834 research outputs found
Caricatures de Jules Baric à sujet médical et pharmaceutique
No full textKarikaturen von Jules Baric mit medizinischen und pharmazeutischen Themen.
Der Verfasser macht auf das Interesse des graphischen Werkes von J. J. A. Baric (1825-1905) für die Geschichte der Volks - Medizin und Pharmakopöe aufmerksam. Er hebt acht Karikaturen dieses Künstlers hervor welche den Verkauf in der Apotheke, herkömmliche Heilmittel (Pflaumen gegen Obstipation, Essig gegen Unwohlsein, Süssholz fur die Atmungswege), die Tuberkulose und das Quacksalberthema betreffen.Caricatures by Jules Baric on medical and pharmaceutical subjects.
The author draws attention to the graphic work of J. J. A. Baric (1825-1905) and its interest for history of popular medicine and pharmacopoeie. He presents eight caricatures by this artist, which have to do with selling in the pharmacy, traditional remedies (prunes for constipation, vinegar for fainting, licorice for the respiratory passages), tuberculosis, and the subject of charlatans.Julien Pierre. Caricatures de Jules Baric à sujet médical et pharmaceutique. In: Revue d'histoire de la pharmacie, 73ᵉ année, n°265, 1985. pp. 116-126
Baric Structures on Triangulated Categories and Coherent Sheaves
No full textWe introduce the notion of a baric structure on a triangulated category, as an abstraction of S. Morel\u27s weight truncation formalism for mixed ℓ-adic sheaves. We study these structures on the derived category of G-equivariant coherent sheaves on a G-scheme X. Our main result shows how to endow this derived category with a family of nontrivial baric structures when G acts on X with finitely many orbits.We also describe a general construction for producing a new t-structure on a triangulated category equipped with given t- and baric structures, and we prove that the staggered t-structures on introduced by Achar arise in this way. © The Author(s) 2010. Published by Oxford University Press. All rights reserved. For permissions
Hyper baric carburising process
No full textAnew patented technology improves low pressure carburising in vacuum furnace and traditionalcarburising in sealed quench furnace.The author, starting from argument that is possible to see in the specialized publications on the subject,has examined by scientific criteria which are the limits and the advantages of both the low pressurecarburising ,or the controlled atmosphere process. He evaluates the technological possibility to overcomesome of the limits that are conditioning the mechanical property of the heat treated pieces. Beforesuggesting new technological solutions that can promote better metallurgical properties together withclean environment, he examine some scientific arguments to make clear the problems.At the end of this research some important technological modification will be realised and the obtainedresults confirm the validity of the new process of hyper baric carburisation.The cause of the defects arising from the traditional technology have been eliminated and themodifications requested on the furnaces are not expensive. In same cases, maybe the new furnaces areeven cheaper, both in the buying phase than in the running cost
A Potential Negative-Strand Open Reading Frame in Zika Virus
No full textZika virus (ZIKV) is a recently emergent flavivirus transmitted by mosquitoes that is medically important due to neurological complications in the fetuses of infected mothers in the form of microcephaly, and less frequently in adults seen with cases of Guillain-Barré syndrome. ZIKV has a positive-sense RNA genome with one open reading frame (ORF) that encodes a single polyprotein. Interestingly, we identified a 550 base potential ORF marked by characteristics of an internal ribosomal entry site and a Kozak sequence on the negative-strand of this positive-sense viral genome that appears to be conserved across all well-characterized strains of the virus. To investigate the effect of this potential open reading frame, we cloned the ZIKV viral genome with a knock-out mutation to ablate the start codon of the negative strand ORF. We determined that the virus was live and viable by infection of C6/36 and Vero cell lines followed by immunostaining. RT-PCR was used to amplify the region of the mutation to confirm the presence of viral RNA in the supernatant and that the knockout had not reverted. Low and high MOI growth curves were conducted with Veros and found that the knockout had greater cytopathic effects with similar rates of replication compared to the wildtype H/PF/2013 strain. This is the first evidence of a negative-strand coding sequence shown to affect the pathogenicity of a positive-sense RNA virus. By further exploring the role of this coding sequence, and reverse complement ORFs in other positive-sense RNA viruses, we can develop a better understanding of the pathogenicity of these viruses and be better prepared for future outbreaks.Bachelor of Scienc
Impact of N69 glycosylation site of premembrane protein on viral fitness in dengue virus
No full textDengue virus (DENV) is a vector-borne, single-stranded positive-sense RNA virus with four distinct serotypes (DENV1-4). The four serotypes of DENV cause about 390 million human infections each year. The maturation of DENV during viral replication affects infectivity and antibody neutralization of the virus. The premembrane (prM) protein composition and the cleavage of the prM protein are determinants of DENV maturation. Across all four serotypes, the prM region is highly conserved. In particular, an N-linked glycosylation site that is located at the prM-N69 amino acid position is conserved across all but two strains of complete genomes provided by the Virus Pathogen Resource (ViPR) database. DENV prM glycosylation has not been extensively studied and there is no known function of the prM-N69 glycosylation site. To investigate the impact of N69 glycosylation of the prM protein, we generated three DENV mutants with loss-of-N69 glycosylation mutations. Subsequently, we derived four more DENV constructs from the previous three mutants with loss-of-N69-glycosylation mutations and a new gain-of-glycosylation mutation at a site proximally near the prM-N69 region. Our results demonstrate no sign of viral production in any of the loss-of-N69-glycosylation constructs. In contrast, we show widespread signs of viral production in one construct, DENV4∆ADD2 (a glycosylation moving mutant). Our result suggests 1) the N69 glycosylation is critical for viral fitness and 2) glycan presence is sufficient for viral fitness. By understanding the importance of the DENV structures like pRM, we’ll be more informed for designing effective DENV vaccines for the future.Bachelor of Scienc
Norovirus immunobiology and vaccine design
No full textNoroviruses are a genus of 40+ diverse positive polarity RNA viruses that cause approximately 23 million cases of gastroenteritis annually in the United States alone. The lack of a cell culture system or small animal model in which to study these human pathogens has hindered development of norovirus vaccines since their discovery in 1972. Because noroviruses have a very low infectious dose and high transmissibility, vaccines would be beneficial for employees and patrons of institutionalized settings such as hospitals, nursing homes, and schools, where outbreaks frequently occur. To begin to unravel how norovirus exposure affects the adaptive immune response, we utilized Venezuelan equine encephalitis virus replicons as immune adjuvants and delivery vectors for norovirus antigens to demonstrate induction of B cell and T cell responses in protective immunity to noroviruses in mice. Norovirus-like particle (VLP) vaccination induces robust IgG and IgA responses in serum, feces, and tissues that can block norovirus binding to ABH histo-blood group antigen receptors in a strain-specific manner but have little cross-reactivity to additional norovirus strains. CD4+ T cells are also activated following vaccination to produce large amounts of the anti-viral compound IFN-[gamma] upon stimulation with homologous norovirus VLPs or peptides in vitro. To effect a broader immune response, we vaccinated mice with a cocktail of VLPs from multiple norovirus strains simultaneously resulting in cross-reactive receptor-blocking antibody responses to heterologous strains not included in the vaccine composition. Furthermore, multivalent vaccination did not diminish specificity or quantity of antibody or T cell responses to individual vaccinating strains. Studies with the newly discovered murine norovirus (MNV) revealed that MNV VLP vaccination protects against MNV infection, and both humoral and cellular immunity are involved in clearance of the virus. Furthermore, adoptive transfer of serum but not CD4+ or CD8+ T cells from vaccinated mice completely protected immunodeficient mice from MNV infection, suggesting pre-existing antibodies can prevent establishment of acute infection. Vaccination with multiple human VLPs also provided significant protection against MNV infection in mice, advocating the development of multivalent human norovirus vaccines for cumulative protection against norovirus challenge
Genetic approaches to the study of coronavirus replication and pathogenesis
No full textThe recently developed coronavirus reverse genetic systems have been a tremendous asset for improving our understanding of the viruses' complex replication strategy, pathogenesis, mechanisms of host-range expansion, and in the development of anti-viral therapies. We completed two studies using coronavirus infectious clones. The first evaluated a severe acute respiratory syndrome coronavirus (SARS-CoV) vaccine to protect against an antigenically divergent strain. The second study determined the requirement for proteolytic processing of a highly conserved region of the replicase polyprotein for efficient replication. Ideally, a SARS-CoV vaccine should confer long-term protection, especially in vulnerable senescent populations, against both the 2003 epidemic strains and zoonotic strains that may yet emerge from animal reservoirs. Using Venezuelan equine encephalitis virus replicon particles (VRP) expressing the 2003 epidemic Urbani SARS-CoV strain spike (S) glycoprotein (VRP-S) or the nucleocapsid (N) protein from the same strain (VRP-N) as candidate vaccines, we tested their ability to protect young and senescent mice when challenged with homologous and heterologous SARS-CoV strains. The novel heterologous SARS-CoV strain (icGDO3-S) was constructed using synthetic biology and reverse genetics to generate a chimeric virus encoding a synthetic S glycoprotein gene of the most genetically divergent human strain, GDO3, which clusters among the zoonotic SARS-CoV, and represents a strain of SARS-CoV that emerged into the human population independently of the epidemic strain. VRP-S, but not VRP-N, provided protection for both young and senescent mice when challenged with the epidemic strain. When challenged with icGDO3-S, VRP-S protected young mice but only partially protected senescent animals. VRP-N vaccinated mice demonstrated enhanced pulmonary inflammation, which included eosinophils among the cellular infiltrates, following SARS-CoV or icGDO3-S challenge. The highly conserved region at the carboxy-terminus of the coronavirus replicase ORF1a polyprotein is processed by the main proteinase (Mpro) into mature products including nsp7, nsp8, nsp9 and nsp10, proteins with predicted or identified activities involved with RNA synthesis. Mpro continuous translation and processing of ORF1ab polyproteins is required for replication, but specific cleavage events may be dispensable. We determined the requirement for the nsp7-10 proteins and their proteolytic processing during the replication of murine hepatitis virus (MHV), which is phylogenetically grouped with the human coronaviruses OC43 and SARS-CoV. Using the MHV reverse genetics system, in frame deletions of the coding sequences for nsp7, 8, 9, and 10 were either deleted, or the flanking cleavage sites ablated, and the effect upon replication determined. Viable viruses were characterized through analysis of Mpro processing, subgenomic RNA transcription, and in vitro growth fitness. Deletion of any of the four regions encoding nsp7 through 10 was lethal. Disruption of the cleavage sites flanking the protein domains were lethal with the exception of the nsp9/10 cleavage site, which resulted in a mutant virus with severely attenuated replication. In order to determine if a distinct function could be attributed to preprocessed forms of the replicase polyprotein including nsp7-10, the genes encoding nsp7 and nsp8 were rearranged. The mutant virus MHV8/7 was not viable, suggesting that the noncleaved intermediate protein may be essential for replication or proteolytic processing
Evaluations Of Severe Acute Respiratory Syndrome Coronavirus Therapeutics And A Viral Capacity For Plasticity And Escape.
No full textThe Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emerged in 2002/2003, causing the deaths of almost a tenth of the 8000 individuals infected worldwide before it was controlled by public health measures. While the 2003 epidemic strain is likely extinct, the importance of coronaviruses as emergent zoonotic viruses was again realized with the emergence of a novel human coronavirus in Saudi Arabia in 2012. Despite a decade of research on SARS-CoV no approved vaccine or therapeutic yet exists, and development of broadly neutralizing and effective therapeutics for coronaviruses remains a priority. Neutralizing antibodies targeting the Spike glycoprotein (S) are both necessary and sufficient for protection against SARS-CoV, but the high genetic diversity and mutability of SARS-CoV in natural infections presents a challenge to both vaccine- and antibody-based therapeutics. Thus, an effective SARS-CoV therapeutic should provide S-specific immunity that is nonetheless broad enough to counter heterologous and derivative S variants. This work was designed to assess immunization strategies towards SARS-CoV, to explore the plasticity and neutralization networks of the Spike glycoprotein, and to assess the utility of molecular models to predict host range and antibody neutralization. In the first study we explored the limitations of a doubly inactivated SARS-CoV vaccine, identifying a vaccine-induced immunopathology and emphasizing the importance of rigorous challenge viruses and animal models that accurately recapitulate age-associated lung pathology. Second, in two collaborative studies we assessed multi-generational monoclonal antibodies designed to be broadly neutralizing or escape resistant, and extended our characterization of the Spike receptor binding domain (RBD) as a highly plastic antiviral target. Finally, we characterized ten recombinant Combinatorial Escape Viruses (CEVs) engineered from a database of antibody escape substitutions in the RBD. These CEVs were designed to assess the plasticity of the S-RBD, the utility of predictive modeling, and the neutralization networks across the RBD. The tools developed this study will assist in the development of predictive models and standardized platforms for combination monoclonal antibody immunotherapies for emergent viruses. These studies of SARS-CoV have extended our understanding of a key neutralizing target and have provided a valuable foundation for the rapid characterization of novel coronaviruses and potential therapeutics.Doctor of Philosoph
SARS coronavirus pathogenesis and therapeutic treatment design
No full textThrough the study of the viral pathogenesis, the mechanisms of disease can be elucidated providing specific targets for therapeutic intervention intended to prevent the development of disease. We conducted four studies to gain a better understanding of SARS-CoV disease pathogenesis and therapeutic design. We conducted two studies to investigate SARS-CoV evolution and adaptation to the human host. We have also investigated the importance of the innate immunity in protection from SARS-CoV disease. Lastly, we evaluated the protective efficacy of vaccination in senescent populations. The prototypic civet SZ16 spike (S) gene was engineered into our epidemic strain infectious clone (icSARS) to create the recombinant icSZ16-S virus. A mutant of icSZ16-S (icSZ16-S K479N) was passaged on human airway epithelial cells (HAE) and resultant "evolved" viruses contained mutations in S that enhanced interactions with the receptor (hACE2) though adaptive mutations differed from those seen during the epidemic. icSARS grew equally well in cells expressing the civet or human receptor while icSZ16-S only grew within civet expressing cells. Dual species tropism is retained by the epidemic strain suggesting it evolved through repeated passage between human and civet hosts. Mice deficient in MyD88 (MyD88-/-), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to mouse adapted SARS-CoV (rMA15) infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue was significantly reduced in MyD88-/- mice compared to wild-type mice suggesting that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection. We have developed a senescent BABL/c mouse model of SARS-CoV pathogenesis where infection with the mouse adapted SARS-CoV bearing a GD03 S glycoprotein (rMA15 GD03-S) mortality in senescent mice. We vaccinated senescent mice with Venezuelan equine encephalitis virus replicon particles (VRP) expressing Urbani-S, GD03-S, SZ16-S, a pool of all three S expressing VRPs or control VRPs in a prime/boost regimen. After rMA15 GD03-S infection, all mice in the VRP HA and SZ16-S groups died while Urbani-S, GD03-S and Pool-S groups demonstrated 11, 29, 33% survival rates, respectively
Mechanisms of GII.4 norovirus antigenic variation and evolution
No full textNoroviruses infect an estimated 21 million people annually in the United States, resulting in ~70,000 hospitalizations and ~800 deaths. These viruses are easily transmitted among people in close proximity, including healthcare and educational settings, cruise ships, military environments, and restaurants. Norovirus symptoms include vomiting and diarrhea over a period of 24-72 hours, but life-threatening or chronic infections can develop in infants and very young children, the elderly and immunocompromised individuals. Unfortunately, there are no licensed norovirus therapeutics or vaccines currently available. One factor complicating vaccine and therapeutic design for noroviruses is antigenic variation in GII.4 norovirus, which account for over 70% of all outbreaks. Every 2-4 years the predominant circulating GII.4 strain is replaced by a new emergent strain. In predominant GII.4 strains, genetic changes are most prevalent in continuously evolving areas of the capsid P2 domain and correlate with antigenic changes. This suggests that GII.4 norovirus strain emergence is driven by changes in neutralization epitopes as a result of escaping herd immunity to the previous strain. Therefore, effectively designed therapeutics and vaccines must be broadly active or easily reformulated to account for the antigenic properties of emergent viruses. Our work aims to define the mechanisms that drive genetic changes leading to antigenic changes in GII.4 noroviruses. In Chapter 2, we use structure-guided approaches to map epitope A, the immunodominant GII.4 blockade (potential neutralizaton) epitope. Chapter 3 characterizes antigenic changes between two successive GII.4 strains, GII.4-2009 New Orleans and GII.4-2012 Sydney. In Chapter 4, we investigate the antigenic change that occurs within an individual chronically infected with norovirus over time, map the varying epitopes and compare the degree of change with population-wide changes. We also propose that broadly-blocking GII.4 human monoclonal antibody 71.4 is a potential treatment for chronic norovirus infection. Chapter 5 proposes a VLP-based vaccine platform that utilizes chimeric particles to induce a broadly-blocking immune response against multiple GII.4 strains. These GII.4 norovirus studies have allowed us to identify major determinants of antigenic change in GII.4 noroviruses that will allow for rapid diagnostic identification of new epidemic strains and direct the rational development of norovirus therapeutics and vaccines.Doctor of Philosoph
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