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No description available.

Many neurons of the vertebrate central nervous system (CNS) express the Ca2+ binding protein calbindin D-28k (CB), including important projection neurons like cerebellar Purkinje cells but also neocortical interneurons. CB has moderate cytoplasmic mobility and comprises at least four EF-hands that function in Ca2+ binding with rapid to intermediate kinetics and affinity. Classically it was viewed as a pure Ca2+ buffer important for neuronal survival. This view was extended by showing that CB is a critical determinant in the control of synaptic Ca2+ dynamics, presumably with strong impact on plasticity and information processing. Already 30 years ago, in vitro studies suggested that CB could have an additional Ca2+ sensor function, like its prominent acquaintance calmodulin (CaM). More recent work substantiated this hypothesis, revealing direct CB interactions with several target proteins. Different from a classical sensor, however, CB appears to interact with its targets both, in its Ca2+-loaded and Ca2+-free forms. Finally, CB has been shown to be involved in buffered transport of Ca2+, in neurons but also in kidney. Thus, CB serves a threefold function as buffer, transporter and likely as a non-canonical sensor.

[pt] Microcáspulas são comumente utilizadas como veículos para a entrega de ativos em locais de interesse. As cápsulas protegem seu conteúdo interno, e são capazes de liberá-los de forma controlada. Além de ser muito utilizada na indústria farmacêutica, alimentícia e cosmética, elas também são uma solução viável na medicina e na indústria de petróleo para se replicarem como células no corpo ou otimizar a recuperação de óleo, respectivamente. No entanto, a utilização de microcápsulas implica em usar uma casca que, devido a urgência pela sustentabilidade, precisa mais do que nunca ser uma substância biodegradável. Neste trabalho, apresentamos um método de liberação controlada de ativos protegidos pelo bio-polímero de goma de gelana utilizando o gatilho de temperatura como ativador da destruição da cápsula. O estudo mostra a diferença que as propriedades físicas das cápsulas causam no tempo de entrega do seu conteúdo interno e como a liberação se comporta com o aumento da taxa de calor envolvida no processo. O controle das propriedades foi realizado através da produção de microcápsulas por microfluídica ao qual os diâmetros variaram entre 190 e 510 micrômetros enquanto as espessuras variaram entre 4 a 50 micrômetros. O estudo mostra que, além do tamanho, o material da casca (gelana), influencia o comportamento de liberação, a partir de certo limite de relação de espessura-diâmetro. Além disso, outro ponto importante é como a natureza da gelana afeta essa liberação visto que os resultados mostram que, quando a gelana está em sua forma desacilada (low-acyl) ela é mais resistente à mudanças, porém quando sua forma natural acilada (high-acyl) é adicionada à cadeia polimérica da mistura, a composição torna-se mais sensível ao gatilho até um certo limite de razão espessura-diâmetro, alterando o comportamento da degradação e a entrega é atrasada. Os resultados indicam que uma das possibilidades de aplicação de microcápsulas de gelana é o processo de recuperação de óleo, pois sua casca é resistente e estável até altas temperaturas, dessa forma servem como agente trasportador até entrar em contato com o óleo à temperatura de poço, liberando seu conteúdo. / [en] Microcapsules are commonly used as vehicles for on-demand delivery of active contents. The capsule protects the internal content from interference of the external environment and deliver it in a controlled manner. In addition to being widely used in the pharmaceutical, food and cosmetic industries, microcapsules can be also a viable solution in medicine and in the petroleum industry to replicate themselves as cells in the body or optimize oil recovery, respectively. However, the use of a microcapsule implies the use of a shell that, due to the urge for sustainability, needs more than ever to be a biodegradable substance.. In this work, we present a method of controlled release of actives protected by a biodegradable gellan-based microcapsule using temperature as the trigger for its destruction. The study shows the effect of physical properties of the capsules in the delivery time of their internal content and how the release behaves with the increase of the heat rate involved in the process. Microcapsules were produced with flow-focusing microfluidic devices with diameters variying between 190 and 510 micrometers while the shell thicknesses varied between 4 and 50 micrometers. The study shows that, in addition to the size, the shell material influences the release behavior. In addition, another important point is how the gellan gum nature affects the thermal trigger event, since the results show that when gellan is in its deacylated form (low-acyl) it is more resistant to changes, but when its natural form (high-acyl) is added to the chain, it becomes more sensitive to the trigger mechanism until a thickness-diameter ratio threshold, where the degradation behavior changes and the delivery is delayed. The results of this work indicate that one of the possibilities for the application of gellan microcapsules is in the oil recovery process, since its shell is resistant and stable until reaching high temperatures, thus acting as a transport agent until it comes into contact with the oil at well temperature, releasing its contents.

A unique dosage form which uses a hydrophilic polymer was developed to provide for a predicable release of several drugs. This drug release could be optimized for controlled release using erosion. It can also be designed to release drug utilizing electrochemical processes. The accuracy of drug delivery in terms of dose and timing is of utmost importance for the patient’s health status and compliance. A well-designed drug delivery technology offers many advantages to the patient. These advantages include: reduction in dose frequency, reduction of drug side effects, reduced unwanted fluctuations in circulating drug levels, and a more uniform effect of the drug over time. The practice of drug delivery has been dramatically developed in the last decade including electronic controlled release innovative dosage forms. In this study the iontophoretic flux of ibuprofen was investigated using side- by-side diffusion cells. Iontophoresis is the process where electric current is applied to enhance transportation of drugs across the skin. The pH change was found to be an important factor in increasing the diffusion of the drug. The principle of using electric current as a driving force to control the drug release was initially demonstrated on an initial setup. Subsequently, a calcium binding polymer was the hydrogel used as a matrix to develop a new electric oral dosage form. The calcium binding polymer is produced in different forms. The production process of these forms suffers several limitations. In order to apply electric current in a practical way to the calcium binding polymer matrix a novel method was developed. The novel method also allowed for addressing the limitations related to the production process of the conventional dosage form made with this polymer. More uniform gel tablets in shape and size were produced. Different formulations were developed. Ibuprofen was the model drug initially used to investigate the factors that affected the release profiles of these tablets. A two-level, three-factor statistical design of experiments (DOE) was performed to evaluate the effect of those factors on certain responses. These responses included the release rate, time needed to release 80% of the model drug, and lag-time. A new formulation with certain adjuvants was developed. This formulation had the ability to release different kinds of drugs in a uniform release rate. A fail-safe tablet that can only release less than 20% of the drug in 24 hours was developed. The drug release was initiated only when the electric current was applied. This new electric dosage form was aimed to overcome the disadvantages related to conventional dosage forms such as the inability to supply drugs on demand. / Pharmaceutical Sciences

Combining foods, combining tools. To date, most of the published works that have attempted to relate aroma release and sensory perception are far from mimicking the real consumption context, as assessments often do not consider food oral processing during mastication and are performed on single or model foods. A multidisciplinary approach integrating in vivo aroma release, oral processing behaviour, and dynamic sensory methods is needed to have a better understanding of how the release, evolution, and fading of the flavour of real complex food matrices are being perceived during consumption. The research described in this thesis aims to investigate the relative contributions that food structure and its composition and oral processing behaviour have on aroma release and perception of food matrices made up of different components and contrasting textures, so-called composite foods. Results showed that the processes of aroma release and perception of composite foods are multidimensional phenomena and seem to be modulated by cross-modal texture-aroma interactions. While aroma release increased when a food was assessed in combination with other foods, consumer’s ability to discriminate between foods was reduced and off-flavours and texture deficiencies were masked. Furthermore, the role of oral processing behaviour on the breakdown of the food impacting aroma release and perception was highlighted. The use of a multidisciplinary approach provided more useful and accurate sensory profile representing an ecological, valid food consumption context that will ultimately offer new strategies for successfully developing healthier food products with lower fat and sugar content or elaborated with plant protein, for which sensory acceptability remains a challenge.

Different Laricobius nigrinus Fender release locations, numbers of predators, and timing of release were evaluated for biological control of the hemlock woolly adelgid (HWA), Adelges tsugae Annand (Hemiptera: Adelgidae). It established at 59% of the sites and location was the most important factor related with establishment and abundance, HWA density, and hemlock vigor index. Cold locations had poor establishment or low abundance, declines in HWA density, and increases in hemlock vigor over time. Paired release and control sites detected a predator impact on HWA density, but densities remained high and tree vigor declined. The phenology of L. nigrinus, L. rubidus LeConte, and HWA were studied at a field insectary and the species were highly synchronized. A cage exclusion study showed that HWA survival and density were lower and ovisac disturbance was higher when exposed to predation. To improve L. nigrinus monitoring, we compared beat sheets for adults or branch clipping for immatures, and the host searching behavior of L. nigrinus was studied to understand how it locates a tree and HWA. In the Appalachians, beat sheet sampling resulted in false negatives as larvae were collected by branch clipping. Adults orientated to a tree visually, fed when prey were present and flew when absent, and showed different search patterns on infested versus uninfested trees. In Seattle, both sampling methods detected L. nigrinus because the predator was common. Predator : prey ratios were high at heavily infested sites in Seattle and low in the eastern US, where is has been released recently. Partial life tables were constructed for HWA sistentes at four sites for 2 yr in Seattle. Unspecified causes of nymph and adult mortality were high and L. nigrinus was the dominant predator of ovisacs. Adult L. nigrinus abundance was positively related to HWA density and immature abundance was related to ovisac density, indicating an aggregation and numerical response to its prey. Laricobius nigrinus has not demonstrated complete biological control of HWA to date, but it may do so in the future and continued release is justified. / Ph. D.

Synthetic antioxidants have traditionally been added directly to food products in a single initial dose to protect against oxidation of lipids and generation of free radicals. Natural antioxidants have been shown to undergo loss of activity and become prooxidants at high concentrations; therefore, a need exists to develop active packaging which can gradually deliver antioxidants in a controlled manner. The objectives of this research were to (1) form and characterize cyclodextrin inclusion complexes with the natural antioxidants, alpha-tocopherol and quercetin, (2) incorporate cyclodextrin inclusion complexes of natural antioxidants into linear low density polyethylene (LLDPE), and (3) measure the release kinetics of inclusion complexes of natural antioxidants from LLDPE into a model food system. Cyclodextrin inclusion complexes of alpha-tocopherol and quercetin were formed by the coprecipitation method and characterized in the solid state by NMR, IR spectroscopy, and thermal analyses. Solid inclusion complex products of alpha-tocopherol:beta-cyclodextrin and quercetin:gamma-cyclodextrin had molar ratios of 1.7:1 as determined by UV spectrophotometry, which were equivalent to 18.1% (w/w) alpha-tocopherol and 13.0% (w/w) quercetin. Free and cyclodextrin complexed antioxidant additives were compounded with a twin-screw mixer into two LLDPE resin types followed by compression molding into films. Release of alpha-tocopherol and quercetin from LLDPE films into coconut oil at 30 °C was quantified by HPLC during 4 weeks of storage. The total release of alpha-tocopherol after 4 weeks was 70% from the free form and 8% from the complexed form averaged across both LLDPE resins. The mechanism by which alpha-tocopherol was released was modified due to its encapsulation inside the beta-cyclodextrin cavity within the LLDPE matrix as indicated by its diffusion coefficient decreasing by two orders of magnitude. Molecular encapsulation of natural antioxidants using cyclodextrins may be used as a controlled release mechanism within polymer food packaging to gradually deliver an effective antioxidant concentration to a food product, thereby, limiting oxidation, maintaining nutritional quality, and extending shelf life. / Ph. D.

The use of sulfur hexafluoride (SF6) as a tracer gas for analyzing underground mine ventilation systems has been practiced for over 30 years. As a result, the methods used to release, sample, and analyze SF6 are well accepted. Although improvements are still being made to enhance the analysis of this tracer, the overall technique remains largely the same. However, as the complexity and size of underground mine ventilation networks increase, coupled with steadily rising SF6 background levels, the ability of a single gas to function as a convenient, rapid means of analysis diminishes. The utilization of multiple tracer gases can mitigate these problems by allowing for a more comprehensive evaluation using multi-zone techniques. A well-documented alternative in HVAC studies to SF6 as a tracer are perfluorocarbon tracers (PFT). Many PFTs exist as volatile liquids at room temperature and pressure. This characteristic prevents a PFT from being released using the same technique as SF6. This paper introduces a passive release method for PMCH. Details about the development of the permeation plug release vessel (PPRV) from creating a GC calibration curve for vapor PMCH to the final field evaluation are presented. The following study successfully developed a mine-scale PPRV. The PPRV is designed to passively deploy PMCH vapor at linear. An equation was derived in this study that allows the prediction of the release rate as a function of temperature and plug thickness. Details regarding the development of the PPRV from preliminary laboratory studies to final field evaluations are provided. / Ph. D.

Corporate managers often pursue voluntary non-GAAP reporting when mandatory reporting is limited, although regulators are concerned with how this reporting is utilized. While the level of flexibility external auditors exhibit during discussions over subjective GAAP reporting choices can influence management's GAAP reporting decisions, it is important to determine if this behavior affects subsequent non-GAAP reporting decisions. Additionally, recent calls for increased audit committee questioning of non-GAAP disclosures may also cause audit committees to influence non-GAAP reporting. In this dissertation, I conduct an experiment to examine how auditor flexibility and audit committee questioning influence non-GAAP preparation and earnings release disclosure choices of senior executives. I predict less flexible auditor behavior will enhance managers' psychological feeling of constraint, while audit committee questioning focused on non-GAAP measures can increase managers' self-assessment of reporting decisions, both of which will translate into more conservative non-GAAP reporting. However, given prior research indicating that corporate governance mechanisms can combine in complex ways, I predict a greater impact of audit committee questioning absent auditor constraint. Results indicate managers make less conservative non-GAAP preparation decisions and disclose more non-GAAP measures in the absence of constraint from inflexible auditors. However, absent this constraint, managers make more conservative non-GAAP preparation choices and present non-GAAP measures less prominently in earnings press releases when the audit committee questions non-GAAP disclosures. These results are driven by a thorough self-assessment of reporting decisions by managers expecting audit committee questioning. This study provides evidence on how external auditors and audit committees influence various voluntary reporting decisions. / Doctor of Philosophy / Corporate managers can report their company's financial information to investors and other stakeholders in various ways. Some financial information is required to be reported in accordance with a set of formal accounting standards called United States Generally Accepted Accounting Principles (GAAP). Beyond this mandatory reporting, other financial information is disclosed voluntarily when company management believes this extra information is beneficial to investors. These voluntary disclosures— called non-GAAP measures— do not follow a set of accounting standards and can be disclosed with more discretion by company management than GAAP measures. The variation in how non-GAAP measures are prepared and disclosed concerns regulators, such as the Securities and Exchange Commission (SEC). Mandatory GAAP financial reporting is overseen by external auditors from public accounting firms, but auditors typically have very little formal oversight over non-GAAP reporting. Although company management ultimately decides how to disclose GAAP information, external auditors influence these reporting decisions by recommending choices during discussions over subjective GAAP issues. Sometimes auditors exhibit inflexible behavior during these discussions by being unwilling to consider management's reporting choices. This inflexibility limits or constrains the GAAP reporting choices of managers. However, prior research has not studied how this constraint impacts how managers make non-GAAP reporting choices. Further, GAAP reporting choices can also be influenced by the audit committee, which is a subgroup of members of the board of directors that is in charge of overseeing financial reporting and disclosure. Recent calls from regulators have asked for increased audit committee questioning of non-GAAP disclosures, which may also cause audit committees to influence non-GAAP reporting. Non-GAAP measures are often presented in earnings press releases, which are public announcements by a company that disclose information regarding results of operations or financial condition for a given period. Managers can make strategic decisions regarding the preparation of non-GAAP measures and the presentation of this information in earnings releases, both of which can influence investors' decision-making. In this dissertation, I conduct an experiment utilizing senior executives to examine how auditor flexibility and audit committee questioning influence these two types of non-GAAP reporting decisions: how to prepare non-GAAP measures and how to disclose them in earnings press releases. I predict less flexible auditor behavior will enhance managers' psychological feeling of constraint, while audit committee questioning focused on non-GAAP measures will increase managers' self-assessment of reporting decisions, both of which will translate into more conservative non-GAAP reporting. However, prior research indicates that corporate governance mechanisms, which are factors intended to help direct and monitor company management (such as auditors and audit committees), can combine in complex ways. Therefore, I predict a greater impact of audit committee questioning absent auditor constraint. The results indicate managers make less conservative non-GAAP preparation decisions (i.e. are more likely to calculate non-GAAP earnings figures that deviate from their GAAP counterparts) and disclose more non-GAAP measures in the absence of constraint from inflexible auditors. However, absent this constraint, managers make more conservative non-GAAP preparation choices and present non-GAAP measures less prominently in earnings press releases when the audit committee questions non-GAAP disclosures. These results are driven by a thorough self-assessment of reporting decisions by managers expecting audit committee questioning. This study provides evidence on how external auditors and audit committees influence various voluntary reporting decisions. Given the ubiquity of non-GAAP reporting in recent years, this dissertation can provide valuable insights to regulators, investors, and other stakeholders on factors that influence managerial decision-making related to non-GAAP disclosures.