Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 88-100).

The evolution of the tetrapod limb from paired fish fins involved drastic changes to the appendicular dermal and endochondral skeleton. Fish fin rays were lost, and the endochondral bone was modified and elaborated to form three distinct segments common to all tetrapod limbs: the stylopod, the zeugopod, and the autopod. Identifying the molecular mechanisms that contributed to these morphological changes presents a unique insight into our own evolutionary history. Chapter II of this thesis focuses on the actinodin gene family and how their disappearance from the tetrapod genome during the fin-to-limb transition may have contributed to the loss of dermal fin rays. The actinodin genes code for structural proteins in the actinotrichia, rigid fibers being the first exoskeletal elements formed during zebrafish fin development. We have identified tisse-specific cis-acting regulatory elements responsible for actinodin1 activation in the fin fold ectoderm and mesenchyme. These elements are only partially functional in transgenic reporter mouse limbs. We therefore propose that changes to actinodin gene regulation contributed to the loss of the actinodin genes during limb evolution. The actinotrichia also serve as a scaffold for the migration of cells from the distal fin mesenchyme, which has been shown to differentiate into fin ray osteoblasts. In fact, both actinotrichia and distal fin mesenchyme migration defects have been proposed as events that may lead to the loss of dermal bone during the fin-to-limb transition. Chapter III of this thesis tests the effects of distal fin mesenchyme ablation on larval and adult zebrafish fin development. Following the chemo/genetic ablation of these cells, zebrafish display actinotrichia, fin fold, and fin ray defects supporting the hypothesis the defects in distal fin mesenchyme may have contributed to the loss of dermal fin rays during tetrapod evolution. Previous research has shown that changes in the regulation of the 5’HoxA/D genes may have had consequences for both actinodin regulation and the migration of distal fin fold mesenchyme. Chapter IV of this thesis examines the contributions of Hoxa11 regulatory changes to the evolution of the pentadactyl, or five-digit state, in tetrapods. Through a novel tetrapod-specific enhancer, Hoxa11 is repressed from the presumptive limb autopod region in mice. In fish, hoxa11b is expressed distally and ectopic expression of Hoxa11 in the distal limb bud produces mice with polydactyly (extra digits), an ancestral tetrapod character state. In conclusion, we have provided evidence that actinotrichia defects (potentially though changes in actinodin regulation) and fin fold mesenchyme defects may have contributed to the loss of fin dermal bone during the fin-to-limb transition. Our data also shows these two events may have been linked as fin fold mesenchyme require actinotrichia to migrate correctly, while actinotrichia maintenance relies on Actinodin secretion from fin fold mesenchyme. Furthermore, we have also contributed to the growing body of evidence that proposes changes in 5’HoxA/D regulation during the fin-to-limb transition underlie changes in appendicular dermal and endochondral bone. Therefore, it is possible that modifications in shared gene regulatory networks underlie both dermal and endochondral bone evolution during the fin-to-limb transition.

The present article describe us an overview of regulatory law, his function and thecharacteristics that it should present to achieve the goal of improve some relevant economic activities for the needs of the society. After that, the author will describe us the present situation of regulation on Argentinian law. / El presente artículo nos describe un panorama del derecho regulatorio, su función y las características que debe poseer, para cumplir su fin de optimizar actividades económicas que importen al bienestar de la sociedad. Luego de ello, pasa a describirnos el actual panorama del derecho regulatorio en Argentina.

As empresas com tarifas reguladas, de maneira geral, fornecem bens públicos. Muitas delas atuam em atividades que são prerrogativas, diretas ou indiretas, do estado. A regulamentação tarifária se justifica pelo fato de essas empresas não atuarem em condições de mercado. A tarifa é definida de maneira a fornecer uma remuneração justa, pelo risco assumido pelo investidor e, concomitantemente, um custo razoável para os consumidores. Existem dois modelos extremos de regime tarifário: cost-plus (pelo custo) ou fixed-price (pelo preço). O primeiro repassa todos os custos incorridos e mais uma margem às tarifas. Por outro lado, os regimes pelo preço fixam a tarifa máxima, que não está necessariamente associada aos custos incorridos. A diferença fundamental entre os dois regimes está no estímulo à eficiência, inexistente nos regimes pelo custo. Na prática, muitos regimes são considerados como híbridos, ou seja, somente alguns custos têm sua recuperação garantida. Nesses regimes, é necessária a existência de algum mecanismo de repasse dos custos recuperáveis. No Brasil, o setor elétrico adotou um modelo no qual a tarifa garante a recuperação dos custos não gerenciáveis (a chamada \"parcela A\"), e os custos gerenciáveis são fixados com base em níveis considerados como eficientes (a chamada \"parcela B\"). Por meio da portaria interministerial MF/MME nº 025/2002, o poder concedente cria um mecanismo para garantir a recuperação dos custos não gerenciáveis - a chamada conta de Compensação da Variação dos Custos da Parcela A (CVA). Segundo esse mecanismo, a diferença entre os custos que compõem essa parcela e o efetivamente incorrido é repassada no próximo reajuste tarifário anual. Caso o saldo não seja integralmente recuperado dentro de um ano, o resíduo é contemplado nos próximos reajustes anuais. O saldo da CVA é atualizado pela SELIC, da data de sua ocorrência até a data de sua liquidação. Com a adoção das normas internacionais de contabilidade, os itens regulatórios foram eliminados das demonstrações contábeis societárias. Devido às suas funções regulatórias, a agência nacional de energia elétrica (ANEEL) decidiu criar a contabilidade regulatória, na qual, entre outras exigências, o reconhecimento da CVA é obrigatório. O presente estudo analisa se a regulamentação tarifária fornece suporte para o reconhecimento contábil dos itens regulatórios, bem como, especificamente o da CVA. O estudo se suporta pela teoria da regulação e pela teoria contábil, com ênfase na estrutura conceitual para elaboração e divulgação de relatório contábil-financeiro (IFRS FOUNDATION, 2010). A pesquisa pode ser rotulada como qualitativa. Conclui-se que os itens regulatórios somente podem ser reconhecidos quando existe um recurso econômico ou uma obrigação econômica presente. Por consequência, apenas devem ser contabilizados os itens regulatórios cuja recuperação ou devolução for garantida. Especificamente para a CVA, não existem evidências objetivas de que seu saldo possa ser recuperado de outra maneira que não seja pela tarifa de fornecimento de energia, não devendo, portanto, ser reconhecido nas demonstrações contábeis societárias. / Rate-regulated companies generally provide public goods. Many of them carry out activities that are prerogative, direct or indirect, of the State. Rate regulations are justified by the fact that these companies do not operate under free market conditions. Rates are set in order to provide a fair return to the risk taken by the investor and concomitantly a reasonable cost to consumers. There are two broad regulatory regimes: cost-plus and fixed-prices. Regimes based on cost allow the recovery of all incurred costs, plus a margin. On the other hand, regimes based on price set a maximum rate, which is not necessarily associated with the incurred costs. The key difference between regimes is the efficiency stimulus, not present in cost regimes. In practice, many regimes are considered hybrid, in other words, just some costs have their recovery guaranteed. Under these regimes, it is necessary a pass-through mechanism for the recoverable costs. In Brazil, the energy sector adopted a model in which the rate allows the recovery of non-manageable cost (called \"Parcel A\"), while manageable costs are recovered based on efficiency levels (called \"Parcel B\"). Through the Portaria Interministerial MF/MME no 025/2005, the grantor creates a mechanism that allows the recovery of non-manageable costs, the so-called \"Conta de Compensação de Variação dos Custos da Parcela A (CVA). By this mechanism, the difference between the costs that are included in \"Parcel A\" and those actually incurred is considered in the next annual rate reset. In the case that it is not wholly recovered within one year, the remainder will be contemplating in the next annual rate resets. The CVA balance is indexed by the SELIC from the date of its occurrence to its settlement. With the International Accounting Standards adoption, the regulatory items are derecognized from the corporate financial statements. Due to its regulatory duties, ANEEL decided to create the Regulatory Accounting, in which amongst other requirements, the recognition of the regulatory items is mandatory. The present study analyses if the rate regulation provides support for the recognition of regulatory items, more specifically, the CVA. The study is based on the Regulation Theory and Accounting Theory with emphasis in the Conceptual Framework for Financial Reporting (IFRS FOUNDATION, 2010). The research can be labelled as qualitative. It was concluded that regulatory items shall only be recognized when there are a present economic resource or a present economic obligation. Consequently, only the regulatory items which the recovery or the devolution is guaranteed can be booked. Specifically for CVA, there are no objective evidences that its balance can be recovery by other mean different than energy supply rate. Therefore, it shall not be recognized in the corporate financial statements.

The need to save energy, cut costs, and increase profit margin in process manufactureincreases continually. There is also a global drive to reduce energy use and cut down co2 emission and combat climate change. These in turn have led to more stringent requirements on process control performance. Hence, the requirements for modern systems are often not achievable using classical control techniques. Therefore, advanced control strategies are often required to ensure optimal process performance. Despite these challenges, PID has continued to be the dominant industrial control scheme. However, for systems with complex dynamics and/or high performance requirements, PID control may not be sufficient. Therefore, a significant number of industrial control loops are not performing optimally and more advanced control than PID may be required in order to achieve optimal performance. MPC is one of the advanced control schemes that has had a significant impact in the industry. Despite the benefits associated with the implementation of MPC, the technology has remained a niche application in process manufacture. This thesis seeks to address these issues by developing ways that could lead to widespread application of MPC. In the first part of this thesis, a study was carried out to understand the characteristics of processes that would benefit from the application of MPC at the regulatory control level even in the single-input single-output (SISO) case. This is a departure from the common practice in which MPC is applied at the supervisory control layer delivering set points to PID controllers at the regulatory control layer. Both numerical simulation and industrial studies were used to show and quantify benefits of MPC for SISO applications at the regulatory control layer. Some issues that have led to the limited application of MPC include the cost and human efforts associated with modelling and controller design. And to achieve high process performance, accurate models are required. To address this issue, in the second part of this thesis, a novel technique for designing MPC from routine plant data – routine data MPC (RMPC) is proposed. The proposed technique was successfully implemented on process models. This technique would reduce the high human cost associated with MPC deployment, which could make it a widespread rather than niche application in the process manufacturing industry.

Diplomová práce se zabývá studiem genové regulace v Clostridium beijerinckii NRRL B-598, pro následné odvození genové regulační sítě bakterie C. beijerinckii NRRL B-598. V teoretické části této práce je uvedena obecná nomenklatura problematiky genové regulace se zaměřením na nomenklaturu genových regulačních sítí. Následně jsou zde popsané laboratorní metody, sloužící pro získání vhodných dat popisující expresi genů. Tato data jsou základem pro studium genové regulace a návrhy genových regulačních sítí. Práce se zaměřuje především na technologii RNA-Seq a stručný popis laboratorních dat získaných ze zmíněné bakterie C. beijerinckii NRRL B-598. V praktické části se práce zabývá předzpracováním těchto surových laboratorních dat a následným studiem genové regulace se zaměřením na odvození operonů a vytvoření prvních genových regulačních sítí pomocí různých přístupů pro C. beijerinckii NRRL B-598.

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Magister Pharmaceuticae - MPharm / Medicines registration decision-making and regulatory best practice involve transparent and consistent rule making and processes with publicly available published assessment decisions and reports (Kaine, 2020). Publication of information relating to evaluation of medicines in the form of Public Assessment Reports (PARs) is one way of ensuring transparency in medicines registration decision making. It is however not clear whether National Medicines Regulatory Authorities (NMRAs) in the Southern African Development Community (SADC) region are in a position to generate or even publish such PARs / summary basis for registration of medicines. Objectives: The study investigated transparency in medicines registration decision-making processes for NMRAs within the SADC region. Specifically, the availability or non-availability of PARs / Summary basis for registration of medicinal products. To establish if all SADC NMRAs have legislative frameworks for regulating medicines and to investigate the sources of funding for SADC NMRAs. Methods: A cross-sectional exploratory descriptive study design with qualitative techniques by questionnaire as a data collection tool was used. Questionnaires were sent via email to senior members / key informants of 11 regulatory authorities belonging to SADC. Trend analysis was conducted based on the emerging themes from questionnaire response. Results The study revealed that currently five (5) NMRAs are operating as semi-autonomous agencies namely: BOMRA, MCAZ, PMRA, SAHPRA and TMDA .While NMRC, DNME of Angola, ACOREP of DRC and DNF of Mozambique are functioning within their respective Ministries of Health Departments. Furthermore, all NMRAs have a legislation framework governing the regulation of medicines in their respective jurisdictions. However, DNME of Angola’s legal framework is not yet officially formalised and as such, they follow a Presidential decree enacted in 2010. Four (4) of nine (9) NMRAs (44 %) reported to have more than 20 internal assessors / evaluators. This indicates a significant milestone for SADC NMRAs in terms of capacity building within the region. The study findings indicated that the SADC NMRAs are receiving funding from multiple sources ranging from a minimum of one to maximum of four funding sources. There were only two NMRAs, MCAZ and PMRA, that were not receiving funding from their governments. The study results further indicates that only TMDA is able to generate and publish PARs amongst SADC NMRAs. Conclusions: The findings in this study suggest that the majority of NMRAs within SADC are not yet matured as compared to countries in the developed world such as the US, Europe, Canada and Australia. It can also be concluded that for SADC NMRAs to be efficient and responsive, they will require massive financial resources. For example, the budget for a matured NMRA such as the US Food and Drug Administration (US FDA) for the 2019 financial year was estimated at US$ 5.7 billion. Literature further indicates that publication of the summary basis of approval or PARs is a norm for mature NMRAs and acts as a tool for regulatory authorities to build and establish confidence in their review processes and provides assurance regarding safety of medicines. The study results indicate that TMDA is publishing PARs or summary of grounds on which approvals are granted. This demonstrates a significant level of transparency in the TMDA medicines registration processes and therefore other SADC NMRAs can benchmark with TMDA to implement this key parameter.

Gene regulation lies at the heart of most biological processes and transcription factors are the key molecules that control tissues specific gene expression. In higher eukaryotes transcription factors control gene expression by binding regulatory DNA segments called cis-regulatory modules (CRMs). The increasing number of sequenced genomes of multicellular eukaryotes along with high-throughput methods such as whole genome microarray expression data allows for systematic characterization of the CRMs that control gene expression. A first step towards understanding gene regulation is the identification of the regulatory elements present in the genome. We take advantage of the large database of spatio-temporal patterns of gene expression in D. melanogaster embryogenesis to identify sets of developmentally co-expressed genes. We developed a computational method that identifies DNA binding sites for transcription factors from families of co-regulated genes that are expressed during Drosophila embryo development. This method discovers over-represented motifs in a set of co-regulated genes using the exhaustive motif enumeration technique. Clustering the predicted motifs identifies the CRMs, which assist in translating a combinatorial code of TF inputs into a specific gene expression output. The predicted CRMs were verified experimentally by searching the whole genome for the predicted CRMs and establishing expression pattern of the genes that are associated with these CRMs. It is well know that the gene expression is substantially controlled through CRMs and those key regulatory sequences are conserved in related species. The conservation of CRMs can be studied by comparing the related genomes and alignment methods are widely used computational tools for comparing the sequences. However, in distantly related species the CRM sequences are simply not align able. To identify the similar CRMs in distantly related species we developed a non-alignment based method for discovering similar CRMs in related species. This method is based on word frequencies where the given sequences are compared using Poisson based metric. When starting with a set of CRMs involved in Drosophila early embryo development, we show here that our non-alignment method successfully detects similar CRMs in distantly related species ( D. ananassae, D. pseudoobscura, D. willisoni, D. mojavensis, D. virilis, D. grimshawi ). This method proved efficient in discriminating the functional CRMs from the non-functional ones.

We recently showed that the Wiskott-Aldrich syndrome protein (WASP) family member,WASH, localizes to endosomal subdomains and regulates endocytic vesicle scission in an Arp2/3-dependent manner. Mechanisms regulating WASH activity are unknown. Here we show that WASH functions in cells within a 500 kDa core complex containing Strumpellin, FAM21, KIAA1033 (SWIP), and CCDC53. Although recombinant WASH is constitutively active toward the Arp2/3 complex, the reconstituted core assembly is inhibited, suggesting that it functions in cells to regulate actin dynamics through WASH. FAM21 interacts directly with CAPZ and inhibits its actin-capping activity. Four of the five core components show distant (approximately 15% amino acid sequence identify) but significant structural homology to components of a complex that negatively regulates the WASP family member, WAVE. Moreover, biochemical and electron microscopic analyses show that the WASH and WAVE complexes are structurally similar. Thus, these two distantly related WASP family members are controlled by analogous structurally related mechanisms. Strumpellin is mutated in the human disease hereditary spastic paraplegia, and its link to WASH suggests that misregulation of actin dynamics on endosomes may play a role in this disorder.