1,642 research outputs found
Enhanced postoperative surveillance versus standard of care to reduce mortality among adult surgical patients in Africa (ASOS-2) : a cluster-randomised controlled trial
No full textFunding Information: R M Pearse reports grants from Edwards Lifesciences and Intersurgical; and personal fees from Edwards Lifesciences and GlaxoSmithKline, outside of the submitted work. R M Pearse also reports being a member of the editorial boards of the British Journal of Anaesthesia and the British Journal of Surgery. A B A Prempah was the recipient of the World Federation of Societies of Anaesthesiologists–International Anesthesia Research Society Clinical Research Fellow in Global Surgery and Anaesthesia in Africa. All other authors declare no competing interests. Funding Information: The ASOS-2 pilot and trial were partially supported by a grant (OPP#1161108) from the Bill & Melinda Gates Foundation, as a subaward from Praekelt. Researchers for the process evaluation were supported by a grant from the World Federation of Societies of Anaesthesiologists. Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licensePeer reviewe
Comparison of ceiling and visibility observations for NWS manned observation sites and ASOS sites
No full textMay 1993.Also issued as Jon C. Cornick's thesis (M.S.) -- Colorado State University, 1993.The National Weather Service modernization program involves, among other things, a shift from manned weather observation to automated, unmanned instrument sensing. The Automated Surface Observing System (ASOS) is the device that will replace the conventional manned weather observation in use today. ASOS observations of ceiling and visibility were compared to the standard manual observations at 16 sites having at least four months of overlap data. The 16 sites were located in the central plains states of Colorado, Nebraska, Missouri, Kansas, Oklahoma, and Texas. The period of study was confined to the precommissioning period of the sites when both conventional data and ASOS data were available. The study spans from mid-September of 1991 to late July 1992, with the greatest amount of data collected between February and June 1992. The overall results show that ASOS ceiling reports were within 1000 ft of conventional ceiling reports 92.7% of the time. Similarly, ASOS derived visibility was within one reportable category of conventionally derived visibility 93.7% of the time. These percentages were determined from a data base composed of approximately 64,000 observations. During periods of active weather that would require a weather type entry into the coded observation, the high level of equality is decreased. The percentage of visibility reports within one reportable category is 60.8% and the percentage of ceilings within 1000 ft of conventional reports is 76%. These percentages were determined from a data base of approximately 9,300 observations containing a current weather entry. There were 5,263 cases of conventionally observed weather that would be categorized as requiring IFR (Instrument Flight Rules) by the FAA (Federal Aviation Administration) for safe air travel. ASOS observations correctly identified 4,499 of these events for an 85.5% equivalency rate. ASOS observations indicated 5,129 IFR occurrences, or nearly the same amount as conventional observations. Fog is the most frequently reported weather phenomena when large discrepancies occur between conventional and ASOS ceiling or visibility reports. This investigation shows that ASOS reported visibilities in foggy conditions are generally higher than those reported by conventional means. Ceilings in foggy conditions as reported by ASOS are generally much lower than those reported conventionally
Equity valuation Asos PLC
No full textThis thesis aims to study the value of Asos PLC. The valuation was based in four methodologies, the Discounted Cash Flow (DCF), the Economic Value Added (EVA), the Trading Multiples and the Transaction Multiples.
Using the DCF method, a price of 3.054p was obtained and the EVA yielded a comparable lower value of 2.528p. Regarding the Relative Valuation, this was the method which delivered the lowest values of 1.573p for the Trading Multiples and 1.253p for the Transaction Multiples.
It was concluded that the four methodologies yielded different prices per share, though the DCF being the most accurate and complete model to demonstrate Asos’ intrinsic value. Given this and comparing the DCF output to the market valuation, Asos’ stock was rated as being Overweight.
Nonetheless, a sensitivity analysis was conducted in order to test how the valuation could change, along with the variation of some of the model’s sources of uncertainty. The conclusion of this analysis was that, changes in both WACC and perpetual growth rate variables, would significantly affect the outcome of the valuation, although the WACC being responsible for greater impacts.
Additionally, a more in-depth analysis to Asos’ stock price performance from 2001 to 2014 was conducted. When applying the Value at Risk statistical technique, it was concluded that, with 99% confidence level, an investor is exposed to the risk of losing 8,90% of the total amount invested in Asos.
Finally, this thesis’ valuation was compared to the most recent J. P. Morgan report about this equity. Both final recommendations were DCF-based and some fundamental inputs were estimated very closely, such as the WACC and the perpetual growth rate. The report presented a final recommendation of Overweight, with a price target of 3.100p, being very approximate to the result of this study of 3.054p
Juvenile G\uf6ttingen minipigs as pediatric safety testing model for antisense oligonucleotides (ASOs)
No full textAbstract: Antisense oligonucleotides (ASOs) belong to a large group of nucleic acid-based therapeutics that utilize synthetic oligonucleotides to modulate RNA translation. As ASOs need to hybridize to their complementary target RNA, nonhuman primates (NHPs) are the preferred non-rodent model due to their close genetic homology and pharmacokinetics with humans. However, the adult G\uf6ttingen Minipig has been recognized as a suitable alternative to NHPs in the safety testing of ASOs, as it showed similar pharmacokinetic, pharmacodynamic, and safety profiles in a previous study. Since ASOs are usually indicated to rare genetic conditions that could start early in life, and as the rapid growth and development of the pediatric population can influence the pharmacokinetics/pharmacodynamics of therapeutic agents, leading to potential toxicities, extending the previous work to the juvenile minipigs was deemed necessary. In this thesis, we evaluated the juvenile G\uf6ttingen Minipig as a pediatric safety testing model for ASOs. As such, we assessed potential differences in exposure/toxicity and pharmacologic effect of a model ASO (RTR5001) in the juvenile G\uf6ttingen Minipig in an 8-week repeat-dose toxicity study (weekly subcutaneous dosing starting at postnatal day 1). Accordingly, the model ASO that had been previously characterized in adult G\uf6ttingen Minipigs and NHPs showed comparable clinical chemistry and toxicity profiles in the juvenile minipigs. However, differences in plasma and tissue exposures, and pharmacologic activity were observed compared to the adult data. The ontogeny evaluation of the key nucleases responsible for ASO metabolism and pharmacologic activity revealed a differential nuclease expression and activity, which could affect the metabolic pathway and pharmacologic effect of ASOs in different tissues and age groups. Likewise, to further understand the species translatability of ASO-induced thrombocytopenia, in vitro platelet activity and aggregometry assays were performed using a panel of tool ASOs with different sequences and modifications. Our data on direct platelet activation and aggregation by ASOs in adult minipig samples are remarkably comparable to human data. Moreover, phosphorothioated ASOs bind to platelet collagen receptor glycoprotein VI (GPVI) and directly activate minipig platelets in vitro, mirroring the findings in human samples. The differential abundance of GPVI (and platelet factor 4) in minipigs provides insight into the influence of ontogeny in potential ASO-induced thrombocytopenia in pediatrics. Therefore, the body of data from this thesis is fundamental for selecting the juvenile G\uf6ttingen Minipig in assessing safety concerns for ASOs intended for the human pediatric population
ASOs targeting a repeat sequence in <i>GCCR</i> are more active than ASOs targeting other regions of the gene.
No full text<p>A) Sequence of part of <i>GCGR</i> intron 1. The first row shows the sequence of the intron 5′ of the repeats. Regions containing repeats (shown in red) are aligned in subsequent rows. A ninth repeat is homologous at 19/20 bases. Sequence of the intron 3′ of the repeats is shown in the bottom row. B) ASOs complementary to the repeat regions and other sequences in intron 1 were tested for ability to reduce levels of <i>GCGR</i> mRNA. Reduction was assessed by qRT/PCR 24 hours after electroporation of HepG2 cells in the presence of 1 µM ASO. Data were normalized to total RNA as measured by Ribogreen assay and are presented as expression in target mRNA relative to mock transfected control (UTC) for duplicate treatments with error bars representing range of activity. ASOs C1 and C2 do not have any perfect antisense alignment to human genes. C) Concentration response of multiple-site (398457) and single-site (395459) ASOs. HepG2 cells were treated with ASOs at concentrations between 0.5 nM and 150 nM in the presence of cationic lipid. <i>GCGR</i> mRNA reduction was assessed by qRT/PCR the following day. D) Concentration response curves of 17-nucleotide gapmer ASOs. <i>GCGR</i> mRNA reduction was assessed following treatment with ASO as detailed above. Red lines correspond to ASOs targeting multiply repeated sites; black lines to ASOs targeting single sites. E) Activity is increased when sites are repeated compared to activity on a transcript with the same single site. HepG2 cells were treated with 17-nucleotide ASOs at concentrations between 0.5 nM and 150 nM. <i>GCGR</i> (red lines) and <i>nucleoporin</i> (black lines) mRNA reduction was assessed by qRT/PCR the following day. Significance of the difference in IC<sub>50</sub> values between ASOs targeting the GCGR multiple site <i>nucleoporin</i> single site as evaluated by Mann-Whitney U Test is shown below the figure.</p
Antisense oligonucleotides (ASOs) as next-generation therapies targeting cardiac remodeling
No full textEl remodelado cardíaco (RC) representa un proceso común y determinante en
la progresión de múltiples enfermedades cardiovasculares, caracterizadas por
su alta prevalencia y carga clínica. Las terapias convencionales no actúan
directamente sobre los mecanismos moleculares responsables del RC, sino que
se limitan a atenuar los estímulos desencadenantes. En este contexto, los
oligonucleótidos antisentido (ASOs) han emergido como una estrategia
terapéutica de nueva generación, capaz de modular con alta especificidad
genes, proteínas y RNA no codificantes (ncRNA) implicados en la hipertrofia y la
fibrosis cardíaca. Este trabajo presenta una revisión de los distintos tipos de
ASOs en desarrollo frente a dianas como lncRNA, miRNA y mRNA, su
mecanismo de acción, y su potencial para reducir el remodelado y/o inducir
remodelado inverso. Asimismo, se exponen sus principales limitaciones, como la
especificidad tisular, la complejidad del transcriptoma cardíaco y los desafíos
inherentes a su diseño y administración. Los ASOs representan un avance
prometedor hacia una medicina cardiovascular más precisa, aunque su
implementación clínica aún requiere superar importantes retos técnicos y
biológicos.Cardiac remodeling (CR) is a common and key process in the development and
progression of many cardiovascular diseases, which are highly prevalent and
clinically challenging. Current therapies do not directly target the molecular
mechanisms involved in CR but instead aim to reduce the triggering stimuli. In
this context, antisense oligonucleotides (ASOs) have emerged as a nextgeneration therapeutic approach capable of selectively targeting and modulating
specific genes, proteins, and non-coding RNAs involved in cardiac hypertrophy
and fibrosis. This is a review provides an overview of the various types of ASOs
under development targeting lncRNAs, mRNAs and miRNAs, their mechanisms
of action, and their potential to reduce cardiac remodeling and to induce reverse
remodeling. Additionally, the main limitations of these therapies are discussed,
including tissue specificity, the complexity of the cardiac transcriptome, and the
challenges associated with ASO design and delivery. ASOs represent a
promising step forward in the development of precision cardiovascular medicine,
although their clinical implementation still requires the resolution of significant
technical and biological challenges.Grado en Medicin
Activities of RNase H-independent 2′MOE ASOs.
No full text<p>A) SOD/TO cells were transfected with a series of 38 2′MOE ASOs and gapmer ASOs of the same sequences (these gapmers were also tested in a separate experiment shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108625#pone-0108625-g002" target="_blank">Figure 2</a>). Following ASO treatment, levels of SOD1 minigene mRNA were analyzed by qRT/PCR. Data are presented as percent spliced mRNA in treated vs. mock-treated cells. Δ = gapmer ASOs, ○ = 2′MOE ASOs. B) SOD/TO or SOD/TO-187 cells were transfected with 50 nM gapmer ASOs 440222 or 440282 and 2′MOE ASOs of the same sequence. Levels of spliced and pre-mRNA were assessed by qRT/PCR using the primer/probes depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108625#pone-0108625-g001" target="_blank">Figure 1</a>. Activity is presented as percent expression relative to levels in mock-transfected cells. Solid bars, SOD/TO spliced mRNA; grey bars, SOD/TO pre-mRNA; striped bars, SOD/TO-187 spliced mRNA; hatched bars, SOD/TO-187 pre-mRNA. C) SOD/TO or SOD/TO-H1 cells were transfected with 30 nM gapmer ASOs 440282 or 440283 and 2′MOE ASOs of the same sequence. Levels of SOD1 minigene spliced and pre-mRNA were assessed by qRT/PCR as described above. Solid bars, SOD/TO spliced mRNA; grey bars, SOD/TO pre-mRNA; striped bars, SOD/TO-H1 spliced mRNA; hatched bars, SOD/TO-H1 pre-mRNA.</p
The case of Inditex and ASOS : mergers and acquisitions
No full textThe apparel and fashion retailing business is currently in transition from brick and mortar to
online. The fast fashion giants Inditex and H&M face competition from fashion e-commerce,
while struggling themselves with their online rollout. Simultaneously, the stars of online-only
fast fashion retailing, like ASOS and Zalando, experience aggressive competition that causes
pricing pressure and shrinking margins. In contrast to ASOS’s market capitalizations over one
year ago, with price-earnings ratios above 100, the stand-alone valuation indicates that ASOS
is currently trading close to fair value, which makes it an attractive takeover target. Acquiring
ASOS would enable Inditex to efficiently enter e-commerce with a famous online-only brand.
ASOS shareholders could exit their investment, leaving the company with a strategic investor
to enable further expansion. The strategic fit allows for synergies to increase the valuation of
the combined firm. Selling Inditex products on the ASOS marketplace and extending ASOS’s
deliver-to store option with the Inditex store network would increase sales. Cost synergies are
expected from the consolidation of sourcing and manufacturing as well as the rationalization
of administrative and organizational redundancies. Overall, synergies of approximately €12bn
would add shareholder value of approximately 11,47% to Inditex’s current market cap. ASOS
shareholders will be offered €66,75 or 2,25 Inditex shares per ASOS share, respectively 30%
premium on fair value. The mix of cash and stock enables Inditex to utilize its cash pile, avoid
leverage and align interests
Stabilin-mediated Cellular Internalization of Phosphorothioate-modified Antisense Oligonucleotides (ASOs)
No full textIntroduction: Antisense oligonucleotides (ASOs) are short chemically modified oligonucleotides (5-7.4 kDa) that can produce a pharmacological effect by binding to RNA and affecting intermediary metabolism. Over 35 phosphorothioate (PS) ASOs are at various stages of clinical development for use as therapeutic agents and pharmacological tools. Antisense therapy is a progressing area of research, as these small strands of nucleotide oligomers can be produced to silence genes that aggravate chronic disorders or infections. An important distinction for ASOs compared to DNA is the substitution of the phosphodiester (PO) backbone with the PS modification. This sulfur substitution allows for these polar polyanionic molecules to have high stability in biological fluids and selective binding to cell surfaces. Although there is a premium for clinical development of these short chain molecules, the current understanding of the pathways for their ability to traverse plasma membranes remains unresolved. Injected gymnotic ASOs have been shown to accumulate in the liver via the organ’s functional scavenging mechanism in highly endocytically active sinusoidal endothelial cells (SECs) and Kupffer cells (KC) compared to hepatocytes. Our work outlines how a non-DNA binding class of scavenger receptors known as Stabilins binds to, and internalizes these small PS ASOs. Methods: Primary cells from rat and mouse were isolated and cultured with 125I-ASOs. Stable cell lines expressing Stabilin-1 and two Stabilin-2 isoforms (315-HARE and 190-HARE), were used to analyze binding affinity, endocytosis and degradation of 125I-ASOs in the cell. Co-localization was also done to analyze trafficking of ASOs once internalized within the cell by use of fluorescent ASO and lysotracker. Results: It was determined that PS ASOs bind with high affinity to the Stabilin class receptors with the majority of internalization performed by clathrin-mediated endocytosis. Binding was determined to be dependent on proper folding of the receptor, along with relying on salt-bridge formation. Once inside the cell via the Stabilin receptors, co-localization analysis showed ASOs being trafficked for degradation in the lysosome. Increased internalization rates of an ASO targeting the non-coding RNA of malat-1, in the Stabilin-expressing cell lines reduced malat-1 expression more efficiently, indicating not all ASOs are trafficked to the lysosome after internalization. Conclusion: Our work shows that ASOs are internalized into the cells of the liver through clathrin-mediated endocytosis. The understanding of the pathway(s) for chemically modified ASO internalization and trafficking with cell surface receptors will aid in future clinical design of ASOs as therapeutic agents
Sühâ ve Pervîn de narsist kimliğin görünümleri
No full textSigmund Freud’un öncülüğüyle gelişen psikanalitik eleştiri yöntemi, sanatçının ruhsal yaşamöyküsünün ve bilinçaltının sanat eserlerinin oluşumundaki etkisini araştırır. Sanatçıların eserlerindeki çeşitli yönelimleri, bu eleştiri yöntemi için veri oluşturur. Yaratmanın kaynağını bulmaya çalışan bu yöntemde, metinde yazarın bilinçaltının tespit edilebileceği iddia edilir ve sanatın neden doğduğu, sanatçının neden yarattığı sorularına cevaplar aranır. Genellikle kurgusal düzlemde “ben”liklerini yeniden inşa ettikleri düşünülürse kimi zaman örtük kimi zaman da açık bir şekilde kullanılan birtakım imge, sembol ve motiflerin, sanatkârın edebî eseri hangi dürtülerle ve neden yarattığı hakkında önemli işlevler icra ettiği görülür. Türk edebiyatının önemli sanatkârlarından Tevfik Fikret de kimi şiirlerinde kendini doğrudan metnin merkezinde konumlandırır ve bir üst-ben yaratma eğilimi gösterir. Hem doğrudan ben merkezli şiirlerinde hem de şiirlerindeki kurgusal kişilerin benliklerinde Fikret’in ruh atmosferini ve sanatının oluşumundaki etkisini görmek mümkündür. Bu çalışmada psikanalitik edebiyat eleştirisinin imkânları doğrultusunda narsisizmin “Sühâ ve Pervîn”deki yansımaları Fikret’in diğer şiirleriyle de karşılaştırmalı ve analitik bir şekilde değerlendirilmeye çalışılmaktadır.Psychoanalytic criticism method, developed by Sigmund Freud, investigates the effects of subconscious and life story of the authors in his/her works. Various tendencies in art works supply data for this method of criticism. Trying to find the source of creation, this method claims to detect subconscious of the authors and tries to answer where art originates, and what urges the authors to create. Based on the notion that authors rebuild the “ego”, some images, symbols and motifs, used both implicitly and explicitly in the text, give an idea about the motives and incentives that push the author to create. Tevfik Fikret, one of the biggest poets in Turkish literature, locates himself in the center of some of his texts, and tends to create a super-ego. Both in his ego-centered poems and in identities in his other poems, spiritual state of Fikret and its effects in creation of his art could be observed. In this study, in line with potentials of psychoanalytic criticism method, reflections of narcissism in “Süha and Pervin” poem will be evaluated analytically in comparison with Fikret’s other poems
- …
