100,350 research outputs found
Investigation of the Penicillium chrysogenum derived antifungal protein (PAF) in animal models
No full textA Penicillium chrysogenum által termelt antifungális fehérje (PAF) gátolja a szaporodását fontos pathogén fonalas gombáknak, köztük az Aspergillus család tagjainak és néhány dermatophytonnak. Továbbá a PAF-ról bebizonyították, hogy nincs toxikus hatása emlős sejtekre in vitro. Annak bizonyítására, hogy a PAF biztonságosan használható lehet a humán terápiában, in vivo kísérleteket végeztünk. Felnőtt egereknek adagoltunk PAF-ot intranasalisan különböző koncentrációkban, maximálisan 2700 μg/kg-ig két hétig naponta. Ez a koncentráció már erősen toxikus in vitro az összes használt érzékeny gombafajra. Tömegspektrometriával bizonyítottuk, hogy mérhető mennyiségű PAF halmozódott fel a tüdőkben a kezelés után. A PAF-fal kezelt egerekből származó tüdőszövet kivonatok szignifikáns antifungális aktivitást mutattak. Még a legmagasabb koncentrációnál sem pusztult el egyetlen egy állat sem a kezelés következtében, illetve nem figyeltünk meg mellékhatásokat. Szövettani vizsgálattal nem találtunk patológiás eltéréseket sem a májban, a vesékben, vagy a tüdőkben. Kisállat pozitron emissziós tomográfiával kimutattuk, hogy sem a fiziológiás sóoldat, sem a PAF nem váltott ki gyulladást, míg a lipopoliszacharid igen. A szer bőrre kifejtett hatását megvizsgáltuk, ahol az egerek füleinek vastagsága nem változott PAF kezelés után, míg a pozitív kontroll PMA adása után igen. Mivel nem találtunk toxikus hatást a PAF adagolása során, invazív pulmonalis aspergillosis (IPA) elleni hatékonyságát teszteltük IPA-ban szenvedő egereken. Felnőtt egereket immunszupprimáltunk, majd megfertőztünk Aspergillus fumigatus-szal. A stabil fertőzés létrehozása után, az állatokat PAF-fal kezeltük intranasalisan naponta kétszer 2,7 mg/kg koncentrációban, ami erősen toxikus in vitro A. fumigatusra. Az állatok mortalitása enyhén lassult, de végül minden állat elpusztult. A szövettani vizsgálatok masszív gombás fertőzést mutattak ki a PAF-fal kezelt és a kezeletlen állatok tüdejében is. Mivel az intranasalisan adagolt PAF képtelen volt legyőzni az IPA-t, módosított és kombinált kezeléseket alkalmaztunk. Az IPA-ban szenvedő állatok intraperitonealis kezelése PAF-fal az állatok túlélését csak 1 nappal hosszabbította meg. Hasonló eredményeket kaptunk amfotericin B-vel (AMB), amely szinergisztikusan hat in vitro a PAF-al. A kombinált kezelés AMB-vel és PAF-fal hatékonyabbnak bizonyult, mint akár az AMB vagy PAF kezelés önmagában. Mivel emlősökben eddig nem derült ki a PAF-nak semmilyen toxikus hatása, továbbá nem jelentettek eddig természetes vagy szerzett PAF rezisztenciával rendelkező A. fumigatus törzseket, érdemes lenne további vizsgálatokat végezni a PAF bevezetéséhez potenciális antifungális szerként a humán terápiába.The antifungal protein of Penicillium chrysogenum (PAF) inhibits the growth of important pathogenic filamentous fungi, including members of the Aspergillus family and some dermatophytes. PAF was proven to have no toxic effects on mammalian cells in vitro. To prove that PAF could be safely used in therapy, experiments were carried out to investigate its in vivo effects. Adult mice were inoculated with PAF intranasally in different concentrations, up to 2700 μg/kg daily, for 2 weeks. Mass spectrometry confirmed that a measurable amount of PAF was accumulated in the lungs after the treatment. Lung tissue extracts from PAF treated mice exerted significant antifungal activity. Even at the highest concentration - a concentration highly toxic in vitro for all affected molds used - animals neither died due to the treatment nor were any side effects observed. Histological examinations did not find pathological reactions in the liver, in the kidney, and in the lungs. Small-animal positron emission tomography revealed that neither the application of physiological saline nor that of PAF induced any inflammation while the positive control lipopolysaccharide did. The effect of the drug on the skin was examined in an irritative dermatitis model where the change in the thickness of the ears following PAF application was found to be the same as in control. Since no toxic effects of PAF were found in intranasal application, the next step was to test its efficacy against invasive pulmonary aspergillosis (IPA), experiments were carried out in mice suffering from IPA. Adult mice were immunosuppressed and then infected with Aspergillus fumigatus. After stable infection, the animals were inoculated with PAF intranasally at a concentration of 2,7 mg/kg twice per day. At this concentration -which is highly toxic in vitro to A. fumigatus- the mortality of the animals was slightly delayed but finally all animals died. Histological examinations revealed massive fungal infections in the lungs of both PAF-treated and untreated animal groups. Because intranasally administered PAF was unable to overcome IPA, modified and combined therapies were introduced. The intraperitoneal application of PAF in animals with IPA prolonged the survival of the animals only 1 day. Similar results were obtained with amfotericin B (AMB), with PAF and AMB being equally effective. Combined therapy with AMB and PAF -which are synergistic in vitro- was found to be more effective than either AMB or PAF treatment alone. As no toxic effects of PAF in mammals have been described thus far, and, moreover, there are so far no A. fumigatus strains with reported inherent or acquired PAF resistance, it is worth carrying out further studies to introduce PAF as a potential antifungal drug in human therapy
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Handwritten biographical information on Paulina T. McClung Merritt
No full textA handwritten biography of Paulina T. McClung Merritt by an unknown author, 1892.
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
No full textIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Pelevin’s Trinity in the novel “t”: author – protagonist – reader
No full textThe article attempts to interpret Pelevin's artistic strategy in the novel "T" by exploring its subject organization and addressing the key problems of the author, the protagonist, and the reader as they are seen by the researcher. The article analyzes the peculiarities of constructing the narrative reality in the novel "T", and goes on to discuss Pelevin's philosophic models of the development of the humankind, and the emergence of his new anthropology
Measuring industry-science links through inventor-author relations: A profiling method
No full textIn this pilot study we examine the performance of text-based profiling in recovering a set of validated inventor-author links. In a first step we match patents and publications solely based on their similarity in content. Next, we compare inventor and author names on the highest ranked matches for the occurrence of name matches. Finally, we compare these candidate matches with the names listed in a validated set of inventor-author names. Our text-based profile methodology performs significantly better than a random matching of patents and publications, suggesting that text-based profiling is a valuable complementary tool to the name searches used in previous studies.innovation; industry-science links; text-based profiling;
Wave turbulence of a rotating array of quantized vortices in the T → 0 temperature limit
No full textThe dynamics of quantized vortices in the zero temperature limit is currently of great interest, particularly in the case of the Fermi superfluid He-B. Here we study wave turbulence, generated by the librating motion of a rotating cylindrical container filled with He-B, in the limit of vanishing viscous forces at temperatures . The polarization of the quantized vortices with respect to the axis of rotation is measured using non-invasive NMR techniques. We observe a decrease of the polarization when the librating motion is started, and a two-stage relaxation process when the modulation of the rotation velocity is stopped. The first relaxation process is associated with the dissipation of large-scale flow stored in inertial waves and the solid body rotation of the vortex array. From the decay of these energy reservoirs we determine the rate of energy dissipation of large-scale flow. The later second process is related to the relaxation of Kelvin waves on individual vortices. This process is monitored by the recovery of the polarization. The existence of a Kelvin wave cascade at the lowest temperatures is currently a central open question. We supply some evidence for the cascade
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
No full textThe majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class Ibinding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitopederived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecificIFN-c-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire
Acoustic radiation due to scattering of T-S wave by the mean-flow distortion induced by steady local suction
No full textSubstantial sound waves can be generated by boundary-layer instability modes when the latter are scattered by a rapid mean-flow distortion. This is a rather generic mechanism and operates when an oncoming T-S wave is scattered by a steady local suction slot. This paper focuses on this problem by extending a recently developed Local Scattering Theory (Wu & Dong, J. Fluid Mech. submitted), where a so-called transmission coefficient, defined as the ratio of the T-S wave amplitude downstream of the scatter to that upstream, is introduced to characterize the effect of a local scatter on boundary-layer instability and transition. As in the earlier work, the mathematical formulation is based on triple-deck formulism, but in order to accommodate the acoustic far field, which was not considered in the paper mentioned, the unsteady terms in the upper deck, which play a leading-order role in radiation, are retained, and the influence of the radiated sound on the near-wall perturbation is included. The upper deck equation for the pressure is the Helmholtz equation rather than the Laplace equation. This leads to a modified pressure-displacement relation, which is coupled with the linearized boundary-layer equations in the lower deck. Discretization of the whole system formulates a generalized eigenvalue problem, which is solved numerically. It is found that suction suppresses oncoming T-S waves, and this effect increases with the suction velocity and the slot width. The directivity is ndependent of the flow parameters only when the Mach number is low. The intensity of the radiated sound in general increases with the frequency, the suction velocity and the width of the suction slot. Interestingly, for O(1) suction velocities, the radiated sound is very weak, indicating that the gain of stabilizing effect does not cause aeroacoustic penalty
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