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The Critical Role of PI3K-AKT-mTOR Pathway for IL-15 Induced NK Cell Effector ResponsesNandagopal, Neethi January 2014 (has links)
Natural killer (NK) cells were so named for their uniqueness in killing certain tumor and virus-infected cells without prior sensitization unlike T lymphocytes. NK cells possess a myriad of activation receptors and cytokine receptors that allow them to recognize stress ligands on infected/tumor cells and respond to the cytokines produced during the inflammatory process. Upon activation, NK cells produce pro-inflammatory cytokines, cytotoxic granules and chemokines to recruit other cells which ultimately result in killing of target cells. These functions of NK cells are modulated in vivo by several immune mediators; IL-15 being the most potent in enabling NK cell homeostasis, maturation and activation. Indeed, IL-15 knockout mice have no detectable NK cells.
During microbial infections, NK cells stimulated with IL-15 display enhanced cytokine responses. This priming effect has previously been shown with respect to increased IFN-γ production in NK cells upon IL-12 and IL-15/IL-2 co-stimulation. In this study, I explored if this effect of IL-15 priming can be extended to other cytokines and observed enhanced NK cell responses to stimulation with IFN-, IL-21, IL-2 and IL-4 in addition to IL-12. Notably, we also observed elevated IFN-γ production in primed NK cells upon stimulation through the Ly49H activation receptor. IL-15 treatments induced NK cell proliferation, enhanced NK cell responses to activating stimuli and equipped them with cytotoxic granules thereby “readying” them for battle against infections and tumors. Here, we try to understand the signaling mechanisms underlying IL-15 treatments that activate NK cells. Currently, the fundamental processes required for priming and whether these signaling pathways work collaboratively or independently for NK cell functions are poorly understood.
To identify the key signaling events, we examined IL-15 priming on NK cells in which the pathways emanating from IL-15 receptor activation were blocked with specific inhibitors. Our results demonstrate that the PI3K-AKT-mTOR pathway is indispensable for cytokine responses in IL-15 primed NK cells. Furthermore, this pathway is also implicated in a broad range of IL-15 induced NK cell effector functions such as proliferation and cytotoxicity. Given that NK cells are critical for control of viral infections like murine cytomegalovirus (MCMV), we decided to analyze the consequences of blocking the PI3K-AKT-mTOR pathway in NK cells on its anti-viral responses. Likewise, NK cells from mice treated with rapamycin to block the mTOR pathway displayed defects in proliferation, IFN-γ and granzyme B production resulting in elevated viral burdens upon MCMV infection. Taken together, our data demonstrates the requirement of PI3K-mTOR pathway for enhanced NK cell functions by IL-15. It also shows that IL-15 primes NK cell responses to several cytokines and to Ly49H activation receptor stimulation. To our knowledge this is first report to demonstrate the requirement of mTOR activity in NK cells for efficient control of acute MCMV infections; thereby coupling the metabolic sensor mTOR to NK cell anti-viral responses.
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Uznávání výnosů v softwarovém průmyslu / Revenue recognition in software industryMarušáková, Tereza January 2014 (has links)
Diploma thesis is dedicated to software revenue recognition under IFRS and US GAAP. It aims to address all specifics related to software industry as well as challenges which arise from sales of intangible assets and intellectual property in form of licenses. Thesis covers both standard software delivery (OnPremise) and delivery in cloud for Software as a service. Significant portion is dedicated to multiple element arrangements which are very common for software industry. It also analyses new revenue recognition standard IFRS 15 Revenues from contracts with customers, which is a result of joined convergence project of IASB and FASB and how it will impact current revenue recognition practices in the industry.
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Efectos del Covid19 en la NIIF 15 y la Pérdida Esperada de acuerdo con la NIIF 9Aguirre, Fernando 21 May 2021 (has links)
Una mirada a las NIIF 15, y sus efectos financieros bajo en contexto del Covid 19.
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Experimentální systém pro produkci IL-15 na virových nosičích / Experimental system for production of IL-15 on viral carriersMusil, Dominik January 2020 (has links)
Interleukin 15 has great application potential such as in the biological treatment of cancer. It is involved in a variety of immunological processes, the most important of these involve influencing and induction of NK cells and T-lymphocytes proliferation. However, its therapeutic usages are limited by a low stability and short half-life. For this reason, there are various approaches of stabilization and expansion of its biological activity being explored. In this work, we analysed and developed a new approach, which uses viral nanostructures derived from major capsid VP1 protein of mouse polyomavirus as a carrier of IL-15. Moreover, VP1 proteins can be relatively easily modified and they are also capable to penetrate into the tumour cells. There were prepared two variants of IL-15 together with control nanostructures in the baculovirus expression system, one was composed of IL-15 and the other of the IL-15 fusion protein and truncated variant of VP1. Protein constructs were characterized by electron microscopy and biochemical methods. The total protein yield of VP1ΔC-IL15-HIS fusion variant was higher (up to 53 mg/L of complete medium) than IL-15 alone (8,5 mg/L). However, testing of the biological activity of the prepared proteins in vitro did not show any induction of proliferation on Jurkat...
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Application of IFRS 15 and its impact on revenue recognition and financial reportingZelinková, Barbora January 2017 (has links)
The diploma thesis deal with the application of the new standard IFRS 15 and ref-ert to changes in revenue recognition and financial reporting process with re-place current standards IAS 11 Construction contracts and IAS 18 Revenue. In theoretic part, there is described reason for implementation of new standard with detailed requirements. The practical part identifies the impact which is affecting timing of revenue recognition in different sectors on financial reporting.
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A systematic review of helminth infections of tragelaphine antelopes in AfricaCilliers, Maruchelle January 2019 (has links)
The tragelaphine antelopes comprise a group of nine species, namely Tragelaphus eurycerus (bongo), Tragelaphus scriptus (bushbuck), Tragelaphus oryx (common eland), Tragelaphus derbianus (giant eland), Tragelaphus strepsiceros (greater kudu), Tragelaphus imberbis (lesser kudu), Tragelaphus buxtoni (mountain nyala), Tragelaphus angasii (nyala) and Tragelaphus spekii (sitatunga) which are all confined to the African continent. Currently, a total of 72 species of helminth parasites from seven tragelaphine antelope species have been recorded, while no records exist for T. imberbis and T. buxtoni. Some helminth species are shared with domestic stock and only a few helminths have zoonotic implications. The clinical significance of most helminth species in tragelaphine antelopes is unknown. This information was compiled based on an extensive search for records in the literature ranging from the early nineteen-hundreds until August 2019. A synopsis of the results is presented in tabular form. / Mini Dissertation (MSc (Tropical Animal Health))--University of Pretoria, 2019. / Veterinary Tropical Diseases / MSc (Tropical Animal Health) / Unrestricted
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Ontogenetic allometry of the postcranial skeleton of the giraffe (Giraffa camelopardalis) with application to giraffe life history evolution and palaeontologyVan Sittert, Sybrand Jacobus January 2015 (has links)
Giraffes (Giraffa camelopardalis) have evolved into a unique and extreme shape. The
principle determinant of its shape is the skeleton and the overarching theme of the study
was to describe how this shape is achieved throughout ontogeny. Accordingly, the study had
three main objectives: 1) To describe the growth of the giraffe postcranial skeleton
allometrically, 2) To interpret the allometric patterns described in an evolutionary and
functional sense and 3) To reconstruct the size and shape of the extinct Giraffa sivalensis
using, if feasible, allometric equations obtained in this study. Secondary objectives were to
a) establish if sexual dimorphism was evident in G. camelopardalis and b) determine if
growth patterns in the foetus differed from those in postnatal G. camelopardalis.
Data were collected from giraffes culled as part of conservancy management in Zimbabwe.
The sample included 59 animals from which vertebral dimensions were taken in 48 animals
and long bone dimensions in 47 animals. Body masses ranged from 21 kg to 77 kg in
foetuses and 147 kg to 1412 kg postnatally, representing 29 males and 30 females. In
addition to body mass, external body dimensions were recorded from each animal. Each
vertebra and unilateral long bone was dissected from the carcasses and cleaned, after which
dimensions were measured with a vernier calliper, measuring board or measuring tape.
Vertebral dimensions measured included body (centrum) length, height and width as well as
vertebral spinous process length. Long bone dimensions included length, two midshaft
diameters and circumference. Allometric equations (y=bxk) were constructed from the data,
with special interest in the scaling exponent (k) to illustrate regions of positively allometric,
isometric or negatively allometric growth. In the first series of analyses the growth patterns of the components of the postcranial axial
skeleton were analysed. The adaptations in vertebral growth to create and maintain
extraordinary shape were identified as disproportionate elongation of the cervical vertebrae
after birth, increasing cross sectional diameters of the cervical vertebrae from cranial to
caudal and positively allometric spinal process growth. The theory of sexual selection as a
driver for neck elongation in giraffes was brought into question by showing that male and
female vertebral elongation rates are similar relative to increases in body mass.
The second series of analyses described the growth pattern of the long bones of the
appendicular skeleton. The allometric exponents seemed unremarkable compared to the
few species described previously, and it was shown that the giraffe appendicular skeleton
does not elongate in the dramatic way the neck does. Limbs at birth, after lengthening with
positive allometry in utero, are already elongated and slender in shape and a further
increase in the gracility of the bones is either not possible or not desirable. This result
implies that it is neck elongation rather than leg elongation that is the dominant factor in
the evolution of the giraffe shape. Nevertheless, the front limb bones and especially the
humerus may show responsiveness to increasing high loads and/ or bending moments,
which may be caused by the neck mass which increases with positive allometry, or with
behaviours such as splaying the forelegs during drinking.
In the third component of the study ontogenetic allometric equations in extant giraffes
were applied to the remains of an extinct giraffid, G. sivalensis. The procedure was unusual
as it employed ontogenetic regressions instead of the more commonly used interspecific
regressions. The appropriateness of each equation to estimate body mass was evaluated by
calculating the prediction error incurred in both extant giraffes and okapis (Okapia
johnstoni). It was concluded that, due to body shape, ontogenetic equations were adequate
and perhaps preferable to interspecific equations to estimate proportions in Giraffa species.
This analysis showed that G sivalensis was smaller than extant giraffes and weighed around
400 kg (range 228 kg 575 kg), with a neck length of about 147 cm and a height of 390 cm.
There may be evidence of sexual dimorphism in this species, with males being about twice
the body weight of females. However, if sexual dimorphism was not present and all the
bones were correctly attributed to this species, then G. sivalensis had a slender neck with a
relatively stocky body.
In conclusion, this study established ontogenetic regression equations for the skeleton of an
animal of which the body shape seems to be at the extreme limits of mammalian possibility.
The value of the current study lies especially in its sample size and quality, which included
an unprecedented number of giraffe body masses, vertebral and long bone dimensions. This
dataset had applications in the giraffe s evolutionary biology, palaeontology and even
ecology. Future studies still need to compare the findings from giraffe growth with similar
data from other taxa, especially those with long legs and necks. Specifically, it would
interesting to determine if positively allometric neck growth combined with isometric leg
growth is found in other mammalian species. In addition, the strength of giraffe long bones and vertebrae needs to be investigated with more accuracy using parameters like second
moment of area. Lastly, further palaeontological studies on other giraffid sizes are necessary
to validate the current and future interpretations of fossil giraffid findings. / Thesis (PhD)--University of Pretoria, 2015. / tm2016 / Production Animal Studies / PhD
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Monitoring adrenocortical function as a measure of stress in blue wildebeest (Connochaetes taurinus)De Haast, Adel Riette January 2016 (has links)
Like many other wildlife species, blue wildebeest (Connochaetes taurinus) are routinely captured for relocation purposes. Several studies have shown that physiologically this is a very stressful period for wild animals and can affect several aspects of their well-being. Little is known about the level of physiological stress experienced by blue wildebeest during capture and confinement before transport. A non-invasive approach to assess adrenocortical function as a measure of physiological stress would be preferable, as animals are not disturbed during sample collection, and therefore sampling is feedback free. Currently, however, such a non-invasive measure has not been evaluated for any wildebeest species.
An adrenocorticotropic hormone (ACTH) challenge test was performed on one sub-adult male and one adult female. We examined the suitability of five enzyme immunoassays (EIAs), detecting faecal glucocorticoid metabolites (fGCM) with a 5?-3?-ol-11-one (3?,11oxo-CM), 5?-pregnane-3?,11?,21-triol-20-one (37e), 11?,21-diol-20-one (corticosterone), 11,17,21-trihydroxypregn-4-ene-3,20-dione (cortisol), and 11,17-dioxoandrostane (11,17-DOA) structure respectively, for monitoring stress-related physiological responses in blue wildebeest. After evaluating all five EIAs, it was concluded that the EIA measuring 11,17-DOA performed the best for detection of fGCMs in blue wildebeest with a 21 fold increase above the baseline in the male and a 4,7 fold increase above the baseline in the female at 12 hours post ACTH injection.
Under field conditions the use of the 11,17-DOA EIA allowed the monitoring of fGCM alterations when wildebeest were captured using a mass capture technique; fGCM concentrations were elevated by 1,5 times in samples collected from animals restrained for up to 10 hours in a truck compared to those collected directly after capture (P <0,001). No significant increase in fGCM concentrations was detected in faecal samples collected directly after capture from animals of the same herd captured either on day 1 or day 2 of mass capture, indicating that the presence of a helicopter during the two days of capture was not associated with a profound stress response in wildebeest that were not captured at the time but were in the vicinity of the capture. Storage of faeces in labelled plastic containers at ambient temperature for up to 48 hours post-defecation resulted in a significant decrease in 11,17-DOA levels from 8 to 48 hours after defecation. Therefore sample collection for 11,17-DOA determination in wildebeest can occur for up to 8 hours post-defecation without the risk of substantial decreases in 11,17-DOA concentrations. By identifying a suitable assay for determining 11,17-DOA concentrations in blue wildebeest, it can now be used by researchers, wildlife managers and veterinarians to reliably monitoring the physiological stress responses to capture or other management procedures with minimum interference to the animals. We have also shown that the presence of a helicopter during capture does not appear to have a lasting influence on wildebeest 11,17-DOA concentrations, but prolonged restraint for 10 hours does. / Dissertation (MSc)--University of Pretoria, 2016. / Paraclinical Sciences / MSc / Unrestricted
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Determination of the pathophysiological consequences of capture and capture-induced hyperthermia in blesbok (Damaliscus pygargus phillipsi)Fitte, Agustina January 2016 (has links)
An unacceptable number of wild animals die or experience morbidity as a result of capture-related
complications. Capture-induced hyperthermia is believed to play a role in the morbidity and
mortality of captured animals. The aims of this research were to gain a better understanding of the
pathophysiological consequences of capture and capture-induced hyperthermia and to better
understand the association between capture-induced hyperthermia and capture myopathy. We
aimed to determine whether cooling could reduce the pathophysiological consequences of capture
and protect against capture related complications like capture myopathy.
Forty wild blesbok were captured from the wild and then housed in bomas at Groenkloof Nature
Reserve for the duration of the study. These animals were divided into three groups which included
a group of animals that were chased and cooled during immobilization (C+C), a group that was
chased but not cooled during immobilization (CNC) and a control group that was not chased before
or cooled during immobilization (Ct). The control group received powder diazepam in their feed two
hours before they were darted to minimize their stress response to capture. The treatment groups
were chased for 15 minutes before they were darted. All the animals were darted and immobilized
with etorphine and azaperone. The chased and cooled group were doused with 10L of 4°C water
over a 10 minute period during the immobilization. The immobilization period lasted for forty
minutes in all the animals.
A number of clinical and physiological parameters were measured in all the animals directly after
induction into immobilization, 40 minutes later, and then on day 2, 16 and 30 post the initial
capture. On these subsequent days the animals were not chased but they were simply all
immobilized in their holding bomas, for data and sample collection, after they received in feed diazepam. The parameters measured and analysed included muscle and rectal temperature,
PaO2, PaCo2, pH, lactate, GGT, GLDH, creatinine, BUN, CK, AST, cardiac troponin I and cortisol.
The animals in the control group had normal values for all the variables measured except they
were hypoxic during the immobilization. The animals that were chased developed hyperthermia,
hypoxia and mild acidaemia, and they had mildly elevated concentrations of GLDH, AST, CK and
creatinine indicating mild hepatic, renal and skeletal muscle damage. These animals also had
severe increases in lactate and cardiac Troponin I concentrations indicating cardiac damage
possibly as a result of the hypoxia that occurred during the chase and the immobilization. Despite
cooling correcting the hyperthermia, it did not prevent or protect against any of these
pathophysiological effects. Therefore, this capture-induced hyperthermia appeared to play a limited
role in causing these effects.
Therefore, capture that involves chasing animals before immobilization appears to primarily cause
cardiac muscle damage. This capture-induce cardiomyopathy may have profound secondary
consequences, which could result in mortality or other capture related complications. / Dissertation (MSc)--University of Pretoria, 2016. / Paraclinical Sciences / MSc / Unrestricted
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L'opposizione ordinaria del terzoGiuliani, Silvia January 2019 (has links)
La prima parte dell’elaborato si occupa della ricerca di una matrice originaria del rimedio in oggetto, nel tentativo di comprenderne la funzione tradizionale in rapporto con gli istituti esistenti, posti a tutela sia delle parti che dei terzi; matrice da individuarsi (potenzialmente) in alcuni istituti del diritto romano. Si dedicherà poi un’attenzione peculiare all’esperienza francese – sia dal punto di vista storico che comparato, e quindi in una prospettiva diacronica e sincronica – per poi soffermarsi sulle peculiarità della dottrina tedesca, la quale, malgrado lo spiccato interesse manifestato tra il XIX e il XX secolo per il tema del presente studio, non è stata recepita dalla propria prassi giudiziaria e ha trovato scarso seguito negli sviluppi successivi. Anche alla luce degli esiti della prima indagine, si tornerà ad analizzare le possibili soluzioni interpretative sorte nel nostro ordinamento attraverso una lunga elaborazione dottrinale e di frequenti – quanto incostanti- pronunce della Suprema Corte di Cassazione.
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