No description available.

Utdelning har sedan tidigt 1600-tal använts av företag som ett verktyg att ge dessinvesterare avkastning för deras investering, vilket än idag är utdelningens huvudsakligafunktion. Vedertagna teorier har dock ifrågasatt företagsledningars motiv till att betalautdelningar, och menar att de kan användas som ett verktyg att signalera om företagetsframtid, något som till viss del fått stöd i tidigare forskning. Däremot har tidigare studierej varit eniga gällande de slutsatser som framtagits, trots att deras undersökningsmetodvarit densamma. Somliga studier har alltså kommit fram till att utdelningar skickarsignaler om ett företags kortsiktigt framtida lönsamhet, upp till ett års tid, medan andrastudier ej funnit något samband alls. De tidigare studier som presenterats är utfördamestadels utfört på de geografiska marknaderna Nordamerika och Östra delar av Asien,i länder som USA, Japan och Sydkorea. Problemområdet har däremot ej tidigare studeratsi det svenska eller nordiska förhållanden, där ägarkoncentration och utdelningsfrekvenstenderar att vara annorlunda. Från denna bakgrund har följande problemformuleringtagits fram: Finns det ett samband mellan en förändring av utdelning per aktie och framtidalönsamhet, bland företag listade på svenska aktiemarknaden? Den här studien är baserad på en regressionsanalys av ett datamaterial inhämtat från OMXStockholm. För att undersöka sambandet mellan förändrad utdelningsnivå och framtidalönsamhet på den svenska marknaden. Om utdelningsförändringar har ettinformationsvärde gällande lönsamhet är detta i högsta grad intressant ur investeraressynvinkel. Detta medför att utdelning kan ha en betydande roll i beslutsfattandet kringpotentiella investeringar. Vidare har författarna antagit en deduktiv forskningsansatsbaserat på en kvantitativ studie där 183 företag undersökts i upp till femton år, vilketbildat grunden studiens datamaterial som behandlades vidare i Microsoft Excel, där ävenberäkningar av studiens deskriptiva statistik utfördes. Därefter genomfördes statistiskatester i programmet Stata. Resultatet i denna studien visade att en ökad utdelning, på kort sikt tenderar att följas aven ökad lönsamhet, för att två år efter utdelningsförändringen övergå till en negativlönsamhetsförändring. De negativa utdelningsförändringarna var däremot barasignifikanta på ett års sikt, där de följs av en minskad lönsamhet. Att ett företag initieraren utdelning, har dock inget signifikant samband med framtida lönsamheten. När dedäremot upphör att ge utdelning, så finns ett svagt samband på ett års sikt med enminskande lönsamhet. Detta innebär att studien funnit stöd för signalteorin sompresenteras i studien, och att utdelningsförändringar skickar signaler som kan minskainformationsasymmetrin mellan investerare och företagsledning.

Idiopathic pulmonary fibrosis is a chronic and fatal disease that causes the stiffening of lung tissue and gradual lung function decline. Currently, there are no effectives therapies for this disease. Fibrotic lungs are characterized by accumulation of smooth muscle α actin- (SMA) expressing myofibroblasts and excessive deposition of a collagen rich extracellular matrix. The differentiation of lung fibroblasts into myofibroblasts is stimulated by numerous growth factors, including transforming growth factor β (TGFβ), and potentiated by a stiff mechanical environment. Our laboratory has identified a secreted matrix protein, aortic carboxypeptidase-like protein (ACLP), which is upregulated in idiopathic pulmonary fibrosis. Additionally, ACLP knockout mice are protected from experimentally induced fibrosis. This led to the hypothesis that ACLP promotes the fibroblast to myofibroblast transition, and the goal of this research was to characterize the mechanism of ACLP action. ACLP expression preceded SMA and collagen type I expression in rapidly differentiating primary mouse lung myofibroblasts. In gain of function studies, recombinant ACLP induced SMA and collagen I expression in both primary differentiating myofibroblasts as well as IMR90 human lung fibroblasts. ACLP knockdown by siRNA slowed myofibroblast differentiation and partially reverted fully differentiated myofibroblasts into fibroblasts. Because of the similarities among ACLP targets and TGFβ targets, it was hypothesized that ACLP stimulates TGFβ signaling. In lung fibroblasts, ACLP induced Smad3 phosphorylation and nuclear translocation, a feature of TGFβ signaling. The effects of ACLP on myofibroblast differentiation were dependent on TGFβ receptor (TβR) kinase activity and ACLP interacted directly with T&betaR II to promote myofibroblast differentiation. A recombinant TβR II Fc chimera was used to inhibit ACLP-induced SMA expression, but this reagent had no effect on ACLP-induced collagen type I expression, which suggests a differential regulation of SMA and collagen by ACLP. Additionally, ACLP modulated changes in differentiation between cells grown on softer versus stiffer matrices. Using recombinant fragments of the ACLP protein, the N-terminal thrombospondin repeat domain was found to be necessary and sufficient to promote myofibroblast differentiation. Taken together, these studies identified a novel mechanism of ACLP action in fibroblasts and may lead to new therapeutic strategies to treat fibrotic disease.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第22283号 / 理博第4597号 / 新制||理||1659(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)准教授 佐藤 ゆたか, 教授 高橋 淑子, 准教授 秋山 秋梅 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Hardware impairments (HWIs) impose a huge challenge on modern wireless commu- nication systems owing to the characteristics like compactness, least complexity, cost ef- fectiveness and high energy efficiency. Numerous techniques are implemented to minimize the detrimental effects of these HWIs ,however, the residual HWIs may still appear as an additive distortion, multiplicative interference, or an aggregate of both. Numerous studies have commenced efforts to model one or the other forms of hardware impairments in the ra- dio frequency (RF) transceivers. Many presented the widely linear model for in-phase and quadrature imbalance (IQI) but failed to recognize the impropriety induced in the system because of the self-interfering signals. Therefore, we have presented not only a rigorous ag- gregate impairment model along with its complete impropriety statistical characterization but also the appropriate performance analysis to quantify their degradation effects. Lat- est advances have endorsed the superiority of incorporating more generalized impropriety phenomenon as opposed to conventional propriety. In this backdrop, we propose the improper Gaussian signaling (IGS) to mitigate the drastic impact of HWIs and improve the system performance in terms of achievable rate and outage probability. Recent contributions have advocated the employment of IGS over traditional proper Gaussian signaling (PGS) in various interference limited scenarios even in the absence of any improper noise/interference. It is pertaining to the additional degree of freedom (DoF) offered by IGS, which can be optimized to reap maximum benefits. This reduced-entropy signaling is the preferred choice to pose minimal interference to a legitimate network yielding another mechanism to tackle undesired interference. Evidently, the incorporation of both inherent and induced impropriety characteristics is critical for effective utilization. Most of the recent research revolves around the theoretical analysis and advantages of improper signaling with minimal focus on its practical realization. We bridge this gap by adopting and optimizing asymmetric signaling (AS) which is the finite discrete implemen- tation of the improper signaling. We propose the design of both structural and stochastic shaping to realize AS. Structural shaping involves geometric shaping (GS) of the symbol constellation using some rotation and translation matrices. Whereas, stochastic shaping as- signs non-uniform prior probabilities to the symbols. Furthermore, hybrid shaping (HS) is also proposed to reap the gains of both geometric and probabilistic shaping. AS is proven superior to the conventional M-ary symmetric signaling in all of its forms. To this end, probabilistic shaping (PS) demonstrates the best trade-off between the performance en- hancement and added complexity. This research motivates further investigation for the utilization of impropriety concepts in the upcoming generations of wireless communications. It opens new paradigms in inter- ference management and another dimension in the signal space. Besides communications, the impropriety characterization has also revealed numerous applications in the fields of medicine, acoustics, geology, oceanography, economics, bioinformatics, forensics, image processing, computer vision, and power grids.

In order to function, proteins must be folded into their native shape. While this can sometimes occur spontaneously, the process can be hindered by thermodynamic barriers, trapped intermediates, and aggregation prone hydrophobic interactions. Molecular chaperones are proteins that help client proteins or substrates overcome these barriers so that they can be folded properly. One such chaperone is the chaperonin CCT, a large MDa protein made up of 16 paralogous subunits that form a double ring structure. CCT encapsulates its substrates in a central cavity, where they are sequestered and folded, using ATP binding and hydrolysis to drive conformational changes in the CCT-substrate complex. CCT mediates the folding of many substrates involved in a variety of cellular process, including the cytoskeletal proteins actin and tubulin, and the G protein subunit Gabg, which signals downstream of GPCRs in a variety of cellular processes. We showed that CCT is responsible for folding the b-propeller containing proteins, mLST8 and Raptor, which are subunits of the mTOR complexes. The mTOR complexes (mTORC1 and mTORC2) are master regulators of cell growth and survival by controlling processes such as protein synthesis, energy metabolism, cell survival pathways and autophagy. CCT folds mLST8 and Raptor and help them assemble into the mTOR complexes. As a result, CCT is required for functional mTOR signaling. Furthermore, we solved a 4.0 Ǻ resolution structure of mLST8 bound to CCT. Surprisingly, mLST8 is found in the center of the folding cavity, in between the rings, despite previous evidence suggesting that substrates bind only in the apical domains. Given its role in folding and assembling the mTOR complexes, G proteins, and many other proteins involved in cell survival pathways, CCT has been implicated in cancer. CCT upregulation often correlates with a worse prognosis, likely because uncontrolled growth requires increased chaperone capacity. The peptide CT20P has been shown to have cytotoxic effects in cancer cells, likely through its binding to CCT. We characterized CT20P, showing that it binds to CCT and inhibits its substrate-folding functions in cells. We specifically showed that a GFP-CT20P fusion protein inhibited the assembly of two important signaling complexes Gbg and mTORC1. These results show that CT20P is a useful inhibitor for the study of CCT function.

No description available.

Objective: We have previously demonstrated that nuclear factor kappa B (NFκB) activation is needed for the development of cardiac hypertrophy in vivo. NFκB is a downstream transcription factor in the Toll-like receptor (TLR)-mediated signaling pathway; therefore, we investigated a role of TLR4 in cardiac hypertrophy in vivo. Methods: TLR4-deficient mice (C.C3H-Tlr4 lps-d, n = 6), wild-type (WT) genetic background mice (BALB/c, n = 6), TLR4-deleted strain (C57BL/10ScCr, n = 8), and WT controls (C57BL/10ScSn, n = 8) were subjected to aortic banding for 2 weeks. Age-matched surgically operated mice served as controls. In a separate experiment, rapamycin (2 mg/kg, daily) was administered to TLR4-deficient mice and WT mice immediately following aortic banding. The ratio of heart weight/body weight (HW / BW) was calculated, and cardiac myocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. NFκB binding activity and the levels of phospho-p70S6K in the myocardium were also examined. Results: Aortic banding significantly increased the ratio of HW / BW by 33.9% (0.601 ± 0.026 vs. 0.449 ± 0.004) and cell size by 68.4% in WT mice and by 10.00% (0.543 ± 0.011 vs. 0.495 ± 0.005) and by 11.8% in TLR4-deficient mice, respectively, compared with respective sham controls. NFκB binding activity and phospho-p70S6K levels were increased by 182.6% and 115.2% in aortic-banded WT mice and by 78.0% and 162.0% in aortic-banded TLR4-deficient mice compared with respective sham controls. In rapamycin-treated aortic-banded mice, the ratio of HW / BW was increased by 18.0% in WT mice and by 3.5% in TLR4-deficient mice compared with respective sham controls. Conclusion: Our results demonstrate that TLR4 is a novel receptor contributing to the development of cardiac hypertrophy in vivo and that both the TLR4-mediated pathway and PI3K/Akt/mTOR signaling are involved in the development of cardiac hypertrophy in vivo.

No description available.

The ophthalmic trigeminal placode (opV) exclusively gives rise to sensory neurons. A number of signaling pathways including Wnt, PDGF, FGF, and Notch are all involved in the progression of an undifferentiated cell in the opV placode to a proneural cell in the condensing opV ganglion. However, the regulatory relationships between these signal transduction pathways are still unknown. To determine if FGF activation acts to modulate Notch signaling in the sensory neurogenesis pathway, a novel multifactorial approach was employed: FGF signaling was inhibited in individual cells and globally with simultaneous inactivation of Notch signaling in chick embryos to investigate if FGF activation downregulates Notch thereby driving neurogenesis. These experiments resulted in few differentiating opV cells in the mesenchymal region of future ganglion formation suggesting an alternate regulatory relationship between FGF and Notch where either reduced Notch activity allows for FGFR4 expression (leading to FGF signaling and neurogenesis), or a parallel relationship where FGF and Notch act independently of one another to induce neurogenesis. To distinguish between these two possibilities Notch signaling was inhibited with DAPT, a gamma-secretase inhibitor, and assayed for FGFR4 mRNA expression. These results indicated FGFR4 is not upregulated by reduced Notch activity, suggesting that FGF and Notch act in parallel to promote neurogenesis. During these experiments it was observed that Notch inhibition resulted in an undefined ectoderm in the opV placode region. To investigate this, FGF and Notch were inhibited by SU5402, an FGF antagonist, and DAPT, and later sectioned and stained for Laminin. In DAPT treated embryos the basement membrane became highly fragmented, a remarkable observation not yet reported. From these data a proposed mechanism was established where activation of FGF with parallel downregulation of Notch leads to disruption of extracellular matrix proteins in the basement membrane resulting in fragmentation and subsequent delamination of differentiating opV placode cells.