rapid Diagnostic Test (RDT) kit for detecting IgG/IgM antibodies against Zika virus (ZIKV) using monoclonal antibodies to the envelope (E) and non-structural protein 1 (NS1) of ZIKV. These proteins were produced using baculovirus expression vector with Sf9 cells. Monoclonal antibodies J2G7 to NS1 and J5E1 to E protein were selected and conjugated with colloidal gold to produce the Zika IgG/IgM RDT kit (Zika RDT). Comparisons with ELISA, plaque reduction neutralization test (PRNT), and PCR were done to investigate the analytical sensitivity of Zika RDT, which resulted in 100% identical results. Sensitivity and specificity of Zika RDT in a field test was determined using positive and negative samples from Brazil and Korea. The diagnostic accuracy of Zika RDT was fairly high; sensitivity and specificity for IgG was 99.0 and 99.3%, respectively, while for IgM it was 96.7 and 98.7%, respectively. Cross reaction with dengue virus was evaluated using anti-Dengue Mixed Titer Performance Panel (PVD201), in which the Zika RDT showed cross-reactions with DENV in 16.7% and 5.6% in IgG and IgM, respectively. Cross reactions were not observed with West Nile, yellow fever, and hepatitis C virus infected sera. Zika RDT kit is very simple to use, rapid to assay, and very sensitive, and highly specific. Therefore, it would serve as a choice of method for point-of-care diagnosis and large scale surveys of ZIKV infection under clinical or field conditions worldwide in endemic areas. |
2,979 | Experimental infection of Cynomolgus Macaques with highly pathogenic H5N1 influenza virus through the aerosol route | Several animal models are used to study influenza viruses. Intranasal inoculation of animals with a liquid inoculum is one of the main methods used to experimentally infect animals with influenza virus; however, this method does not reflect the natural infection with influenza virus by contact or aerosol route. Aerosol inhalation methods have been established with several influenza viruses for mouse and ferret models, but few studies have evaluated inoculation routes in a nonhuman primates (NHP) model. Here, we performed the experimental infection of NHPs with a highly pathogenic H5N1 influenza virus via the aerosol route and demonstrated that aerosol infection had no effect on clinical outcome, but caused broader infection throughout all of the lobes of the lung compared with a non-aerosolized approach. Aerosol infection therefore represents an option for inoculation of NHPs in future studies. |
2,980 | Dengue viruses cleave STING in humans but not in nonhuman primates, their presumed natural reservoir | Human dengue viruses emerged from primate reservoirs, yet paradoxically dengue does not reach high titers in primate models. This presents a unique opportunity to examine the genetics of spillover versus reservoir hosts. The dengue virus 2 (DENV2) - encoded protease cleaves human STING, reducing type I interferon production and boosting viral titers in humans. We find that both human and sylvatic (reservoir) dengue viruses universally cleave human STING, but not the STING of primates implicated as reservoir species. The special ability of dengue to cleave STING is thus specific to humans and a few closely related ape species. Conversion of residues 78/79 to the human-encoded ‘RG’ renders all primate (and mouse) STINGs sensitive to viral cleavage. Dengue viruses may have evolved to increase viral titers in the dense and vast human population, while maintaining decreased titers and pathogenicity in the more rare animals that serve as their sustaining reservoir in nature. |
2,981 | Potentially modifiable respiratory variables contributing to outcome in ICU patients without ARDS: a secondary analysis of PRoVENT | BACKGROUND: The majority of critically ill patients do not suffer from acute respiratory distress syndrome (ARDS). To improve the treatment of these patients, we aimed to identify potentially modifiable factors associated with outcome of these patients. METHODS: The PRoVENT was an international, multicenter, prospective cohort study of consecutive patients under invasive mechanical ventilatory support. A predefined secondary analysis was to examine factors associated with mortality. The primary endpoint was all-cause in-hospital mortality. RESULTS: 935 Patients were included. In-hospital mortality was 21%. Compared to patients who died, patients who survived had a lower risk of ARDS according to the ‘Lung Injury Prediction Score’ and received lower maximum airway pressure (P(max)), driving pressure (ΔP), positive end-expiratory pressure, and FiO(2) levels. Tidal volume size was similar between the groups. Higher P(max) was a potentially modifiable ventilatory variable associated with in-hospital mortality in multivariable analyses. ΔP was not independently associated with in-hospital mortality, but reliable values for ΔP were available for 343 patients only. Non-modifiable factors associated with in-hospital mortality were older age, presence of immunosuppression, higher non-pulmonary sequential organ failure assessment scores, lower pulse oximetry readings, higher heart rates, and functional dependence. CONCLUSIONS: Higher P(max) was independently associated with higher in-hospital mortality in mechanically ventilated critically ill patients under mechanical ventilatory support for reasons other than ARDS. Trial Registration ClinicalTrials.gov (NCT01868321). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13613-018-0385-7) contains supplementary material, which is available to authorized users. |
2,982 | Testing therapeutics in cell-based assays: Factors that influence the apparent potency of drugs | Identifying effective antivirals for treating Ebola virus disease (EVD) and minimizing transmission of such disease is critical. A variety of cell-based assays have been developed for evaluating compounds for activity against Ebola virus. However, very few reports discuss the variable assay conditions that can affect the results obtained from these drug screens. Here, we describe variable conditions tested during the development of our cell-based drug screen assays designed to identify compounds with anti-Ebola virus activity using established cell lines and human primary cells. The effect of multiple assay readouts and variable assay conditions, including virus input, time of infection, and the cell passage number, were compared, and the impact on the effective concentration for 50% and/ or 90% inhibition (EC(50), EC(90)) was evaluated using the FDA-approved compound, toremifene citrate. In these studies, we show that altering cell-based assay conditions can have an impact on apparent drug potency as measured by the EC(50). These results further support the importance of developing standard operating procedures for generating reliable and reproducible in vitro data sets for potential antivirals. |
2,983 | Molecular basis of binding between the global post-transcriptional regulator CsrA and the T3SS chaperone CesT | The T3SS chaperone CesT is recently shown to interact with the post-transcriptional regulator CsrA to modulate post-attachment signaling in enteropathogenic and enterohemorrhagic Escherichia coli. The molecular basis of the CesT/CsrA binding, however, remains elusive. Here, we show that CesT and CsrA both created two ligand binding sites in their homodimers, forming irregular multimeric complexes in solution. Through construction of a recombinant CsrA-dimer (Re-CsrA) that contains a single CesT binding site, the atomic binding features between CesT and CsrA are delineated via the structure of the CesT/Re-CsrA complex. In contrast to a previously reported N-terminally swapped dimer-form, CesT adopts a dimeric architecture with a swapped C-terminal helix for CsrA engagement. In CsrA, CesT binds to a surface patch that extensively overlaps with its mRNA binding site. The binding mode therefore justifies a mechanism of CsrA-modulation by CesT via competitive inhibition of the CsrA/mRNA interactions. |
2,984 | A pilot study on primary cultures of human respiratory tract epithelial cells to predict patients’ responses to H7N9 infection | Avian influenza A(H7N9) virus infections frequently lead to acute respiratory distress syndrome and death in humans. We aimed to investigate whether primary cultures of human respiratory tract epithelial cells are helpful to understand H7N9 virus pathogenesis and tissue tropism, and to evaluate how patient-related characteristics can affect the host's response to infection. Normal human bronchial epithelial cells (isolated from two different donors) and primary epithelial cells (harvested from 27 patients undergoing airway surgery) were experimentally infected with H7N9 and/or H1N1pdm for 72 h. After virus infection, the culture media were collected for viral RNA quantitation and cytokine detection. Both H7N9 and H1N1pdm viruses replicated and induced a cytokine response differently for each donor in the normal human bronchial epithelial model. H7N9 replicated equivalently in epithelial cells harvested from the inferior turbinate and paranasal sinus, and those from the larynx and bronchus, at 72 h post-infection. Viral RNA quantity at 72 h was significantly higher in patients aged 21–64 years than in patients aged ≥ 65 years; however, no effects of sex, medical comorbidities, and obesity were noted. H7N9-infected cultured cells released multiple cytokines within 72 h. Levels of interleukin-1β, interleukin-6, interleukin-8, interferon-γ, and tumor necrosis factor-α were associated differently with patient-related characteristics (such as age, sex, obesity, and medical comorbidities). In the era of precision medicine, these findings illustrate the potential utility of this primary culture approach to predict a host's response to H7N9 infection or to future infection by newly emerging viral infections, and to dissect viral pathogenesis. |
2,985 | Factors Informing Outcomes for Older Cats and Dogs in Animal Shelters | SIMPLE SUMMARY: Historically, older cats and dogs have been particularly at-risk for euthanasia in animal shelters due to their lower perceived appeal for adoption. This study found that the condition at intake had the greatest impact on the outcomes of older cats and dogs. Additionally, the application of specialized veterinary care, such as orthopedic surgery or chronic disease maintenance, is discussed as factors that inform higher rates of live outcomes for these senior companion animals. These findings demonstrate that if shelters integrate practices that address the specific needs of ageing companion animals, the live outcomes for this population can increase. ABSTRACT: With advances in veterinary medicine that can increase the lifespan of cats and dogs and the effectiveness of spay/neuter programs in reducing the juvenile population of pets, animal shelters are experiencing an increasing population of older companion animals in their care. The purpose of this study was to assess the factors that inform the outcomes of these older cats and dogs. The sample consisted of 124 cats and 122 dogs that were over the age of 84 months (seven years) who were taken into a shelter over a one-year period. To assess the impact of condition at intake on the outcome for the senior animals, a multinomial logistic regression was performed. These findings indicate that preventative programming that can address the reasons these older animals are surrendered, as well as advancements in specialized medical or behavioral programs for ageing companion animals, may support an increase in live outcomes for older cats and dogs in shelters. Further study is needed to evaluate how the quality of life of older animals is impacted by remaining in the care of shelters rather than being euthanized. |
2,986 | Severe influenza A(H1N1)pdm09 in pregnant women and neonatal outcomes, State of Sao Paulo, Brazil, 2009 | To investigate the factors associated with death and describe the gestational outcomes in pregnant women with influenza A(H1N1)pdm09, we conducted a case-control study (deaths and recovered) in hospitalized pregnant women with laboratory-confirmed influenza A(H1N1)pdm09 with severe acute respiratory illness (SARI) in the state of São Paulo from June 9 to December 1, 2009. All cases were evaluated, and four controls that were matched by the epidemiological week of hospitalization of the case were randomly selected for each case. Cases and controls were selected from the National Disease Notification System-SINAN Influenza-web. The hospital records from 126 hospitals were evaluated, and home interviews were conducted using standardized forms. A total of 48 cases and 185 controls were investigated. Having had a previous health visit to a healthcare provider for an influenza episode before hospital admission was a risk factor for death (adjusted OR (OR(adj)) of 7.93, 95% CI 2.19–28.69). Although not significant in the multiple analysis (OR(adj) of 2.13, 95% CI 0.91–5.00), the 3(rd) trimester deserves attention, with an OR = 2.22, 95% CI 1.13–4.37 in the univariate analysis. Antiviral treatment was a protective factor when administered within 48 hours of symptom onset (OR(adj) = 0.16, 95% CI 0.05–0.50) and from 48 to 72 hours (OR(adj) = 0.09, 95% CI 0.01–0.87). There was a higher proportion of fetal deaths and preterm births among cases (p = 0.001) and live births with low weight (p = 0.019), compared to control subjects who gave birth during hospitalization. After discharge, control subjects had a favorable neonatal outcome. Early antiviral treatment during the presence of a flu-like illness is an important factor in reducing mortality from influenza in pregnant women and unfavorable neonatal outcomes. It is important to monitor pregnant women, particularly in the 3(rd) trimester of gestation, with influenza illness for diagnosis and early treatment. |
2,987 | Oral Immunization against PEDV with Recombinant Lactobacillus casei Expressing Dendritic Cell-Targeting Peptide Fusing COE Protein of PEDV in Piglets | Porcine epidemic diarrhea (PED) is a highly contagious disease in newborn piglets. In our previous study, a genetically engineered Lactobacillus casei oral vaccine (pPG-COE-DCpep/L393) expressing a dendritic cell (DC)-targeting peptide fused with porcine epidemic diarrhea virus (PEDV) COE antigen was developed. This vaccine induced significant levels of anti-PEDV specific IgG and IgA antibody responses in mice, indicating a potential strategy against PEDV infection. In this study, pPG-COE-DCpep/L393 was used for oral vaccination of newborn piglets against PEDV. We then assessed the immune responses and protection efficacy of pPG-COE-DCpep/L393. An indirect enzyme-linked immunosorbent assay (ELISA) showed that the recombinant Lactobacillus vaccine elicits a specific systemic and mucosal immune response. The T-helper cells mediated by pPG-COE-DCpep/L393 and PEDV infection display a Th1 phenotype. The histopathological results showed that pPG-COE-DCpep/L393 promotes lymphocyte proliferation and effectively protects piglets against PEDV infection. The transforming growth factor-β level indicated that the recombinant Lactobacillus vaccine plays a role in anti-inflammatory responses in mesenteric lymph nodes during PEDV infection. These results show that pPG-COE-DCpep/L393 is a potential vaccine against PEDV infection. |
2,988 | Genome-wide analysis of codon usage bias in four sequenced cotton species | Codon usage bias (CUB) is an important evolutionary feature in a genome which provides important information for studying organism evolution, gene function and exogenous gene expression. The CUB and its shaping factors in the nuclear genomes of four sequenced cotton species, G. arboreum (A(2)), G. raimondii (D(5)), G. hirsutum (AD(1)) and G. barbadense (AD(2)) were analyzed in the present study. The effective number of codons (ENC) analysis showed the CUB was weak in these four species and the four subgenomes of the two tetraploids. Codon composition analysis revealed these four species preferred to use pyrimidine-rich codons more frequently than purine-rich codons. Correlation analysis indicated that the base content at the third position of codons affect the degree of codon preference. PR2-bias plot and ENC-plot analyses revealed that the CUB patterns in these genomes and subgenomes were influenced by combined effects of translational selection, directional mutation and other factors. The translational selection (P2) analysis results, together with the non-significant correlation between GC12 and GC3, further revealed that translational selection played the dominant role over mutation pressure in the codon usage bias. Through relative synonymous codon usage (RSCU) analysis, we detected 25 high frequency codons preferred to end with T or A, and 31 low frequency codons inclined to end with C or G in these four species and four subgenomes. Finally, 19 to 26 optimal codons with 19 common ones were determined for each species and subgenomes, which preferred to end with A or T. We concluded that the codon usage bias was weak and the translation selection was the main shaping factor in nuclear genes of these four cotton genomes and four subgenomes. |
2,989 | Development and evaluation of a novel high-throughput image-based fluorescent neutralization test for detection of Zika virus infection | Zika virus (ZIKV) is an emerging arbovirus belonging to the genus flavivirus that comprises other important public health viruses, such as dengue (DENV) and yellow fever (YFV). In general, ZIKV infection is a self-limiting disease, however cases of Guillain-Barré syndrome and congenital brain abnormalities in newborn infants have been reported. Diagnosing ZIKV infection remains a challenge, as viral RNA detection is only applicable until a few days after the onset of symptoms. After that, serological tests must be applied, and, as expected, high cross-reactivity between ZIKV and other flavivirus serology is observed. Plaque reduction neutralization test (PRNT) is indicated to confirm positive samples for being more specific, however it is laborious intensive and time consuming, representing a major bottleneck for patient diagnosis. To overcome this limitation, we developed a high-throughput image-based fluorescent neutralization test for ZIKV infection by serological detection. Using 226 human specimens, we showed that the new test presented higher throughput than traditional PRNT, maintaining the correlation between results. Furthermore, when tested with dengue virus samples, it showed 50.53% less cross reactivity than MAC-ELISA. This fluorescent neutralization test could be used for clinical diagnosis confirmation of ZIKV infection, as well as for vaccine clinical trials and seroprevalence studies. |
2,990 | Rapid detection of potyviruses from crude plant extracts | Potyviruses (genus Potyvirus; family Potyviridae) are widely distributed and represent one of the most economically important genera of plant viruses. Therefore, their accurate detection is a key factor in developing efficient control strategies. However, this can sometimes be problematic particularly in plant species containing high amounts of polysaccharides and polyphenols such as yam (Dioscorea spp.). Here, we report the development of a reliable, rapid and cost-effective detection method for the two most important potyviruses infecting yam based on reverse transcription-recombinase polymerase amplification (RT-RPA). The developed method, named ‘Direct RT-RPA’, detects each target virus directly from plant leaf extracts prepared with a simple and inexpensive extraction method avoiding laborious extraction of high-quality RNA. Direct RT-RPA enables the detection of virus-positive samples in under 30 min at a single low operation temperature (37 °C) without the need for any expensive instrumentation. The Direct RT-RPA tests constitute robust, accurate, sensitive and quick methods for detection of potyviruses from recalcitrant plant species. The minimal sample preparation requirements and the possibility of storing RPA reagents without cold chain storage, allow Direct RT-RPA to be adopted in minimally equipped laboratories and with potential use in plant clinic laboratories and seed certification facilities worldwide. |
2,991 | Skipping Multiple Exons to Treat DMD—Promises and Challenges | Duchenne muscular dystrophy (DMD) is a lethal disorder caused by mutations in the DMD gene. Antisense-mediated exon-skipping is a promising therapeutic strategy that makes use of synthetic nucleic acids to skip frame-disrupting exon(s) and allows for short but functional protein expression by restoring the reading frame. In 2016, the U.S. Food and Drug Administration (FDA) approved eteplirsen, which skips DMD exon 51 and is applicable to approximately 13% of DMD patients. Multiple exon skipping, which is theoretically applicable to 80–90% of DMD patients in total, have been demonstrated in animal models, including dystrophic mice and dogs, using cocktail antisense oligonucleotides (AOs). Although promising, current drug approval systems pose challenges for the use of a cocktail AO. For example, both exons 6 and 8 need to be skipped to restore the reading frame in dystrophic dogs. Therefore, the cocktail of AOs targeting these exons has a combined therapeutic effect and each AO does not have a therapeutic effect by itself. The current drug approval system is not designed to evaluate such circumstances, which are completely different from cocktail drug approaches in other fields. Significant changes are needed in the drug approval process to promote the cocktail AO approach. |
2,992 | In Vivo Characterisation of Five Strains of Bovine Viral Diarrhoea Virus 1 (Subgenotype 1c) | Bovine viral diarrhoea virus 1 (BVDV-1) is strongly associated with several important diseases of cattle, such as bovine respiratory disease, diarrhoea and haemoragic lesions. To date many subgenotypes have been reported for BVDV-1, currently ranging from subgenotype 1a to subgenotype 1u. While BVDV-1 has a world-wide distribution, the subgenotypes have a more restricted geographical distribution. As an example, BVDV-1 subgenotypes 1a and 1b are frequently detected in North America and Europe, while the subgenotype 1c is rarely detected. In contrast, BVDV-1 subgenotype 1c is by far the most commonly reported in Australia. Despite this, uneven distribution of the biological importance of the subgenotypes remains unclear. The aim of this study was to characterise the in vivo properties of five strains of BVDV-1 subgenotype 1c in cattle infection studies. No overt respiratory signs were reported in any of the infected cattle regardless of strain. Consistent with other subgenotypes, transient pyrexia and leukopenia were commonly identified, while thrombocytopenia was not. The quantity of virus detected in the nasal secretions of transiently infected animals suggested the likelihood of horizontal transmission was very low. Further studies are required to fully understand the variability and importance of the BVDV-1 subgenotype 1c. |
2,993 | Species C Rotaviruses in Children with Diarrhea in India, 2010–2013: A Potentially Neglected Cause of Acute Gastroenteritis | All over the world, children and adults are severely affected by acute gastroenteritis, caused by one of the emerging enteric pathogens, rotavirus C (RVC). At present, no extensive surveillance program is running for RVC in India, and its prevalence is largely unknown except cases of local outbreaks. Here, we intended to detect the presence of RVC in diarrheic children visiting or admitted to hospitals in Haldwani (state of Uttarakhand, India), a city located in the foothills of the Himalayas. During 2010–2013, we screened 119 samples for RVC by an RVC VP6 gene-specific RT-PCR. Of these, 38 (31.93%) were found positive, which is higher than the incidence rates reported so far from India. The phylogenetic analysis of the derived nucleotide sequences from one of the human RVC (HuRVC) isolates, designated as HuRVC/H28/2013/India, showed that the study isolate belongs to genotype I2, P2 and E2 for RVC structural genes 6 and 4 (VP6, and VP4) and non-structural gene 4 (NSP4), respectively. Furthermore, the VP6 gene of HuRVC/H28/2013/India shows the highest similarity to a recently-reported human-like porcine RVC (PoRVC/ASM140/2013/India, KT932963) from India suggesting zoonotic transmission. We also report a full-length NSP4 gene sequence of human RVC from India. Under the One-health platforms there is a need to launch combined human and animal RVC surveillance programs for a better understanding of the epidemiology of RVC infections and for implementing control strategies. |
2,994 | Enterokinase Enhances Influenza A Virus Infection by Activating Trypsinogen in Human Cell Lines | Cleavage and activation of hemagglutinin (HA) by trypsin-like proteases in influenza A virus (IAV) are essential prerequisites for its successful infection and spread. In host cells, some transmembrane serine proteases such as TMPRSS2, TMPRSS4 and HAT, along with plasmin in the bloodstream, have been reported to cleave the HA precursor (HA(0)) molecule into its active forms, HA(1) and HA(2). Some trypsinogens can also enhance IAV proliferation in some cell types (e.g., rat cardiomyoblasts). However, the precise activation mechanism for this process is unclear, because the expression level of the physiological activator of the trypsinogens, the TMPRSS15 enterokinase, is expected to be very low in such cells, with the exception of duodenal cells. Here, we show that at least two variant enterokinases are expressed in various human cell lines, including A549 lung-derived cells. The exogenous expression of these enterokinases was able to enhance the proliferation of IAV in 293T human kidney cells, but the proliferation was reduced by knocking down the endogenous enterokinase in A549 cells. The enterokinase was able to enhance HA processing in the cells, which activated trypsinogen in vitro and in the IAV-infected cells also. Therefore, we conclude that enterokinase plays a role in IAV infection and proliferation by activating trypsinogen to process viral HA in human cell lines. |
2,995 | Avian Respiratory Coinfection and Impact on Avian Influenza Pathogenicity in Domestic Poultry: Field and Experimental Findings | The avian respiratory system hosts a wide range of commensal and potential pathogenic bacteria and/or viruses that interact with each other. Such interactions could be either synergistic or antagonistic, which subsequently determines the severity of the disease complex. The intensive rearing methods of poultry are responsible for the marked increase in avian respiratory diseases worldwide. The interaction between avian influenza with other pathogens can guarantee the continuous existence of other avian pathogens, which represents a global concern. A better understanding of the impact of the interaction between avian influenza virus and other avian respiratory pathogens provides a better insight into the respiratory disease complex in poultry and can lead to improved intervention strategies aimed at controlling virus spread. |
2,996 | Risk factors for hematemesis in Hoima and Buliisa Districts, Western Uganda, September-October 2015 | INTRODUCTION: On 17 September 2015, Buliisa District Health Office reported multiple deaths due to haemorrhage to the Uganda Ministry of Health. We conducted an investigation to verify the existence of an outbreak and to identify the disease nature, mode of transmission and risk factors. METHODS: We defined a suspected case as onset of hematemesis between 1 June 2015 and 15 October 2015 in a resident of Hoima, Buliisa or neighbouring districts. We identified cases by reviewing medical records and actively searching in the community. We interviewed case-patients and health-care workers and performed descriptive epidemiology to generate hypotheses on possible exposures. In a case-control study we compared exposures between 21 cases and 81 controls, matched by age (± 10 years), sex and village of residence. We collected 22 biological specimens from 19 case-patients to test for Viral Haemorrhagic Fevers (VHF). We analysed the data using the Mantel-Haenszel method to account for the matched study design. RESULTS: We identified 56 cases with onset from June to October (attack rate 15/100,000 in Buliisa District and 5.2/100,000 in Hoima District). The age-specific attack rate was highest in persons aged 31-60 years (15/100,000 in Hoima and 47/100,000 in Buliisa); no persons below 15 years of age had the illness. In the case-control study, 42% (5/12) of cases vs. 0.0% (0/77) of controls had liver disease (OR(M-H) = ∞; 95%CI = 3.7-∞); 71% (10/14) of cases vs. 35% (28/81) of controls had ulcer disease (OR(M-H) = 13; 95% CI = 1.6-98); 27% (3/11) of cases vs. 14% (11/81) of controls used indomethacin prior to disease onset (OR(M-H) = 6.0; 95% CI = 1.0-36). None of the blood samples were positive for any of the VHFs. CONCLUSION: This reported cluster of hematemesis illness was due to predisposing conditions and use of Non-Steroidal Anti-inflammatory Drugs (NSAID). Health education should be conducted on the danger of NSAIDs misuse, especially in persons with pre-disposing conditions. |
2,997 | Proteomic fingerprinting in HIV/HCV co-infection reveals serum biomarkers for the diagnosis of fibrosis staging | BACKGROUND: Hepatic complications of hepatitis C virus (HCV), including fibrosis and cirrhosis are accelerated in human immunodeficiency virus (HIV)-infected individuals. Although, liver biopsy remains the gold standard for staging HCV-associated liver disease, this test can result in serious complications and is subject to sampling errors. These challenges have prompted a search for non-invasive methods for liver fibrosis staging. To this end, we compared serum proteome profiles at different stages of fibrosis in HIV/HCV co- and HCV mono-infected patients using surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). METHODS: Sera from 83 HIV/HCV co- and 68 HCV mono-infected subjects in 4 stages of fibrosis were tested. Sera were fractionated, randomly applied to protein chip arrays (IMAC, CM10 and H50) and spectra were generated at low and high laser intensities. RESULTS: Sixteen biomarkers achieved a p value < 0.01 (ROC values > 0.75 or < 0.25) predictive of fibrosis status in co-infected individuals and 14 in mono infected subjects. Five of these candidate biomarkers contributed to both mono- and co-infected subjects. Candidate diagnostic algorithms were created to distinguish between non-fibrotic and fibrotic individuals using a panel of 4 biomarker peaks. CONCLUSION: These data suggest that SELDI MS profiling can identify diagnostic serum biomarkers for fibrosis that are both common and distinct in HIV/HCV co-infected and HCV mono-infected individuals. |
2,998 | Immune regulation of the unfolded protein response at the mucosal barrier in viral infection | Protein folding in the endoplasmic reticulum (ER) is subject to stringent quality control. When protein secretion demand exceeds the protein folding capacity of the ER, the unfolded protein response (UPR) is triggered as a consequence of ER stress. Due to the secretory function of epithelial cells, UPR plays an important role in maintaining epithelial barrier function at mucosal sites. ER stress and activation of the UPR are natural mechanisms by which mucosal epithelial cells combat viral infections. In this review, we discuss the important role of UPR in regulating mucosal epithelium homeostasis. In addition, we review current insights into how the UPR is involved in viral infection at mucosal barriers and potential therapeutic strategies that restore epithelial cell integrity following acute viral infections via cytokine and cellular stress manipulation. |
2,999 | Preprints: An underutilized mechanism to accelerate outbreak science | In an Essay, Michael Johansson and colleagues advocate the posting of research studies addressing infectious disease outbreaks as preprints. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.