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3,000 | Time-series analysis for porcine reproductive and respiratory syndrome in the United States | Industry-driven voluntary disease control programs for swine diseases emerged in North America in the early 2000’s, and, since then, those programs have been used for monitoring diseases of economic importance to swine producers. One example of such initiatives is Dr. Morrison’s Swine Health Monitoring Project, a nation-wide monitoring program for swine diseases including the porcine reproductive and respiratory syndrome (PRRS). PRRS has been extensively reported as a seasonal disease in the U.S., with predictable peaks that start in fall and are extended through the winter season. However, formal time series analysis stratified by geographic region has never been conducted for this important disease across the U.S. The main objective of this study was to use approximately seven years of PRRS incidence data in breeding swine herds to conduct time-series analysis in order to describe the temporal patterns of PRRS outbreaks at the farm level for five major swine-producing states across the U.S. including the states of Minnesota, Iowa, North Carolina, Nebraska and Illinois. Data was aggregated retrospectively at the week level for the number of herds containing animals actively shedding PRRS virus. Basic descriptive statistics were conducted followed by autoregressive integrated moving average (ARIMA) modelling, conducted separately for each of the above-mentioned states. Results showed that there was a difference in the nature of PRRS seasonality among states. Of note, when comparing states, the typical seasonal pattern previously described for PRRS could only be detected for farms located in the states of Minnesota, North Carolina and Nebraska. For the other two states, seasonal peaks every six months were detected within a year. In conclusion, we showed that epidemic patterns are not homogeneous across the U.S, with major peaks of disease occurring through the year. These findings highlight the importance of coordinating alternative control strategies in different regions considering the prevailing epidemiological patterns. |
3,001 | A Critical Domain of Ebolavirus Envelope Glycoprotein Determines Glycoform and Infectivity | Ebolaviruses comprises 5 species that exert varying degrees of mortality/infectivity in humans with Reston ebolaviruses (REBOV) showing the lowest and Zaire ebolaviruses (ZEBOV) showing the highest. However, the molecular basis of this differential mortality/infectivity remains unclear. Here, we report that the structural features of ebolavirus envelope glycoproteins (GPs) and one of their counter receptors, macrophage galactose-type calcium-type lectin (MGL/CD301), play crucial roles in determining viral infectivity. The low infectivity of REBOV mediated by the interaction between GPs and MGL/CD301 dramatically increased when the N-terminal 18 amino acids (33rd through 50th) of GPs were replaced with that of ZEBOV. Furthermore, structural analysis of glycans of GPs revealed that N-glycans were more extended in REBOV than in ZEBOV. N-glycan extension was reversed by the replacement of aforementioned N-terminal 18 amino acid residues. Therefore, these data strongly suggest that extended N-glycans on GPs reduce MGL/CD301-mediated viral infectivity by hindering the interaction between GPs and MGL/CD301 preferentially binds O-glycans. |
3,002 | Risk Factors for Avian Influenza H9 Infection of Chickens in Live Bird Retail Stalls of Lahore District, Pakistan 2009–2010 | This study was conducted to identify risk factors associated with AIV infections in live bird retail stalls (LBRS) in Lahore District, Pakistan. A cross-sectional survey of LBRS was conducted from December 2009-February 2010 using two-stage cluster sampling based on probability proportional to size. A total of 280 oropharyngeal swab sample pools were collected from 1400 birds in 8 clusters and tested by qRT-PCR for the matrix (M) gene of type A influenza virus and HA gene subtypes H9, H5 and H7. Thirty-four (34) samples were positive for the M gene, of which 28 were also positive for H9. No sample was found positive for H5 or H7. Data for 36 potential risk factors, collected by questionnaire, were analyzed by survey-weighted logistic regression and prevalence odds ratios (OR) for associated risk factors were calculated. A final multivariable model identified three risk factors for H9 infection in LRBS, namely obtaining birds from mixed sources (OR 2.28, CI(95%): 1.4–3.7), keeping birds outside cages (OR 3.10, CI(95%): 1.4–7.0) and keeping chicken breeds other than broilers (OR 6.27, CI(95%): 1.7–23.2). Sourcing birds from dealers/wholesalers, keeping birds inside cages and avoiding mixing different breeds in cages could reduce the risk of H9 infections in LRBS. |
3,003 | Ventilator Dependence Risk Score for the Prediction of Prolonged Mechanical Ventilation in Patients Who Survive Sepsis/Septic Shock with Respiratory Failure | We intended to develop a scoring system to predict mechanical ventilator dependence in patients who survive sepsis/septic shock with respiratory failure. This study evaluated 251 adult patients in medical intensive care units (ICUs) between August 2013 to October 2015, who had survived for over 21 days and received aggressive treatment. The risk factors for ventilator dependence were determined. We then constructed a ventilator dependence (VD) risk score using the identified risk factors. The ventilator dependence risk score was calculated as the sum of the following four variables after being adjusted by proportion to the beta coefficient. We assigned a history of previous stroke, a score of one point, platelet count less than 150,000/μL a score of one point, pH value less than 7.35 a score of two points, and the fraction of inspired oxygen on admission day 7 over 39% as two points. The area under the curve in the derivation group was 0.725 (p < 0.001). We then applied the VD risk score for validation on 175 patients. The area under the curve in the validation group was 0.658 (p = 0.001). VD risk score could be applied to predict prolonged mechanical ventilation in patients who survive sepsis/septic shock. |
3,004 | DIVA metabolomics: Differentiating vaccination status following viral challenge using metabolomic profiles | Bovine Respiratory Disease (BRD) is a major source of economic loss within the agricultural industry. Vaccination against BRD-associated viruses does not offer complete immune protection and vaccine failure animals present potential routes for disease spread. Serological differentiation of infected from vaccinated animals (DIVA) is possible using antigen-deleted vaccines, but during virus outbreaks DIVA responses are masked by wild-type virus preventing accurate serodiagnosis. Previous work by the authors has established the potential for metabolomic profiling to reveal metabolites associated with systemic immune responses to vaccination. The current study builds on this work by demonstrating for the first time the potential to use plasma metabolite profiling to differentiate between vaccinated and non-vaccinated animals following infection-challenge. Male Holstein Friesian calves were intranasally vaccinated (Pfizer RISPOVAL(®)PI3+RSV) and subsequently challenged with Bovine Parainfluenza Virus type-3 (BPI3V) via nasal inoculation. Metabolomic plasma profiling revealed that viral challenge led to a shift in acquired plasma metabolite profiles from day 2 to 20 p.i., with 26 metabolites identified whose peak intensities were significantly different following viral challenge depending on vaccination status. Elevated levels of biliverdin and bilirubin and decreased 3-indolepropionic acid in non-vaccinated animals at day 6 p.i. may be associated with increased oxidative stress and reactive oxygen scavenging at periods of peak virus titre. During latter stages of infection, increased levels of N-[(3α,5β,12α)-3,12-dihydroxy-7,24-dioxocholan-24-yl]glycine and lysophosphatidycholine and decreased enterolactone in non-vaccinated animals may reflect suppression of innate immune response mechanisms and progression to adaptive immune responses. Levels of hexahydrohippurate were also shown to be significantly elevated in non-vaccinated animals from days 6 to 20 p.i. These findings demonstrate the potential of metabolomic profiling to identify plasma markers that can be employed in disease diagnostic applications to both differentially identify infected non-vaccinated animals during disease outbreaks and provide greater information on the health status of infected animals. |
3,005 | Translational profiling of B cells infected with the Epstein-Barr virus reveals 5′ leader ribosome recruitment through upstream open reading frames | The Epstein-Barr virus (EBV) genome encodes several hundred transcripts. We have used ribosome profiling to characterize viral translation in infected cells and map new translation initiation sites. We show here that EBV transcripts are translated with highly variable efficiency, owing to variable transcription and translation rates, variable ribosome recruitment to the leader region and coverage by monosomes versus polysomes. Some transcripts were hardly translated, others mainly carried monosomes, showed ribosome accumulation in leader regions and most likely represent non-coding RNAs. A similar process was visible for a subset of lytic genes including the key transactivators BZLF1 and BRLF1 in cells infected with weakly replicating EBV strains. This suggests that ribosome trapping, particularly in the leader region, represents a new checkpoint for the repression of lytic replication. We could identify 25 upstream open reading frames (uORFs) located upstream of coding transcripts that displayed 5′ leader ribosome trapping, six of which were located in the leader region shared by many latent transcripts. These uORFs repressed viral translation and are likely to play an important role in the regulation of EBV translation. |
3,006 | Network perturbation analysis of gene transcriptional profiles reveals protein targets and mechanism of action of drugs and influenza A viral infection | Genome-wide transcriptional profiling provides a global view of cellular state and how this state changes under different treatments (e.g. drugs) or conditions (e.g. healthy and diseased). Here, we present ProTINA (Protein Target Inference by Network Analysis), a network perturbation analysis method for inferring protein targets of compounds from gene transcriptional profiles. ProTINA uses a dynamic model of the cell-type specific protein–gene transcriptional regulation to infer network perturbations from steady state and time-series differential gene expression profiles. A candidate protein target is scored based on the gene network's dysregulation, including enhancement and attenuation of transcriptional regulatory activity of the protein on its downstream genes, caused by drug treatments. For benchmark datasets from three drug treatment studies, ProTINA was able to provide highly accurate protein target predictions and to reveal the mechanism of action of compounds with high sensitivity and specificity. Further, an application of ProTINA to gene expression profiles of influenza A viral infection led to new insights of the early events in the infection. |
3,007 | Efficacy and synergy of live-attenuated and inactivated influenza vaccines in young chickens | Outbreaks of novel highly pathogenic avian influenza viruses have been reported in poultry species in the United States since 2014. These outbreaks have proven the limitations of biosecurity control programs, and new tools are needed to reinforce the current avian influenza control arsenal. Some enzootic countries have implemented inactivated influenza vaccine (IIV) in their control programs, but there are serious concerns that a long-term use of IIV without eradication may result in the selection of novel antigenically divergent strains. A broadly protective vaccine is needed, such as live-attenuated influenza vaccine (LAIV). We showed in our previous studies that pc4-LAIV (a variant that encodes a C-terminally truncated NS1 protein) can provide significant protection against heterologous challenge virus in chickens vaccinated at 2–4 weeks of age through upregulation of innate and adaptive immune responses. The current study was conducted to compare the performances of pc4-LAIV and IIV in young chickens vaccinated at 1 day of age. A single dose of pc4-LAIV was able to induce stronger innate and mucosal IgA responses and protect young immunologically immature chickens better than a single dose of IIV. Most importantly, when 1-day-old chickens were intranasally primed with pc4-LAIV and subcutaneously boosted with IIV three weeks later, they showed a rapid, robust, and highly cross-reactive serum antibody response and a high level of mucosal IgA antibody response. This vaccination regimen warrants further optimization to increase its range of protection. |
3,008 | Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study | BACKGROUND: Research has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated. METHODS: From 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders. RESULTS: Among the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81–1.16) and 0.96 (0.80–1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46–14.1). CONCLUSION: Compared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-018-4292-y) contains supplementary material, which is available to authorized users. |
3,009 | Assessment of the ability of V920 recombinant vesicular stomatitis-Zaire ebolavirus vaccine to replicate in relevant arthropod cell cultures and vector species | V920, rVSVΔG-ZEBOV-GP, is a recombinant vesicular stomatitis-Zaire ebolavirus vaccine which has shown an acceptable safety profile and provides a protective immune response against Ebola virus disease (EVD) induced by Zaire ebolavirus in humans. The purpose of this study was to determine whether the V920 vaccine is capable of replicating in arthropod cell cultures of relevant vector species and of replicating in live mosquitoes. While the V920 vaccine replicated well in Vero cells, no replication was observed in Anopheles or Aedes mosquito, Culicoides biting midge, or Lutzomyia sand fly cells, nor in live Culex or Aedes mosquitoes following exposure through intrathoracic inoculation or feeding on a high-titer infectious blood meal. The insect taxa selected for use in this study represent actual and potential epidemic vectors of VSV. V920 vaccine inoculated into Cx. quinquefasciatus and Ae. aegypti mosquitoes demonstrated persistence of replication-competent virus following inoculation, consistent with the recognized biological stability of the vaccine, but no evidence for active virus replication in live mosquitoes was observed. Following administration of an infectious blood meal to Ae. aegypti and Cx. quinquefasciatus mosquitoes at a titer several log(10) PFU more concentrated than would be observed in vaccinated individuals, no infection or dissemination of V920 was observed in either mosquito species. In vitro and in vivo data gathered during this study support minimal risk of the vector-borne potential of the V920 vaccine. |
3,010 | Quantitative determination of residual 1,4-dioxane in three-dimensional printed bone scaffold | BACKGROUND/OBJECTIVE: A novel porous scaffold poly (lactide-co-glycolide) and tricalcium phosphate (PLGA/TCP) was developed by three-dimensional printing technology for bone defect repair. As a Class 2 solvent with less severe toxicity, content of residual 1,4-dioxane in this newly developed scaffold should be rigorously controlled when it is translated to clinical use. In this study, a headspace gas chromatography-mass spectrometric (HS-GC-MS) method and related testing protocol were developed for quantitative determination of 1,4-dioxane in the PLGA/TCP composite scaffolds. METHODS: Matrix effect analysis was used to optimise the pretreatment method of the scaffolds. Then, the procedure for testing 1,4-dioxane using HS-GC-MS was set up. The accuracy, precision, and robustness of this newly developed quantitative method were also validated before quantification of 1,4-dioxane in the scaffolds with different drying procedures. RESULTS: Dimethyl formamide (DMF) was the optimal solvent for dissolving scaffolds for GC-MS with proper sensitivity and without matrix effect. Then, the optimised procedure was determined as: the scaffolds were dissolved in DMF and kept at 90°C for 40 minutes, separated on a HP-5MS column, and detected by mass spectroscopy. Recovery experiments gave 97.9–100.7% recovery for 1,4-dioxane. The linear range for 1,4-dioxane was determined as 1–40 ppm with linear correlation coefficient ≥ 0.9999. Intraday and interday precision was determined as being within relative standard deviation of below 0.68%. The passable drying procedure was related to lyophilising (−50°C, 50 Pa) the scaffolds for 2 days and drying in vacuum (50 Pa) for 7 days. CONCLUSION: This is the first quantitative method established to test 1,4-dixoane in a novel scaffold. This method was validated with good accuracy and reproducibility, and met the methodological requirements of the Guideline 9101 documented in the Chinese Pharmacopoeia 2015 Edition. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This quantitative method for determination of residual 1,4-dioxane in the novel scaffolds is a key technical method during its translation into clinical use because this method is an important and indispensable file in the enterprise standard when the porous scaffold is registered as a Class III implanted medical device for bone defect repair, which is used to guarantee the safety of the scaffolds. It is also applied to optimise the drying process of scaffolds and to monitor the quality of scaffolds in the industrialisation process. Further, this method provides references for other solvents quantitative determination in porous scaffolds or materials. |
3,011 | Simultaneous Detection of Key Bacterial Pathogens Related to Pneumonia and Meningitis Using Multiplex PCR Coupled With Mass Spectrometry | Pneumonia and meningitis continue to present an enormous public health burden and pose a major threat to young children. Among the causative organisms of pneumonia and meningitis, bacteria are the most common causes of serious disease and deaths. It is challenging to accurately and rapidly identify these agents. To solve this problem, we developed and validated a 12-plex PCR coupled with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) method (bacterial pathogen-mass spectrometry, BP-MS) that can be used to simultaneously screen for 11 key bacterial pathogens related to pneumonia and meningitis. Forty-six nasopharyngeal swabs and 12 isolates were used to determine the specificity of the method. The results showed that, using the BP-MS method, we could accurately identify the expected bacteria without cross-reactivity with other pathogens. For the 11 target bacterial pathogens, the analytical sensitivity of the BP-MS method was as low as 10 copies/reaction. To further evaluate the clinical effectiveness of this method, 204 nasopharyngeal swabs from hospitalized children with suspected pneumonia were tested using this method. In total, 81.9% (167/204) of the samples were positive for at least one of the 11 target pathogens. Among the 167 bacteria-positive samples, the rate of multiple infections was 55.7% (93/167), and the most frequent combination was Streptococcus pneumoniae with Haemophilus influenzae, representing 46.2% (43/93) two-pathogen mixed infections. We used real-time PCR and nested PCR to confirm positive results, with identical results obtained for 81.4% (136/167) of the samples. The BP-MS method is a sensitive and specific molecular detection technique in a multiplex format and with high sample throughput. Therefore, it will be a powerful tool for pathogen screening and antibiotic selection at an early stage of disease. |
3,012 | Physicians’ and nurses’ thoughts and concerns about introducing neonatal male circumcision in Thailand: a qualitative study | BACKGROUND: Neonatal male circumcision (NMC) is an alternative approach to adult male circumcision for HIV prevention. Recent studies found that NMC was rarely performed in Thailand and that most Thai health professionals did not recognize that NMC could reduce the risk of HIV infection and would not want NMC services in their hospitals. This study explored the thoughts and concerns of Thai government health staff regarding the introduction of NMC in government health facilities as a public health measure. METHODS: In-depth interviews with physicians, nurses and physician administrators from four different levels of government hospitals in four provinces representing 4 regions of Thailand were conducted after provision of education regarding the benefits and risks of NMC. Interviews were audio recorded and analyzed using Atlas.ti software to develop themes. RESULTS: Six themes emerged from the data of 42 respondents: understanding of the benefits of NMC; risks of NMC; need for a pilot project; need for staff training and hospital readiness; need for parental/family education; and need for public awareness educational campaign. Major concerns included possible medical complications of NMC, infringement of child rights, and lack of understanding from staff and parents. The respondents emphasized the need for a clear policy, proper training of staff, financial and equipment support, and piloting NMC rollout before this measure could be fully implemented. CONCLUSIONS: Thai health professionals who took part in this study expressed several concerns if NMC had to be performed in their health care facilities. There is significant preparation that needs to be done before NMC can be introduced in the country. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12913-018-3093-y) contains supplementary material, which is available to authorized users. |
3,013 | Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability | Deubiquitinating enzymes (DUBs) are important regulators of ubiquitin signaling. Here, we report the discovery of deubiquitinating activity in ZUFSP/C6orf113. High-resolution crystal structures of ZUFSP in complex with ubiquitin reveal several distinctive features of ubiquitin recognition and catalysis. Our analyses reveal that ZUFSP is a novel DUB with no homology to any known DUBs, leading us to classify ZUFSP as the seventh DUB family. Intriguingly, the minimal catalytic domain does not cleave polyubiquitin. We identify two ubiquitin binding domains in ZUFSP: a ZHA (ZUFSP helical arm) that binds to the distal ubiquitin and an atypical UBZ domain in ZUFSP that binds to polyubiquitin. Importantly, both domains are essential for ZUFSP to selectively cleave K63-linked polyubiquitin. We show that ZUFSP localizes to DNA lesions, where it plays an important role in genome stability pathways, functioning to prevent spontaneous DNA damage and also promote cellular survival in response to exogenous DNA damage. |
3,014 | Modulating Metabolism to Improve Cancer-Induced Muscle Wasting | Muscle wasting is one of the main features of cancer cachexia, a multifactorial syndrome frequently occurring in oncologic patients. The onset of cachexia is associated with reduced tolerance and response to antineoplastic treatments, eventually leading to clinical conditions that are not compatible with survival. Among the mechanisms underlying cachexia, protein and energy dysmetabolism play a major role. In this regard, several potential treatments have been proposed, mainly on the basis of promising results obtained in preclinical models. However, at present, no treatment yet reached validation to be used in the clinical practice, although several drugs are currently tested in clinical trials for their ability to improve muscle metabolism in cancer patients. Along this line, the results obtained in both experimental and clinical studies clearly show that cachexia can be effectively approached by a multidirectional strategy targeting nutrition, inflammation, catabolism, and inactivity at the same time. In the present study, approaches aimed to modulate muscle metabolism in cachexia will be reviewed. |
3,015 | Host shifts result in parallel genetic changes when viruses evolve in closely related species | Host shifts, where a pathogen invades and establishes in a new host species, are a major source of emerging infectious diseases. They frequently occur between related host species and often rely on the pathogen evolving adaptations that increase their fitness in the novel host species. To investigate genetic changes in novel hosts, we experimentally evolved replicate lineages of an RNA virus (Drosophila C Virus) in 19 different species of Drosophilidae and deep sequenced the viral genomes. We found a strong pattern of parallel evolution, where viral lineages from the same host were genetically more similar to each other than to lineages from other host species. When we compared viruses that had evolved in different host species, we found that parallel genetic changes were more likely to occur if the two host species were closely related. This suggests that when a virus adapts to one host it might also become better adapted to closely related host species. This may explain in part why host shifts tend to occur between related species, and may mean that when a new pathogen appears in a given species, closely related species may become vulnerable to the new disease. |
3,016 | Isolation and characterization of a multifunctional flavonoid glycosyltransferase from Ornithogalum caudatum with glycosidase activity | Glycosyltransferases (GTs) are bidirectional biocatalysts catalyzing the glycosylation of diverse molecules. However, the extensive applications of GTs in glycosides formation are limited due to their requirements of expensive nucleotide diphosphate (NDP)-sugars or NDP as the substrates. Here, in an effort to characterize flexible GTs for glycodiversification of natural products, we isolated a cDNA, designated as OcUGT1 from Ornithogalum caudatum, which encoded a flavonoid GT that was able to catalyze the trans-glycosylation reactions, allowing the formation of glycosides without the additions of NDP-sugars or NDP. In addition, OcUGT1 was observed to exhibit additional five types of functions, including classical sugar transfer reaction and three reversible reactions namely NDP-sugar synthesis, sugars exchange and aglycons exchange reactions, as well as enzymatic hydrolysis reaction, suggesting OcUGT1 displays both glycosyltransferase and glycosidase activities. Expression profiles revealed that the expression of OcUGT1 was development-dependent and affected by environmental factors. The unusual multifunctionality of OcUGT1 broadens the applicability of OcUGT1, thereby generating diverse carbohydrate-containing structures. |
3,017 | Bovine Nebovirus Interacts with a Wide Spectrum of Histo-Blood Group Antigens | Some viruses within the Caliciviridae family initiate their replication cycle by attachment to cell surface carbohydrate moieties, histo-blood group antigens (HBGAs), and/or terminal sialic acids (SAs). Although bovine nebovirus (BNeV), one of the enteric caliciviruses, is an important causative agent of acute gastroenteritis in cattle, its attachment factors and possibly other cellular receptors remain unknown. Using a comprehensive series of protein-ligand biochemical assays, we sought to determine whether BNeV recognizes cell surface HBGAs and/or SAs as attachment factors. It was found that BNeV virus-like particles (VLPs) bound to A type/H type 2/Le(y) HBGAs expressed in the bovine digestive tract and are related to HBGAs expressed in humans and other host species, suggesting a wide spectrum of HBGA recognition by BNeV. BNeV VLPs also bound to a large variety of different bovine and human saliva samples of all ABH and Lewis types, supporting previously obtained results and suggesting a zoonotic potential of BNeV transmission. Removal of α1,2-linked fucose and α1,3/4-linked fucose epitopes of target HBGAs by confirmation-specific enzymes reduced the binding of BNeV VLPs to synthetic HBGAs, bovine and human saliva, cultured cell lines, and bovine small intestine mucosa, further supporting a wide HBGA binding spectrum of BNeV through recognition of α1,2-linked fucose and α1,3/4-linked fucose epitopes of targeted HBGAs. However, removal of terminal α2,3- and α2,6-linked SAs by their specific enzyme had no inhibitory effects on binding of BNeV VLPs, indicating that BNeV does not use terminal SAs as attachment factors. Further details of the binding specificity of BNeV remain to be explored. IMPORTANCE Enteric caliciviruses such as noroviruses, sapoviruses, and recoviruses are the most important etiological agents of severe acute gastroenteritis in humans and many other mammalian host species. They initiate infection by attachment to cell surface carbohydrate moieties, HBGAs, and/or terminal SAs. However, the attachment factor(s) for BNeV, a recently classified enteric calicivirus genus/type species, remains unexplored. Here, we demonstrate that BNeV VLPs have a wide spectrum of binding to synthetic HBGAs, bovine and human saliva samples, and bovine duodenal sections. We further discovered that α1,2-linked fucose and α1,3/4-linked fucose epitopes are essential for binding of BNeV VLPs. However, BNeV VLPs do not bind to terminal SAs on cell carbohydrates. Continued investigation regarding the proteinaceous receptor(s) will be necessary for better understanding of the tropism, pathogenesis, and host range of this important viral genus. |
3,018 | Stem cell-derived mitochondria transplantation: a novel strategy and the challenges for the treatment of tissue injury | Damage of mitochondria in the initial period of tissue injury aggravates the severity of injury. Restoration of mitochondria dysfunction and mitochondrial-based therapeutics represent a potentially effective therapeutic strategy. Recently, mitochondrial transfer from stem cells has been demonstrated to play a significant role in rescuing injured tissues. The possible mechanisms of mitochondria released from stem cells, the pathways of mitochondria transfer between the donor stem cells and recipient cells, and the internalization of mitochondria into recipient cells are discussed. Moreover, a novel strategy for tissue injury based on the concept of stem cell-derived mitochondrial transplantation is pointed out, and the advantages and challenges are summarized. |
3,019 | Descriptive study of severe hospitalized cases of laboratory-confirmed influenza during five epidemic seasons (2010–2015) | OBJECTIVE: The Plan of Information on Acute Respiratory Infections in Catalonia (PIDIRAC) included the surveillance of severe hospitalized cases of laboratory-confirmed influenza (SHCLCI) in 2009. The objective of this study was to determine the clinical, epidemiological and virological features of SHCLCI recorded in 12 sentinel hospitals during five influenza seasons. RESULTS: From a sample of SHCLCI recorded during the 5 influenza epidemics seasons from 2010–2011 to 2014–2015, Cases were confirmed by PCR and/or viral isolation in cell cultures from respiratory samples. A total of 1400 SHCLCI were recorded, 33% required ICU admission and 12% died. The median age of cases was 61 years (range 0–101 years); 70.5% were unvaccinated; 80.4% received antiviral treatment (in 79.6 and 24% of cases within 48 h after hospital admission and the onset of symptoms, respectively); influenza virus A [37.9% A (H1N1)pdm09, 29.3% A (H3N2)] was identified in 87.7% of cases. Surveillance of SHCLCI provides an estimate of the severity of seasonal influenza epidemics and the identification and characterization of at-risk groups in order to facilitate preventive measures such as vaccination and early antiviral treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13104-018-3349-y) contains supplementary material, which is available to authorized users. |
3,020 | Accurate prediction of functional, structural, and stability changes in PITX2 mutations using in silico bioinformatics algorithms | Mutations in PITX2 have been implicated in several genetic disorders, particularly Axenfeld-Rieger syndrome. In order to determine the most reliable bioinformatics tools to assess the likely pathogenicity of PITX2 variants, the results of bioinformatics predictions were compared to the impact of variants on PITX2 structure and function. The MutPred, Provean, and PMUT bioinformatic tools were found to have the highest performance in predicting the pathogenicity effects of all 18 characterized missense variants in PITX2, all with sensitivity and specificity >93%. Applying these three programs to assess the likely pathogenicity of 13 previously uncharacterized PITX2 missense variants predicted 12/13 variants as deleterious, except A30V which was predicted as benign variant for all programs. Molecular modeling of the PITX2 homoedomain predicts that of the 31 known PITX2 variants, L54Q, F58L, V83F, V83L, W86C, W86S, and R91P alter PITX2’s structure. In contrast, the remaining 24 variants are not predicted to change PITX2’s structure. The results of molecular modeling, performed on all the PITX2 missense mutations located in the homeodomain, were compared with the findings of eight protein stability programs. CUPSAT was found to be the most reliable in predicting the effect of missense mutations on PITX2 stability. Our results showed that for PITX2, and likely other members of this homeodomain transcription factor family, MutPred, Provean, PMUT, molecular modeling, and CUPSAT can reliably be used to predict PITX2 missense variants pathogenicity. |
3,021 | Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic Candida albicans Infection | A balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminated Candida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and C. albicans is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with C. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasive C. albicans appears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67(phox). Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior to C. albicans infection. IFN-β treatment promoted pathology and death from C. albicans infection. We provide evidence that IFIT2 increases the pathological effects of invasive C. albicans and that administration of IFN-β has deleterious effects during infection. |
3,022 | Fungal infections in adult patients on extracorporeal life support | BACKGROUND: Patients on extracorporeal membrane oxygenation (ECMO) are often among the most severely ill in the intensive care unit. They are often receiving broad-spectrum antibiotics; they have multiple entry points for pathogens; and their immune system is impaired by blood circuit interaction. These factors are thought to predispose them to fungal infections. We thus aimed to evaluate the prevalence, risk factors, and prognosis of fungal infections in adults on ECMO. METHODS: We conducted a retrospective cohort study using the Extracorporeal Life Support Organization registry, which compiles data on ECMO use from hundreds of international centers. We included all adult patients from 2006 to 2016 on any mode of ECMO with either a diagnosis of fungal infection or a positive fungal culture. RESULTS: Our study comprised 2129 adult patients (10.8%) with fungal colonization or infection. Aspergillus involvement (colonization or infection) was present in 272 patients (1.4%), of whom 35.7% survived to hospital discharge. There were 245 patients (1.2%) with Candida invasive bloodstream infection, with 35.9% survival. Risk factors for Aspergillus involvement included solid organ transplant (OR 1.83; p = 0.008), respiratory support (OR 2.75; p < 0.001), and influenza infection (OR 2.48; p < 0.001). Risk factors for candidemia included sepsis (OR 1.60; p = 0.005) and renal replacement therapy (OR 1.55; p = 0.007). In multivariable analysis, Aspergillus involvement (OR 0.40; p < 0.001) and candidemia (OR 0.47; p < 0.001) were both independently associated with decreased survival. CONCLUSIONS: The prevalence of Aspergillus involvement and Candida invasive bloodstream infection were not higher in patients on ECMO than what has been reported in the general intensive care population. Both were independently associated with a reduced survival. Aspergillus involvement was strongly associated with ECMO for respiratory support and influenza. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13054-018-2023-z) contains supplementary material, which is available to authorized users. |
3,023 | Regulatory and Operational Complexities of Conducting a Clinical Treatment Trial During an Ebola Virus Disease Epidemic | The first phase II and III clinical trials for Ebola virus disease treatments were conducted during the West Africa outbreak. We report the operational practicalities of conducting a phase II clinical trial of TKM-130803 to international standards during this outbreak. |
3,024 | Review of targeted therapy in chronic lymphocytic leukemia: what a radiologist needs to know about CT interpretation | The last 5 years have been marked by profound innovation in the targeted treatment of chronic lymphocytic leukemia (CLL) and indolent lymphomas. Using CLL as a case study, we present a timeline and overview of the current treatment landscape for the radiologist, including an overview of clinical and radiological features of CLL, discussion of the targeted agents themselves, and the role of imaging in response and toxicity assessment. The goal is to familiarize the radiologist with multiple Food and Drug Administration (FDA)-approved targeted agents used in this setting and associated adverse events which are commonly observed in this patient population. |
3,025 | Comparison of Respiratory Pathogen Detection in Upper versus Lower Respiratory Tract Samples Using the BioFire FilmArray Respiratory Panel in the Immunocompromised Host | BACKGROUND: The FilmArray Respiratory Panel (FARP) (BioFire Diagnostics, Inc.) is a multiplex, polymerase chain reaction (PCR) technique that can detect 17 respiratory viruses and 3 bacterial targets in a single reaction. Immunocompromised hosts (ICH) with respiratory illnesses often undergo bronchoscopy with bronchoalveolar lavage (BAL). This prospective study aimed to evaluate the yield and concordance of NP and BAL FARP testing when performed on the same patient concurrently. METHODS: From February to December 2016, 125 patients (100 ICH and 25 non-ICH) were enrolled. NP swabs and BAL samples were sent for FARP testing. RESULTS: The yield of the BAL FARP among ICH and non-ICH was 24% (24/100) and 8% (2/25), respectively. The yield of positive NP swabs in ICH was 27% (27/100) versus 4% (1/25) in non-ICH. The majority of patients (89%; 111/125) had concordant results between NP and BAL specimens. Of the 24 ICH patients who had a positive BAL FARP, the majority (79%) had the same pathogen detected from the NP swab. CONCLUSION: The FARP may be useful in the ICH. Given the high concordance, in patients whom a pathogen is identified on the NP FARP, a FARP performed on BAL will likely yield the same result. However, if the NP FARP is negative, performing the test on a BAL sample may have an incremental yield. |
3,026 | Respiratory syncytial virus evaluation among asymptomatic and symptomatic subjects in a university hospital in Sao Paulo, Brazil, in the period of 2009‐2013 | BACKGROUND: The respiratory syncytial virus (RSV) is recognized as an important cause of respiratory tract infections. Immunocompromised patients, healthcare workers (HCWs) and children contacts are at increased risk of acquiring the infection. However, the impact of asymptomatic infection in transmission has not been well studied. Objectives: this study evaluated the frequency and viral load (VL) of RSV in nasal swab samples of individuals with different risk factors for acquiring infection in a university hospital in Sao Paulo, Brazil. METHODS: We included 196 symptomatic children and their 192 asymptomatic caregivers, 70 symptomatic and 95 asymptomatic HCWs, 43 samples from symptomatic HIV‐positive outpatients, and 100 samples of asymptomatic HIV patients in the period of 2009‐2013. RESULTS: RSV infection was detected in 10.1% (70/696) of samples, 4.4% (17/387) of asymptomatic patients, and 17.1% (53/309) from symptomatic patients. (P < .0001). The VL of symptomatic patients (4.7 log copies/mL) was significantly higher compared to asymptomatic patients (2.3 log copies/mL). RSV detection among asymptomatic caregivers (6.8%; 13/192) was significantly higher compared to other asymptomatic adults, HIV and HCWs (2.0%; 4/195; P = .0252). A close contact with an infected child at home was an important risk to RSV acquisition [OR 22.6 (95% CI 4.8‐106.7)]. Children who possibly transmitted the virus to their asymptomatic contacts had significantly higher viral load than children who probably did not transmit (P < .0001). CONCLUSIONS: According to our results, it is important to know if people circulating inside the hospital have close contact with acute respiratory infected children. |
3,027 | Treatment of Paraquat-Induced Lung Injury With an Anti-C5a Antibody: Potential Clinical Application* | OBJECTIVES: Complement activation product C5a plays a critical role in systemic inflammatory response syndrome induced by viruses, bacteria, and toxic agents including paraquat poisoning. This study is to explore the efficiency of anti-C5a–based intervention on systemic inflammatory responses induced by paraquat poisoning. DESIGN: Study of cynomolgus macaque model and plasma from paraquat-poisoning patients. SETTING: Laboratory investigation. SUBJECTS: Cynomolgus macaque (n = 12) and samples of plasma from patients (n = 16). INTERVENTIONS: The neutralizing antihuman C5a antibody (IFX-1) was administered to investigate the new treatment strategy for paraquat-induced systemic inflammatory responses in cynomolgus macaque model. In addition, C5a activation in plasma of paraquat patients was blocked by IFX-1 to investigate the blockade role of anti-C5a antibody in activation of inflammatory cells. MEASUREMENTS AND MAIN RESULTS: Dysregulated complement activation and the subsequent cytokine storm were found in patients with acute lung injury and in a primate model of paraquat poisoning. Targeted inhibition of C5a by IFX-1 led to marked alleviation of systemic inflammatory responses and multiple organ damage in the primate model. In addition, blockade of C5a activity in plasma from patients completely inhibited activation of CD11b on blood granulocytes from normal donors, suggesting that IFX-1 may alleviate the excessive activation of inflammatory responses and have clinical utility for patients with acute lung injury. CONCLUSIONS: Anti-C5a antibodies such as IFX-1 may be used as effective therapeutics for treatment of those suffering from systemic inflammatory responses induced by chemical poisoning like paraquat. |
3,028 | Development of a quantitative loop-mediated isothermal amplification assay for the field detection of Erysiphe necator | Plant pathogen detection systems have been useful tools to monitor inoculum presence and initiate management schedules. More recently, a loop-mediated isothermal amplification (LAMP) assay was successfully designed for field use in the grape powdery mildew pathosystem; however, false negatives or false positives were prevalent in grower-conducted assays due to the difficulty in perceiving the magnesium pyrophosphate precipitate at low DNA concentrations. A quantitative LAMP (qLAMP) assay using a fluorescence resonance energy transfer-based probe was assessed by grape growers in the Willamette Valley of Oregon. Custom impaction spore samplers were placed at a research vineyard and six commercial vineyard locations, and were tested bi-weekly by the lab and by growers. Grower-conducted qLAMP assays used a beta-version of the Smart-DART handheld LAMP reaction devices (Diagenetix, Inc., Honolulu, HI, USA), connected to Android 4.4 enabled, Bluetooth-capable Nexus 7 tablets for output. Quantification by a quantitative PCR assay was assumed correct to compare the lab and grower qLAMP assay quantification. Growers were able to conduct and interpret qLAMP results; however, the Erysiphe necator inoculum quantification was unreliable using the beta-Smart-DART devices. The qLAMP assay developed was sensitive to one spore in early testing of the assay, but decreased to >20 spores by the end of the trial. The qLAMP assay is not likely a suitable management tool for grape powdery mildew due to losses in sensitivity and decreasing costs and portability for other, more reliable molecular tools. |
3,029 | Volatile fingerprinting of human respiratory viruses from cell culture | Volatile metabolites are currently under investigation as potential biomarkers for the detection and identification of pathogenic microorganisms, including bacteria, fungi, and viruses. Unlike bacteria and fungi, which produce distinct volatile metabolic signatures associated with innate differences in both primary and secondary metabolic processes, viruses are wholly reliant on the metabolic machinery of infected cells for replication and propagation. In the present study, the ability of volatile metabolites to discriminate between respiratory cells infected and uninfected with virus, in vitro, was investigated. Two important respiratory viruses, namely respiratory syncytial virus (RSV) and influenza A virus (IAV), were evaluated. Data were analyzed using three different machine learning algorithms (random forest (RF), linear support vector machines (linear SVM), and partial least squares-discriminant analysis (PLS-DA)), with volatile metabolites identified from a training set used to predict sample classifications in a validation set. The discriminatory performances of RF, linear SVM, and PLS-DA were comparable for the comparison of IAV-infected versus uninfected cells, with area under the receiver operating characteristic curves (AUROCs) between 0.78 and 0.82, while RF and linear SVM demonstrated superior performance in the classification of RSV-infected versus uninfected cells (AUROCs between 0.80 and 0.84) relative to PLS-DA (0.61). A subset of discriminatory features were assigned putative compound identifications, with an overabundance of hydrocarbons observed in both RSV- and IAV-infected cell cultures relative to uninfected controls. This finding is consistent with increased oxidative stress, a process associated with viral infection of respiratory cells. |
3,030 | Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone | Discriminating sterile inflammation from infection, especially in cases of aseptic loosening versus an actual prosthetic joint infection, is challenging and has significant treatment implications. Our goal was to evaluate a novel human monoclonal antibody (mAb) probe directed against the Gram-positive bacterial surface molecule lipoteichoic acid (LTA). Specificity and affinity were assessed in vitro. We then radiolabeled the anti-LTA mAb and evaluated its effectiveness as a diagnostic imaging tool for detecting infection via immunoPET imaging in an in vivo mouse model of prosthetic joint infection (PJI). In vitro and ex vivo binding of the anti-LTA mAb to pathogenic bacteria was measured with Octet, ELISA, and flow cytometry. The in vivo PJI mouse model was assessed using traditional imaging modalities, including positron emission tomography (PET) with [(18)F]FDG and [(18)F]NaF as well as X-ray computed tomography (CT), before being evaluated with the zirconium-89-labeled antibody specific for LTA ([(89)Zr]SAC55). The anti-LTA mAb exhibited specific binding in vitro to LTA-expressing bacteria. Results from imaging showed that our model could reliably simulate infection at the surgical site by bioluminescent imaging, conventional PET tracer imaging, and bone morphological changes by CT. One day following injection of both the radiolabeled anti-LTA and isotype control antibodies, the anti-LTA antibody demonstrated significantly greater (P < 0.05) uptake at S. aureus-infected prosthesis sites over either the same antibody at sterile prosthesis sites or of control non-specific antibody at infected prosthesis sites. Taken together, the radiolabeled anti-LTA mAb, [(89)Zr]SAC55, may serve as a valuable diagnostic molecular imaging probe to help distinguish between sterile inflammation and infection in the setting of PJI. Future studies are needed to determine whether these findings will translate to human PJI. |
3,031 | Viral pneumonia in adults and older children in sub-Saharan Africa — epidemiology, aetiology, diagnosis and management | Community-acquired pneumonia causes substantial morbidity and mortality in sub-Saharan Africa with an estimated 131 million new cases each year. Viruses — such as influenza virus, respiratory syncytial virus and parainfluenza virus — are now recognised as important causes of respiratory disease in older children and adults in the developed world following the emergence of sensitive molecular diagnostic tests, recent severe viral epidemics, and the discovery of novel viruses. Few studies have comprehensively evaluated the viral aetiology of adult pneumonia in Africa, but it is likely to differ from Western settings due to varying seasonality and the high proportion of patients with immunosuppression and co-morbidities. Emerging data suggest a high prevalence of viral pathogens, as well as multiple viral and viral/bacterial infections in African adults with pneumonia. However, the interpretation of positive results from highly sensitive polymerase chain reaction tests can be challenging. Therapeutic and preventative options against viral respiratory infections are currently limited in the African setting. This review summarises the current state of the epidemiology, aetiology, diagnosis and management of viral pneumonia in sub-Saharan Africa. |
3,032 | Standardisation and evaluation of a quantitative multiplex real-time PCR assay for the rapid identification of Streptococcus pneumoniae | Rapid diagnosis of Streptococcus pneumoniae can play a significant role in decreasing morbidity and mortality of infection. The accurate diagnosis of pneumococcal disease is hampered by the difficulties in growing the isolates from clinical specimens and also by misidentification. Molecular methods have gained popularity as they offer improvement in the detection of causative pathogens with speed and ease. The present study aims at validating and standardising the use of 4 oligonucleotide primer-probe sets (pneumolysin [ply], autolysin [lytA], pneumococcal surface adhesion A [psaA] and Spn9802 [DNA fragment]) in a single-reaction mixture for the detection and discrimination of S. pneumoniae. Here, we validate a quantitative multiplex real-time PCR (qmPCR) assay with a panel consisting of 43 S. pneumoniae and 29 non-pneumococcal isolates, 20 culture positive, 26 culture negative and 30 spiked serum samples. A standard curve was obtained using S. pneumoniae ATCC 49619 strain and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene was used as an endogenous internal control. The experiment showed high sensitivity with lower limit of detection equivalent to 4 genome copies/µl. The efficiency of the reaction was 100% for ply, lytA, Spn9802 and 97% for psaA. The test showed sensitivity and specificity of 100% with culture isolates and serum specimens. This study demonstrates that qmPCR analysis of sera using 4 oligonucleotide primers appears to be an appropriate method for the genotypic identification of S. pneumoniae infection. |
3,033 | Cancer patients with community-acquired pneumonia treated in intensive care have poorer outcomes associated with increased illness severity and septic shock at admission to intensive care: a retrospective cohort study | Patients with community-acquired pneumonia (CAP) and an underlying diagnosis of cancer have worse outcomes. However, the characteristics of cancer patients with CAP admitted to intensive care units (ICUs) are not well established. In a retrospective observational study, patients admitted to a London university hospital ICU between January 2006 and October 2011 with a primary diagnosis of CAP were included. Demographic, clinical, laboratory, and outcome data were collected from the ICU and hospital pathology databases. The analysis included 96 patients with CAP, 19 of whom had an existing diagnosis of cancer. Patients with cancer had a longer median time interval between hospital and ICU admission (1 vs 2 days, p = 0.049). On admission to ICU, there were no differences in white cell count, C-reactive protein, clotting, renal function, liver function, heart rate, temperature, systolic blood pressure or oxygenation index between patients with or without cancer. However, patients with cancer had significantly lower haemoglobin levels (median 8.6 vs 10.0 g/dl, p = 0.010) and lowest diastolic blood pressure (median 40 vs 50 mmHg, p = 0.026), and higher sodium levels (median 142 vs 139 mmol/l), p = 0.020), APACHE II (median 25 vs 20, p = 0.009), SAPS II (median 51 vs 43, p = 0.039) and SOFA (median 12 vs 9, p = 0.018) scores. There were no statistically significant differences in the proportion of patients receiving mechanical ventilation or renal support, the duration of mechanical ventilation or ICU or hospital length of stay. Patients with cancer were more likely to receive vasopressors (89.5% vs 63.6%, p = 0.030) and had increased ICU (68.4% vs 31.2%, p = 0.004) and hospital (78.9% vs 33.8%, p = 0.001) mortality. The limitations of this study are its relatively small sample size and those associated with the retrospective study design. In conclusion, cancer patients with CAP had an increased risk of death that was associated with increased illness severity and prevalence of septic shock at the time of ICU admission, suggesting there may be a delay in recognition for the need for intensive care support in these patients. |
3,034 | Acute fibrinous and organising pneumonia following lung transplantation is associated with severe allograft dysfunction and poor outcome: a case series | Acute fibrinous and organising pneumonia (AFOP) is a histopathologic variant of acute lung injury that has been associated with infection and inflammatory disorders and has been reported as a complication of lung transplantation. A retrospective chart review was performed for all patients transplanted at the University of Wisconsin Hospital and Clinics from January 1995 to December 2013 (n = 561). We identified 6 recipients whose clinical course was complicated by AFOP. All recipients were found to have AFOP on lung biopsy or at post-mortem examination, and 5 of the 6 patients suffered progressive allograft dysfunction that led to fatal outcome. Only 1 of the 6 patients stabilised with augmented immunosuppression and had subsequent improvement and stabilisation of allograft function. We could not clearly identify any specific cause of AFOP, such as drug toxicity or infection. Lung transplantation can be complicated by lung injury with an AFOP pattern on histopathologic examination of lung biopsy specimens. The presence of an AFOP pattern was associated with irreversible decline in lung function that was refractory to therapeutic interventions in 5 of our 6 cases and was associated with severe allograft dysfunction and death in these 5 individuals. AFOP should be considered as a potential diagnosis when lung transplant recipients develop progressive decline in lung function that is consistent with a clinical diagnosis of chronic lung allograft dysfunction. |
3,035 | Selection and Characterization of Rupintrivir-Resistant Norwalk Virus Replicon Cells In Vitro | Human norovirus (HuNoV) is a major cause of nonbacterial gastroenteritis worldwide, yet despite its impact on society, vaccines and antivirals are currently lacking. A HuNoV replicon system has been widely applied to the evaluation of antiviral compounds and has thus accelerated the process of drug discovery against HuNoV infection. Rupintrivir, an irreversible inhibitor of the human rhinovirus 3C protease, has been reported to inhibit the replication of the Norwalk virus replicon via the inhibition of the norovirus protease. Here we report, for the first time, the generation of rupintrivir-resistant human Norwalk virus replicon cells in vitro. Sequence analysis revealed that these replicon cells contained amino acid substitutions of alanine 105 to valine (A105V) and isoleucine 109 to valine (I109V) in the viral protease NS6. The application of a cell-based fluorescence resonance energy transfer (FRET) assay for protease activity demonstrated that these substitutions were involved in the enhanced resistance to rupintrivir. Furthermore, we validated the effect of these mutations using reverse genetics in murine norovirus (MNV), demonstrating that a recombinant MNV strain with a single I109V substitution in the protease also showed reduced susceptibility to rupintrivir. In summary, using a combination of different approaches, we have demonstrated that, under the correct conditions, mutations in the norovirus protease that lead to the generation of resistant mutants can rapidly occur. |
3,036 | New Insights from Elucidating the Role of LMP1 in Nasopharyngeal Carcinoma | Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) oncogenic protein that has no intrinsic enzymatic activity or sequence homology to cellular or viral proteins. The oncogenic potential of LMP1 has been ascribed to pleiotropic signaling properties initiated through protein-protein interactions in cytosolic membrane compartments, but the effects of LMP1 extend to nuclear and extracellular processes. Although LMP1 is one of the latent genes required for EBV-immortalization of B cells, the biology of LMP1 in the pathogenesis of the epithelial cancer nasopharyngeal carcinoma (NPC) is more complex. NPC is prevalent in specific regions of the world with high incidence in southeast China. The epidemiology and time interval from seroconversion to NPC onset in adults would suggest the involvement of multiple risk factors that complement the establishment of a latent and persistent EBV infection. The contribution of LMP1 to EBV pathogenesis in polarized epithelia has only recently begun to be elucidated. Furthermore, the LMP1 gene has emerged as one of the most divergent sequences in the EBV genome. This review will discuss the significance of recent advances in NPC research from elucidating LMP1 function in epithelial cells and lessons that could be learned from mining LMP1 sequence diversity. |
3,037 | Identification of Ellagic Acid from Plant Rhodiola rosea L. as an Anti-Ebola Virus Entry Inhibitor | The recent 2014–2016 West African Ebola virus epidemic underscores the need for the development of novel anti-Ebola therapeutics, due to the high mortality rates of Ebola virus infections and the lack of FDA-approved vaccine or therapy that is available for the prevention and treatment. Traditional Chinese medicines (TCMs) represent a huge reservoir of bioactive chemicals and many TCMs have been shown to have antiviral activities. 373 extracts from 128 TCMs were evaluated using a high throughput assay to screen for inhibitors of Ebola virus cell entry. Extract of Rhodiola rosea displayed specific and potent inhibition against cell entry of both Ebola virus and Marburg virus. In addition, twenty commercial compounds that were isolated from Rhodiola rosea were evaluated using the pseudotyped Ebola virus entry assay, and it was found that ellagic acid and gallic acid, which are two structurally related compounds, are the most effective ones. The activity of the extract and the two pure compounds were validated using infectious Ebola virus. The time-of-addition experiments suggest that, mechanistically, the Rhodiola rosea extract and the effective compounds act at an early step in the infection cycle following initial cell attachment, but prior to viral/cell membrane fusion. Our findings provide evidence that Rhodiola rosea has potent anti-filovirus properties that may be developed as a novel anti-Ebola treatment. |
3,038 | Imaging, Tracking and Computational Analyses of Virus Entry and Egress with the Cytoskeleton | Viruses have a dual nature: particles are “passive substances” lacking chemical energy transformation, whereas infected cells are “active substances” turning-over energy. How passive viral substances convert to active substances, comprising viral replication and assembly compartments has been of intense interest to virologists, cell and molecular biologists and immunologists. Infection starts with virus entry into a susceptible cell and delivers the viral genome to the replication site. This is a multi-step process, and involves the cytoskeleton and associated motor proteins. Likewise, the egress of progeny virus particles from the replication site to the extracellular space is enhanced by the cytoskeleton and associated motor proteins. This overcomes the limitation of thermal diffusion, and transports virions and virion components, often in association with cellular organelles. This review explores how the analysis of viral trajectories informs about mechanisms of infection. We discuss the methodology enabling researchers to visualize single virions in cells by fluorescence imaging and tracking. Virus visualization and tracking are increasingly enhanced by computational analyses of virus trajectories as well as in silico modeling. Combined approaches reveal previously unrecognized features of virus-infected cells. Using select examples of complementary methodology, we highlight the role of actin filaments and microtubules, and their associated motors in virus infections. In-depth studies of single virion dynamics at high temporal and spatial resolutions thereby provide deep insight into virus infection processes, and are a basis for uncovering underlying mechanisms of how cells function. |
3,039 | Full-Genome Characterization and Genetic Evolution of West African Isolates of Bagaza Virus | Bagaza virus is a mosquito-borne flavivirus, first isolated in 1966 in Central African Republic. It has currently been identified in mosquito pools collected in the field in West and Central Africa. Emergence in wild birds in Europe and serological evidence in encephalitis patients in India raise questions on its genetic evolution and the diversity of isolates circulating in Africa. To better understand genetic diversity and evolution of Bagaza virus, we describe the full-genome characterization of 11 West African isolates, sampled from 1988 to 2014. Parameters such as genetic distances, N-glycosylation patterns, recombination events, selective pressures, and its codon adaptation to human genes are assessed. Our study is noteworthy for the observation of N-glycosylation and recombination in Bagaza virus and provides insight into its Indian origin from the 13th century. Interestingly, evidence of Bagaza virus codon adaptation to human house-keeping genes is also observed to be higher than those of other flaviviruses well known in human infections. Genetic variations on genome of West African Bagaza virus could play an important role in generating diversity and may promote Bagaza virus adaptation to other vertebrates and become an important threat in human health. |
3,040 | Interferon Independent Non-Canonical STAT Activation and Virus Induced Inflammation | Interferons (IFNs) are a group of secreted proteins that play critical roles in antiviral immunity, antitumor activity, activation of cytotoxic T cells, and modulation of host immune responses. IFNs are cytokines, and bind receptors on cell surfaces to trigger signal transduction. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, a complex pathway involved in both viral and host survival strategies. On the one hand, viruses have evolved strategies to escape from antiviral host defenses evoked by IFN-activated JAK/STAT signaling. On the other hand, viruses have also evolved to exploit the JAK/STAT pathway to evoke activation of certain STATs that somehow promote viral pathogenesis. In this review, recent progress in our understanding of the virus-induced IFN-independent STAT signaling and its potential roles in viral induced inflammation and pathogenesis are summarized in detail, and perspectives are provided. |
3,041 | Role of the ERK1/2 Signaling Pathway in the Replication of Junín and Tacaribe Viruses | We have previously shown that the infection of cell cultures with the arenaviruses Junín (JUNV), Tacaribe (TCRV), and Pichindé promotes the phosphorylation of mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinases 1 and 2 (ERK1/2) and that this activation is required for the achievement of a productive infection. Here we examined the contribution of ERK1/2 in early steps of JUNV and TCRV multiplication. JUNV adsorption, internalization, and uncoating were not affected by treatment of cultured cells with U0126, an inhibitor of the ERK1/2 signaling pathway. In contrast, U0126 caused a marked reduction in viral protein expression and RNA synthesis, while JUNV RNA synthesis was significantly augmented in the presence of an activator of the ERK1/2 pathway. Moreover, U0126 impaired the expression of a reporter gene in a TCRV-based replicon system, confirming the ability of the compound to hinder arenavirus macromolecular synthesis. By using a cell-based assay, we determined that the inhibitor did not affect the translation of a synthetic TCRV-like mRNA. No changes in the phosphorylation pattern of the translation factor eIF2α were found in U0126-treated cells. Our results indicate that U0126 impairs viral RNA synthesis, thereby leading to a subsequent reduction in viral protein expression. Thus, we conclude that ERK1/2 signaling activation is required for an efficient arenavirus RNA synthesis. |
3,042 | Overview of Virus Metagenomic Classification Methods and Their Biological Applications | Metagenomics poses opportunities for clinical and public health virology applications by offering a way to assess complete taxonomic composition of a clinical sample in an unbiased way. However, the techniques required are complicated and analysis standards have yet to develop. This, together with the wealth of different tools and workflows that have been proposed, poses a barrier for new users. We evaluated 49 published computational classification workflows for virus metagenomics in a literature review. To this end, we described the methods of existing workflows by breaking them up into five general steps and assessed their ease-of-use and validation experiments. Performance scores of previous benchmarks were summarized and correlations between methods and performance were investigated. We indicate the potential suitability of the different workflows for (1) time-constrained diagnostics, (2) surveillance and outbreak source tracing, (3) detection of remote homologies (discovery), and (4) biodiversity studies. We provide two decision trees for virologists to help select a workflow for medical or biodiversity studies, as well as directions for future developments in clinical viral metagenomics. |
3,043 | Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema | Acute exacerbation (AE) is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF). In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF. |
3,044 | Nucleolar-nucleoplasmic shuttling of TARG1 and its control by DNA damage-induced poly-ADP-ribosylation and by nucleolar transcription | Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors. TARG1 localized to transcriptionally active nucleoli, which occurred independently of ADP-ribose binding. TARG1 shuttled continuously between nucleoli and nucleoplasm. In response to DNA damage, which activates ARTD1/2 (PARP1/2) and promotes synthesis of poly-ADP-ribose chains, TARG1 re-localized to the nucleoplasm. This was dependent on the ability of TARG1 to bind to poly-ADP-ribose. These findings are consistent with the observed ability of TARG1 to competitively interact with RNA and PAR chains. We propose a nucleolar role of TARG1 in ribosome assembly or quality control that is stalled when TARG1 is re-located to sites of DNA damage. |
3,045 | A Combined Syndromic Approach to Examine Viral, Bacterial, and Parasitic Agents among Febrile Patients: A Pilot Study in Kilombero, Tanzania | The use of fever syndromic surveillance in sub-Saharan Africa is an effective approach to determine the prevalence of both malarial and nonmalarial infectious agents. We collected both blood and naso/oro-pharyngeal (NP/OP) swabs from consecutive consenting patients ≥ 1 year of age, with an axillary temperature ≥ 37.5°C, and symptom onset of ≤ 5 days. Specimens were analyzed using both acute febrile illness (AFI) and respiratory TaqMan array cards (Resp TAC) for multiagent detection of 56 different bloodstream and respiratory agents. In addition, we collected epidemiologic data to further characterize our patient population. We enrolled 205 febrile patients, including 70 children (1 < 15 years of age; 34%) and 135 adults (≥ 15 years of age; 66%). AFI TAC and Resp TAC were performed on 191 whole blood specimens and 115 NP/OP specimens, respectively. We detected nucleic acid for Plasmodium (57%), Leptospira (2%), and dengue virus (1%) among blood specimens. In addition, we detected 17 different respiratory agents, most notably, Haemophilus influenzae (64%), Streptococcus pneumonia (56%), Moraxella catarrhalis (39%), and respiratory syncytial virus (11%) among NP/OP specimens. Overall median cycle threshold was measured at 26.5. This study provides a proof-of-concept for the use of a multiagent diagnostic approach for exploratory research on febrile illness and underscores the utility of quantitative molecular diagnostics in complex epidemiologic settings of sub-Saharan Africa. |
3,046 | Generalists and Specialists: A New View of How MHC Class I Molecules Fight Infectious Pathogens | In comparison with the major histocompatibility complexes (MHCs) of typical mammals, the chicken MHC is simple and compact with a single dominantly expressed class I molecule that can determine the immune response. In addition to providing useful information for the poultry industry and allowing insights into the evolution of the adaptive immune system, the simplicity of the chicken MHC has allowed the discovery of phenomena that are more difficult to discern in the more complicated mammalian systems. This review discusses the new concept that poorly expressed promiscuous class I alleles act as generalists to protect against a wide variety of infectious pathogens, while highly expressed fastidious class I alleles can act as specialists to protect against new and dangerous pathogens. |
3,047 | Outpatient Infection Prevention: A Practical Primer | As more patients seek care in the outpatient setting, the opportunities for health care–acquired infections and associated outbreaks will increase. Without uptake of core infection prevention and control strategies through formal initiation of infection prevention programs, outbreaks and patient safety issues will surface. This review provides a step-wise approach for implementing an outpatient infection control program, highlighting some of the common pitfalls and high-priority areas. |
3,048 | Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss | Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. Results We identified a cosegregating heterozygous missense mutation, c.296G>A (p.Arg99His) in the gene encoding interferon lambda receptor 1 (IFNLR1) – a protein that functions in the Jak/ STAT pathway– are associated with ADNSHL. Morpholino knockdown of ifnlr1 leads to a significant decrease in hair cells and non-inflation of the swim bladder in late-stage zebrafish, which can be reversed by injection with normal Zebrafish ifnlr1 mRNA. Knockdown of ifnlr1 in zebrafish causes significant upregulation of cytokine receptor family member b4 (interleukin-10r2), jak1, tyrosine kinase 2, stat3, and stat5b in the Jak1/STAT3 pathway at the mRNA level. Conclusion IFNLR1 function is required in the auditory system and that IFNLR1 mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function. |
3,049 | Clinical and Molecular Epidemiology of Human Parainfluenza Viruses 1–4 in Children from Viet Nam | HPIVs are serologically and genetically grouped into four species that account for up to 10% of all hospitalizations due to acute respiratory infection in children under the age of five. Genetic and epidemiological data for the four HPIVs derived from two pediatric cohorts in Viet Nam are presented. Respiratory samples were screened for HPIV1–4 by real-time PCR. Demographic and clinical data of patients infected with different HPIV were compared. We used a hemi-nested PCR approach to generate viral genome sequences from HPIV-positive samples and conducted a comprehensive phylogenetic analysis. In total, 170 samples tested positive for HPIV. HPIV3 was most commonly detected in our cohort and 80 co-detections of HPIV with other respiratory viruses were found. Phylogenetic analyses suggest local endemic circulation as well as punctuated introductions of new HPIV lineages. Viral gene flow analysis revealed that Viet Nam is a net importer of viral genetic diversity. Epidemiological analyses imply similar disease severity for all HPIV species. HPIV sequences from Viet Nam formed local clusters and were interspersed with sequences from diverse geographic regions. Combined, this new knowledge will help to investigate global HPIV circulation patterns in more detail and ultimately define more suitable vaccine strains. |
3,050 | Exploring Leptospiral proteomes to identify potential candidates for vaccine design against Leptospirosis using an immunoinformatics approach | Leptospirosis is the most widespread zoonotic disease, estimated to cause severe infection in more than one million people each year, particularly in developing countries of tropical areas. Several factors such as variable and nonspecific clinical manifestation, existence of large number of serovars and asymptomatic hosts spreading infection, poor sanitation and lack of an effective vaccine make prophylaxis difficult. Consequently, there is an urgent need to develop an effective vaccine to halt its spread all over the world. In this study, an immunoinformatics approach was employed to identify the most vital and effective immunogenic protein from the proteome of Leptospira interrogans serovar Copenhageni strain L1-130 that may be suitable to stimulate a significant immune response aiding in the development of peptide vaccine against leptospirosis. Both B-cell and T-cell (Helper T-lymphocyte (HTL) and cytotoxic T lymphocyte (CTL)) epitopes were predicted for the conserved and most immunogenic outer membrane lipoprotein. Further, the binding interaction of CTL epitopes with Major Histocompatibility Complex class I (MHC-I) was evaluated using docking techniques. A Molecular Dynamics Simulation study was also performed to evaluate the stability of the resulting epitope-MHC-I complexes. Overall, this study provides novel vaccine candidates and may prompt further development of vaccines against leptospirosis. |
3,051 | Ebolaviruses: New roles for old proteins | In 2014, the world witnessed the largest Ebolavirus outbreak in recorded history. The subsequent humanitarian effort spurred extensive research, significantly enhancing our understanding of ebolavirus replication and pathogenicity. The main functions of each ebolavirus protein have been studied extensively since the discovery of the virus in 1976; however, the recent expansion of ebolavirus research has led to the discovery of new protein functions. These newly discovered roles are revealing new mechanisms of virus replication and pathogenicity, whilst enhancing our understanding of the broad functions of each ebolavirus viral protein (VP). Many of these new functions appear to be unrelated to the protein’s primary function during virus replication. Such new functions range from bystander T-lymphocyte death caused by VP40-secreted exosomes to new roles for VP24 in viral particle formation. This review highlights the newly discovered roles of ebolavirus proteins in order to provide a more encompassing view of ebolavirus replication and pathogenicity. |
3,052 | Towards the Application of Human Defensins as Antivirals | Defensins are antimicrobial peptides that participate in the innate immunity of hosts. Humans constitutively and/or inducibly express α- and β-defensins, which are known for their antiviral and antibacterial activities. This review describes the application of human defensins. We discuss the extant experimental results, limited though they are, to consider the potential applicability of human defensins as antiviral agents. Given their antiviral effects, we propose that basic research be conducted on human defensins that focuses on RNA viruses, such as human immunodeficiency virus (HIV), influenza A virus (IAV), respiratory syncytial virus (RSV), and dengue virus (DENV), which are considered serious human pathogens but have posed huge challenges for vaccine development for different reasons. Concerning the prophylactic and therapeutic applications of defensins, we then discuss the applicability of human defensins as antivirals that has been demonstrated in reports using animal models. Finally, we discuss the potential adjuvant-like activity of human defensins and propose an exploration of the ‘defensin vaccine’ concept to prime the body with a controlled supply of human defensins. In sum, we suggest a conceptual framework to achieve the practical application of human defensins to combat viral infections. |
3,053 | Microbiota epitope similarity either dampens or enhances the immunogenicity of disease-associated antigenic epitopes | The microbiome influences adaptive immunity and molecular mimicry influences T cell reactivity. Here, we evaluated whether the sequence similarity of various antigens to the microbiota dampens or increases immunogenicity of T cell epitopes. Sets of epitopes and control sequences derived from 38 antigenic categories (infectious pathogens, allergens, autoantigens) were retrieved from the Immune Epitope Database (IEDB). Their similarity to microbiome sequences was calculated using the BLOSUM62 matrix. We found that sequence similarity was associated with either dampened (tolerogenic; e.g. most allergens) or increased (inflammatory; e.g. Dengue and West Nile viruses) likelihood of a peptide being immunogenic as a function of epitope source category. Ten-fold cross-validation and validation using sets of manually curated epitopes and non-epitopes derived from allergens were used to confirm these initial observations. Furthermore, the genus from which the microbiome homologous sequences were derived influenced whether a tolerogenic versus inflammatory modulatory effect was observed, with Fusobacterium most associated with inflammatory influences and Bacteroides most associated with tolerogenic influences. We validated these effects using PBMCs stimulated with various sets of microbiome peptides. “Tolerogenic” microbiome peptides elicited IL-10 production, “inflammatory” peptides elicited mixed IL-10/IFNγ production, while microbiome epitopes homologous to self were completely unreactive for both cytokines. We also tested the sequence similarity of cockroach epitopes to specific microbiome sequences derived from households of cockroach allergic individuals and non-allergic controls. Microbiomes from cockroach allergic households were less likely to contain sequences homologous to previously defined cockroach allergens. These results are compatible with the hypothesis that microbiome sequences may contribute to the tolerization of T cells for allergen epitopes, and lack of these sequences might conversely be associated with increased likelihood of T cell reactivity against the cockroach epitopes. Taken together this study suggests that microbiome sequence similarity influences immune reactivity to homologous epitopes encoded by pathogens, allergens and auto-antigens. |
3,054 | Clinical study of children with cryofibrinogenemia: a retrospective study from a single center | BACKGROUND: This study aimed to evaluate the demographic, clinical features, laboratory data, pathology and other survey in pediatric patients with cryofibrinogenemia. METHODS: A 12-year retrospective chart review identified eight pediatric patients at Mackay Memorial Hospital, Taipei, Taiwan. RESULTS: The female-to-male ratio was 3:1. The mean age at symptom onset and of diagnosis was 10.3 ± 4.6 years and 12.3 ± 4 years, respectively. One child (12.5%) had primary cryofibrinogenemia. The common symptoms were purpura, arthralgia, and muscle weakness (100%). On laboratory examination, cryofibrinogen was positive in all patients. All patients had increased anti-thrombin III while 87.5% and 62.5% had abnormal protein S and protein C, respectively. All eight also complained of neurologic symptoms. One had vertebral artery narrowing, two showed increased T2-weighted signal intensity on the thalamus or white matter, and one had acute hemorrhagic encephalomyelitis on brain magnetic resonance imaging. CONCLUSIONS: This study reports on the presentations of cryofibrinogenemia, which is rare in children. Most cases are associated with autoimmune disease and have severe and complex presentations. Central nervous system involvement is common. |
3,055 | Low acclimation capacity of narrow‐ranging thermal specialists exposes susceptibility to global climate change | Thermal acclimation is hypothesized to offer a selective advantage in seasonal habitats and may underlie disparities in geographic range size among closely‐related species with similar ecologies. Understanding this relationship is also critical for identifying species that are more sensitive to warming climates. Here, we study North American plethodontid salamanders to investigate whether acclimation ability is associated with species’ latitudinal extents and the thermal range of the environments they inhabit. We quantified variation in thermal physiology by measuring standard metabolic rate (SMR) at different test and acclimation temperatures for 16 species of salamanders with varying latitudinal extents. A phylogenetically‐controlled Markov chain Monte Carlo generalized linear mixed model (MCMCglmm) was then employed to determine whether there are differences in SMR between wide‐ and narrow‐ranging species at different acclimation temperatures. In addition, we tested for a relationship between the acclimation ability of species and the environmental temperature ranges they inhabit. Further, we investigated if there is a trade‐off between critical thermal maximum (CTMax) and thermal acclimation ability. MCMCglmm results show a significant difference in acclimation ability between wide and narrow‐ranging temperate salamanders. Salamanders with wide latitudinal distributions maintain or slightly increase SMR when subjected to higher test and acclimation temperatures, whereas several narrow‐ranging species show significant metabolic depression. We also found significant, positive relationships between acclimation ability and environmental thermal range, and between acclimation ability and CTMax. Wide‐ranging salamander species exhibit a greater capacity for thermal acclimation than narrow‐ranging species, suggesting that selection for acclimation ability may have been a key factor enabling geographic expansion into areas with greater thermal variability. Further, given that narrow‐ranging salamanders are found to have both poor acclimation ability and lower tolerance to warm temperatures, they are likely to be more susceptible to environmental warming associated with anthropogenic climate change. |
3,056 | Predictors of In-Hospital Mortality among Patients with Pulmonary Tuberculosis: A Systematic Review and Meta-analysis | Background: There is uncertainty regarding which factors are associated with in-hospital mortality among patients with pulmonary TB (PTB). The aim of this systematic review and meta-analysis is to identify predictors of in-hospital mortality among patients with PTB. Methods: We searched MEDLINE, EMBASE, and Global Health, for cohort and case-control studies that reported risk factors for in-hospital mortality in PTB. We pooled all factors that were assessed for an association, and presented relative associations as pooled odds ratios (ORs). Results: We identified 2,969 records, of which we retrieved 51 in full text; 11 cohort studies that evaluated 5,468 patients proved eligible. Moderate quality evidence suggested an association with co-morbid malignancy and in-hospital mortality (OR 1.85; 95% CI 1.01–3.40). Low quality evidence showed no association with positive sputum smear (OR 0.99; 95% CI 0.40–2.48), or male sex (OR 1.09, 95% CI 0.84–1.41), and very low quality evidence showed no association with diabetes mellitus (OR 1.31, 95% IC 0.38–4.46), and previous TB infection (OR 2.66, 95% CI 0.48–14.87). Conclusion: Co-morbid malignancy was associated with increased risk of in-hospital death among pulmonary TB patients. There is insufficient evidence to confirm positive sputum smear, male sex, diabetes mellitus, and previous TB infection as predictors of in-hospital mortality in TB patients. |
3,057 | Mental health of nurses after the Fukushima complex disaster: a narrative review | Work-related mental health impairment is recognized as a real problem in the context of helping responders, including health professionals, due to adverse health outcomes after a severe disaster. The Great East-Japan Earthquake, which occurred on 11 March 2011, was an unprecedented complex disaster that caused a nuclear accident at the Fukushima Daiichi Nuclear Power Plant (NPP). In addition to disaster stress and daily work, medical and health-care professionals, particularly nurses, provided counseling services to residents concerned about radiation health risks or mental health issues. This review focuses on the psychological aspects of the complex nuclear disaster, which was a combined artificial nuclear accident and natural disaster, and we investigated the psychological effects on hospital nurses associated with their experiences during the disaster. We looked at several investigations into the mental health of nurses after a nuclear disaster and in other situations. It was shown that mental health of nurses is impacted, not only after nuclear disasters but also in other circumstances. Furthermore, we noted the effects of extended periods of a heavy workload and daily life. Regarding anxiety about radiation exposure, nurses who had more knowledge of radiation tended to have better mental health, suggesting that education about the health risks of radiation exposure is important for health-care professionals. In summary, it is essential that nurses are provided with education about radiation exposure and its associated health risks, and also that there is a comprehensive approach to mental health care for nurses during the chronic phase of a disaster. |
3,058 | Differential Regulation of Toll-Like Receptor-Mediated Cytokine Production by Unfolded Protein Response | The ability of the host immune response is largely mediated by the proinflammatory cytokine production. Physiological and pathological conditions of endoplasmic reticulum (ER) trigger unfolded protein response and contribute to the development or pathology of inflammatory diseases. Under ER stress, unfolded protein response (UPR) signaling pathways participate in upregulating inflammatory cytokine production via NF-kappaB, MAPK, and GSK-3β. Moreover, it has been suggested that ER stress crosstalks with toll-like receptor (TLR) signaling pathway to promote the production of proinflammatory cytokines. In addition, TLR stimulation can lead to UPR activation to promote inflammation. In this review, we will cover how proinflammatory cytokine production by UPR signaling can be induced or amplified in the presence or absence of TLR activation. |
3,059 | Recyclable Keggin Heteropolyacids as an Environmentally Benign Catalyst for the Synthesis of New 2-Benzoylamino-N-phenyl-benzamide Derivatives under Microwave Irradiations at Solvent-Free Conditions and the Evaluation of Biological Activity | 2-Benzoylamino-N-phenyl-benzamide derivatives (5a–h) were prepared from 2-phenyl-3,1-(4H)-benzoxazin-4-one 3 and substituted anilines 4a–h in the presence of a Keggin-type heteropolyacids series (H(3)PW(12)O(40)·13H(2)O; H(4)SiW(12)O(40)·13H(2)O; H(4)SiMo(12)O(40)·13H(2)O; and H(3)PMo(12)O(40)·13H(2)O) as catalysts without solvent and under microwave irradiation. We found that the use of H(3)PW(12)O(40)·13H(2)O acid coupled to microwave irradiation allowed obtaining a high-yielding reaction with a short time. The compound structures were established by (1)H-NMR and (13)C-NMR. The antibacterial and antifungal activities of the synthesized compounds exhibited an inhibition of the growth of bacteria and fungi. |
3,060 | Beyond molecular tumor heterogeneity: protein synthesis takes control | One of the daunting challenges facing modern medicine lies in the understanding and treatment of tumor heterogeneity. Most tumors show intra-tumor heterogeneity at both genomic and proteomic levels, with marked impacts on the responses of therapeutic targets. Therapeutic target-related gene expression pathways are affected by hypoxia and cellular stress. However, the finding that targets such as eukaryotic initiation factor (eIF) 4E (and its phosphorylated form, p-eIF4E) are generally homogenously expressed throughout tumors, regardless of the presence of hypoxia or other cellular stress conditions, opens the exciting possibility that malignancies could be treated with therapies that combine targeting of eIF4E phosphorylation with immune checkpoint inhibitors or chemotherapy. |
3,061 | Potential mechanism and drug candidates for sepsis-induced acute lung injury | The present study aimed to explore the mechanisms underlying sepsis-induced acute lung injury (ALI) and identify more effective therapeutic strategies to treat it. The gene expression data set GSE10474 was downloaded and assessed to identify differentially expressed genes (DEGs). Principal component analysis, functional enrichment analysis and differential co-expression analysis of DEGs were performed. Furthermore, potential target drugs for key DEGs were assessed. A total of 209 DEGs, including 107 upregulated and 102 downregulated genes were screened. A number of DEGs, including zinc finger and BTB domain containing 17 (ZBTB17), heat shock protein 90 kDa β, member 1 (HSP90B1) and major histocompatibility complex, class II, DR α were identified. Furthermore, gene ontology terms including antigen processing and presentation, glycerophospholipid metabolism, transcriptional misregulation in cancer, thyroid hormone synthesis and pathways associated with diseases, such as asthma were identified. In addition, a differential co-expression network containing ubiquitin-conjugating enzyme E2 D4, putative and tubulin, γ complex associated protein 3 was constructed. Furthermore, a number of gene-drug interactions, including between HSP90B1 and adenosine-5′-diphosphate and radicicol, were identified. Therefore, DEGs, including ZBTB17 and HSP90B1, may be important in the pathogenesis of sepsis-induced ALI. Furthermore, drugs including adenosine-5′-diphosphate may be novel drug candidates to treat patients with ALI. |
3,062 | Synthesis and In vitro Leishmanicidal Activities of Six Quercetin Derivatives | BACKGROUND: Today, leishmaniasis is a widespread, infectious parasitic disease caused by Leishmania spp. Natural-derived compounds are likely to provide a valuable source of new pharmaceuticals, and among them, quercetin derivatives may have antileishmanial effects. The antileishmanial activity of 3,5,7,3’,4’-pentahydroxyflavonol (quercetin) derivatives is partly attributed to the position and pKa of phenolic or catechol hydroxyl groups. Therefore, to optimize their leishmanicidal effect, the structural features of quercetin and its derivatives were improved by acylation or alkylation of hydroxyl groups and changing their pKa and consequently their activities. MATERIALS AND METHODS: In this study, during a regioselective method, quercetin derivatives were synthesized. The structures of synthesized compounds were confirmed by mass, IR, (1)H-, and (13)C-NMR spectral data. The antileishmanial activities of compounds 1–6 were compared with glucantime as the standard drug against promastigotes of Leishmania major using standard cell-based leishmanicidal assay. RESULTS: In this study, during a regioselective method, two 7-O-quercetin derivatives (5 and 6), and three quercetin acetate derivatives (2, 3, and 4) were synthesized. In detail, the IC(50) values found against L. major were (1) 2.5 ± 0.92; (2) 2.85 ± 0.99; (3) 15.5 ± 1.95; (4) 13.5 ± 3.5; (5) 2.6 ± 0.57; and (6) 1.3 ± 0.35 μM while IC(50) value of glucantime as the standard drug was 88.5 ± 9.47 μM. CONCLUSIONS: The present study showed an effective antileishmanial activity of quercetin semisynthetic compounds (1–6) against in vitro promastigotes of L. major. Among them, quercetin analogs with more lipophilic and iron-chelating activity showed more antiparasite activity. |
3,063 | Development of a cell-based assay to identify hepatitis B virus entry inhibitors targeting the sodium taurocholate cotransporting polypeptide | Sodium taurocholate cotransporting polypeptide (NTCP) is a major entry receptor of hepatitis B virus (HBV) and one of the most attractive targets for anti-HBV drugs. We developed a cell-mediated drug screening method to monitor NTCP expression on the cell surface by generating a HepG2 cell line with tetracycline-inducible expression of NTCP and a monoclonal antibody that specifically detects cell-surface NTCP. Using this system, we screened a small molecule library for compounds that protected against HBV infection by targeting NTCP. We found that glabridin, a licorice-derived isoflavane, could suppress viral infection by inducing caveolar endocytosis of cell-surface NTCP with an IC(50) of ~40 μM. We also found that glabridin could attenuate the inhibitory effect of taurocholate on type I interferon signaling by depleting the level of cell-surface NTCP. These results demonstrate that our screening system could be a powerful tool for discovering drugs targeting HBV entry. |
3,064 | Progression of the Radiologic Severity Index predicts mortality in patients with parainfluenza virus-associated lower respiratory infections | BACKGROUND: Radiologic severity may predict adverse outcomes after lower respiratory tract infection (LRI). However, few studies have quantified radiologic severity of LRIs. We sought to evaluate whether a semi-quantitative scoring tool, the Radiologic Severity Index (RSI), predicted mortality after parainfluenza virus (PIV)-associated LRI. METHODS: We conducted a retrospective review of consecutively-enrolled adult patients with hematologic malignancy or hematopoietic stem cell transplantation and with PIV detected in nasal wash who subsequently developed radiologically-confirmed LRI. We measured RSI (range 0–72) in each chest radiograph during the first 30 days after LRI diagnosis. We used extended Cox proportional hazards models to identify factors associated with mortality after onset of LRI with all-cause mortality as our failure event. RESULTS: After adjustment for patient characteristics, each 1-point increase in RSI was associated with an increased hazard of death (HR 1.13, 95% confidence interval [CI] 1.05–1.21, p = 0.0008). Baseline RSI was not predictive of death, but both peak RSI and the change from baseline to peak RSI (delta-RSI) predicted mortality (odds ratio for mortality, peak: 1.11 [95%CI 1.04–1.18], delta-RSI: 1.14 [95%CI 1.06–1.22]). A delta-RSI of ≥19.5 was 89% sensitive and 91% specific in predicting 30-day mortality. CONCLUSIONS: We conclude that the RSI offers precise, informative and reliable assessments of LRI severity. Progression of RSI predicts 30-day mortality after LRI, but baseline RSI does not. Our results were derived from a cohort of patients with PIV-associated LRI, but can be applied in validated in other populations of patients with LRI. |
3,065 | Computer-aided design of amino acid-based therapeutics: a review | During the last two decades, the pharmaceutical industry has progressed from detecting small molecules to designing biologic-based therapeutics. Amino acid-based drugs are a group of biologic-based therapeutics that can effectively combat the diseases caused by drug resistance or molecular deficiency. Computational techniques play a key role to design and develop the amino acid-based therapeutics such as proteins, peptides and peptidomimetics. In this study, it was attempted to discuss the various elements for computational design of amino acid-based therapeutics. Protein design seeks to identify the properties of amino acid sequences that fold to predetermined structures with desirable structural and functional characteristics. Peptide drugs occupy a middle space between proteins and small molecules and it is hoped that they can target “undruggable” intracellular protein–protein interactions. Peptidomimetics, the compounds that mimic the biologic characteristics of peptides, present refined pharmacokinetic properties compared to the original peptides. Here, the elaborated techniques that are developed to characterize the amino acid sequences consistent with a specific structure and allow protein design are discussed. Moreover, the key principles and recent advances in currently introduced computational techniques for rational peptide design are spotlighted. The most advanced computational techniques developed to design novel peptidomimetics are also summarized. |
3,066 | Evaluation of the hepatoprotective effect of combination between hinokiflavone and Glycyrrhizin against CCl(4) induced toxicity in rats | Liver diseases are one of the fatal syndromes due to the vital role of the liver. Most of the effective treatment of liver conditions are of natural origin. Silymarin (SI) is the standard drug used for treatment of impaired liver functions. Two natural compounds possessing promising liver protection and with different chemical structures namely; the bioflavonoid hinokiflavone (HF) isolated from Junipers phoenicea family Cupressaceae and the sweet saponin Glycyrrhizin (GL) present in Glycyrrhiza glabra (liquorice) were selected for the current study. Since the two compounds are of different nature, they may act by different mechanisms and express synergistic effect. Combination of the two compounds using to dose levels were challenged with single doses of HF, GL and SI as well. The comparison was monitored via measuring serum biochemical parameters including, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltranspeptidase (GGT), alkaline phosphatase (ALP) and total bilirubin, tissue parameters such as MDA, NP-SH and TP, histopathological study using light and electron microscope. Protective effect on kidney was also monitored histopathologically and biochemically through observing the levels of LDH, creatinine, creatinine-kinase, urea and uric acid. The combinations of HF and GL showed protective effect more than the used single doses of HF and GL alone. However, SI was superior to the used combination in the two used doses in all the measured parameters. The liver and kidney cells appearance under normal and electron microscope showed that SI treated groups showed almost normal cells with slight toxic signs. Cells from group treated with the higher doses of the combination of HF and GL showed slight signs of intoxication under light and electron microscope indicating good level of protection. Although the combination of HF and GL expressed good protection in the higher dose, however, the combination did not exceed the protective effect of SI. |
3,067 | High Level Antibody Response to Pandemic Influenza H1N1/09 Virus Is Associated With Interferon-Induced Transmembrane Protein-3 rs12252-CC in Young Adults | Background: The C allele of the interferon-induced transmembrane protein-3 (IFITM3) SNP rs12252, a common allele in South East Asia and China, is strongly associated with severe influenza infection. However, despite the high occurrence of rs12252-CC genotype in Chinese population (~25%), severe influenza infection is rare. The aim of study is to determine whether rs12252-CC individuals have pre-existing antibody responses to previous seasonal influenza infections. Cohort and Method: A total 99 young healthy volunteers (18–20 years) were recruited and received an influenza seasonal Vaccination [A/Switzerland/9715293/2013(H3N2), A/California/7/2009 (pdm09H1N1) and B/Jeep/3073/2013-like virus (Flu-B)]. Plasma and gDNA was isolated from each volunteer before, and 14, 28, 180, 360, and 540 days after vaccination. Additionally, 68 elderlies (>65 years) were also recruited as a control group to compare the levels of antibodies at baseline between the young adults and the elderly. For each sample IFITM3 rs12252 genotype was determined and antibody levels in response to pdmH1N1, H3N2 and Influenza B infection were measured for each time point. Results: We found a significantly higher level of pre-existing antibodies to pandemic influenza H1N1/09 virus (pdm09H1N1) but not to H3N2 or FluB in CC donors in comparison with CT/TT donors prior to vaccination. No impact of IFITM3 genotype in boosting influenza specific antibodies in young adults within 1 year after receiving seasonal influenza vaccination was observed. In addition, there was no difference in pdm09H1N1 specific antibody levels observed in the elderly cohort between volunteers carrying different IFITM3 genotypes. Higher levels of antibodies to pdmH1N1 were observed in elderly CC carriers when compared to the young CC carriers, but this trend was not replicated in TT carriers. Conclusion: IFITM3-rs12252 CC carriers exhibit a high level of pre-existing immunity to pdm09H1N1 compared to TT carriers in the young cohort. This suggests that compensatory mechanisms exist which might contribute to viral control in patients carrying the rs12252-CC genotype who do not become sick after flu infection. However, such a potential compensatory effect appears to be lost overtime, as evidenced in the elderly cohort. If this compensatory mechanism is lost, it may make the CC carrying elderly more susceptible to severe influenza infection. |
3,068 | Comprehensive Analysis and Comparison on the Codon Usage Pattern of Whole Mycobacterium tuberculosis Coding Genome from Different Area | Phenomenon of unequal use of synonymous codons in Mycobacterium tuberculosis is common. Codon usage bias not only plays an important regulatory role at the level of gene expression, but also helps in improving the accuracy and efficiency of translation. Meanwhile, codon usage pattern of Mycobacterium tuberculosis genome is important for interpreting evolutionary characteristics in species. In order to investigate the codon usage pattern of the Mycobacterium tuberculosis genome, 12 Mycobacterium tuberculosis genomes from different area are downloaded from the GeneBank. The correlations between G(3), GC(12), whole GC content, codon adaptation index, codon bias index, and so on of Mycobacterium tuberculosis genomes are calculated. The ENC-plot, relationship between A(3)/(A(3) + T(3)) and G(3)/(G(3) + C(3)), GC(12) versus GC(3) plot, and the RSCU of overall/separated genomes all show that the codon usage bias exists in all 12 Mycobacterium tuberculosis genomes. Lastly, relationship between CBI and the equalization of ENC shows a strong negative correlation between them. The relationship between protein length and GC content (GC(3) and GC(12)) shows that more obvious differences in the GC content may be in shorter protein. These results show that codon usage bias existing in the Mycobacterium tuberculosis genomes could be used for further study on their evolutionary phenomenon. |
3,069 | Revalidation and genetic characterization of new members of Group C (Orthobunyavirus genus, Peribunyaviridae family) isolated in the Americas | Group C serogroup includes members of the Orthobunyavirus genus (family Peribunyaviridae) and comprises 15 arboviruses that can be associated with febrile illness in humans. Although previous studies described the genome characterization of Group C orthobunyavirus, there is a gap in genomic information about the other viruses in this group. Therefore, in this study, complete genomes of members of Group C serogroup were sequenced or re-sequenced and used for genetic characterization, as well as to understand their phylogenetic and evolutionary aspects. Thus, our study reported the genomes of three new members in Group C virus (Apeu strain BeAn848, Itaqui strain BeAn12797 and Nepuyo strain BeAn10709), as well as re-sequencing of original strains of five members: Caraparu (strain BeAn3994), Madrid (strain BT4075), Murucutu (strain BeAn974), Oriboca (strain BeAn17), and Marituba (strain BeAn15). These viruses presented a typical genomic organization related to members of the Orthobunyavirus genus. Interestingly, all viruses of this serogroup showed an open reading frame (ORF) that encodes the putative nonstructural NSs protein that precedes the nucleoprotein ORF, an unprecedented fact in Group C virus. Also, we confirmed the presence of natural reassortment events. This study expands the genomic information of Group C viruses, as well as revalidates the genomic organization of viruses that were previously reported. |
3,070 | Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties | BACKGROUND: The structural modification of natural products with the aim to improve the anticancer activity is a popular current research direction. The pentacyclic triterpenoid compounds oleanolic acid (OA) and glycyrrhetinic acid (GA) are distributed widely in nature. METHODS: In this study, various oleanolic acids and glycyrrhetinic acids were designed and synthesized by using the combination principle. The in vitro anticancer activities of new OA and GA derivatives were tested by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method with SGC-7901 (gastric cancer), MCF-7 (breast cancer), Eca-109 (esophageal cancer), HeLa (cervical cancer), Hep-G2 (hepatoma cancer) and HSF (normal human skin fibroblast) cells. RESULTS AND CONCLUSION: The screening results showed that the compound 3m presented the highest inhibitory activities against SGC-7901, MCF-7 and Eca-109 cell lines with IC(50) values of 7.57±0.64 μM, 5.51±0.41 μM and 5.03±0.56 μM, respectively. In addition, this compound also showed effective inhibition of Hep-G2 cells with an IC(50) value of 4.11±0.73 μM. Moreover, compound 5b showed the strongest inhibitory activity against Hep-G2 cells with an IC(50) value of 3.74±0.18 μM and compound 3l showed strong selective inhibition of the HeLa cells with the lowest IC(50) value of 4.32±0.89 μM. A series of pharmacology experiments indicated that compound 5b could induce Hep-G2 cells autophagy and apoptosis. These compounds will expand the structural diversity of anti-cancer targets and confirm the prospects for further research. |
3,071 | A road for a promising future for China’s primates: The potential for restoration | China is one of the most dynamic countries of the world and it shelters some amazing levels of biodiversity, including some very special primate species. However, primarily as a result of forest loss, most of which occurred in historical times, approximately 70% of China’s primate species have less than 3 000 individuals. Here I evaluate one road for future conservation/development that could produce very positive gains for China’s primates; namely forest restoration. I argue that for a large scale restoration project to be possible two conditions must be met; the right societal conditions must exist and the right knowledge must be in hand. This evaluation suggests that the restoration of native forest to support many of China’s primates holds great potential to advance conservation goals and to promote primate population recovery. |
3,072 | Therapeutics and Immunoprophylaxis Against Noroviruses and Rotaviruses: The Past, Present, and Future | BACKGROUND: Noroviruses and rotaviruses are important viral etiologies of severe gastroenteritis. Noroviruses are the primary cause of nonbacterial diarrheal outbreaks in humans, whilst rotaviruses are a major cause of childhood diarrhea. Although both enteric pathogens substantially impact human health and economies, there are no approved drugs against noroviruses and rotaviruses so far. On the other hand, whilst the currently licensed rotavirus vaccines have been successfully implemented in over 100 countries, the most advanced norovirus vaccine has recently completed phase-I and II trials. METHODS: We performed a structured search of bibliographic databases for peer-reviewed research litera-ture on advances in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis. RESULTS: Technological advances coupled with a proper understanding of viral morphology and replication over the past decade has facilitated pioneering research on therapeutics and immunoprophylaxis against noroviruses and rotaviruses, with promising outcomes in human clinical trials of some of the drugs and vaccines. This review focuses on the various developments in the fields of norovirus and rotavirus thera-peutics and immunoprophylaxis, such as potential antiviral drug molecules, passive immunotherapies (oral human immunoglobulins, egg yolk and bovine colostral antibodies, llama-derived nanobodies, and anti-bodies expressed in probiotics, plants, rice grains and insect larvae), immune system modulators, probiot-ics, phytochemicals and other biological substances such as bovine milk proteins, therapeutic nanoparti-cles, hydrogels and viscogens, conventional viral vaccines (live and inactivated whole virus vaccines), and genetically engineered viral vaccines (reassortant viral particles, virus-like particles (VLPs) and other sub-unit recombinant vaccines including multi-valent viral vaccines, edible plant vaccines, and encapsulated viral particles). CONCLUSIONS: This review provides important insights into the various approaches to therapeutics and im-munoprophylaxis against noroviruses and rotaviruses.. |
3,073 | Consensus statement for cancer patients requiring intensive care support | This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00277-018-3312-y) contains supplementary material, which is available to authorized users. |
3,074 | Cytokines IL-17 and IL-22 in the host response to infection | Cytokines IL-17 and IL-22 play pivotal roles in host defense against microbes and in the development of chronic inflammatory diseases. These cytokines are produced by cells that are often located in epithelial barriers, including subsets of T cells and innate lymphoid cells. In general, IL-17 and IL-22 can be characterized as important cytokines in the rapid response to infectious agents, both by recruiting neutrophils and by inducing the production of antimicrobial peptides. Although each cytokine induces an innate immune response in epithelial cells, their functional spectra are generally distinct: IL-17 mainly induces an inflammatory tissue response and is involved in the pathogenesis of several autoimmune diseases, whereas IL-22 is largely protective and regenerative. In this review, we compare IL-17 and IL-22, describing overlaps and differences in their cellular sources as well as their regulation, signaling, biological functions and roles during disease, with a focus on the contribution of these cytokines to the gut mucosal barrier during bacterial infection. |
3,075 | Zika Virus Induces Autophagy in Human Umbilical Vein Endothelial Cells | Autophagy is a common strategy for cell protection; however, some viruses can in turn adopt cellular autophagy to promote viral replication. Zika virus (ZIKV) is the pathogen that causes Zika viral disease, and it is a mosquito-borne virus. However, its pathogenesis, especially the interaction between ZIKV and target cells during the early stages of infection, is still unclear. In this study, we demonstrate that infecting human umbilical vein endothelial cells (HUVEC) with ZIKV triggers cellular autophagy. We observed both an increase in the conversion of LC3-I to LC3-II and increased accumulation of fluorescent cells with LC3 dots, which are considered to be the two key indicators of autophagy. The ratio of LC3-II/GAPDH in each group was significantly increased at different times after ZIKV infection at different MOIs, indicating that the production of lipidated LC3-II increased. Moreover, both the ratio of LC3-II/GAPDH and the expression of viral NS3 protein increased with increasing time of viral infection. The expression level of p62 decreased gradually from 12 h post-infection. Expression profile of double fluorescent protein labelling LC3 indicated that the autophagy induced by ZIKV infection was a complete process. We further investigated the role of autophagy in ZIKV replication. We demonstrated that either the treatment with inhibitors of autophagosomes formation or short hairpin RNA targeting the Beclin-1 gene, which is critical for the formation of autophagosomes, significantly reduced viral production. Taken together, our results indicate that ZIKV infection induces autophagy of HUVEC, and inhibition of ZIKV-induced autophagy restrains viral replication. |
3,076 | Strain-Specific Antagonism of the Human H1N1 Influenza A Virus against Equine Tetherin | Tetherin/BST-2/CD317 is an interferon-induced host restriction factor that can block the budding of enveloped viruses by tethering them to the cell surface. Many viruses use certain proteins to counteract restriction by tetherin from their natural hosts, but not from other species. The influenza A virus (FLUAV) has a wide range of subtypes with different host tropisms. Human tetherin (huTHN) has been reported to restrict only specific FLUAV strains and the viral hemagglutinin (HA) and neuraminidase (NA) genes determine the sensitivity to huTHN. Whether tetherins from other hosts can block human FLUAV is still unknown. Here, we evaluate the impact of equine tetherin (eqTHN) and huTHN on the replication of A/Sichuan/1/2009 (H1N1) and A/equine/Xinjiang/1/2007 (H3N8) strains. Our results show that eqTHN had higher restriction activity towards both viruses, and its shorter cytoplasmic tail contributed to that activity. We further demonstrated that HA and NA of A/Hamburg/4/2009 (H1N1) could counteract eqTHN. Notably, our results indicate that four amino acids, 13T and 49L of HA and 32T and 80V of NA, were involved in blocking the restriction activity of eqTHN. These findings reveal interspecies restriction by eqTHN towards FLUAV, and the role of the HA and NA proteins in overcoming this restriction. |
3,077 | Therapeutic Potential of Annexin A1 in Ischemia Reperfusion Injury | Cardiovascular disease (CVD) continues to be the leading cause of death in the world. Increased inflammation and an enhanced thrombotic milieu represent two major complications of CVD, which can culminate into an ischemic event. Treatment for these life-threatening complications remains reperfusion and restoration of blood flow. However, reperfusion strategies may result in ischemia–reperfusion injury (I/RI) secondary to various cardiovascular pathologies, including myocardial infarction and stroke, by furthering the inflammatory and thrombotic responses and delivering inflammatory mediators to the affected tissue. Annexin A1 (AnxA1) and its mimetic peptides are endogenous anti-inflammatory and pro-resolving mediators, known to have significant effects in resolving inflammation in a variety of disease models. Mounting evidence suggests that AnxA1, which interacts with the formyl peptide receptor (FPR) family, may have a significant role in mitigating I/RI associated complications. In this review article, we focus on how AnxA1 plays a protective role in the I/R based vascular pathologies. |
3,078 | Juglanin ameliorates UVB-induced skin carcinogenesis via anti-inflammatory and proapoptotic effects in vivo and in vitro | Ultraviolet (UV) radiation induces skin injury, and is associated with the development and formation of melanoma, which is a highly lethal form of skin cancer. Juglanin is a natural product, which is predominantly extracted from Polygonum aviculare, and is considered a functional component among its various compounds. Juglanin has been reported to exert marked protective effects in various diseases via the inhibition of inflammation and tumor cell growth. The present study aimed to explore the effects of juglanin on human skin cancer induced by UV and to reveal the underlying molecular mechanism. In the present study, immunohistochemical analysis, western blot analysis, RT-qPCR analysis and flow cytometry assays were mainly used in vivo and/or in vitro. The results indicated that in mice, UVB exposure increased susceptibility to carcinogens, and accelerated disease pathogenesis. Conversely, juglanin was able to ameliorate this condition via inhibition of inflammation, suppression of cell proliferation and induction of apoptosis via p38/c-Jun N-terminal kinase (JNK) blockage, nuclear factor (NF)-κB inactivation and caspase stimulation in vivo. In addition, in vitro, the present study demonstrated that treatment of UVB-stimulated B16F10 melanoma cells with juglanin resulted in a dose-dependent decrease in cell viability, as well as increased apoptosis via the upregulation of caspase expression and poly (ADP-ribose) polymerase cleavage. In addition, juglanin markedly attenuated p38/JNK signaling, inactivated the phosphoinositide 3-kinase/protein kinase B pathway and suppressed UVB-induced NF-κB activation. Taken together, these results indicated the possibility of applying juglanin in combination with UVB as a potential therapeutic strategy for preventing skin cancer. |
3,079 | Galactose-1-phosphate uridyltransferase (GalT), an in vivo-induced antigen of Actinobacillus pleuropneumoniae serovar 5b strain L20, provided immunoprotection against serovar 1 strain MS71 | GALT is an important antigen of Actinobacillus pleuropneumoniae (APP), which was shown to provide partial protection against APP infection in a previous study in our lab. The main purpose of the present study is to investigate GALT induced cross-protection between different APP serotypes and elucidate key mechanisms of the immune response to GALT antigenic stimulation. Bioinformatic analysis demonstrated that galT is a highly conserved gene in APP, widely distributed across multiple pathogenic strains. Homologies between any two strains ranges from 78.9% to 100% regarding the galT locus. Indirect enzyme-linked immunosorbent assay (ELISA) confirmed that GALT specific antibodies could not be induced by inactivated APP L20 or MS71 whole cell bacterin preparations. A recombinant fusion GALT protein derived from APP L20, however has proven to be an effective cross-protective antigen against APP sevorar 1 MS71 (50%, 4/8) and APP sevorar 5b L20 (75%, 6/8). Histopathological examinations have confirmed that recombinant GALT vaccinated animals showed less severe pathological signs in lung tissues than negative controls after APP challenge. Immunohistochemical (IHC) analysis indicated that the infiltration of neutrophils in the negative group is significantly increased compared with that in the normal control (P<0.001) and that in surviving animals is decreased compared to the negative group. Anti-GALT antibodies were shown to mediate phagocytosis of neutrophils. After interaction with anti-GALT antibodies, survival rate of APP challenged vaccinated animals was significantly reduced (P<0.001). This study demonstrated that GALT is an effective cross-protective antigen, which could be used as a potential vaccine candidate against multiple APP serotypes. |
3,080 | Use of Hemagglutinin Stem Probes Demonstrate Prevalence of Broadly Reactive Group 1 Influenza Antibodies in Human Sera | A better understanding of the seroprevalence and specificity of influenza HA stem-directed broadly neutralizing antibodies (bNAbs) in the human population could significantly inform influenza vaccine design efforts. Here, we utilized probes comprising headless, HA stabilized stem (SS) to determine the prevalence, binding and neutralization breadth of antibodies directed to HA stem-epitope in a cross-sectional analysis of the general population. Five group-1 HA SS probes, representing five subtypes, were chosen for this analyses. Eighty-four percent of samples analyzed had specific reactivity to at least one probe, with approximately 60% of the samples reactive to H1 probes, and up to 45% reactive to each of the non-circulating subtypes. Thirty percent of analyzed sera had cross-reactivity to at least four of five probes and this reactivity could be blocked by competing with F10 bNAb. Binding cross-reactivity in sera samples significantly correlated with frequency of H1(+)H5(+) cross-reactive B cells. Interestingly, only 33% of the cross-reactive sera neutralized both H1N1 and H5N1 pseudoviruses. Cross-reactive and neutralizing antibodies were more prevalent in individuals >50 years of age. Our data demonstrate the need to use multiple HA-stem probes to assess for broadly reactive antibodies. Further, a universal vaccine could be designed to boost pre-existing B-cells expressing stem-directed bNAbs. |
3,081 | The dual use of research ethics committees: why professional self-governance falls short in preserving biosecurity | BACKGROUND: Dual Use Research of Concern (DURC) constitutes a major challenge for research practice and oversight on the local, national and international level. The situation in Germany is shaped by two partly competing suggestions of how to regulate security-related research: The German Ethics Council, as an independent political advisory body, recommended a series of measures, including national legislation on DURC. Competing with that, the German National Academy of Sciences and the German Research Foundation, as two major professional bodies, presented a strategy which draws on the self-control of science and, inter alia, suggests expanding the scope of research ethics committees (RECs) to an evaluation of DURC. MAIN BODY: This situation is taken as an occasion to further discuss the scope and limits of professional self-control with respect to security-related research. The role of RECs as professional bodies of science is particularly analyzed, referring to the theoretical backgrounds of professionalism. Two key sociological features of professionalism – ethical orientation and professional self-control – are discussed with respect to the practice of biomedical science. Both attributes are then analyzed with respect to the assessment of DURC by RECs. CONCLUSION: In conclusion, it is stated that issues of biosecurity transcend the boundaries of the scientific community and that a more comprehensive strategy should be implemented encompassing both professional self-control and legal oversight. |
3,082 | Fluorogen-activating proteins: beyond classical fluorescent proteins | Fluorescence imaging is a powerful technique for the real-time noninvasive monitoring of protein dynamics. Recently, fluorogen activating proteins (FAPs)/fluorogen probes for protein imaging were developed. Unlike the traditional fluorescent proteins (FPs), FAPs do not fluoresce unless bound to their specific small-molecule fluorogens. When using FAPs/fluorogen probes, a washing step is not required for the removal of free probes from the cells, thus allowing rapid and specific detection of proteins in living cells with high signal-to-noise ratio. Furthermore, with different fluorogens, living cell multi-color proteins labeling system was developed. In this review, we describe about the discovery of FAPs, the design strategy of FAP fluorogens, the application of the FAP technology and the advances of FAP technology in protein labeling systems. |
3,083 | Multifunctional biophotonic nanostructures inspired by longtail glasswing butterfly for medical devices | Numerous living organisms possess biophotonic nanostructures that provide coloration and other diverse functions for survival. While such structures have been actively studied and replicated in the laboratory, it remains unclear whether they can be used for biomedical applications. Here we show a transparent photonic nanostructure inspired by the longtail glasswing (Chorinea faunus) butterfly and demonstrate its use in intraocular pressure (IOP) sensors in vivo. We exploit the phase separation between two immiscible polymers (poly(methyl methacrylate) and polystyrene) to form nanostructured features on top of a Si(3)N(4) substrate. The membrane thus formed shows good angle-independent white light transmission, strong hydrophilicity and anti-biofouling properties that prevent adhesion of proteins, bacteria, and eukaryotic cells. We then developed a microscale implantable IOP sensor using our photonic membrane as an optomechanical sensing element. Finally, we performed in vivo testing on New Zealand white rabbits and show that our device reduces the mean IOP measurement variation compared to conventional rebound tonometry without signs of inflammation. |
3,084 | Zika virus-induced acute myelitis and motor deficits in adult interferon αβ/γ receptor knockout mice | Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13365-017-0595-z) contains supplementary material, which is available to authorized users. |
3,085 | Changing Priorities in Vaccinology: Antibiotic Resistance Moving to the Top | Antimicrobial resistance (AMR) is currently the most alarming issue for human health. AMR already causes 700,000 deaths/year. It is estimated that 10 million deaths due to AMR will occur every year after 2050. This equals the number of people dying of cancer every year in present times. International institutions such as G20, World Bank, World Health Organization (WHO), UN General Assembly, European Union, and the UK and USA governments are calling for new antibiotics. To underline this emergency, a list of antibiotic-resistant “priority pathogens” has been published by WHO. It contains 12 families of bacteria that represent the greatest danger for human health. Resistance to multiple antibiotics is particularly relevant for the Gram-negative bacteria present in the list. The ability of these bacteria to develop mechanisms to resist treatment could be transmitted with genetic material, allowing other bacteria to become drug resistant. Although the search for new antimicrobial drugs remains a top priority, the pipeline for new antibiotics is not promising, and alternative solutions are needed. A possible answer to AMR is vaccination. In fact, while antibiotic resistance emerges rapidly, vaccines can lead to a much longer lasting control of infections. New technologies, such as the high-throughput cloning of human B cells from convalescent or vaccinated people, allow for finding new protective antigens (Ags) that could not be identified with conventional technologies. Antibodies produced by convalescent B cell clones can be screened for their ability to bind, block, and kill bacteria, using novel high-throughput microscopy platforms that rapidly capture digital images, or by conventional technologies such as bactericidal, opsono-phagocytosis and FACS assays. Selected antibodies expressed by recombinant DNA techniques can be used for passive immunization in animal models and tested for protection. Antibodies providing the best protection can be employed to identify new Ags and then used for generating highly specific recombinant Fab fragments. Co-crystallization of Ags bound to Fab fragments will allow us to determine the structure and characteristics of new Ags. This structure-based Ag design will bring to a new generation of vaccines able to target previously elusive infections, thereby offering an effective solution to the problem of AMR. |
3,086 | Serum Amyloid A Protein Concentration in Blood is Influenced by Genetic Differences in the Cheetah (Acinonyx jubatus) | Systemic amyloid A (AA) amyloidosis is a major cause of morbidity and mortality among captive cheetahs. The self-aggregating AA protein responsible for this disease is a byproduct of serum amyloid A (SAA) protein degradation. Transcriptional induction of the SAA1 gene is dependent on both C/EBPβ and NF-κB cis-acting elements within the promoter region. In cheetahs, 2 alleles exist for a single guanine nucleotide deletion in the putative NF-κB binding site. In this study, a novel genotyping assay was developed to screen for the alleles. The results show that the SAA1A(−97delG) allele is associated with decreased SAA protein concentrations in the serum of captive cheetahs (n = 58), suggesting genetic differences at this locus may be affecting AA amyloidosis prevalence. However, there was no significant difference in the frequency of the SAA1A(−97delG) allele between individuals confirmed AA amyloidosis positive versus AA amyloidosis negative at the time of necropsy (n = 48). Thus, even though there is evidence that having more copies of the SAA1A(−97delG) allele results in a potentially protective decrease in serum concentrations of SAA protein in captive cheetahs, genotype is not associated with this disease within the North American population. These results suggest that other factors are playing a more significant role in the pathogenesis of AA amyloidosis among captive cheetahs. |
3,087 | Viral Fitness Correlates with the Magnitude and Direction of the Perturbation Induced in the Host’s Transcriptome: The Tobacco Etch Potyvirus—Tobacco Case Study | Determining the fitness of viral genotypes has become a standard practice in virology as it is essential to evaluate their evolutionary potential. Darwinian fitness, defined as the advantage of a given genotype with respect to a reference one, is a complex property that captures, in a single figure, differences in performance at every stage of viral infection. To what extent does viral fitness result from specific molecular interactions with host factors and regulatory networks during infection? Can we identify host genes in functional classes whose expression depends on viral fitness? Here, we compared the transcriptomes of tobacco plants infected with seven genotypes of tobacco etch potyvirus that differ in fitness. We found that the larger the fitness differences among genotypes, the more dissimilar the transcriptomic profiles are. Consistently, two different mutations, one in the viral RNA polymerase and another in the viral suppressor of RNA silencing, resulted in significantly similar gene expression profiles. Moreover, we identified host genes whose expression showed a significant correlation, positive or negative, with the virus' fitness. Differentially expressed genes which were positively correlated with viral fitness activate hormone- and RNA silencing-mediated pathways of plant defense. In contrast, those that were negatively correlated with fitness affect metabolism, reducing growth, and development. Overall, these results reveal the high information content of viral fitness and suggest its potential use to predict differences in genomic profiles of infected hosts. |
3,088 | viGEN: An Open Source Pipeline for the Detection and Quantification of Viral RNA in Human Tumors | An estimated 17% of cancers worldwide are associated with infectious causes. The extent and biological significance of viral presence/infection in actual tumor samples is generally unknown but could be measured using human transcriptome (RNA-seq) data from tumor samples. We present an open source bioinformatics pipeline viGEN, which allows for not only the detection and quantification of viral RNA, but also variants in the viral transcripts. The pipeline includes 4 major modules: The first module aligns and filter out human RNA sequences; the second module maps and count (remaining un-aligned) reads against reference genomes of all known and sequenced human viruses; the third module quantifies read counts at the individual viral-gene level thus allowing for downstream differential expression analysis of viral genes between case and controls groups. The fourth module calls variants in these viruses. To the best of our knowledge, there are no publicly available pipelines or packages that would provide this type of complete analysis in one open source package. In this paper, we applied the viGEN pipeline to two case studies. We first demonstrate the working of our pipeline on a large public dataset, the TCGA cervical cancer cohort. In the second case study, we performed an in-depth analysis on a small focused study of TCGA liver cancer patients. In the latter cohort, we performed viral-gene quantification, viral-variant extraction and survival analysis. This allowed us to find differentially expressed viral-transcripts and viral-variants between the groups of patients, and connect them to clinical outcome. From our analyses, we show that we were able to successfully detect the human papilloma virus among the TCGA cervical cancer patients. We compared the viGEN pipeline with two metagenomics tools and demonstrate similar sensitivity/specificity. We were also able to quantify viral-transcripts and extract viral-variants using the liver cancer dataset. The results presented corresponded with published literature in terms of rate of detection, and impact of several known variants of HBV genome. This pipeline is generalizable, and can be used to provide novel biological insights into microbial infections in complex diseases and tumorigeneses. Our viral pipeline could be used in conjunction with additional type of immuno-oncology analysis based on RNA-seq data of host RNA for cancer immunology applications. The source code, with example data and tutorial is available at: https://github.com/ICBI/viGEN/. |
3,089 | Comparison data of a two-target real-time PCR assay with and without an internal control in detecting Salmonella enterica from cattle lymph nodes | A real-time PCR (qPCR) assay targeting on invA and pagC genes was developed and validated for the detection and quantification of Salmonella enterica strains (Bai et al., 2018) [1]. A host gene, normally an endogenous housekeeping gene (Beer-Davidson et al., 2018; Poon et al., 2004) [2,3], or an irrelevant exogenous gene (Cheng et al., 2015; Sedlak et al., 2014) [4,5] has been widely used as an internal control to monitor nucleic acid extraction efficiencies and potential PCR inhibitions in PCR-based detection assays. An endogenous internal control designed based on the 18S rRNA gene was used in the above-mentioned qPCR assay. This 18S rRNA internal control amplifies the target gene in multiple species including bovine, swine, ovine, caprine and cervine. Data was generated by the duplex qPCR assay on 138 enriched cattle lymph node samples without the internal control, and compared with data on the same samples tested by the triplex qPCR assay that has the 18S rRNA gene as internal control. Threshold cycle (Ct) data for the duplex and the triplex qPCR on the 138 samples were similar, and are presented in this brief report. |
3,090 | Generation and comparative genomics of synthetic dengue viruses | BACKGROUND: Synthetic virology is an important multidisciplinary scientific field, with emerging applications in biotechnology and medicine, aiming at developing methods to generate and engineer synthetic viruses. In particular, many of the RNA viruses, including among others the Dengue and Zika, are widespread pathogens of significant importance to human health. The ability to design and synthesize such viruses may contribute to exploring novel approaches for developing vaccines and virus based therapies. RESULTS: Here we develop a full multidisciplinary pipeline for generation and analysis of synthetic RNA viruses and specifically apply it to Dengue virus serotype 2 (DENV-2). The major steps of the pipeline include comparative genomics of endogenous and synthetic viral strains. Specifically, we show that although the synthetic DENV-2 viruses were found to have lower nucleotide variability, their phenotype, as reflected in the study of the AG129 mouse model morbidity, RNA levels, and neutralization antibodies, is similar or even more pathogenic in comparison to the wildtype master strain. Additionally, the highly variable positions, identified in the analyzed DENV-2 population, were found to overlap with less conserved homologous positions in Zika virus and other Dengue serotypes. These results may suggest that synthetic DENV-2 could enhance virulence if the correct sequence is selected. CONCLUSIONS: The approach reported in this study can be used to generate and analyze synthetic RNA viruses both on genotypic and on phenotypic level. It could be applied for understanding the functionality and the fitness effects of any set of mutations in viral RNA and for editing RNA viruses for various target applications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12859-018-2132-3) contains supplementary material, which is available to authorized users. |
3,091 | Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease | BACKGROUND: Angiotensin converting enzyme 2 (ACE2) is an endogenous regulator of the renin angiotensin system. Increased circulating ACE2 predicts adverse outcomes in patients with heart failure (HF), but it is unknown if elevated plasma ACE2 activity predicts major adverse cardiovascular events (MACE) in patients with obstructive coronary artery disease (CAD). METHODS: We prospectively recruited patients with obstructive CAD (defined as ≥50% stenosis of the left main coronary artery and/or ≥70% stenosis in ≥ 1 other major epicardial vessel on invasive coronary angiography) and measured plasma ACE2 activity. Patients were followed up to determine if circulating ACE2 activity levels predicted the primary endpoint of MACE (cardiovascular mortality, HF or myocardial infarction). RESULTS: We recruited 79 patients with obstructive coronary artery disease. The median (IQR) plasma ACE2 activity was 29.3 pmol/ml/min [21.2–41.2]. Over a median follow up of 10.5 years [9.6–10.8years], MACE occurred in 46% of patients (36 events). On Kaplan-Meier analysis, above-median plasma ACE2 activity was associated with MACE (log-rank test, p = 0.035) and HF hospitalisation (p = 0.01). After Cox multivariable adjustment, log ACE2 activity remained an independent predictor of MACE (hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.24–4.72, p = 0.009) and HF hospitalisation (HR: 4.03, 95% CI: 1.42–11.5, p = 0.009). CONCLUSIONS: Plasma ACE2 activity independently increased the hazard of adverse long-term cardiovascular outcomes in patients with obstructive CAD. |
3,092 | A barnavirus sequence mined from a transcriptome of the Antarctic pearlwort Colobanthus quitensis | Because so few viruses in the family Barnaviridae have been reported, we searched for more of them in public sequence databases. Here, we report the complete coding sequence of Colobanthus quitensis associated barnavirus 1, mined from a transcriptome of the Antarctic pearlwort Colobanthus quitensis. The 4.2-kb plus-strand sequence of this virus encompasses four main open reading frames (ORFs), as expected for barnaviruses, including ORFs for a protease-containing polyprotein, an RNA-dependent RNA polymerase whose translation appears to rely on − 1 ribosomal frameshifting, and a capsid protein that is likely to be translated from a subgenomic RNA. The possible derivation of this virus from a fungus associated with C. quitensis is discussed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00705-018-3794-x) contains supplementary material, which is available to authorized users. |
3,093 | Experimental murine acute lung injury induces increase of pulmonary TIE2-expressing macrophages | BACKGROUND: Breakdown of the alveolo-capillary wall is pathognomonic for Acute Lung Injury (ALI). Angiopoietins, vascular-specific growth factors, are linked to endothelial barrier dysfunction, and elevated Angiopoietin-2 (ANG2) levels are associated with poor outcome of ALI patients. Specialized immune cells, referred to as ‘TIE2-expressing monocytes and macrophages’ (TEM), were shown to specifically respond to ANG2 binding. However, their involvement in acute inflammatory processes is so far completely undescribed. Thus, our aim was to assess the dynamics of TEMs in a murine model of ALI. RESULTS: Intratracheal instillation of LPS induced a robust pulmonary pro-inflammatory response with endothelial barrier dysfunction and significantly enhanced ANG2 expression. The percentage number of TEMs, assessed by FACS analysis, was more than trebled compared to controls, with TEM count in lungs reaching more than 40% of all macrophages. Such distinct dynamic was absent in all other analyzed compartments (alveolar space, spleen, blood). Incubation of the monocytic cell line THP-1 with LPS or TNF-α resulted in a dose-dependent, significant upregulation of TIE2, suggesting that not recruitment from extra-pulmonary compartments but TIE2 upregulation in resident macrophages accounts for increased lung TEM frequencies. CONCLUSIONS: For the first time, our data provide evidence that the activity of TEMs changes at sites of acute inflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12950-018-0188-5) contains supplementary material, which is available to authorized users. |
3,094 | Improving early epidemiological assessment of emerging Aedes-transmitted epidemics using historical data | Model-based epidemiological assessment is useful to support decision-making at the beginning of an emerging Aedes-transmitted outbreak. However, early forecasts are generally unreliable as little information is available in the first few incidence data points. Here, we show how past Aedes-transmitted epidemics help improve these predictions. The approach was applied to the 2015–2017 Zika virus epidemics in three islands of the French West Indies, with historical data including other Aedes-transmitted diseases (chikungunya and Zika) in the same and other locations. Hierarchical models were used to build informative a priori distributions on the reproduction ratio and the reporting rates. The accuracy and sharpness of forecasts improved substantially when these a priori distributions were used in models for prediction. For example, early forecasts of final epidemic size obtained without historical information were 3.3 times too high on average (range: 0.2 to 5.8) with respect to the eventual size, but were far closer (1.1 times the real value on average, range: 0.4 to 1.5) using information on past CHIKV epidemics in the same places. Likewise, the 97.5% upper bound for maximal incidence was 15.3 times (range: 2.0 to 63.1) the actual peak incidence, and became much sharper at 2.4 times (range: 1.3 to 3.9) the actual peak incidence with informative a priori distributions. Improvements were more limited for the date of peak incidence and the total duration of the epidemic. The framework can adapt to all forecasting models at the early stages of emerging Aedes-transmitted outbreaks. |
3,095 | Risk factors for infectious complications of ANCA-associated vasculitis: a cohort study | BACKGROUND: Severe infections are common complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal involvement. We investigated the clinical characteristics and risk factors of severe infection in Chinese patients with AAV after immunosuppressive therapy. METHODS: A total of 248 patients with a new diagnosis of ANCA-associated vasculitis were included in this study. The incidence, time, site, and risk factors of severe infection by the induction therapies were analysed. Multivariate Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). RESULTS: A total of 103 episodes of severe infection were identified in 86 (34.7%, 86/248) patients during a median follow-up of 15 months. The incidence of infection during induction therapy was 38.5% for corticosteroids (CS), 39.0% for CS+ intravenous cyclophosphamide (IV-CYC), 33.8% for CS+ mycophenolate mofetil and 22.5% for CS + tripterygium glycosides, 76 (73.8%) infection episodes occurred within 6 months, while 66 (64.1%) occurred within 3 months. Pneumonia (71.8%, 74/103) was the most frequent type of infection, and the main pathogenic spectrum included bacteria (78.6%), fungi (12.6%), and viruses (8.7%). The risk factors associated with infection were age at the time of diagnosis (HR = 1.003, 95% CI = 1.000–1.006), smoking (HR = 2.338, 95% CI = 1.236–4.424), baseline secrum creatinine (SCr) ≥5.74 mg/dl (HR = 2.153, 95% CI = 1.323–3.502), CD4(+) T cell< 281 μl (HR = 1.813, 95% CI = 1.133–2.900), and intravenous cyclophosphamide regimen (HR = 1.951, 95% CI =1.520–2.740). Twelve (13.9%) patients died of severe pneumonia. CONCLUSION: The infection rate during induction therapy was high in patients with AAV. Bacterial pneumonia was the main type of infection encountered. Age at the time of diagnosis, smoking, baseline SCr ≥5.74 mg/dl, CD4(+) T cell< 281 μl, and IV-CYC therapy were identified as risk factors for infection. |
3,096 | Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model | The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H(2)) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H(2) attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H(2) administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H(2) on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H(2)-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H(2) administration. Overall, these findings indicate that maternal H(2) administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life. |
3,097 | Performance of TEM-PCR vs Culture for Bacterial Identification in Pediatric Musculoskeletal Infections | Improved diagnostics are needed for children with musculoskeletal infections (MSKIs). We assessed the performance of target-enriched multiplex polymerase chain reaction (TEM-PCR) in children with MSKI. TEM-PCR was concordant with culture in pathogen identification and antibiotic susceptibility testing, while increasing the overall yield of pathogen detection. This technology has the potential to inform judicious antimicrobial use early in the disease course. |
3,098 | ZIKV Infection Induces an Inflammatory Response but Fails to Activate Types I, II, and III IFN Response in Human PBMC | The recent epidemic in the Americas caused by Zika virus (ZIKV), Asian lineage, spurred the research towards a better understanding of how ZIKV infection affects the host immune response. The aim of this study was to evaluate the effects of Asian and East African ZIKV strain infection on the induction of IFN and proinflammatory and Th2 cytokines in human PBMC. We reported a slight modulation of type II IFN in PBMC exposed to Asian strain, but not to African strain, and a complete lack of type I and III IFN induction by both strains, suggesting the ability of ZIKV to evade the IFN system not only inhibiting the antiviral IFN response but also IFN production. Moreover, we highlighted a polyfunctional immune activation only in PBMC exposed to Asian strain, due to the induction of an inflammatory profile (IL-6, IL-8) and of a Th9 (IL-9) response. Overall, our data show a different ability of the ZIKV Asian strain, with respect to the African strain, to activate host immune response that may have pathogenetic implications for virus spread in vivo, including mother-to-child transmission and induction of severe fetal complications, as birth defects and neurological disorders. |
3,099 | Fusion Inhibitory Lipopeptides Engineered for Prophylaxis of Nipah Virus in Primates | BACKGROUND: The emerging zoonotic paramyxovirus Nipah virus (NiV) causes severe respiratory and neurological disease in humans, with high fatality rates. Nipah virus can be transmitted via person-to-person contact, posing a high risk for epidemic outbreaks. However, a broadly applicable approach for human NiV outbreaks in field settings is lacking. METHODS: We engineered new antiviral lipopeptides and analyzed in vitro fusion inhibition to identify an optimal candidate for prophylaxis of NiV infection in the lower respiratory tract, and we assessed antiviral efficiency in 2 different animal models. RESULTS: We show that lethal NiV infection can be prevented with lipopeptides delivered via the respiratory route in both hamsters and nonhuman primates. By targeting retention of peptides for NiV prophylaxis in the respiratory tract, we avoid its systemic delivery in individuals who need only prevention, and thus we increase the safety of treatment and enhance utility of the intervention. CONCLUSIONS: The experiments provide a proof of concept for the use of antifusion lipopeptides for prophylaxis of lethal NiV. These results advance the goal of rational development of potent lipopeptide inhibitors with desirable pharmacokinetic and biodistribution properties and a safe effective delivery method to target NiV and other pathogenic viruses. |
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