International Telemetering Conference Proceedings / October 18-21, 2004 / Town & Country Resort, San Diego, California / The use of traditional telemetry decommutation equipment can be easily expanded to create a real-time pulse code modulation (PCM) telemetry data recorder. However, there are two areas that create unique demands where architectural investment is required: the PCM output stage and the storage stage. This paper details the efforts to define the requirements and limits of a traditional telemetry system when used as a real-time, multistream PCM data recorder with time tagging.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine. Johannesburg, June 2017 / Introduction: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease of unknown aetiology. There is growing evidence environmental factor(s) trigger the disease in the genetically susceptible host. Fragment crystallisable receptor (FCR) genes encode receptors that recognise the fragment crystallisable (Fc) portion of immunoglobulins (IgG) play an important role in the removal of antigen-antibody complexes from the circulation. Genes that code for these receptors have shown to be associated with susceptibility to SLE in various populations. The aim of the present study is to determine the role of single nucleotide polymorphisms (SNPs), allotypes and copy number variations of FC Gamma receptor genes IIIA and IIIB in susceptibility for the Black South Africans with SLE. Methods: DNA from 162 Black South African SLE patients and 155 matched controls were investigated using Taqman assays to determine SNP genotyping differences (FCGRIIIA) and copy number variation (CNV) number (FCGRIIIB). A PCR was optimised in order to determine the allotype differences (FCGRIIIB) via agarose gel electrophoresis. Statistical analyses were then performed on the data to see if the results displayed significance in susceptibility to SLE. Results: The minor allele of the allotypes (FCGRIIIB) and the rs396991 SNP (FCGRIIIA) were not statistically significant in conferring susceptibility to SLE in cases or controls. The rs10127393 SNP (FCGRIIIA) was shown to be monomorphic within both cases and controls for the T allele and is not associated with SLE. The cumulative percentage of copy numbers (FCGRIIIB) ≤2 copies were 0.6% larger in cases than seen in controls. Although this was not significant, this was what has been previously suggested in the literature. Almost half of the cases (43.8%) had lupus nephritis (LN). Upon investigation the NA1/NA2 alleles were found to confer susceptibility to LN (p=0.018), whereas the rs396991 G allele did not (p=0.643). Conclusion: In this study the allotypes, SNPs and CNV investigated were not found to confer susceptibility to SLE. However, subtle trends suggest that further studies are required with larger sample sizes to acquire more data. Almost half of the cases were diagnosed with LN and the NA2 allele was shown to be a risk factor in developing LN. / MT2017

Therapeutic antibodies have achieved exceptional clinical success in the treatment of cancer and other human diseases. Now, new approaches are required to enhance the potency of antibodies to further increase the number of patients responding to therapy. By engineering the antibody Fc domain through mutation of the amino acid sequence, binding affinity to activating or inhibitory Fc receptors on effector cells can be increased to modulate the cellular immune response. However, attaining selectivity for closely related Fc receptors has proved challenging and the technique has not been applied to access the function of antibody isotypes other than IgG. Here we present new methods for enhancing antibody potency using both hybrid IgA/G and aglycosylated Fc domains. In the first instance, a chimeric antibody Fc domain has been created by combining residues from IgA with those from IgG. The new variant, MutD, introduces binding to FcαRI while retaining affinity for certain members of the FcγR family. ADCC assays show MutD, when part of a full length trastuzumab antibody against Her2 antigen, can kill Her2-overexpressing tumor cell lines as effectively as IgA antibodies. Moreover, MutD shows improved assembly compared to IgA and thus provides access to potent FcαRI function while overcoming the expression and purification barriers that have limited the use of IgA as a therapeutic. Alternatively, aglycosylated antibodies may be engineered for exceptional effector function. Glycans anchored to residue N297 of the antibody IgG Fc domain are typically critical in mediating binding toward the FcγRs. Yet, using a full length bacterial IgG display system, we have isolated aglycosylated Fc1004 with mutations that confer a 160-fold increase in the affinity toward the low affinity FcγRIIa-R131 allele as well as high selectivity against binding to the remarkably homologous inhibitory receptor, FcγRIIb. Incorporation of this engineered Fc into trastuzumab resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with medium Her2-expressing cancer cells. In vivo testing of Fc1004 using NOD/SCID mouse model, reconstituted by adoptive transfer of leukocytes from FcγRIIa-R131 homozygous donors, showed a promising reduction in tumor burden in SkBr-3 Her2+ xenografts. / text

No description available.

Diss. (sammanfattning) Uppsala : Univ., 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xxi, 203 p.; also includes graphics. Includes bibliographical references (p. 191-203).

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 185-219).

A large body of data exists demonstrating the key role of FcRn in extending the half-life of therapeutic antibodies by rescuing them from lysosomal degradation. This led to the widely accepted hypothesis that FcRn binding of an IgG via the CH2-CH3 interface of Fc correlates with IgG half-life. Several studies have demonstrated that in vivo half-life can be modified by changing the binding affinity of IgG to FcRn. These modifications were generated by mutating the coding sequence for the Fc region that resulted in enhanced or reduced FcRn binding at endosomal pH without enhancing binding at neutral pH. In contrast to this, we have observed that the half-lifes of IgG molecules that had showed no target-mediated disposition or off-target binding varies widely, even when they share identical Fc domains. This led us to hypothesize that domains of IgG molecules other than Fc could contribute to the modulation of FcRn binding and affect in vivo half-life. This hypothesis was strengthened by recent publications by other groups showing a correlation between antibody charge and the FcRn affinity and/or in vivo half-life. In this study we explored the role of IgG domains other than the FcRn binding domain in altering the affinity between IgG and FcRn and its relation to the in vivo half-life. Here we describe a surface plasmon resonance (SPR) based assay developed to examine the steady-state binding affinity (KD) of IgG molecules to FcRn. We systematically dissected the contributions of IgG variable domain regions in modulating the affinity between FcRn and IgG. Through analysis of a broad collection of therapeutic antibodies containing more than 100 unique IgG molecules against more than 25 different therapeutic targets we have demonstrated that variable domains and in particular CDRs significantly alter binding affinity to FcRn, by 10 to 80-fold, whereas heavy and light chain isotypes do not. Because CDRs modulate the affinity between IgG and FcRn in our in vitro studies, it is important to understand the role they play in modulation of IgG half-life in vivo as this would have far-reaching implications in the half-life optimization efforts of IgG therapeutics.

Fuel cells are a promising alternate power source of electricity. Despite of sig- nificant improvement that was reached by research throughout recent decades, the technology is not still ready to large scale commercial use. The catalyst of fuel cell (FC) should be still investigated due to fact that the only reliable functional catalyst is Platinum, a noble and expensive metal, which makes the use of this technology not competitive. In this thesis, investigation of Platinum doped ceria catalyst and its modification prepared by physical technique of deposition which is magnetron sputtering is presented. The catalyst was studied using standard sur- face analytic techniques (PES, SEM, AFM, XANES) as well as electrochemical measurement (CV, PEIS). The principal part of this thesis reports direct analyses of catalyst in fuel cell using an individually designed fuel cell test station. Con- sidering the high power density (PD) about 1 W cm−2 and substantially higher specific power per gram of Platinum (SP) 1.6 kW mg−1 in comparison with com- mercial Pt-Ru/Pt-C reference catalyst and additionally the relatively longtime stability, the sputtered Platinum doped cerium oxide based catalyst was found a suitable catalyst for PEM FC. Moreover, possible substitution of Pt and CeO2 by other elements was shown. Beside of...

The development of antibody-based drugs is continuing to expand at a rapid pace, especially for use at mucosal surfaces to prevent or treat infectious diseases and other conditions. A better understanding of how the Fc region of antibodies interacts with Fc-binding proteins at mucosal sites can inform an optimal design for antibody-based drugs. The Human Contraception Antibody (HCA) is a human IgG1 monoclonal antibody currently under development as a topical vaginal contraceptive. HCA binds to sperm via its Fab domains and causes rapid agglutination with other sperm in close proximity resulting in near complete immobilization of sperm over a wide area. In order to determine whether HCA participates in Fc-mediated functions in the female reproductive tract (FRT), we assessed the activity of HCA and engineered variants in three assays of Fc-mediated functions: complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and mucus trapping. The physiological relevance of CDC was confirmed by characterizing complement levels and activity in cervical mucus. Finally, we described the activity of a novel Fc receptor expressed by vaginal epithelium. With complement, HCA significantly reduced sperm motility and increased the number of lysed sperm via CDC. Additionally, human cervical mucus was found to have sufficient levels of complement to induce the classical complement cascade. HCA-opsonized sperm associated with macrophages and were phagocytosed via ADCP. HCA also trapped sperm in ovulatory human cervical mucus, significantly reducing their progression. Variants of HCA with mutated or obstructed Fc domains had decreased abilities to perform these Fc functions, while multivalent IgM-like and IgA variants of HCA were very effective in both sperm agglutination and Fc assays. We also investigated the novel expression of Fc alpha RI (CD89) by human vaginal epithelium and provide evidence that this Fc receptor may transport IgA through the mucosa. Basal application of IgA resulted in IgA in apical supernatants which was significantly reduced following treatment with a CD89 blocker. In summary, these studies provide an improved understanding of the possible Fc functions of HCA and other antibodies in the human FRT, including interactions with complement, cervical mucus, and Fc receptors. Determining which interactions can occur in vivo and which are desired for a specific indication can inform the design of mucosally applied antibody-based drugs like HCA, a much-needed novel contraceptive antibody.