No description available.

This study presents continued development of the Nenes and Seinfeld (2003) cloud droplet activation parameterization. First, we expanded the formulation to i) allow for a lognormal representation of aerosol size distribution, and, ii) include a size-dependant mass transfer coefficient for the growth of water droplets to accommodate the effect of size (and potentially organic films) on the droplet growth rate. The performance of the new scheme is evaluated by comparing the parameterized cloud droplet number concentration with that of a detailed numerical activation cloud parcel model. The resulting modified parameterization robustly and closely tracks the parcel model simulations, even for low values of the accommodation coefficient (average error 4.11.3%). The modifications to include the effect of accommodation coefficient do not increase the computational cost but substantially improves the parameterization performance. This work offers a robust, computationally efficient and first-principles approach for directly linking complex chemical effects (e.g., surface tension depression, changes in water vapor accommodation, solute contribution from partial solubility) on aerosol activation within a global climate modeling framework.

Neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are increasingly common in our ageing society, are remain incurable. A major obstacle encountered by researchers in their attempts to find effective therapies is represented by the current lack of understanding of the molecular origins of these disorders. It is becoming clear that, although the aggregation of specific proteins, including amyloid β (Aβ) and tau in AD and α-synuclein in PD, hallmark these disorders, such behaviour is a consequence of a wider, system-level disruption of protein homeostasis. In order to identify the genetic factors contributing to such a disruption, the transcriptional changes that occur during neurodegenerative disease progression have received considerable scientific attention in recent years. In our approach, we considered another hallmark of these diseases - their characteristic patterns of spreading across the brain - to identify the nature of the transcriptional signature which underlies tissue vulnerability to protein aggregation. By understanding why tissues succumb in their characteristic sequential pattern in neurodegenerative diseases, and why some tissues remain almost completely resistant throughout, we hoped to obtain insight into the molecular origins of these disorders. Our results show that the AD progression can be predicted from a transcriptional signature in healthy brains related to the protein aggregation homeostasis of Aβ, tau, and the wider proteome. We highlight a relationship between a specific subproteome at high risk of aggregation (formed by supersaturated proteins), and the vulnerability to neurodegenerative diseases. We thus identify an AD-specific supersaturated set of proteins - termed the metastable subproteome, whose expression in normal brains recapitulates the staging of AD, with more vulnerable tissues having higher metastable subproteome expression. We find evidence of these vulnerability signatures transcending the tissue level of interrogation, with cellular and subcellular analysis also showing elevated levels of proteins known and predicted to predispose the aberrant aggregation of Aβ and tau. These results characterise the key protein homeostasis pathways in the inception and progression of AD, and establish an approach with the potential to be applied to other protein misfolding diseases, in the brain and beyond.

Title of thesis: Polymeric stabilizers maintaining the saturation solubility of itraconazole nanocrystals after dissolution process Author: Jana Kubačková Department: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Specialized supervisor: Assoc. Prof. Leena Peltonen, Ph.D. The increase of bioavailability of poorly water soluble drugs is still an issue. One of the techniques improving aqueous drug substance solubility, and consequently enhancing bioavailability, is formation of nanoparticles. However, the bioavailability is determined by the concentration of the dissolved drug achieved at the time of absorption. This fact emphasizes the importance of the maintenance of the high solubility until the absorption area is reached. Sufficiently stabilised nanocrystalline drugs offer a solution to this problem. In this thesis, the solid nanoparticle formations of an antifungal agent itraconazole (ITZ) are presented. Wet milling was employed to create the nanosuspension stabilised by binary mixture of stabilisers or by a single stabiliser. An aggregation inhibitor Poloxamer 407 (F127) in the combination with a polymeric precipitation inhibitor hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP) at different ratios, or a single precipitation inhibitor, were utilised. The...

Carbonate sediments are often highly heterogeneous due to the numerous factors that control deposition. Understanding the processes and controls that are responsible for such complexity has, however, proved problematic. In addition, several of these processes are non-linear, so that depositional stratigraphies may consequently form complicated, perhaps even chaotic, geometries. Forward modelling can help us to understand the interactions between the various processes involved. Here a new three-dimensional forward model of carbonate production and deposition is presented, Carbonate GPM, which is specifically designed to test the interactions between the three main carbonate production controls: light intensity, wave power and carbonate supersaturation, the latter of which is unique to this model. The model also includes transport processes specific to the reef sediment only. The effect of supersaturation and reef transport is demonstrated by comparing the output of three, otherwise, identical runs. From these simulations the need to accurately model the flow of water around a reef system and to correctly take into the account the binding nature of reefal sediments can be seen. Analysis of the stratigraphy generated by changing the antecedent topography by 1m in one locality over a 50km square platform suggest that it may be impossible to predict in detail the stratigraphy of carbonate deposits due to its sensitivity to initial conditions or controlling parameters. This reinforces the conclusions reached using previous process models. However, unlike previous models, our model does not explicitly include nonlinear biological interactions as a control. Instead it shows that similar sensitive behaviour may originate from physicochemical processes alone. External factors, such as sea-level changes, will also influence the complex stratigraphy generated by the model. The effect of several different relative sea-level curves was assessed, each corresponding to a combination of three different hierarchies of sea-level oscillations. Large-scale external processes dominate internal processes, dampening their effect on stratigraphy. However, small-scale, high frequency external processes coupled with autocyclic processes do not show any discernable stratigraphic differences from autocyclcic processes alone. The model also produces an exponential cycle thickness distributions that are similar to those found in ancient deposits.

Supersaturating formulations have become a popular approach for enhancing the oral bioavailability of poorly water-soluble drugs. These formulation strategies can increase the intraluminal concentration by generating and maintaining supersaturation, which provides an enhanced driving force for <i>in vivo</i> absorption. Due to their inherent metastability however, crystallization in these systems can occur, negatively impacting their bioperformance. Therefore, it is critical to characterize the phase behavior and crystallization tendency of supersaturated solutions under biorelevant conditions in order to assess their potential for maximized oral absorption. Biorelevant media are commonly employed to simulate the presence of bile salts and phospholipids found in the human intestinal fluids. Currently, there is little knowledge of how simulated and aspirated intestinal media can impact the complex phase behavior of supersaturated solutions. More importantly, commonly-used simulated media rely on oversimplified recipes in terms of bile salt composition. As a result, comprehensive understanding of how well simulated media correlate with aspirated media with respect to supersaturation stability and phase transition outcomes, is still lacking. The work presented within this thesis aims to address the knowledge gap by assessing the phase behavior of supersaturated solutions using complementary analytical approaches. Depending on the type of medium used to evaluate supersaturation, variations in solubility, supersaturation thermodynamics and crystallization kinetics can be observed. This understanding can aid future efforts to optimize simulated media, design supersaturating formulations and predict their <i>in vivo</i> performance.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19020号 / 農博第2098号 / 新制||農||1030(附属図書館) / 学位論文||H27||N4902(農学部図書室) / 31971 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 加納 健司, 教授 宮川 恒, 教授 三上 文三 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Lipid-based drug delivery systems (LBDDSs) are becoming an increasingly popular approach to improve the oral absorption of poorly-water soluble drugs. Several possible mechanisms have been proposed to explain the means by which LBDDSs act in vivo to enhance absorption. The goal of the current dissertation is to provide a better understanding of one proposed mechanism; the capability of lipoidal components in LBDDS formulations to create and maintain a drug in a supersaturated state under simulated GI conditions. Moreover, molecular details of equilibrium solubilization of a drug in a series of model lipid assemblies were examined. The results of these studies will aid formulators in choosing the optimal LBDDS to improve oral absorption of poorly water-soluble drugs. Time-dependent solubilization behavior of progesterone, 17β-estradiol and nifedipine in a simple model LBDDS composed of Polysorbate 80 was assessed employing the in vitro dynamic lipolysis model. The results illustrated the extent to which the supersaturated state was dependent on the extent of lipolysis of Polysorbate 80 and the initial drug concentration. Area-under-the curve-supersaturation was proposed as a means of quantifying the time-dependent extent of supersaturation in LBDDSs in simulated intestinal conditions. Concurrently, a series of model mixed micellar solutions, composed of Polysorbate 80 and oleic acid, were prepared to represent the lipid assemblies produced during the lipolysis experiments. The ability of these aggregates to solubilize progesterone, 17β-estradiol and nifedipine were evaluated and the aggregate/water partition coefficients were determined. The Treinor model was found to successfully fit the partition coefficients of the drugs in a range of mixed micelles. The equilibrium solubility of drugs in the mixed micelles was calculated and compared to that found under lipolytic conditions. The best agreement between calculated and experimental conditions was observed for nifedipine. These studies have established a foundation for the evaluation of time-dependent extent of supersaturation with more complex LBDDS formulations exposed to lipolytic conditions.

No description available.

Torres de resfriamento são equipamentos muito utilizados na indústria e que muitas vezes operam sob condições adversas, particularmente, temperatura de água acima dos 50°C na entrada da torre. Nesta condição, tem-se alta taxa de evaporação e eventualmente condição de alto transporte de massa, normalmente não considerado no equacionamento de torres de resfriamento. Apresenta-se assim uma análise comparativa de diferentes métodos de cálculo de torres de resfriamento: Merkel, Poppe e o modelo proposto. No modelo proposto neste estudo, consideram-se os balanços diferenciais de massa e energia e os mecanismos de transporte simultâneo de calor e massa, na condição de alto transporte de massa e de supersaturação do ar, caso o vapor de água condense na forma de névoa. Para os casos em que há saturação do ar, os balanços diferenciais de massa e energia passam a contemplar este fenômeno a partir do momento em que ocorre a saturação. O modelo matemático desenvolvido consiste de equações diferenciais ordinárias e equações auxiliares, e foi implementado em uma interface Matlab. Os principais parâmetros investigados foram: as vazões de água e ar, a temperatura de bulbo úmido do ar, a temperatura da água na entrada da coluna e a altura da torre. A partir das simulações matemáticas, foram obtidos resultados de temperaturas do ar, da água e da umidade do ar ao longo da coluna, para os diferentes métodos. / Cooling towers are equipment widely used in industrial plants, where these operate under severe conditions such as cooling water inlet temperatures above 50oC. Under this condition, there are high evaporation of water and high mass transfer, generally not considered in performance analysis of a cooling tower. This work presents and analyzes the differences between the proposed model and the Merkel and Poppe approaches. The proposed model in this work is based on differential equations for energy and mass balances and on the mechanisms of combined heat and mass transfers, at high mass transfer condition and considering the supersaturated air from the height of the tower that the excess of water vapor condenses as a mist. At the point that the air became supersaturated, the differential equations for energy and mass balances start to consider the supersaturation phenomena. The mathematical model developed in this work is composed by ordinary differential equations and auxiliary equations which were solved at Matlab. The parameters investigated were water and air mass flow rates, air wet bulb temperature, water inlet temperature and tower height. The results of air and water temperatures, humidity air across the tower height are presented for each method analyzed.