The perception is that inborn errors of metabolism (IEM) are rare, but the reality is that more than 600 lEMs are now recognized. The organic aciduria, 3-methylcrotonyl-CoA carboxylase (MCC) deficiency arises when 3-methylcrotonyl-Coenzyme A (CoA) carboxylase that participates in the fourth step of the leucine catabolism is defective. Tandem mass spectrometry (MS/MS) based screening programmes in North America, Europe and Australia, showed that MCC deficiency is the most frequent organic aciduria detected, with an average frequency of 1:50 000. Therefore MCC deficiency is considered an emerging disease in these regions. The incidence of MCC deficiency in the Republic of South Africa (RSA) is not yet known. However, one 48 year old male Caucasian individual (HGS) was diagnosed suffering from mild MCC deficiency, since elevated levels of 3-hydroxyisovaleric acid, 3- hydroxyisovalerylcarnitine, 3-methylcrotonylglycine was present in his urine. Several groups are currently working on various aspects of this emerging disease with the focus on the molecular characterisation of MCC deficiency. In the RSA no molecular based diagnostic method which complements MS/MS screening programmes have yet been implemented. Therefore, the aim of this study was to implement the necessary techniques for the molecular characterisation of MCC deficiency, the determination of the sequence of the open reading frame (ORF) of mccA and mccB subunits to determine which mutation(s) are present in the South African MCC deficient patient. For the implementation of the molecular characterisation, a two-pronged approached was used to characterize MCC of a MCC non-deficient individual (CFC). This approach included the reverse transcriptase polymerase chain reaction (RT-PCR) amplification of the ORFs of the associated genes [mccA (19 exons) and mccB (17 exons] and the PCR amplification of selected (genomic deoxyribonucleic acid (gDNA) regions (exons mccA8, mccA11 , mccB5, mccB6 and mccB5-intron 5-6 exon 6 (mccB5-6) which have been found to have mutations associated with MCC deficiency in Caucasians. The sequence analyses produced surprising results of the amplified ORFs (CFCmccA and CFCmccB) of the MCC non-deficient individual CFC. A non-synonymous single nucleotide polymorphism (SNP) (1391C→A, H464P) associated with MCC deficiency (Gallardo et al., 2001) was identified in the CFCmccA subunit. Another SNP (1368G→A, A456A) recently listed in GenBank was observed in the amplified CFCmccB ORF. No significant novel variations or described mutations were identified in the amplified genomic regions mccA8, mccA11 ,mccB5, mccB6 and mccB5-6. The implemented molecular approach was used to characterise MCC of our MCC deficient patient (HGS). The patient did not have any mutation in the four selected exons mccA8, mccA11, mccB5, mccB6 or the genomic region mccB5-6. The RT-PCR amplification of both ORFs (HGSmccA and HGSmccB) resulted in multiple amplicons. Gel extracted amplicons of the expected size were sequenced. Of the 36 exons, 34 exons were sequenced. This includes all 19 exons of HGSmccA and 15 of 17 exons of HGSmccB (exons 1-6 and exons 9-17). The non-synonymous SNP (1391C→A, H464P) detected in CFCmccA (MCC non-deficient individual), seems to be present in the HGSmccA subunit of the MCC deficient individual, HGS. The HGSmccB amplicons could not be entirely sequenced. However, the region exon 1-6 and 9-17 was sequenced but no described or novel mutations were identified. The lack of sequence data of region exon 7-8 led to an incomplete molecular characterisation of the MCC deficiency in HGS. In conclusion, the basic methods and techniques for the molecular characterisation of MCC deficient patients have been implemented locally. A few additional sequencing primers need to be designed to cover mccB7 and mccB8 as well as the entire coding and non-coding strands of each MCC gene (mccA and mccB). The primers for RT-PCR of both mccA and mccB need to be further refined to ensure better specificity. / Thesis (M.Sc. (Biochemistry))--North-West University, Potchefstroom Campus, 2007.

The aim of this master„s thesis is detailed study of multipilot airliner?s crew in sence of optimalization of its actions, which is known as Crew Resource Management (CRM). This paper shows what is the main purpose of CRM through the air crash investigations and human factor analysis. According to this findings, the last chapter presents problems of flight crew planning and personnel selection.

yes / Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is recognised as the causative factor in the majority of MCC cases. The MCPyV small tumour antigen (ST) is considered to be the main viral transforming factor, however potential mechanisms linking ST expression to the highly metastatic nature of MCC are yet to be fully elucidated. Metastasis is a complex process, with several discrete steps required for the formation of secondary tumour sites. One essential trait that underpins the ability of cancer cells to metastasise is how they interact with adjoining tumour cells and the surrounding extracellular matrix. Here we demonstrate that MCPyV ST expression disrupts the integrity of cell-cell junctions, thereby enhancing cell dissociation and implicate the cellular sheddases, A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins in this process. Inhibition of ADAM 10 and 17 activity reduced MCPyV ST-induced cell dissociation and motility, attributing their function as critical to the MCPyV-induced metastatic processes. Consistent with these data, we confirm that ADAM 10 and 17 are upregulated in MCPyV-positive primary MCC tumours. These novel findings implicate cellular sheddases as key host cell factors contributing to virus-mediated cellular transformation and metastasis. Notably, ADAM protein expression may be a novel biomarker of MCC prognosis and given the current interest in cellular sheddase inhibitors for cancer therapeutics, it highlights ADAM 10 and 17 activity as a novel opportunity for targeted interventions for disseminated MCC. / In parts by the Medical Research Council (95505126) to AW, Royal Society (UF100419) to JM and Biotechnology and Biological Sciences Research Council (BB/R000352/1) to GEB and AW.

No description available.

International Telemetering Conference Proceedings / October 26-29, 1998 / Town & Country Resort Hotel and Convention Center, San Diego, California / Universal acceptance of the Windows NT operating system has made utilization of the personal computer (PC) platform for critical space operations a reality. The software attributes of the operating system allow PC products to attain the reliability necessary for secure control of on-orbit assets. Not only is the software more reliable, it supports better networking interfaces at higher speeds. The software upgrades that the Microsoft Corporation generates on a regular basis allow PCs to offer capabilities previously available only with UNIX-based solutions. As technology matures, PCs will operate faster, offer more graphical user interfaces, and give customers a lower cost versus performance choice. These reasons, and others to be discussed further, clearly demonstrate that PCs will soon take their place at the forefront of mission-critical ground station applications.

Colorectal cancer (CRC) remains a significant burden in contemporary society due to an aging population, unhealthy dietary choices and an increasingly sedentary lifestyle. While the underlying defects for many hereditary forms of CRC have been determined, many genetic and epigenetic changes promoting common sporadic CRCs have yet to be identified. The Mutated in Colorectal Cancer (MCC) gene, identified in 1991, was initially thought to be responsible for the hereditary form of CRC, familial adenomatous polyposis, before the discovery of the susceptibility gene Adenomatous Polyposis Coli (APC), which then became the focus of intense research. Recent data, however, suggests that MCC may also be important in the development of CRC. I have investigated the mechanism of MCC gene silencing, the putative structure, and multiple functions of MCC. MCC was frequently silenced by promoter hypermethylation in CRC cell lines and primary tumours. MCC methylation showed strong molecular and clinicopathological associations with hallmarks of the serrated neoplasia pathway. Furthermore, MCC methylation was more frequent in serrated precursor lesions compared with adenomas, thus occurring early during carcinogenesis. MCC is highly conserved in complex multicellular organisms. Re-introduction of MCC in CRC cell lines resulted in partial G1 to S phase, and G2/M phase cell cycle blocks, potentially by upregulating cell cycle inhibitor gene transcription and interfering with the process of mitotic checkpoints and division, respectively. Changes in MCC levels also modulated NF?B pathway signalling, the pathway required for maintaining cell viability and proliferation in colonic epithelial cells. In particular, MCC overexpression suppressed both TNF? and LPS-induced NF?B activation, decreasing both the magnitude and rate of cellular responses. Overexpression also resulted in downregulation of proteins involved in canonical NF?B pathway signalling, while increasing the transcription of non-canonical NF?B genes. Therefore, MCC may direct activation of this pathway to a specific subset of NF?B-regulated genes. These data provide a molecular basis for the role of MCC as a tumour suppressor gene in CRC. MCC may have multiple functions, regulating cell cycle progression and modulating NF?B pathway signalling, either through direct involvement in pathway signalling cascades, or by providing a scaffold on which signalling events can occur.

Colorectal cancer (CRC) remains a significant burden in contemporary society due to an aging population, unhealthy dietary choices and an increasingly sedentary lifestyle. While the underlying defects for many hereditary forms of CRC have been determined, many genetic and epigenetic changes promoting common sporadic CRCs have yet to be identified. The Mutated in Colorectal Cancer (MCC) gene, identified in 1991, was initially thought to be responsible for the hereditary form of CRC, familial adenomatous polyposis, before the discovery of the susceptibility gene Adenomatous Polyposis Coli (APC), which then became the focus of intense research. Recent data, however, suggests that MCC may also be important in the development of CRC. I have investigated the mechanism of MCC gene silencing, the putative structure, and multiple functions of MCC. MCC was frequently silenced by promoter hypermethylation in CRC cell lines and primary tumours. MCC methylation showed strong molecular and clinicopathological associations with hallmarks of the serrated neoplasia pathway. Furthermore, MCC methylation was more frequent in serrated precursor lesions compared with adenomas, thus occurring early during carcinogenesis. MCC is highly conserved in complex multicellular organisms. Re-introduction of MCC in CRC cell lines resulted in partial G1 to S phase, and G2/M phase cell cycle blocks, potentially by upregulating cell cycle inhibitor gene transcription and interfering with the process of mitotic checkpoints and division, respectively. Changes in MCC levels also modulated NF?B pathway signalling, the pathway required for maintaining cell viability and proliferation in colonic epithelial cells. In particular, MCC overexpression suppressed both TNF? and LPS-induced NF?B activation, decreasing both the magnitude and rate of cellular responses. Overexpression also resulted in downregulation of proteins involved in canonical NF?B pathway signalling, while increasing the transcription of non-canonical NF?B genes. Therefore, MCC may direct activation of this pathway to a specific subset of NF?B-regulated genes. These data provide a molecular basis for the role of MCC as a tumour suppressor gene in CRC. MCC may have multiple functions, regulating cell cycle progression and modulating NF?B pathway signalling, either through direct involvement in pathway signalling cascades, or by providing a scaffold on which signalling events can occur.

No description available.

No description available.

Les relations entre les Etats-Unis et l’Amérique latine entre 1988 et 2008 ont connu de nombreux bouleversements et chambardements. Les nombreuses raisons qui en sont les causes ont été abordées dans cette thèse. Après avoir étudié les enjeux théoriques de leurs relations nous nous sommes demandés si la politique étrangère était une politique publique comme les autres. Suite à une comparaison générale nous avons étudié les spécificités de l’aide publique au développement et le cas d’une théorie promue par George Bush Jr qui est la « diplomatie transformationnelle ». Dans un second temps, nous avons étudié les bouleversements diplomatiques apparus dans un certain nombre de pays de cette région du fait de l’arrivée de gouvernements de gauche. Les pages consacrées aux trois programmes élaborés par Washington dans les années 2000 (MCA, les deux plans Colombie et le Plan Merida) montrent leur originalité mais aussi leur application et leurs résultats mitigés tant du point de vue de l’efficacité, de l’efficience que de la consolidation des relations diplomatiques avec les pays de cette région. Enfin, nous avons décrit et analysé l’importance des enjeux énergétiques avec l’Amérique latine pour les Etats-Unis puis développé les raisons qui les poussent à vouloir constituer la ZLEA. Cela démontre l’imbrication des questions économiques, diplomatiques et sécuritaires pour les décideurs américains. / The relations between the United States and Latin America between 1988 and 2008 had known a lot of upheavals. The different reasons which were at the origin of that were approached in this dissertation. After having studied the theorical stakes concerning their relations we asked ourself if foreign policy was a classic public policy. Then, we studied development aid’s specificities and a theory promoted by George W. Bush which is the « transformational diplomacy ». In a second part, we studied diplomatical upheavals appeared in some countries of the region, consequence of the election of left wing governments. Pages dedicated to the three programs worked out by Washington during the 2000’s (MCA, both Colombian plans and Merida Initiative) showed the originality but also their application and their reserved results so much from the point of view of the efficiency and the consolidation of the diplomatical relations with the countries of this region. At last, we described and analyzed the importance the energy challenges with Latin America for the United States and developed reasons which urge them to want to constitute the FTAA. This show The interweaving of the economic, diplomatic and security questions for the American decision-makers.