A comprehensive model for quantum noise characterization in digital mammography.

NlmCategory="UNASSIGNED">A version of cascaded systems analysis was developed specifically with the aim of studying quantum noise propagation in x-ray detectors. Signal and quantum noise propagation was then modelled in four types of x-ray detectors used for digital mammography: four flat panel systems, one computed radiography and one slot-scan silicon wafer based photon counting device. As required inputs to the model, the two dimensional (2D) modulation transfer function (MTF), noise power spectra (NPS) and detective quantum efficiency (DQE) were measured for six mammography systems that utilized these different detectors. A new method to reconstruct anisotropic 2D presampling MTF matrices from 1D radial MTFs measured along different angular directions across the detector is described; an image of a sharp, circular disc was used for this purpose. The effective pixel fill factor for the FP systems was determined from the axial 1D presampling MTFs measured with a square sharp edge along the two orthogonal directions of the pixel lattice. Expectation MTFs were then calculated by averaging the radial MTFs over all possible phases and the 2D EMTF formed with the same reconstruction technique used for the 2D presampling MTF. The quantum NPS was then established by noise decomposition from homogenous images acquired as a function of detector air kerma. This was further decomposed into the correlated and uncorrelated quantum components by fitting the radially averaged quantum NPS with the radially averaged EMTF(2). This whole procedure allowed a detailed analysis of the influence of aliasing, signal and noise decorrelation, x-ray capture efficiency and global secondary gain on NPS and detector DQE. The influence of noise statistics, pixel fill factor and additional electronic and fixed pattern noises on the DQE was also studied. The 2D cascaded model and decompositions performed on the acquired images also enlightened the observed quantum NPS and DQE anisotropy.

A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX.

Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.

Scale-up model obtained from the rheological analysis of highly concentrated emulsions prepared at three scales

We examine the scale invariants in the preparation of highly concentrated w/o emulsions at different scales and in varying conditions. The emulsions are characterized using rheological parameters, owing to their highly elastic behavior. We first construct and validate empirical models to describe the rheological properties. These models yield a reasonable prediction of experimental data. We then build an empirical scale-up model, to predict the preparation and composition conditions that have to be kept constant at each scale to prepare the same emulsion. For this purpose, three preparation scales with geometric similarity are used. The parameter N¿D^α, as a function of the stirring rate N, the scale (D, impeller diameter) and the exponent α (calculated empirically from the regression of all the experiments in the three scales), is defined as the scale invariant that needs to be optimized, once the dispersed phase of the emulsion, the surfactant concentration, and the dispersed phase addition time are set. As far as we know, no other study has obtained a scale invariant factor N¿Dα for the preparation of highly concentrated emulsions prepared at three different scales, which covers all three scales, different addition times and surfactant concentrations. The power law exponent obtained seems to indicate that the scale-up criterion for this system is the power input per unit volume (P/V).

The attenuation of concentrations model: a new method for assessing mercury mobility in sediments

In this work we propose a new approach for the determination of the mobility of mercury in sediments based on spatial distribution of concentrations. We chose the Tainheiros Cove, located in the Todos os Santos Bay, Brazil, as the study area, for it has a history of mercury contamination due to a chloro-alkali plant that was active during 12 years. Twenty-six surface sediment samples were collected from the area and mercury concentrations were measured by cold vapour atomic absorption spectrophotometry. A contour map was constructed from the results, indicating that mercury accumulated in a "hot spot" where concentrations reach more than 1 µg g-1. The model is able to estimate mobility of mercury in the sediments based on the distances between iso-concentration contours that determines an attenuation of concentrations factor. Values of attenuation ranged between 0.0729 (East of the hot spot, indicating higher mobility) to 0.7727 (North of the hot spot, indicating lower mobility).

Dual Action of BPC194: A Membrane Active Peptide Killing Bacterial Cells

Membrane active peptides can perturb the lipid bilayer in several ways, such as poration and fusion of the target cell membrane, and thereby efficiently kill bacterial cells. We probe here the mechanistic basis of membrane poration and fusion caused by membrane-active, antimicrobial peptides. We show that the cyclic antimicrobial peptide, BPC194, inhibits growth of Gram-negative bacteria and ruptures the outer and inner membrane at the onset of killing, suggesting that not just poration is taking place at the cell envelope. To simplify the system and to better understand the mechanism of action, we performed Förster resonance energy transfer and cryogenic transmission electron microscopy studies in model membranes and show that the BPC194 causes fusion of vesicles. The fusogenic action is accompanied by leakage as probed by dual-color fluorescence burst analysis at a single liposome level. Atomistic molecular dynamics simulations reveal how the peptides are able to simultaneously perturb the membrane towards porated and fused states. We show that the cyclic antimicrobial peptides trigger both fusion and pore formation and that such large membrane perturbations have a similar mechanistic basis

Optimisation of the lipase-catalysed preparation of a nucleoside prodrug model using an experimental design methodology

The preparation of 2', 3'-di-O-hexanoyluridine (2) by a Candida antarctica B lipase-catalysed alcoholysis of 2', 3', 5'-tri-O-hexanoyluridine (1) was optimised using an experimental design. At 25 ºC better experimental conditions allowed an increase in the yield of 2 from 80% to 96%. In addition to the yield improvement, the volume reaction could be diminished in a factor of 5 and the reaction time significantly shortened.

Sinusoidal Endothelial Dysfunction Precedes Inflammation and Fibrosis in a Model of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation.

Model-based study of a chemical-looping combustion process

Chemical-looping combustion (CLC) is a novel combustion technology with inherent separation of the greenhouse gas CO2. The technique typically employs a dual fluidized bed system where a metal oxide is used as a solid oxygen carrier that transfers the oxygen from combustion air to the fuel. The oxygen carrier is looping between the air reactor, where it is oxidized by the air, and the fuel reactor, where it is reduced by the fuel. Hence, air is not mixed with the fuel, and outgoing CO2 does not become diluted by the nitrogen, which gives a possibility to collect the CO2 from the flue gases after the water vapor is condensed. CLC is being proposed as a promising and energy efficient carbon capture technology, since it can achieve both an increase in power station efficiency simultaneously with low energy penalty from the carbon capture. The outcome of a comprehensive literature study concerning the current status of CLC development is presented in this thesis. Also, a steady state model of the CLC process, based on the conservation equations of mass and energy, was developed. The model was used to determine the process conditions and to calculate the reactor dimensions of a 100 MWth CLC system with bunsenite (NiO) as oxygen carrier and methane (CH4) as fuel. This study has been made in Oxygen Carriers and Their Industrial Applications research project (2008 – 2011), funded by the Tekes – Functional Material program. I would like to acknowledge Tekes and participating companies for funding and all project partners for good and comfortable cooperation.

Competitors' Financial Performance Monitoring Model

The objective of the thesis was to develop a competitors’ financial performance monitoring model for management reporting. The research consisted of the selections of the comparison group and the performance meters as well as the actual creation of the model. A brief analysis of the current situation was also made. The aim of the results was to improve the financial reporting quality in the case organization by adding external business environment observation to the management reports. The comparison group for the case company was selected to include five companies that were all involved in power equipment engineering and project type business. The most limiting factor related to the comparison group selection was the availability of quarterly financial reporting. The most suitable performance meters were defined to be the developments of revenue, order backlog and EBITDA. These meters should be monitored systematically on quarterly basis and reported to the company management in a brief and informative way. The monitoring model was based on spreadsheet construction with key characteristics being usability, flexibility and simplicity. The model acts as a centered storage for financial competitor information as well as a reporting tool. The current market situation is strongly affected by the economic boom in the recent years and future challenges can be clearly seen in declining order backlogs. The case company has succeeded well related to its comparison group during the observation period since its business volume and profitability have developed in the best way.

A risk infection simulation model for fusarium head blight of wheat

Fusarium Head Blight (FHB) is a disease of great concern in wheat (Triticum aestivum). Due to its relatively narrow susceptible phase and environmental dependence, the pathosystem is suitable for modeling. In the present work, a mechanistic model for estimating an infection index of FHB was developed. The model is process-based driven by rates, rules and coefficients for estimating the dynamics of flowering, airborne inoculum density and infection frequency. The latter is a function of temperature during an infection event (IE), which is defined based on a combination of daily records of precipitation and mean relative humidity. The daily infection index is the product of the daily proportion of susceptible tissue available, infection frequency and spore cloud density. The model was evaluated with an independent dataset of epidemics recorded in experimental plots (five years and three planting dates) at Passo Fundo, Brazil. Four models that use different factors were tested, and results showed all were able to explain variation for disease incidence and severity. A model that uses a correction factor for extending host susceptibility and daily spore cloud density to account for post-flowering infections was the most accurate explaining 93% of the variation in disease severity and 69% of disease incidence according to regression analysis.

Role and regulatory mechanisms of heat shock factor 2

Protein homeostasis is essential for cells to prosper and survive. Various forms of stress, such as elevated temperatures, oxidative stress, heavy metals or bacterial infections cause protein damage, which might lead to improper folding and formation of toxic protein aggregates. Protein aggregation is associated with serious pathological conditions such as Alzheimer’s and Huntington’s disease. The heat shock response is a defense mechanism that protects the cell against protein-damaging stress. Its ancient origin and high conservation among eukaryotes suggest that the response is crucial for survival. The main regulator of the heat shock response is the transcription factor heat shock factor 1 (HSF1), which induces transcription of genes encoding protective molecular chaperones. In vertebrates, a family of four HSFs exists (HSF1-4), with versatile functions not only in coping with acute stress, but also in development, longevity and cancer. Thus, knowledge of the HSFs will aid in our understanding on how cells survive suboptimal circumstances, but will also provide insights into normal physiological processes as well as diseaseassociated conditions. In this study, the function and regulation of HSF2 have been investigated. Earlier gene inactivation experiments in mice have revealed roles for HSF2 in development, particularly in corticogenesis and spermatogenesis. Here, we demonstrate that HSF2 holds a role also in the heat shock response and influences stress-induced expression of heat shock proteins. Intriguingly, DNA-binding activity of HSF2 upon stress was dependent on the presence of intact HSF1, suggesting functional interplay between HSF1 and HSF2. The underlying mechanism for this phenomenon could be configuration of heterotrimers between the two factors, a possibility that was experimentally verified. By changing the levels of HSF2, the expression of HSF1-HSF2 heterotrimer target genes was altered, implementing HSF2 as a modulator of HSF-mediated transcription. The results further indicate that HSF2 activity is dependent on its concentration, which led us to ask the question of how accurate HSF2 levels are achieved. Using mouse spermatogenesis as a model system, HSF2 was found to be under direct control of miR-18, a miRNA belonging to the miR-17~92 cluster/Oncomir-1 and whose physiological function had remained unclear. Investigations on spermatogenesis are severely hampered by the lack of cell systems that would mimic the complex differentiation processes that constitute male germ cell development. Therefore, to verify that HSF2 is regulated by miR-18 in spermatogenesis, a novel method named T-GIST (Transfection of Germ cells in Intact Seminiferous Tubules) was developed. Employing this method, the functional consequences of miR-18-mediated regulation in vivo were demonstrated; inhibition of miR- 18 led to increased expression of HSF2 and altered the expression of HSF2 target genes Ssty2 and Speer4a. Consequently, the results link miR-18 to HSF2-mediated processes such as germ cell maturation and quality control and provide miR-18 with a physiological role in gene expression during spermatogenesis.Taken together, this study presents compelling evidence that HSF2 is a transcriptional regulator in the heat shock response and establishes the concept of physical interplay between HSF2 and HSF1 and functional consequences thereof. This is also the first study describing miRNA-mediated regulation of an HSF.

Auger-type granular fertylizer distributor: matemathical model and dynamic simulation

The objective of this study was to model mathematically and to simulate the dynamic behavior of an auger-type fertilizer applicator (AFA) in order to use the variable-rate application (VRA) and reduce the coefficient of variation (CV) of the application, proposing an angular speed controller θ' for the motor drive shaft. The input model was θ' and the response was the fertilizer mass flow, due to the construction, density of fertilizer, fill factor and the end position of the auger. The model was used to simulate a control system in open loop, with an electric drive for AFA using an armature voltage (V A) controller. By introducing a sinusoidal excitation signal in V A with amplitude and delay phase optimized and varying θ' during an operation cycle, it is obtained a reduction of 29.8% in the CV (constant V A) to 11.4%. The development of the mathematical model was a first step towards the introduction of electric drive systems and closed loop control for the implementation of AFA with low CV in VRA.

The Dual Role of HIF Hydroxylase PHD3 in Cancer Cell Survival

Most advanced tumours face periods of reduced oxygen availability i.e. hypoxia. During these periods tumour cells undergo adaptive changes enabling their survival under adverse conditions. In cancer hypoxia-induced cellular changes cause tumour progression, hinder cancer treatment and are indicative of poor prognosis. Within cells the main regulator of hypoxic responses is the hypoxia-inducible factor (HIF). HIF governs the expression of over a hundred hypoxia-inducible genes that regulate a number of cellular functions such as angiogenesis, glucose metabolism and cell migration. Therefore the activity of HIF must be tightly governed. HIF is regulated by a family of prolyl hydroxylase enzymes, PHDs, which mark HIF for destruction in normoxia. Under hypoxic conditions PHDs lose much of their enzymatic activity as they need molecular oxygen as a cofactor. Out of the three PHDs (PHD1, 2 and 3) PHD2 has been considered to be the main HIF-1 regulator in normoxic conditions. PHD3 on the other hand shows the most robust induction in response to oxygen deprivation and it has been implied as the main HIF-1 regulator under prolonged hypoxia. SQSTM1/p62 (p62) is an adaptor protein that functions through its binding motifs to bring together proteins in order to regulate signal transduction. In non-stressed situations p62 levels are kept low but its expression has been reported to be upregulated in many cancers. It has a definitive role as an autophagy receptor and as such it serves a key function in cancer cell survival decisions. In my thesis work I evaluated the significance of PHD3 in cancer cell and tumour biology. My results revealed that PHD3 has a dual role in cancer cell fate. First, I demonstrated that PHD3 forms subcellular protein aggregates in oxygenated carcinoma cells and that this aggregation promotes apoptosis induction in a subset of cancer cells. In these aggregates an adaptor protein SQSTM1/p62 interacts with PHD3 and in so doing regulates PHD3 expression. SQSTM1/p62 expression is needed to keep PHD3 levels low in normoxic conditions. Its levels rapidly decrease in response to hypoxia allowing PHD3 protein levels to be upregulated and the protein to be diffusely expressed throughout the cell. The interaction between PHD3 and SQSTM1/p62 limits the ability of PHD3 to function on its hydroxylation target protein HIF-1alpha. Second, the results indicate that when PHD3 is upregulated under hypoxia it protects cancer cells by allowing cell cycle to proceed from G1 to S-phase. My data demonstrates that PHD3 may either cause cell death or protect the cells depending on its expression pattern and the oxygen availability of tumours.

The Effects of Fibroblast Growth Factor 8b on Reproductive Organs and Prostate Tumorigenesis

Fibroblast growth factors (FGFs) are involved in the development and homeostasis of the prostate and other reproductive organs. FGF signaling is altered in prostate cancer. Fibroblast growth factor 8 (FGF8) is a mitogenic growth factor and its expression is elevated in prostate cancer and in premalignant prostatic intraepithelial neoplasia (PIN) lesions. FGF8b is the most transforming isoform of FGF8. Experimental models show that FGF8b promotes several phases of prostate tumorigenesis - including cancer initiation, tumor growth, angiogenesis, invasion and development of bone metastasis. The mechanisms activated by FGF8b in the prostate are unclear. In the present study, to examine the tumorigenic effects of FGF8b on the prostate and other FGF8b expressing organs, an FGF8b transgenic (TG) mouse model was generated. The effect of estrogen receptor beta (ERβ) deficiency on FGF8binduced prostate tumorigenesis was studied by breeding FGF8b-TG mice with ERβ knockout mice (BERKOFVB). Overexpression of FGF8b caused progressive histological and morphological changes in the prostate, epididymis and testis of FGF8b-TG-mice. In the prostate, hyperplastic, preneoplastic and neoplastic changes, including mouse PIN (mPIN) lesions, adenocarcinomas, sarcomas and carcinosarcomas were present in the epithelium and stroma. In the epididymis, a highly cancer-resistant tissue, the epithelium contained dysplasias and the stroma had neoplasias and hyperplasias with atypical cells. Besides similar histological changes in the prostate and epididymis, overexpression of FGF8b induced similar changes in the expression of genes such as osteopontin (Spp1), connective tissue growth factor (Ctgf) and FGF receptors (Fgfrs) in these two tissues. In the testes of the FGF8b-TG mice, the seminiferous epithelium was frequently degenerative and the number of spermatids was decreased. A portion of the FGF8b-TG male mice was infertile. Deficiency of ERβ did not accelerate prostate tumorigenesis in the FGF8b-TG mice, but increased significantly the frequency of mucinous metaplasia and slightly the frequency of inflammation in the prostate. This suggests putative differentiation promoting and anti-inflammatory roles for ERβ. In summary, these results underscore the importance of FGF signaling in male reproductive organs and provide novel evidence for a role of FGF8b in stromal activation and prostate tumorigenesis.

Creating an open-books implementation framework for a maintenance-related value-based life-cycle model

This study is a qualitative action research by its nature with elements of personal design in the form of a tangible model implementation framework construction. Utilized empirical data has been gathered via two questionnaires in relation to the arranged four workshop events with twelve individual participants. Five of them represented maintenance customers, three maintenance service providers and four equipment providers respectively. Further, there are two main research objectives in proportion to the two complementary focusing areas of this thesis. Firstly, the value-based life-cycle model, which first version has already been developed prior to this thesis, requires updating in order to increase its real-life applicability as an inter-firm decision-making tool in industrial maintenance. This first research objective is fulfilled by improving appearance, intelligibility and usability of the above-mentioned model. In addition, certain new features are also added. The workshop participants from the collaborating companies were reasonably pleased with made changes, although further attention will be required in future on the model’s intelligibility in particular as main results, charts and values were all reckoned as slightly hard to understand. Moreover, upgraded model’s appearance and added new features satisfied them the most. Secondly and more importantly, the premises of the model’s possible inter-firm implementation process need to be considered. This second research objective is delivered in two consecutive steps. At first, a bipartite open-books supported implementation framework is created and its different characteristics discussed in theory. Afterwards, the prerequisites and the pitfalls of increasing inter-organizational information transparency are studied in empirical context. One of the main findings was that the organizations are not yet prepared for network-wide information disclosure as dyadic collaboration was favored instead. However, they would be willing to share information bilaterally at least. Another major result was that the present state of companies’ cost accounting systems will definitely need implementation-wise enhancing in future since accurate and sufficiently detailed maintenance data is not available. Further, it will also be crucial to create supporting and mutually agreed network infrastructure. There are hardly any collaborative models, methods or tools currently in usage. Lastly, the essential questions about mutual trust and predominant purchasing strategies are cooperation-wise important. If inter-organizational activities are expanded, a more relational approach should be favored in this regard. Mutual trust was also recognized as a significant cooperation factor, but it is hard to measure in reality.