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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
371

Roles of cellular FLICE-inhibitory protein (c-FLIP) and Pl3K/Akt in Fas (CD95)-induced NF-[kappa]B activation and apoptosis through death effector domains

Lu, Bin, January 2005 (has links)
Thesis (Ph. D.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains viii, 95 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 82-95).
372

Periytyvän rintasyöpäalttiusmutaation (BRCA1/2) kantajamiesten hypoteettinen perinnöllisyysneuvontamalli

Kajula, O. (Outi) 06 March 2018 (has links)
Abstract The purpose of this study was to develop a hypothetical model of genetic counseling for male hereditary breast cancer mutation (BRCA1/2) carriers. The methodological approach involved mixed methods. The aim of the first phase was to describe male BRCA1/2 mutation carriers’ genetic counseling, experiences and needs for developing genetic counseling. Quantitative data were acquired using a patient counseling questionnaire (n=35) based on consecutive sampling, whereas theme-based interviews (n=31) were conducted as a qualitative approach. In the second phase, the theme-based interview data were used to describe males’ experiences after identification as BRCA1/2 mutation carriers and effects of identification as a carrier on their lives (n=31). The data were analyzed using descriptive statistics and inductive content analysis. The results of the study were combined into a model describing genetic counseling for male BRCA1/2 mutation carriers. Based on the quantitative data, the genetic counseling was evaluated as good. Psychosocial support was insufficient. According to the qualitative data, there was lack of noticing individual wishes and needs during the genetic counseling process. Operational conditions of departments of clinical genetics and genetic healthcare professionals’ readiness to provide gentic counseling were varied. Identification as a BRCA1/2 mutation carrier caused varied emotional reactions associated with identification as a carrier, hereditary transmission of the mutation, cancer risks and possibility of developing cancer. However, the duration of the reactions varied. Identification as a carrier had effects on male carriers’ health and social wellbeing. According to the hypothetical model, genetic counseling was based on the backgrounds and individual needs of the male BRCA1/2 mutation carriers, which was implemented with appropriate operational conditions. It included sufficient psychological support, which genetics healthcare professionals had professional responsibility for implementing. The information study provided can be used to broaden the knowledge base of nursing science in clinical genetics. The information may also be utilized in continued nursing education. / Tiivistelmä Tutkimuksen tarkoituksena oli kehittää periytyvän rintasyöpäalttiusmutaation (BRCA1/2) kantajamiesten hypoteettinen perinnöllisyysneuvontamalli. Tutkimuksessa käytettiin monimenetelmämetodologiaa. Ensimmäisessä vaiheessa kuvattiin BRCA1/2-alttiusmutaation kantajamiesten perinnöllisyysneuvontaa, perinnöllisyysneuvontakokemuksia ja kehittämistarpeita. Aineisto kerättiin kokonaisotannalla kvantitatiivisesti Potilasohjaus-kyselylomakkeella (n=35) ja kvalitatiivisesti teemahaastatteluilla (n=31). Toisessa vaiheessa kuvattiin ensimmäisessä vaiheessa kerätyllä haastatteluaineistolla kantajamiesten kokemuksia alttiusmutaation kantajuudesta ja kantajuuden vaikutuksista elämään (n=31). Tutkimuksen aineistot analysoitiin tilastollisin menetelmin ja induktiivisella sisällönanalyysillä. Tutkimuksen tulosten perusteella muodostettiin BRCA1/2-alttiusmutaation kantajamiesten perinnöllisyysneuvontamalli. Kvantitatiivisen tutkimuksen perusteella perinnöllisyysneuvonta arvioitiin hyväksi. Psykososiaalisen tuen saaminen oli vähäistä. Kvalitatiivisen tutkimuksen mukaan kantajamiesten yksilöllisten toiveiden ja tarpeiden huomioiminen perinnöllisyysneuvontaprosessin aikana oli puutteellista. Kliinisen genetiikan yksiköiden toimintaedellytyksissä ja perinnöllisyysneuvonnan antajien ohjausvalmiuksissa oli vaihtelevuutta. BRCA1/2-alttiusmutaation kantajuus aiheutti kantajamiehille eriasteisia ja -kestoisia emotionaalisia tunteita, jotka liittyivät kantajuuteen, alttiusmutaation periytymiseen, syöpäriskiin ja syöpään sairastumiseen. Kantajuudella oli lisäksi vaikutusta kantajamiesten terveydelliseen ja sosiaaliseen hyvinvointiin. Periytyvän rintasyöpäalttiusgeenin hypoteettisen mallin perusteella perinnöllisyysneuvonta oli BRCA1/2-alttiusmutaation kantajamiehen taustatilanteeseen ja yksilölliseen tarpeeseen perustuva neuvonta, joka oli toteutettu asianmukaisin toimintaedellytyksin. Se sisälsi riittävästi psykososiaalista tukea ja sen antajalla oli ammatillinen vastuu perinnöllisyysneuvonnan toteuttamisesta. Tutkimuksessa tuotetun tiedon avulla lisätään hoitotieteellistä tietoperustaa perinnöllisyyslääketieteen alueelle. Tietoa voidaan hyödyntää myös hoitotyön täydennyskoulutuksessa.
373

The Impact of Genetic Carrier Testing in Reproductive Decision-Making: FMR1 Testing in Women With Diminished Ovarian Reserve

Walker, Elizabeth R., Clark, Myra L., Stelling, James, Timko, Michael P., Pastore, Lisa M. 01 January 2017 (has links) (PDF)
Background: This study examined how FMR1 genetic testing impacts the reproductive decision-making of women with diminished ovarian reserve (DOR). Methods: 120 women clinically diagnosed with DOR (elevated FSH and/or low AMH and/or low at trial follicle count, with regular menses), and without a family history of fragile X syndrome, received fragile X genetic testing (FMR1) and completed pretest questionnaires. A subset (n=7) were interviewed pretest. Surveys and interviews were analyzed separately and then integrated using sequential explanatory mixed methods. Results: Approximately50% regarded carrying the FMR1 pre mutation as a serious condition, while 37.5% had a neutral position. Women were significantly more likely to be upset about being a carrier if they perceived the FMR1 pre mutation to be a serious condition (p< 0.01).Interviews reflect several inheritance concerns (immediate next generation, future generations, and extended family members) and the impact the test results might have on their future reproductive decisions. Discussion: These qualitative/quantitative responses indicated that FMR1 screening (1) informed DOR patients’ view of an infertility diagnosis (2) prepared them for potential health consequences in future offspring and (3) impacted their future reproductive decisions.
374

Softwarový přijímač GNSS / Software GNSS receiver

Jedlička, Petr January 2020 (has links)
The thesis deals with the analysis and the reception of the freely available signals of the navigation satellites in the L1 and E1 bands of the GPS and Galileo systems. The described signal reception sections include the process of the acquisition, the carrier frequency and phase synchronization and tracking, the spreading code phase tracking, the signal demodulation and the channel decoding. The simulation of the entire receiver is performed in MATLAB. The deeply analyzed signal reception component is the one responsible for the carrier phase and frequency synchronization and tracking. In that case, more methods and their comparison are usually listed. The signal reception component, which is responsible for the carrier phase and frequency tracking and the spreading code phase tracking, is also implemented in FPGA.
375

Molecular epidemiology and diagnosis of SAT-type foot-and-mouth disease in southern Africa

Slager-Bastos, Armanda Duarte 27 February 2006 (has links)
Foot-and-mouth disease (FMD) is an economically devastating picornaviral disease affecting over 40 species of cloven-hoofed animals. The virus occurs as seven immunologically distinct serotypes which are characterized by high levels of intra- and intertypic variation. The three South African Territories (SAT) serotypes 1-3 are endemic to sub-Saharan Africa, a region where the epidemiology of the disease is particularly complex due to the presence of six of the seven serotypes, the role of wildlife in virus maintenance and the apparently higher levels of variation in the endemic serotypes. These factors make it imperative to establish methods suited to elucidating the regional epidemiology. One of the integral parts of this process is the genetic characterization of regionally representative viruses in order to assess the variation in the field and to clarify the role of wildlife. Nucleotide sequence data and methods suited to studying the SAT-types are however limited. A first priority was therefore to establish a PCR-based nucleotide sequencing technique targeting the highly immunogenic and phylogenetically informative 1D genome region encoding the VP1 protein. The screening of multiple serotypes and subtypes prevalent on the African continent confirmed that this method was robust and well-suited to molecular epidemiological studies in the southern Africa region. The method was first applied in the characterization of FMD virus recovered from the reproductive tract of free-living African buffalo in the Kruger National Park. Nucleotide sequencing assisted in authentication of the results and indicated that carrier status was likely, but it was not possible to unequivocally demonstrate persistent infection of FMDV. In a separate study, the role of impala antelope (Aepyceros melampus) in the epidemiology of the disease in South Africa was assessed. Genetic characterization of impala and African buffalo (Syncerus caffer) viruses collected over an eleven year period confirmed that inter-species transmission occurred on several occasions and that virus can persist in impala populations for more than 12 months. Inter-species transmission and investigation of the possible mechanisms facilitating virus transmission from persistently infected buffalo focussed on the Kruger National Park in South Africa. In order to ensure regional relevance the study was broadened to incorporate buffalo populations throughout southern Africa. Viruses of the three SAT-types recovered from diverse African buffalo populations were therefore characterized. The results reveal that independently evolving viral lineages occur in distinct geographical regions for each of the SAT-types examined and that the levels of intratypic variation are in the order of 52 - 55 % on nucleotide level across the genome region characterized. Given the strict locality-specific grouping of buffalo viruses the likely usefulness of this database for tracing the origin and course of contemporary and historical SAT-type outbreaks was investigated. Molecular epidemiological studies conclusively show that buffalo are indeed the ultimate source of infection for susceptible cloven-hoofed animals occurring in close proximity, that interspecies transmission occurs between cattle and antelope and that trans-boundary transmission of virus remains a threat to disease security in southern African countries. / Thesis (PhD (Microbiology))--University of Pretoria, 2007. / Microbiology and Plant Pathology / unrestricted
376

Requirement analysis of international wholesale telecommunications for Carrier Ethernet services

Garbaruk, Ekaterina January 2012 (has links)
The development of Internet applications, as well as new technologies to provide Internet access to users, has caused a massive increase in the amount of data traffic in networks and the need of cost-efficient solutions for various networks. This motivated the development of such technologies as Internet Protocol (IP) and Ethernet. Ethernet originally aimed to serve the needs of Local Area Networks. The deployment of Ethernet in metropolitan area networks worldwide (also known as Carrier Ethernet) has made it both a competitive and preferable technology in comparison to technologies such as SONET/SDH and wavelength division multiplexing (WDM). This thesis research investigates the requirement of various stakeholders to Carrier Ethernet technology. The following stakeholders were identified during the research: customers, standardization bodies, vendors, and providers. Each stakeholder was closely investigated and its needs, requirements and interconnection with other target groups were analysed and gathered into one communication map called Carrier Ethernet eco-system. Moreover this thesis identifies more specific recommendations to each stakeholder that could improve the development of Carrier Ethernet technology in general and ensure the satisfaction of the customer and leave more space for future innovation. / Internettillämpningars utveckling har framkallat en massiv ökning av datatrafiken i näten och dess krav har drivit fram införande av Internet Protocol (IP) och Ethernet-teknologi i globala nätverk. Ethernets teknologi har ursprungligen utvecklades för Local Area Networks. Ethernets spridning i globala näten (också känd som Carrier Ethernet) har gjort det till en både konkurrenskraftig och eftersökt teknologi i jämförelse med SONET/SDH och Våglängdsmultiplexering (WDM) tekniker. Denna rapport utreder kraven på Carrier Ethernet som kommer från följande intressenter: kunder, standardiseringsorgan, telekommunikations företag, och leverantörer. Detta examensarbete undersöker varje intressent och identifierar vilka funktioner de behöver och hur de är i förbindelse med andra målgrupper. Resultatet av analysen samlades i en karta som kallades Carrier Ethernet ekosystem. Dessutom kommer denna uppsats identifierar mer specifika rekommendationer för varje aktör som kan ge en förbättrad utveckling av Carrier Ethernet-teknik i allmänhet och motivera framtida innovationer i tekniken.
377

VoIP Operators : From a Carrier Point of View

Sidiropoulou, Christina January 2011 (has links)
Voice over Internet Protocol (VoIP) is a service that has recently gained a lot of attention from the telecommunications (telecom) world since both Internet service providers (ISPs) and telecommunications operators have realized the important advantages that it can offer. Although traditional telephony is well established both in the telecom world and in our daily lives, VoIP is now competing with it by offering cost savings, simplicity, and introducing new ways of communicating. Internet service providers have already started deploying efficient VoIP services for their customers and carriers are transforming their network infrastructures in order to be able to accommodate the requirements of VoIP traffic. There are a lot of essential factors that both providers and carriers have to take into consideration in order to efficiently build and operate VoIP technologies. Proper service planning and well-established monitoring and troubleshooting procedures are vital for successful VoIP service. This thesis focuses on commercial VoIP implementation at the carrier’s side and investigates how a carrier can efficiently maintain and troubleshoot their VoIP infrastructure so as to comply with the Service Level Agreements (SLAs) they have signed with their customers (ISP providers), as well as analyses proactive actions that can betaken for minimizing the resources required for customer support. As an outcome, this thesis presents efficient ways of network planning and monitoring, as well as it provides conclusions regarding what are the efficient methods for troubleshooting the carrier’s VoIP products inboth technical and organizational level. / Röst över Internet Protokoll (VoIP) är en tjänst som nyligen har fått ökad uppmärksamhet inom telekommunikations (telecom) branschen eftersom att både Internetleverantörer (ISPs) och telecom operatörer har insett vilka fördelar som tjänsten erbjuder. Även om traditionell telefoni är väl etablerad i både telecombranschen och vår vardag, så kan VoIP konkurrera genom att erbjuda kostnadsbesparingar, förenkling, och introducera nya sätt att kommunicera på. IP leverantörer har redan påbörjat lansering av effektiva VoIP tjänster till sina kunder och telecom carriers bygger om sin nätverksstruktur för att möta kraven av VoIP traffik. Det finns många faktorer att bejaka för både IP leverantörer och telecom carriers för att effektivt bygga och driva VoIP nätverk. Noggrann produktplanering och väletablerad övervakning samt felsökningsprocedurer är en vital del i en framgångsrik VoIP tjänst. Denna avhandling fokuserar på VoIP implementering hos en telecom carrier och hur en telecom carrier effektivt kan underhålla och felsöka VoIP infrastruktur för att möta de servicenivåavtal de har skrivit med sina kunder (IP leverantörer), samt analysera det förebyggande åtgärder som kan tas för att minimera de resurser som behövs till kundtjänst. Denna avhandling presenteras effektiva tillvägagångssätt för planering och övervakning samt erbjuder effektiva,teknisk och organisationella metoder för felsökning av en telecom carriers VoIP produkter.
378

In silico structure-based optimisation of pyrrolidine carboxamides as Mycobacterium tuberculosis enoyl-ACP reductase inhibitors / In silico Struktur-basierte Optimierung von Pyrrolidin-Carbonsäureamiden als Mycobacterium tuberculosis Enoyl-ACP-Reduktase-Inhibitoren

Narkhede, Yogesh January 2018 (has links) (PDF)
The high infection rates and recent emergence of extremely drug resistant forms of Mycobacterium tuberculosis pose a significant challenge for global health. The NADH- dependent enoyl-ACP-reductase InhA of the type II mycobacterial fatty acid biosynthesis pathway is a well-validated target for inhibiting mycobacterial growth. InhA has been shown to be inhibited by a variety of compound series. Prominent classes of InhA inhibitors from literature include diaryl ethers, pyrrolidine carboxamides and arylamides which can be subjected to further development. Despite the progress in this area, very few compounds are in clinical development phase. The present work involves a detailed computational investigation of the binding modes and structure-based optimisation of pyrrolidine carboxamides as InhA inhibitors. With substituents of widely varying bulkiness, the pyrrolidine carboxamide dataset presented a challenge for prediction of binding mode as well as affinity. Using advanced docking protocols and in-house developed pose selection procedures, the binding modes of 44 compounds were predicted. The poses from docking were used in short molecular dynamics (MD) simulations to ascertain the dominant binding conformations for the bulkier members of the series. Subsequently, an activity-based classification strategy could be developed to circumvent the affinity prediction problems observed with this dataset. The prominent motions of the bound ligand and the active site residues were then ascertained using Essential Dynamics (ED). The information from ED and literature was subsequently used to design a total of 20 compounds that were subjected to extensive in-silico evaluations. Finally, the molecular determinants of rapid-reversible binding of pyrrolidine carboxamides were investigated using long MD simulations. / Hohe Infektionsraten und das Auftreten von multiresistenten Formen von Mycobacterium tuberculosis stellen eine große Herausforderung f ̈ ur das globale Gesundsheitswesen dar. Die NADH-abh ̈angige Enoyl-ACP-Reduktase des mykobakteriellen Fetts ̈aure-Biosynthesewegs II, InhA, ist ein gut validiertes Target zur Hemmung des mykobakteriellen Wachstums. Es wurde gezeigt, dass InhA durch eine Vielzahl von unterschiedlichen Verbindungs- klassen gehemmt wird. Zu den bekanntesten Klassen von InhA-Inhibitoren aus der Literatur geh ̈ oren Diphenylether, Pyrrolidincarboxamide und Arylamide, die zur weiteren Entwicklung verwendet werden k ̈onnen. Trotz der Fortschritte in diesem Bereich sind sehr wenige Verbindungen in einer klinischen Entwicklungsphase. Die vorliegende Arbeit beinhaltet eine detaillierte computergest ̈ utzte Untersuchung der Bindungsmodi und die strukturbasierte Optimierung von Pyrrolidincarboxamiden als InhA-Inhibitoren. Aufgrund von Substituenten mit stark variierendem Raumanspruch stellt der Pyrrolidin- carboxamid-Datensatz eine Herausforderung f ̈ ur die Vorhersage von Bindungsmodi und Affinitit ̈aten dar. Mit aufw ̈andigen Docking-Protokollen und speziell zu diesem Zweck entwickelten Posen-Auswahlverfahren wurden die Bindungsmodi f ̈ ur 44 Verbindungen vorhergesagt. Die Posen des Dockings wurden in kurzen Molekulardynamik (MD) Sim- ulationen verwendet, um die bevorzugten Bindungskonformationen f ̈ ur die r ̈ aumlich anspruchsvollen Vertreter des Datensatzes zu ermitteln. Anschließend konnte eine akt- ivit ̈atsbasierte Klassifizierungsstrategie entwickelt werden, um die in diesem Datensatz beobachteten Probleme in der Affinit ̈ atsvorhersage zu umgehen. Die wesentlichen Bewe- gungen des gebundenen Liganden und der Aminos ̈auren der Bindetasche wurden daraufhin mit Essential Dynamics (ED) ermittelt. Informationen aus der ED-Analyse und der Literatur wurden anschließend verwendet, um insgesamt 20 Verbindungen zu entwerfen, die umfangreichen in-silico-Bewertungen unterzogen wurden. Schließlich wurden die molekularen Determinanten der schnell-reversiblen Bindung von Pyrrolidincarboxamiden unter Verwendung von langen MD Simulationen untersucht.
379

Modulation and Synchronization for Aeronautical Telemetry

Shaw, Christopher G. 14 March 2014 (has links) (PDF)
Aeronautical telemetry systems have historically been implemented with constant envelope modulations like CPM. Shifts in system constraints including reduced available bandwidth and increased throughput demands have caused many in the field to reevaluate traditional methods and design practices. This work examines the costs and benefits of using APSK for aeronautical telemetry instead of CPM. Variable rate turbo codes are used to improve the power efficiency of 16- and 32-APSK. Spectral regrowth in nonlinear power amplifiers when driven by non-constant envelope modulation is also considered. Simulation results show the improved spectral efficiency of this modulation scheme over those currently defined in telemetry standards. Additionally, the impact of transitioning from continuous transmission to burst-mode is considered. Synchronization loops are ineffective in burst-mode communication. Data-aided feed forward algorithms can be used to estimate offsets in carrier phase, frequency, and symbol timing between the transmitter and the receiver. If a data-aided algorithm is used, a portion of the transmitted signal is devoted to a known sequence of pilot symbols. Optimum pilot sequences for the three synchronization parameters are obtained analytically and numerically for different system constraints. The alternating sequence is shown to be optimal given a peak power constraint. Alternatively, synchronization can be accomplished using blind algorithms that do not rely on a priori knowledge of a pilot sequence. If blind algorithms are used, the observation interval can be longer than for data-aided algorithms. There are combinations of pilot sequence length and packet length where data-aided algorithms perform better than blind algorithms and vice versa. The conclusion is that a sequential arrangement of blind algorithms operating over an entire burst performs better than a CRB-achieving data-aided algorithm operating over a short pilot sequence.
380

Antigenic Determinants Of Chicken Riboflavin Carrier Protein: Structural And Functional Aspects

Beena, T K 10 1900 (has links)
Investigations detailed in this thesis constitute a part of the continuing programme of research undertaken in our laboratory on the riboflavin carrier protein (RCP) with partic­ular reference to identification and synthesis of neutralizing antigenic determinants, design of relevant epitope mimetics with improved immunogenic characteristics and relationship between their secondary structures and immunological properties. The riboflavin carrier protein is elaborated as a reproductive stratagem to ensure ade­quate vitamin deposition in the developing oocyte in the chickens. The protein is scrupu­lously conserved through evolution in terms of physico chemical and immunological char­acteristics from fish through birds to mammals, including primates. In rodents and sub­human primates immunization with the heteroantigen viz., chicken egg white RCP leads to functional neutralization of the endogenous maternal protein resulting in curtailment of early pregnancy. Thus, the crucial role of RCP in maintenance of pregnancy is established and the protein identified as a potential candidate vaccine for immimocontraception. Fur­ther studies with the reduced and carboxymethylated (RCM) RCP as the immunogen re­veal that antibodies induced by RCM-RCP are equally effective in bioneutralization of the endogenous protein. So it can be surmised that the native folded structure of RCP is not obligatory for eliciting bioneutralizing antibodies. In an attempt to identify functionally relevant regions of the protein, a panel of monoclonal antibodies (MAbs) have been raised and characterized. One of the MAbs viz., 6J32Ci2 could bring about early fetal resorp-tion when injected to mice with confirmed pregnancies. These results prompted a detail molecular immunological approach to understand underlying mechanisms. The principal aims of the present investigations include: (1) identification of neutralizing epitopes; (2) synthesis of peptidyl sequences incorporating these determinants; (3) an understanding of the structure, antigenic and immunogenic characteristics of these peptides; (4) correlation of conformational and antigenic characteristics; (5) rational design and synthesis of peptide analogs with greater propensity to assume predicted secondary structures; (6) analysis of conformation dependency of peptide antigens and the importance of such conformation in generating an optimal B-cell response; (7) the efficacy of the antibodies elicited by these Peptide antigens in neutralizing endogenous protein with the ultimate aim of designing synthetic vaccines. Chapter 1 of this thesis deals with a general introduction summarizing the current status of knowledge regarding the chemistry and biology of RCP as well as synthetic pep­tides as potential immunogens. Chapter 2 outlines details of the experimental procedures adopted. Chapter 3 describes the results of investigations on the C-terminal fragment (residues 200-219) of cRCR The main consideration in selecting this sequence for the design of a potential peptide-based vaccine relied on the epitopic specificity of the neu­tralizing MAb 6S2C12. Epitope mapping using the Pepscan method revealed that the monoclonal antibody recognizes a core sequence corresponding to residues 203-210 of the cRCP. A 21-residue synthetic peptide (C-21) comprising this epitope was synthesized and antibodies elicited to the peptide conjugated to two different carriers, namely diphtheria toxoid and purified protein derivative (PPD) for T-cell help. In both active and passive immunoneutralization experiments, the peptide specific neutralizing antibodies interfered with the biological function of the protein and hence either protected from pregnancy or caused early fetal resorption in rodents as well as in sub-human primates. The conforma-tional properties of the peptide in aqueous buffers were analyzed from circular dichroism which revealed the absence of any ordered structure in the native C-21 peptide. Theoreti­cal predictions of secondary structure suggested a propensity for an t*-helical structure for this fragment in the native protein. Therefore, influence of the helix-promoting solvent, vizM 2,2,2,trifluroethanol (TFE) on the C-21 peptide was investigated. Addition of TFE resulted in spectral changes with negative bands at 208 and 222 nm and a positive band at 190 rim which are typical of an a-helix. To gain more information on the conformational characteristics of this peptide, it was considered worthwhile to stabilize the native peptide in an a-helical conformation based on simple rational design principles. Towards this end, four analogs of the parent peptide were synthesized and helix stabilization was sought to be achieved by introducing either salt bridges or back-bone conformational constraints such as by incorporating a-amino isobutyric acid at appropriate positions. In all the analogs, the core sequence, recognised by the neutralizing MAb 6B2C12 was maintained intact to ensure induction of antibodies capable of recognizing the native protein. CD spectral analysis of the analog peptides indicated that all the engineered peptides had varying degrees of enhanced helicities as compared to the parent peptide. The immunogenicity of each analog was studied by to the relevant peptide-diphtheria toxoid conjugates and analyzing their reactivities with the native protein by direct and competitive ELISA. The results revealed that these engi­neered conformational analogs axe highly immunogenic eliciting high titers of anti-protein antibodies. The relative affinities of these antibodies to bind cRCP were investigated. The antibodies to peptide analogs had higher affinities for the native protein and a positive correlation was found between the helical content of the peptide antigen in question and the relative affinity of corresponding antibody. The antibodies directed to all the peptide analogs could block the function of RCP resulting in early embryonic resorption when ad­ministered to pregnant mice. An interesting pattern of immunological cross-reactivity has been observed with the native and designed peptides. Antibodies raised to constrained helical analogs could bind the C-21 peptide which is structurally flexible. In contrast, the antibodies raised to the flexible native peptide antigen were inefficient in recognizing the structured peptides. The ability of all the peptide antibody to bind the native protein has been interpreted in terms of a conformationally flexible C-terminus region in cRCP. Chapter 4 details investigations on a 21-residue peptide (N- 21) from the N-terminiis (4-24) of the protein. Selection of this peptidyl sequence relied on theoretical prediction of potential sequential determinants on RCP other than at C-terminus as well as on the outcome of immunoneutralisation experiments using antibodies to egg yolk RCP which lacks the relevant C-terminal determinants. The structure of this peptide in solution was analyzed by two dimensional NMR and CD. NMR experiments revealed the presence of two structured regions in the peptide. Diagnostic nuclear Overhauser effects characteristics of reverse turns or short frayed helical segments over residues 3-9 and 18-21 of the peptide were obtained. CD spectra showed the presence of a strong, negative band at 204 nm over a wide range of solvent conditions, a feature which has been interpreted in terms of a "polyproline Il-like" segment encompassing residues 11-16 which corresponds to an interesting (X-Pro)^ repeat in the N-21 sequence. Specific antibodies were generated to this peptide as a conjugate with diphtheria tox­oid. Administration of the antipeptide antibodies could neutralize the protein in vivo as demonstrated by early embryonic loss in pregnant mice. In limited experiments the anti­peptide antibodies showed propensity to protect bonnet monkeys from pregnancy over a few consecutive ovulatory cycles when titres are maintained elevated by periodic boosting. To address the relationship between peptide structures and antigenicity, epitope mapping of this antipeptide antibodies as well- as the polyclonal antibodies to native RCP was undertaken using the Pepscan method. The results reveal that antigenic regions correspond well to conformationally well-defined elements of structure with the polyproline II-like seg­ment being a common antigenic determinant on both the peptide and the native protein. These observations are suggestive of the involvement of both the N and C-terminal regions of RCP in terms of its binding to putative plasma membrane receptors.

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