niryuu/sni-each-converted huggingface dataset:
Herpes simplex virus (HSV) infection of mice can induce viral encephalitis. Using two-fluorochrome immunofluorescence, our present study shows that though there is extensive myelin loss and necrosis in the brain stem of mice with HSV encephalitis, only some oligodendrocytes, astrocytes and microglial cells are infected. T cells that express CD4 or CD8 and a large number of CD4 +, F4/80 + macrophages are present in perivascular infiltrates close to and in contact with HSV-infected cells in areas of massive myelin loss. These findings suggest that the resultant infiltration of immune cells into the brain during HSV-1 infection may cause as much damage as the virus itself. 0165-5728/89/$03.50 
Output: Infiltration of immune T cells in the brain of mice with herpes simplex virus-induced encephalitis
Background: The nasal avian schistosome Trichobilharzia regenti spends part of its intravertebrate period of life within the central nervous system. Migration of the parasites can be accompanied by neuromotor disorders or paralysis in natural definitive hosts (ducks) and even in laboratory mammals. Cercariae are also able to penetrate human skin and induce cercarial dermatitis. While the cellular and antibody responses against cercariae and migrating schistosomula have been investigated in mice, little is known about immune reactions in birds. This study first describes the dynamics of antibody response in infected ducks and identifies frequently recognized antigens that may serve as diagnostic markers of infection by T. regenti. Methods: Groups of 35 domestic ducks and 10 mallards were exposed to different doses of T. regenti cercariae. Sera were collected at predefined time intervals and tested by ELISA for the presence of specific anti-cercarial IgY and IgM. Antigens recognized by the antibodies were identified on Western blots of cercariae and schistosomula. The applicability in immunodiagnostics was statistically evaluated by expression of specificity and sensitivity values for individual antigens. Results: In ELISA, the levels of anti-cercarial IgM peaked on day 15 pi. Increased production of IgY associated with the later phases of infection was observed in most individuals around 20 dpi and culminated 30 dpi. The time course of antibody response did not differ among experimental groups, variations were only observed in the levels of specific IgY which depended rather on the age of ducks at the time of infection than on the infectious dose. On Western blots, 40 cercarial and 7 schistosomular antigens were recognized by IgY from infected ducks. Among them, 4 cercarial antigens of 50, 47, 32 and 19 kDa provided the most sensitive and specific reactions. Conclusions: Antigens of cercariae and schistosomula elicited distinct antibody response in ducks, which correlated positively with the age of animals at the time of infection. Several antigens originating in cercariae and fewer in schistosomula were recognized by IgY with diverse sensitivity and specificity; only a few seemed to be common to both stages. Four of them were considered as the most promising candidates for immunodiagnostics.
Output: Antibody response of definitive hosts against antigens of two life stages of the neuropathogenic schistosome Trichobilharzia regenti
Porcine deltacoronavirus (PDCoV), a member of genus Deltacoronavirus, is an emerging swine enteropathogenic coronavirus (CoV). Although outstanding efforts have led to the identification of Alphacoronavirus and Betacoronavirus receptors, the receptor for Deltacoronavirus is unclear. Here, we compared the amino acid sequences of several representative CoVs. Phylogenetic analysis showed that PDCoV spike (S) protein was close to the cluster containing transmissible gastroenteritis virus (TGEV), which utilizes porcine aminopeptidase N (pAPN) as a functional receptor. Ectopic expression of pAPN in non-susceptible BHK-21 cells rendered them susceptible to PDCoV. These results indicate that pAPN may be a functional receptor for PDCoV infection. However, treatment with APN-specific antibody and inhibitors did not completely block PDCoV infection in IPI-2I porcine intestinal epithelial cells. pAPN knockout in IPI-2I cells completely blocked TGEV infection but only slightly decreased PDCoV infection. Homologous modeling of pAPN with the S1 C-terminal domain (S1-CTD) of PDCoV or TGEV showed that TGEV S1-CTD adopted β-turns (β1-β2 and β3-β4), forming the tip of a β-barrel, to recognize pAPN. However, only the top residues in the β1-β2 turn of PDCoV S1-CTD had the possibility to support an interaction with pAPN, and the β3-β4 turn failed to contact pAPN. We also discuss the evolution and variation of PDCoV S1-CTD based on structure information, providing clues to explain the usage of pAPN by PDCoV. Taken together, the results presented herein reveal that pAPN is likely not a critical functional receptor for PDCoV, although it is involved in PDCoV infection.
Output: Contribution of porcine aminopeptidase N to porcine deltacoronavirus infection
Hantaviruses (HVs) are rodent-transmitted viruses that can cause hantavirus cardiopulmonary syndrome (HCPS) in the Americas and hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Together, these viruses have annually caused approximately 200,000 human infections worldwide in recent years, with a case fatality rate of 5-15% for HFRS and up to 40% for HCPS. There is currently no effective treatment available for either HFRS or HCPS. Only whole virus inactivated vaccines against HTNV or SEOV are licensed for use in the Republic of Korea and China, but the protective efficacies of these vaccines are uncertain. To a large extent, the immune correlates of protection against hantavirus are not known. In this review, we summarized the epidemiology, virology, and pathogenesis of four HFRS-causing viruses, HTNV, SEOV, PUUV, and DOBV, and two HCPS-causing viruses, ANDV and SNV, and then discussed the existing knowledge on vaccines and therapeutics against these diseases. We think that this information will shed light on the rational development of new vaccines and treatments.
Output: Vaccines and Therapeutics Against Hantaviruses
Rotavirus infection is a major cause of severe dehydrating diarrhea in infants younger than 5 y old and in particular cases of immunocompromised patients irrespective to the age of the patients. Although vaccines have been developed, antiviral therapy is an important complement that cannot be substituted. Because of the lack of specific approved treatment, it is urgent to facilitate the cascade of further understanding of the infection biology, identification of druggable targets and the final development of effective antiviral therapies. PI3K-Akt-mTOR signaling pathway plays a vital role in regulating the infection course of many viruses. In this study, we have dissected the effects of PI3K-Akt-mTOR signaling pathway on rotavirus infection using both conventional cell culture models and a 3D model of human primary intestinal organoids. We found that PI3K-Akt-mTOR signaling is essential in sustaining rotavirus infection. Thus, blocking the key elements of this pathway, including PI3K, mTOR and 4E-BP1, has resulted in potent anti-rotavirus activity. Importantly, a clinically used mTOR inhibitor, rapamycin, potently inhibited both experimental and patient-derived rotavirus strains. This effect involves 4E-BP1 mediated induction of autophagy, which in turn exerts anti-rotavirus effects. These results revealed new insights on rotavirus-host interactions and provided new avenues for antiviral drug development.
Output: PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target
Intracellular events in the synthesis, glycosylation, and transport of the lymphocytic choriomeningitis virus (LCMV) glycoproteins have been examined. We have shown by N-glycanase digestion that LCMV strain Arm-4 bears five oligosaccharides on GP-1 and two on GP-2. By pulse-chase labeling experiments in the presence of drugs which inhibit Nlinked oligosaccharide addition and processing we demonstrate that addition of high mannose precursor oligosaccharides is necessary for transport and cleavage of the viral GP-C glycoprotein. Moreover, in the presence of tunicamycin which inhibits en bloc addition of these mannose-rich side chains, virus budding was substantially decreased and infectious virions were reduced by more than lOOO-fold in the supernatant medium. Incubation in the presence of castantospermine, which permits addition of oligomannosyl-rich chains but blocks further processing, restored transport and cleavage of GP-C and maturation of virions. Finally, by temperature block experiments we have determined that maturation of GP-C oligosaccharides to an endoglycosidase H resistant form precedes cleavage to GP-1 and GP-2. The latter process is most likely to occur in the Golgi or post-Golgi compartment. o 1990AcademicPress, IW. ' Present address:
Output: Post-translational Processing of the Glycoproteins of Lymphocytic Choriomeningitis Virus
Dendritic cells (DC) are critical to an integrated immune response and serve as the key link between the innate and adaptive arms of the immune system. Under steady state conditions, brain DC's act as sentinels, continually sampling their local environment. They share this function with macrophages derived from the same basic hemopoietic (bone marrow-derived) precursor and with parenchymal microglia that arise from a unique nonhemopoietic origin. While multiple cells may serve as antigen presenting cells (APCs), dendritic cells present both foreign and self-proteins to naïve T cells that, in turn, carry out effector functions that serve to protect or destroy. The resulting activation of the adaptive response is a critical step to resolution of injury or infection and is key to survival. In this review we will explore the critical roles that DCs play in the brain's response to neuroinflammatory disease with emphasis on how the brain's microenvironment impacts these actions.
Output: Immune Heterogeneity in Neuroinflammation: Dendritic Cells in the Brain
Background: Middle East Respiratory Syndrome (MERS) is a respiratory disease caused by a novel coronavirus that was identified in 2012 in Saudi Arabia. It is associated with significant mortality and morbidity. We identified factors associated with the Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) infection among suspected cases presented with sign and symptoms of upper respiratory infection or exposure to the virus. We also looked at the impact of medication history on virus transmission. Method: We included subjects with suspected MERS-CoV infection and confirmed cases of MERS infection. Subjects were excluded if there were any missing data that prevent the final analysis. Descriptive statistics were used to report demographic data. Percentages and frequencies were used to summarize the categorical variables, while means and standard deviations were calculated for continuous variables. Logistic regression was used to assess the risk of MERS-CoV infection among the suspected cases. A value of p < 0.05 was considered statistically significant. Results: A total of 16,189 suspected cases were identified, complete data were analyzed for 3154 to assess factors that are independently associated with MERS-CoV infection. MERS-CoV infection was associated with age (adjusted odds ratio [AOR] = 1.06; 95% CI [1.02-1.098], P-value = 0.004), male gender (AOR = 1.617; 95% CI [1.365-1.77], P-value < 0.001) and diabetes (AOR = 1.68; 95% CI [1.346-1.848], P-value = 0.002. There was no significant association with the other comorbidities. Medication history was not associated with an increase or decrease the likelihood of the infection. Conclusions: MERS-Cov infection is more common in male, advanced age and diabetes. No medications were associated with an increase or decrease the likelihood of the infection. This is important to focus on screening and detection to this patient population.
Output: Identifying factors and target preventive therapies for Middle East Respiratory Syndrome sucsibtable patients
Background: Infectious bronchitis virus (IBV) is a Gammacoronavirus of the family Coronaviridae and is a causative agent of an economically important disease in poultry. The spike glycoprotein of IBV is essential for host cell attachment, neutralization, and is involved in the induction of protective immunity. Previously obtained sequence data of the spike gene of IBV QX-like and Massachusetts strains were subjected to bioinformatics analysis. Findings: On analysis of potential phosphorylation sites, the Ser542 and Ser563 sites were not present in Massachusetts strains, while QX-like isolates did not have the Ser534 site. Massachusetts and QX-like strains showed different cleavage site motifs. The N-glycosylation sites ASN-XAA-SER/THR-55, 147, 200 and 545 were additionally present in QX-like strains. The leucine-rich repeat regions in Massachusetts strains consisted of stretches of 63 to 69 amino acids, while in the QX-like strains they contained 59 amino acids in length. An additional palmitoylation site was observed in CK/SWE/082066/2010 a QX-like strain. Primary structure data showed difference in the physical properties and hydrophobic nature of both genotypes. The comparison of secondary structures revealed no new structural domains in the genotypic variants. The phylogenetic analyses based on avian and mammalian coronaviruses showed the analysed IBV as closely related to turkey coronaviruses and distantly related to thrush and munia coronaviruses. Conclusion: The study demonstrated that spike glycoprotein of the Massachusetts and the QX-like variants of IBV are molecularly distinct and that this may reflect in differences in the behavior of these viruses in vivo.
Output: Bioinformatics and evolutionary insight on the spike glycoprotein gene of QX-like and Massachusetts strains of infectious bronchitis virus
The current Ebola virus outbreak has highlighted the uncertainties surrounding many aspects of Ebola virus virology, including routes of transmission. The scientific community played a leading role during the outbreak-potentially, the largest of its kind-as many of the questions surrounding ebolaviruses have only been interrogated in the laboratory. Scientists provided an invaluable resource for clinicians, public health officials, policy makers, and the lay public in understanding the progress of Ebola virus disease and the continuing outbreak. Not all of the scientific communication, however, was accurate or effective. There were multiple instances of published articles during the height of the outbreak containing potentially misleading scientific language that spurred media overreaction and potentially jeopardized preparedness and policy decisions at critical points. Here, we use articles declaring the potential for airborne transmission of Ebola virus as a case study in the inaccurate reporting of basic science, and we provide recommendations for improving the communication about unknown aspects of disease during public health crises. Basic scientific research is now considered an integral component of the fight against emerging infectious diseases like Ebola virus. The recent Ebola outbreak, however, demonstrates how the ineffective communication of basic science can stoke public panic more than it provides helpful tools to responders; basic science trades in probabilities and uncertainty, while public communication tends to favor more categorical claims. Here, we discuss the ethics of communicating scientific results, using, as a case study, the recent controversy over whether basic life sciences research demonstrates that Ebola could become transmissible via airborne respiratory droplet nuclei-popularly known as a virus becoming "airborne." We show how the science does not demonstrate this possibility, despite claims made in the popular and scientific press. We then recommend that uncertain scientific results in the context of public health crises ought to be communicated with humility, an emphasis on what is unknown, and a clear outline of the kinds of evidence that would give proof to controversial claims.
Output: Effectively Communicating the Uncertainties Surrounding Ebola Virus Transmission
Objective: To describe aspects found on HRCT scans of the chest in patients infected with the influenza A (H1N1) virus. Methods: We retrospectively analyzed the HRCT scans of 71 patients (38 females and 33 males) with H1N1 infection, confirmed through laboratory tests, between July and September of 2009. The HRCT scans were interpreted by two thoracic radiologists independently, and in case of disagreement, the decisions were made by consensus. Results: The most common HRCT findings were ground-glass opacities (85%), consolidation (64%), or a combination of ground-glass opacities and consolidation (58%). Other findings were airspace nodules (25%), bronchial wall thickening (25%), interlobular septal thickening (21%), crazy-paving pattern (15%), perilobular pattern (3%), and air trapping (3%). The findings were frequently bilateral (89%), with a random distribution (68%). Pleural effusion, when observed, was typically minimal. No lymphadenopathy was identified. Conclusions: The most common findings were ground-glass opacities and consolidations, or a combination of both. Involvement was commonly bilateral with no axial or craniocaudal predominance in the distribution. Although the major tomographic findings in H1N1 infection are nonspecific, it is important to recognize such findings in order to include infection with the H1N1 virus in the differential diagnosis of respiratory symptoms. Objetivo: Descrever os aspectos encontrados em TCAR do tórax de pacientes infectados pelo vírus influenza A (H1N1). Métodos: Foram analisadas retrospectivamente as TCAR de 71 pacientes (38 femininos e 33 masculinos) com diagnóstico confirmado de influenza A (H1N1) através da identificação laboratorial do vírus, estudados no período entre julho e setembro de 2009. A interpretação das TCAR foi realizada por dois radiologistas torácicos de forma independente, e, em caso de discordância, as decisões foram tomadas por consenso. Resultados: Os achados de TCAR mais comuns foram opacidades em vidro fosco (85%), consolidação (64%) ou a combinação de opacidades em vidro fosco e consolidação (58%). Outros achados foram nódulos do espaço aéreo (25%), espessamento das paredes brônquicas (25%), espessamento de septos interlobulares (21%), padrão de pavimentação em mosaico (15%), espessamento perilobular (3%) e aprisionamento aéreo (3%). As alterações foram frequentemente bilaterais (89%), com distribuição não específica (68%). Derrame pleural, quando observado, foi, em geral, de pequena monta. Não foram observadas linfonodomegalias. Conclusões: As alterações predominantes foram opacidades em vidro fosco, consolidações ou a combinação de ambas. O acometimento foi frequentemente bilateral e não houve predomínio quanto à distribuição (axial ou craniocaudal). Apesar de inespecíficos, é importante reconhecer os principais aspectos tomográficos da infecção por influenza A (H1N1) a fim de incluir essa possibilidade no diagnóstico diferencial de sintomas respiratórios. Descritores: Pneumonia viral; Tomografia computadorizada por raios X; Vírus da influenza A subtipo H1N1.
Output: Influenza A (H1N1) pneumonia: HRCT findings* Pneumonia por vírus influenza A (H1N1): aspectos na TCAR
When bad men combine, the good must associate; else they will fall one by one, an unpitied sacrifice in a contemptible struggle. The study of this chapter will enable you to: 1. Discuss the definitions of terrorism and weapons of mass destruction and their relation to the illicit use of biological agents. 2. List all legislative and administrative documents that address the legal aspects of the unlawful use of biological agents. 4. Discuss the prohibited uses of biological agents under international law. 5. List and briefly discuss the Homeland Security Presidential Directives that apply to biosecurity and biodefense.
Output: Legal Aspects of Biosecurity
Background: From October 2010 through February 2016, Arizona conducted surveillance for severe acute respiratory infections (SARI) among adults hospitalized in the Arizona-Mexico border region. There are few accurate mortality estimates in SARI patients, particularly in adults ≥ 65 years old. The purpose of this study was to generate mortality estimates among SARI patients that include deaths occurring shortly after hospital discharge and identify risk factors for mortality. Methods: Patients admitted to two sentinel hospitals between 2010 and 2014 who met the SARI case definition were enrolled. Demographic data were used to link SARI patients to Arizona death certificates. Mortality within 30 days after the date of admission was calculated and risk factors were identified using logistic regression models. Results: Among 258 SARI patients, 47% were females, 51% were white, non-Hispanic and 39% were Hispanic. The median age was 63 years (range, 19 to 97 years) and 80% had one or more pre-existing health condition; 9% died in hospital. Mortality increased to 12% (30/258, 30% increase) when electronic vital records and a 30-day posthospitalization time frame were used. Being age ≥ 65 years (OR = 4.0; 95% CI: 1.6-9.9) and having an intensive care unit admission (OR = 7.4; 95% CI: 3.0-17.9) were independently associated with mortality. Conclusion: The use of electronic vital records increased SARI-associated mortality estimates by 30%. These findings may help guide prevention and treatment measures, particularly in high-risk persons in this highly fluid border population.
Output: Mortality estimates among adult patients with severe acute respiratory infections from two sentinel hospitals in southern Arizona, United States, 2010-2014
The complex relationships between the human and animal species have never ceased to evolve since the emergence of the human species and have resulted in a human-animal interface that has promoted the cross-species transmission, emergence and eventual evolution of a plethora of infectious pathogens. Remarkably, most of the characteristics of the human-animal interface-as we know it today-have been established long before the end of our species prehistorical development took place, to be relentlessly shaped throughout the history of our species. More recently, changes affecting the modern human population worldwide as well as their dramatic impact on the global environment have taken domestication, agriculture, urbanization, industrialization, and colonization to unprecedented levels. This has created a unique global multi-faceted humananimal interface, associated with a major epidemiological transition that is accompanied by an unexpected rise of new and emerging infectious diseases. Importantly, these developments are largely paralleled by medical, technological, and scientific progress, continuously spurred by our never-ending combat against pathogens. The human-animal interface has most likely contributed significantly to the evolutionary shaping and historical development of our species. Investment in a better understanding of this human-animal interface will offer humankind a future head-start in the never-ending battle against infectious diseases.
Output: The Importance of Understanding the Human-Animal Interface From Early Hominins to Global Citizens
Despite the clinical relevance, dengue virus (DENV) research has been hampered by the absence of robust reverse genetic systems to manipulate the viral serotypes for propagation and generation of mutant viruses. In this article, we describe application of an infectious clone system for DENV serotype 1 (DENV1). Similar to previous clones in both flaviviruses and coronaviruses, the approach constructs a panel of contiguous cDNAs that span the DENV genome and can be systematically and directionally assembled to produce viable, full-length viruses. Comparison of the virus derived from the infectious clone with the original viral isolate reveals identical sequence, comparable endpoint titers, and similar focus staining. Both focus-forming assays and percent infection by flow cytometry revealed overlapping replication levels in two different cell types. Moreover, serotype-specific monoclonal antibodies (MAbs) bound similarly to infectious clone and the natural isolate. Using the clone, we were able to insert a DENV4 type-specific epitope recognized by primate MAb 5H2 into envelope (E) protein domain I (EDI) of DENV1 and recover a viable chimeric recombinant virus. The recombinant DENV1 virus was recognized and neutralized by the DENV4 type-specific 5H2 MAb. The introduction of the 5H2 epitope ablated two epitopes on DENV1 EDI recognized by human MAbs (1F4 and 14C10) that strongly neutralize DENV1. Together, the work demonstrates the utility of the infectious clone and provides a resource to rapidly manipulate the DENV1 serotype for generation of recombinant and mutant viruses.
Output: Epitope Addition and Ablation via Manipulation of a Dengue Virus Serotype 1 Infectious Clone
Autophagy is a cellular process in degradation of long-lived proteins and organelles in the cytosol for maintaining cellular homeostasis, which has been linked to a wide range of human health and disease states, including viral infection. The viral infected cells exhibit a complicated cross-talking between autophagy and virus. It has been shown that autophagy interacts with both adaptive and innate immunity. For adaptive immunity, viral antigens can be processed in autophagosomes by acidic proteases before major histocompatibility complex (MHC) class II presentation. For innate immunity, autophagy may assist in the delivery of viral nucleic acids to endosomal TLRs and also functions as a part of the TLR-or-PKR-downstream responses. Autophagy was also reported to suppress the magnitude of host innate antiviral immunity in certain cases. On the other hand, viruses has evolved many strategies to combat or utilize the host autophagy for their own benefit. In this review we discussed recent advances toward clarifying the cross-talking between autophagy and viral infection in mammalian cells.
Output: Cross-talking between autophagy and viral infection in mammalian cells
Background. Recent trials suggest procalcitonin-based guidelines can reduce antibiotic use for respiratory infections. However, the accuracy of procalcitonin to discriminate between viral and bacterial pneumonia requires further dissection. Methods. We evaluated the association between serum procalcitonin concentration at hospital admission with pathogens detected in a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia. Systematic pathogen testing included cultures, serology, urine antigen tests, and molecular detection. Accuracy of procalcitonin to discriminate between viral and bacterial pathogens was calculated. Results. Among 1735 patients, pathogens were identified in 645 (37%), including 169 (10%) with typical bacteria, 67 (4%) with atypical bacteria, and 409 (24%) with viruses only. Median procalcitonin concentration was lower with viral pathogens (0.09 ng/ mL; interquartile range [IQR], <0.05-0.54 ng/mL) than atypical bacteria (0.20 ng/mL; IQR, <0.05-0.87 ng/mL; P = .05), and typical bacteria (2.5 ng/mL; IQR, 0.29-12.2 ng/mL; P < .01). Procalcitonin discriminated bacterial pathogens, including typical and atypical bacteria, from viral pathogens with an area under the receiver operating characteristic (ROC) curve of 0.73 (95% confidence interval [CI], .69-.77). A procalcitonin threshold of 0.1 ng/mL resulted in 80.9% (95% CI, 75.3%-85.7%) sensitivity and 51.6% (95% CI, 46.6%-56.5%) specificity for identification of any bacterial pathogen. Procalcitonin discriminated between typical bacteria and the combined group of viruses and atypical bacteria with an area under the ROC curve of 0.79 (95% CI, .75-.82). Conclusions. No procalcitonin threshold perfectly discriminated between viral and bacterial pathogens, but higher procalcitonin strongly correlated with increased probability of bacterial pathogens, particularly typical bacteria.
Output: Clinical Infectious Diseases Clinical Infectious Diseases ® 2017;65(2):183-90 Procalcitonin as a Marker of Etiology in Adults Hospitalized With Community-Acquired Pneumonia
Facing the threats of infectious diseases, we take various actions to protect ourselves, but few studies considered an evolving system with competing strategies. In view of that, we propose an evolutionary epidemic model coupled with human behaviors, where individuals have three strategies: vaccination, self-protection and laissez faire, and could adjust their strategies according to their neighbors' strategies and payoffs at the beginning of each new season of epidemic spreading. We found a counter-intuitive phenomenon analogous to the well-known Braess's Paradox, namely a better condition may lead to worse performance. Specifically speaking, increasing the successful rate of self-protection does not necessarily reduce the epidemic size or improve the system payoff. The range and degree of the Braess's Paradox are sensitive to both the parameters characterizing the epidemic spreading and the strategy payoff, while the existence of the Braess's Paradox is insensitive to the network topologies. This phenomenon can be well explained by a mean-field approximation. Our study demonstrates an important fact that a better condition for individuals may yield a worse outcome for the society.
Output: Braess's Paradox in Epidemic Game: Better Condition Results in Less Payoff
Identity (ID) badges and lanyards worn by pediatric health care workers (HCWs) have been shown to be potential vectors of nosocomial bacterial infections. This cross-sectional study determined the contamination of ID badges and lanyards worn by pediatric HCWs with common respiratory and gastrointestinal viruses. The results showed that ID badges and lanyards are not significantly contaminated with common respiratory or gastrointestinal viruses and are unlikely to be a significant vector for nosocomial infection.
Output: Are identity badges and lanyards in pediatrics potentially contaminated with viral pathogens?
The human severe acute respiratory syndrome coronavirus (SARS-CoV) and the NL63 coronaviruses are human respiratory pathogens for which no effective antiviral treatment exists. The papain-like cysteine proteases encoded by the coronavirus (SARS-CoV: PLpro; NL63: PLP1 and PLP2) represent potential targets for antiviral drug development. Three recent inhibitor-bound PLpro structures highlight the role of an extremely flexible six-residue loop in inhibitor binding. The high binding site plasticity is a major challenge in computational drug discovery/design efforts. From conventional molecular dynamics and accelerated molecular dynamics (aMD) simulations, we find that with conventional molecular dynamics simulation, PLpro translationally samples the open and closed conformation of BL2 loop on a picosecond-nanosecond timescale but does not reproduce the peptide bond inversion between loop residues Tyr269 and Gln270 that is observed on inhibitor GRL0617 binding. Only aMD simulation, starting from the closed loop conformation, reproduced the 180°ϕ-ψ dihedral rotation back to the open loop state. The Tyr-Gln peptide bond inversion appears to involve a progressive conformational change of the full loop, starting at one side, and progressing to the other. We used the SARS-CoV apo X-ray structure to develop a model of the NL63-PLP2 catalytic site. Superimposition of the PLP2 model on the PLpro X-ray structure identifies binding site residues in PLP2 that contribute to the distinct substrate cleavage site specificities between the two proteases. The topological and electrostatic differences between the two protease binding sites also help explain the selectivity of non-covalent PLpro inhibitors.
Output: Comparison of SARS and NL63 Papain-Like Protease Binding Sites and Binding Site Dynamics: Inhibitor Design Implications
A major advantage of DNA vaccination is the ability to induce both humoral and cellular immune responses. DNA vaccines are currently used in veterinary medicine, but have not achieved widespread acceptance for use in humans due to their low immunogenicity in early clinical studies. However, recent clinical data have re-established the value of DNA vaccines, particularly in priming high-level antigenspecific antibody responses. Several approaches have been investigated for improving DNA vaccine efficacy, including advancements in DNA vaccine vector design, the inclusion of genetically engineered cytokine adjuvants, and novel non-mechanical delivery methods. These strategies have shown promise, resulting in augmented adaptive immune responses in not only mice, but also in large animal models. Here, we review advancements in each of these areas that show promise for increasing the immunogenicity of DNA vaccines.
Output: Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity
Starting in the 1960s, the human adenovirus type 12 (Ad12) system has been used in my laboratory to investigate basic mechanisms in molecular biology and viral oncology. Ad12 replicates in human cells but undergoes a completely abortive cycle in Syrian hamster cells. Ad12 induces neuro-ectodermal tumors in newborn hamsters (Mesocricetus auratus). Each tumor cell or Ad12-transformed hamster cell carries multiple copies of integrated Ad12 DNA. Ad12 DNA usually integrates at one chromosomal site which is not specific since Ad12 DNA can integrate at many different locations in the hamster genome. Epigenetic research occupies a prominent role in tumor biology. We have been using the human Ad12 Syrian hamster cell system for the analysis of epigenetic alterations in Ad12infected cells and in Ad12-induced hamster tumors. Virion or free intracellular Ad12 DNA remains unmethylated at CpG sites, whereas the integrated viral genomes become de novo methylated in specific patterns. Inverse correlations between promoter methylation and activity were described for the first time in this system and initiated active research in the field of DNA methylation and epigenetics. Today, promoter methylation has been recognized as an important factor in long-term genome silencing. We have also discovered that the insertion of foreign (Ad12, bacteriophage lambda, plasmid) DNA into mammalian genomes can lead to genome-wide alterations in methylation and transcription patterns in the recipient genomes. This concept has been verified recently in a pilot study with human cells which had been rendered transgenomic for a 5.6 kbp bacterial plasmid. Currently, we study epigenetic effects on cellular methylation and transcription patterns in Ad12-infected cells and in Ad12-induced hamster tumor cells. These epigenetic alterations are considered crucial elements in (viral) oncogenesis.
Output: Discoveries in Molecular Genetics with the Adenovirus 12 System: Integration of Viral DNA and Epigenetic Consequences of hamster cells with Ad12 • Adenovirus type 12 (Ad12) • Ad12-induced hamster tumors • Ad12 viral oncogenesis • A model
Avian paramyxoviruses (APMVs) are frequently isolated from domestic and wild birds throughout the world and are separated into nine serotypes (APMV-1 to -9). Only in the case of APMV-1, the infection of non-avian species has been investigated. The APMVs presently are being considered as human vaccine vectors. In this study, we evaluated the replication and pathogenicity of all nine APMV serotypes in hamsters. The hamsters were inoculated intranasally with each virus and monitored for clinical disease, pathology, histopathology, virus replication, and seroconversion. On the basis of one or more of these criteria, each of the APMV serotypes was found to replicate in hamsters. The APMVs produced mild or inapparent clinical signs in hamsters except for APMV-9, which produced moderate disease. Gross lesions were observed over the pulmonary surface of hamsters infected with APMV-2 & -3, which showed petechial and ecchymotic hemorrhages, respectively. Replication of all of the APMVs except APMV-5 was confirmed in the nasal turbinates and lungs, indicating a tropism for the respiratory tract. Histologically, the infection resulted in lung lesions consistent with bronchointerstitial pneumonia of varying severity and nasal turbinates with blunting or loss of cilia of the epithelium lining the nasal septa. The majority of APMV-infected hamsters exhibited transient histological lesions that self resolved by 14 days post infection (dpi). All of the hamsters infected with the APMVs produced serotype-specific HI or neutralizing antibodies, confirming virus replication. Taken together, these results demonstrate that all nine known APMV serotypes are capable of replicating in hamsters with minimal disease and pathology.
Output: Experimental infection of hamsters with avian paramyxovirus serotypes 1 to 9
The membrane protein gene(M) of transmissible gastroenteritis virus (TGEV) strain HB06, isolated from the feces of piglets infected with TGEV on a pig farm in Hebei province, was amplified by reverse transcriptasepolymerase chain reaction (RT-PCR). The amplified PCR products of TGEV HB06 were cloned, sequenced, and compared with other TGEV strains genes selected from the GenBank. Then, the recombinant fragment in pMD18-T was subcloned into corresponding sites of prokaryotic expression vector pGEX-6P-1 after digestion with EcoRI and XhoI to construct a recombinant fusion expression vector pGEX-6P-M. Then, the verified recombinant plasmid was transformed into Escherichia coli Rossetta (DE3), and the expression of M fusion protein was induced by using isopropylthio-beta-D-galactoside (IPTG) as inducer. The results showed that the gene fragment of M at a length of 789 bp was amplified and cloned into the vector pMD18-T successfully, and sequence comparison with that reported in GenBank revealed that the M gene complete sequence shares more than 94% homology in nucleotide. The result of SDS-PAGE showed that the recombinant membrane protein had a molecular mass of approximately 56 kDa, which was the same as the expected results. It was proven by Western blotting that the recombinant membrane protein had strong positive reactions with TGEV-specific antibody. Therefore, the expressed fusion protein has a good antigenicity. This work established a good foundation for further studies on the production of anti-TGEV vaccines.
Output: Cloning and expression of the membrane protein gene of TGEV HB06 strain
The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-kB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections.
Output: A20 (Tnfaip3) Deficiency in Myeloid Cells Protects against Influenza A Virus Infection
The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site Ø. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site Ø in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site Ø, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site Ø, each diverging at a conserved proline residue located in the middle of an α-helix. These data suggest that antigenic site Ø exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates. Respiratory syncytial virus (RSV) is a pervasive pathogen that causes severe lower respiratory tract infections, leading to~100,000 deaths globally each year and hundreds of millions of dollars in healthcare costs. However, despite its prevalence, there is no vaccine for RSV and the only available therapy is limited to high-risk infants, leaving the vast majority of people with no effective means of prevention or treatment. The RSV fusion (F) protein is a major target of neutralizing antibodies, including extremely potent antibodies that PLOS Pathogens | https://doi.recognize prefusion-specific epitopes. In this study, we determined the crystal structures of two neutralizing human antibodies bound to prefusion RSV F. Our results reveal that each antibody recognizes a different conformation of a neutralization-sensitive epitope, suggesting that this region is inherently flexible and may be important for RSV F function. These results should guide future vaccine-design efforts and help elucidate the mechanisms of RSV F triggering and fusion. Conformational flexibility of antigenic site Ø PLOS Pathogens | https://doi.
Output: Alternative conformations of a major antigenic site on RSV F
Partitiviridae Evolutio a b s t r a c t The population genetics of the family Partitiviridae was studied within the European race of the conifer pathogen Gremmeniella abietina. One hundred sixty-two isolates were collected from different countries, including Canada, the Czech Republic, Finland, Italy, Montenegro, Serbia, Spain, Switzerland, Turkey and the United States. A unique species of G. abietina RNA viruseMS1 (GaRV-MS1) appears to occur indistinctly in G. abietina biotypes A and B, without a particular geographical distribution pattern. Forty-six isolates were shown to host GaRV-MS1 according to direct specific RT-PCR screening, and the virus was more common in biotype A than B. Phylogenetic analysis based on 46 partial coat protein (CP) cDNA sequences divided the GaRV-MS1 population into two closely related clades, while RNA-dependent RNA polymerase (RdRp) sequences revealed only one clade. The evolution of the virus appears to mainly occur through purifying selection but also through recombination. Recombination events were detected within alignments of the three complete CP and RdRp sequences of GaRV-MS1. This is the first time that recombination events have been directly identified in fungal partitiviruses and in G. abietina in particular. The results suggest that the population dynamics of GaRV-MS1 do not have a direct impact on the genetic structure of its host, G. abietina, though they might have had an innocuous ancestral relationship.
Output: The European race of Gremmeniella abietina hosts a single species of Gammapartitivirus showing a global distribution and possible recombinant events in its history
Thread-based microfluidics Point-of-care Cotton Colorimetric Electrochemical A B S T R A C T Over the past decades, researchers have been seeking attractive substrate materials to keep microfluidics improving to outbalance the drawbacks and issues. Cellulose substrates, including thread, paper and hydrogels are alternatives due to their distinct structural and mechanical properties for a number of applications. Thread have gained considerable attention and become promising powerful tool due to its advantages over paper-based systems thus finds numerous applications in the development of diagnostic systems, smart bandages and tissue engineering. To the best of our knowledge, no comprehensive review articles on the topic of thread-based microfluidics have been published and it is of significance for many scientific communities working on Microfluidics, Biosensors and Lab-on-Chip. This review gives an overview of the advances of thread-based microfluidic diagnostic devices in a variety of applications. It begins with an overall introduction of the fabrication followed by an in-depth review on the detection techniques in such devices and various applications with respect to effort and performance to date. A few perspective directions of thread-based microfluidics in its development are also discussed. Thread-based microfluidics are still at an early development stage and further improvements in terms of fabrication, analytical strategies, and function to become low-cost, low-volume and easy-to-use pointof-care (POC) diagnostic devices that can be adapted or commercialized for real world applications.
Output: Recent advances in thread-based microfluidics for diagnostic applications
In August 2014, children's hospitals in Kansas City, Missouri and Chicago, Illinois notified the Centers for Disease Control and Prevention (CDC) about increased numbers of pediatric patients hospitalized with severe respiratory illness (SRI). In response to CDC reports, Public Health Ontario Laboratories (PHOL) launched an investigation of patients being tested for enterovirus D-68 (EV-D68) in Ontario, Canada. The purpose of this investigation was to enhance our understanding of EV-D68 epidemiology and clinical features. Data for this study included specimens submitted for EV-D68 testing at PHOL from September 1, 2014 to October 31, 2014. Comparisons were made between patients who tested positive for the virus (cases) and those testing negative (controls). EV-D68 was identified in 153/907 (16.8%) of patients tested. In the logistic regression model adjusting for age, sex, setting and time to specimen collection, individuals younger than 20 years of age were more likely to be diagnosed with EV-D68 compared to those 20 and over, with peak positivity at ages 5-9 years. Cases were not more likely to be hospitalized than controls. Cases were more likely to be identified in September than October (OR 8.07; 95% CI 5.15 to 12.64). Routine viral culture and multiplex PCR were inadequate methods to identify EV-D68 due to poor sensitivity and inability to differentiate EV-D68 from other enterovirus serotypes or rhinovirus. Testing for EV-D68 in Ontario from July to December, 2014 detected the presence of EV-D68 virus among young children during September-October, 2014, with most cases detected in September. There was no difference in hospitalization status between cases and controls. In order to better understand the epidemiology of this virus, surveillance for EV-D68 should include testing of symptomatic individuals from all treatment settings and patient age groups, with collection and analysis of comprehensive clinical and epidemiological data.
Output: Epidemiology of Enterovirus D68 in Ontario