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Boston University. University Professors Program Senior theses. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2999-01-01

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2016-2017 / Chez l’humain, les lymphocytes B mémoires IgG+ et IgA+ sont des cellules clés de l’immunité humorale. Ces cellules mémoires sont maintenues à long-terme dans notre organisme. Elles représentent une défense rapide et efficace contre toutes les infections que nous avons déjà vaincues pendant notre vie. Ces cellules mémoires qui rencontrent à nouveau leur antigène se différencient rapidement en plasmocytes à courte vie, et permettent la sécrétion massive d’immunoglobuline (Ig). La contrepartie mémoire de ces cellules sont les plasmocytes à longue vie qui sont présents dans les niches de la moelle osseuse et y sécrètent en permanence des anticorps protecteurs qui circulent dans le sang. Ces cellules sécrétrices peuvent avoir une durée de vie allant de dizaines d’années à la vie entière de l’individu. Les patients qui reçoivent des traitements de chimiothérapie ou de radiothérapie sont privés de ces cellules mémoires détruites par ces traitements au même titre que les cellules cancéreuses. Ces patients deviennent vulnérables aux infections et leur survie dépend de la régénération rapide de leur système hématopoïétique. Notre équipe a déjà mis au point une méthode pour préparer de grandes quantités des cellules mémoires capables de sécréter des IgG et des IgA. Les présents travaux visent à générer des plasmocytes fonctionnels et capables de survivre à long terme in vitro. La stratégie expérimentale visait à établir des conditions permettant de se rapprocher de l’environnement de la moelle osseuse. Dans un premier temps, nous avons étudié les paramètres permettant la différenciation des lymphocytes B mémoires en plasmocytes. Étant donné l’importance du potentiel redox dans l’environnement de la moelle osseuse, nous avons d’abord tenté d’en contrôler l’impact avec un antioxydant, le N-acétyle cystéine (NAC). Nos résultats ont démontré que le NAC avait un effet significatif et diminuait la phosphorylation de la protéine STAT3 en raison d’une inhibition des kinases JAK2 et JAK3. Étonnamment, cet antioxydant retardait la différenciation de nos lymphocytes B qui étaient stimulés avec une forte interaction CD40-CD154. Par la suite, la comparaison des interactions CD40-CD154 et CD27-CD70 a permis de conclure qu’il était essentiel de réduire à son minimum l’interaction CD40-CD154 et qu’il fallait ajouter les cytokines IL-6 et IL-10. Les cellules CD31+CD38+CD138+ générées présentaient un phénotype similaire à celui des plasmocytes de la moelle osseuse. Malheureusement la fréquence de ces cellules était faible et leur viabilité insuffisante. Afin d’augmenter la survie de ces cellules le dernier volet de nos travaux visait à se rapprocher des niches de la moelle osseuse. Notre but a été atteint en ajoutant des cellules mésenchymateuses issues de la moelle osseuse en présence de 8% de dioxygène (O2). Les cellules CD31+CD38+CD138+ générées ont une excellente viabilité et représentent plus de 50% des cellules totales en culture. De plus, le modèle de culture est maintenant établi dans un milieu exempt de sérum et de protéines animales. Dans l’ensemble, nos résultats permettent de proposer la production ex vivo de plasmocytes autologues avec une perspective thérapeutique pour réduire les risques d’infections des patients devenues immunodéficients, suite à un traitement de radiothérapie ou de chimiothérapie. / In Humans, IgG+- and IgA+ memory B lymphocytes are key cells for the maintenance of humoral immunity. Memory B lymphocytes are long-lived cells maintained as a memory repertoire throughout our lives. Memory B lymphocytes can establish an efficient and rapid defense against previously encountered infections. These cells rapidly differentiate into short-lived plasma cells secreting high levels of antibodies. Their counterpart, the long-lived plasma cells are the memory populations present in the bone marrow microenvironment. The long-lived plasma cells release protective antibodies into the peripheral blood, maintaining a permanent immune protection. Plasma cells can remain active for years or even for the entire life of an individual. Conversely, patients treated for cancer receive massive doses of chemotherapy or radiotherapy, which are detrimental for immune memory cells as well as cancerous cells. Those patients become highly vulnerable to infectious diseases and their survival depends on the regeneration of their hematopoietic system. Our research group has established an in vitro model enabling to prepare large quantities of IgG and IgA-secreting memory B lymphocytes. The present study aims to further investigate in vitro conditions to generate plasma cells with high survival capacity and able to secrete antibodies. Our experimental strategy intends to establish culture conditions similar to the bone marrow environment. The first step was to study parameters involved into differentiation of memory B lymphocytes into plasma cells. The importance of the redox balance in the bone marrow environment led us to measure the impact of Nacetyl cysteine (NAC), an antioxidant. Our results showed that NAC decreased STAT3 activation by inhibiting the phosphorylation of two kinases namely JAK2 and JAK3. Surprisingly, the addition of NAC had a negative effect on the differentiation of memory B lymphocytes in our culture conditions using a high level of CD40 stimulation. By comparing the levels of CD40-CD154 and CD27-CD70 interactions, we then confirmed that a low level of CD40-CD154 interaction was essential. We also established that addition of IL-6 and IL-10 was better to favor plasma cell generation. The cells obtained in this model were CD31+CD38+CD138+, showing a phenotype close to that of plasma cells found in the bone marrow. Unfortunately, those cells were produced in low frequency and were characterized by a low viability. To increase the survival of these in vitro generated plasma cells, we tried to generate culture conditions that resemble the bone marrow environment. We have achieved this by adding mesenchymal stem cells from bone marrow and maintained the cells at a low O2 level (8%). Cells CD31+CD38+CD138+ obtained at the end of the culture periods showed a high viability, and corresponded to more than 50% of total cultured cells. As expected, those cells were non-proliferating and able to secrete IgG. Furthermore, this in vitro culture model was established with a serum free media. In conclusion, our findings pave the way for the ex vivo production of autologous plasma cell for therapeutic purposes in order to reduce the risks of infection of immune-deficient patients.

Thesis (MSc)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: Geographic variation in the presence/absence of generation glands in females of the cordylus-niger-oelofseni complex was described and correlated with climatic variables. Preserved and live specimens from 96 localities in the area south of 32°30' S and west of 19°45' E in the Western Cape, South Africa, were examined for the presence or absence of generation glands. Females from western coastal localities and from the Cape Fold Mountains generally lack generation glands, while females from inland lowland localities generally possess glands. A GIS analysis was performed to determine mean annual minimum temperature, mean annual maximum temperature, potential evaporation, mean annual precipitation, mean annual fog and mean annual cloud cover measured at 14:00 for each locality. Discriminant function and canonical analyses showed a highly significant correlation between the presence and absence of generation glands and five of the six climatic variables. It is suggested that the high incidence of fog and lower temperatures experienced along the west coast as a result of the cold Benguela Current, and the high incidence of orographic fog and cloud cover in the Cape Fold Mountains may affect energy allocation in females. In order to maintain their reproductive output, females may be forced to invest less energy in secondary sexual characters such as generation glands. Interspecific variation in the location, occurrence, number, and age of gland differentiation was investigated for cordylid lizards. For several species, data were obtained from the literature and for others data were obtained from material housed in the Ellerman Collection of the University of Stellenbosch. Cordylus cordylus and C. cataphractus were used for an evaluation of inter- and intrapopulation variation. Data for C. cordylus were obtained from five populations on the coastal lowlands of the Western Cape, while data on C. cataphractus come from the literature. The sex, snout-vent length, and number of generation glands were recorded for a representative sample of lizards at each locality. While in all species generation glands were located in the femoral region, Cordylus giganteus and C. microlepidotus had additional generation glands elsewhere on the body. It is suggested that additional generation glands in these species may be related to an increased need for chemical communication in a low-visibility environment in the case of C. giganteus, and in low population densities in the case of C. microlepidotus. Generation glands are present in all cordylid males, but females of some species may lack these glands. All cordylids display sexual dimorphism with regards to the presence and number of generation glands, with males having significantly more glands than females, indicating that these glands may play a more important role in males than in females. Low sexual dimorphism in at least two species suggests that generation glands may be equally important in both sexes of these species. In females, the presence of generation glands is closely regulated by climate. There is no indication of differences in generation gland profile between ground-dwelling and rock-dwelling species, except that in at least three ground-dwelling species, generation glands are already present at birth. In other species these glands differentiate only later in life. In the males of most species, generation glands start to differentiate prior to or at sexual maturity with a drastic increase in number when asymptotic body size is reached. The considerable inter- and intrapopulation variation in gland number in females, but not in males, underscores the hypothesis that the presence of generation glands in females is energy-linked and closely regulated by climate. An opposite geographic pattern of generation gland number in C. cataphractus, suggests that other factors than climate must be responsible for a difference in gland number and a difference in population density is suggested as explanation. To test for differences in aggression levels, females with and those without generation glands were staged in two experiments. In one experiment, females from different localities were staged against each other, while females from the same locality were paired in another experiment. No significant difference in aggression levels between females with and those without generation glands were observed in both experiments. It is suggested that generation glands do not exclusively function in territorial marking, but rather as a scent enhancer for femoral gland secretions. Inorder to elucidate the functional significance of generation glands, male response to female gland stimuli was investigated for 12 male C. cordylus. Males were presented with different female gland secretions (femoral, generation, and femoral and generation gland secretion combined) and water was used as a control. Total number of tongue-flicks and number of tongue-flicks directed at the secretion were counted. No significant difference was observed in the number of tongue-flicks between the different treatment groups. Males did, however, display leg-waving and head-rubbing behaviour. At present, the behaviour displayed by male C. cordylus in the presence of female gland stimuli, is unclear. The general absence of tongue-flicking of sandpaper labelled by female gland stimuli may be because of a flaw in the experimental design or because the experiment was conducted outside the breeding season. The display ofleg-waving and head-rubbing behaviour, however, suggests that cordylids do not exclusively rely on tongue-flicking for detection of conspecifics. The real function of generation glands thus still remains unresolved and further studies are needed to clarify this. / AFRIKAANSE OPSOMMING: Geografiese variasie in die aan-/afwesigheid van generasiekliere in wyfies van die cordylus-niger-oelofseni kompleks is beskryf en met klimaatsveranderlikes gekorreleer. Gepreserveerde en lewende materiaal, afkomstig van 96 lokaliteite in die area suid van 32°30' S en wes van 19°45'0 in die Wes-Kaap, Suid-Afrika, is vir die aan- ofafwesigheid van generasiekliere ondersoek. Generasiekliere is oor die algemeen afwesig in wyfies van westelike kuslokaliteite en die Kaapse Plooiberge, terwyl dit aanwesig is in wyfies van die binnelandse laagland lokaliteite. 'n GIS-analise is gedoen om die gemiddelde jaarlikse minimum temperatuur, gemiddelde jaarlikse maksimum temperatuur, potensiële verdamping, gemiddelde jaarlikse neerslag, gemiddelde jaarlikse mis en gemiddelde jaarlikse wolkbedekking, gemeet teen 14:00, vir elke lokaliteit te bepaal. Diskriminantefunksie en kanonieke analises toon 'n hoogs beduidende korrelasie tussen die aan- en afwesigheid van kliere en vyf van die ses klimaatsveranderlikes. Daar word voorgestel dat die hoë voorkoms van mis en lae temperature wat langs die weskus ervaar word as gevolg van die koue Benguela Seestroom, en die hoë voorkoms van orografiese mis en wolkbedekking in die Kaapse Plooiberge, die energie-toekenning in wyfies beïnvloed. Om hulle voortplantingsuitset te handhaaf, word wyfies moontlik gedwing om minder energie in sekondêre geslagskenmerke, soos generasiekliere, te belê. Interspesifieke variasie in die posisie, voorkoms, aantal en tyd van klierontwikkeling is vir verskeie gordelakkedisspesies ondersoek. Data vir verskeie spesies is vanuit die literatuur verkry, terwyl data vir ander spesies vanafmaterial in die Ellerman-versameling van die Universiteit van Stellenbosch verkry is. Cordylus cordylus en C. cataphractus is vir 'n evaluering van inter- en intrapopulasie variasie gebruik. Data vir C. cordylus is vanafvyfpopulasie wat op die kuslaaglande van die Wes-Kaap voorkom, ingesamel, terwyl data oor C. cataphractus vanuit die literatuur verkry is. Geslag, snoet-kloaak-lengte en die aantal generasiekliere is aangeteken vir 'n verteenwoordigende aantal individue van elke populasie. Terwyl generasiekliere in die femorale wyk van alle spesies aangetref word, het Cordylus giganteus en C. microlepidotus ook addisionele generasiekliere in ander dele van die liggaam. Daar is tot die gevolgtrekking gekom dat addisionele generasiekliere in hierdie spesies moontlik verwant is aan 'n groter behoefte aan chemiese kommunikasie in 'n lae sigbaarheidsomgewing in die geval van C. giganteus, en in 'n lae populasiedigtheid in die geval van C. microlepidotus. Generasiekliere word in alle gordelakkedis mannetjies aangetref, maar kan afwesig wees in wyfies van sommige spesies. Alle gordelakkedisse toon geslagsdimorfisme met betrekking tot die aanwesigheid en aantal generasiekliere, en mannetjies het beduidend meer kliere as wyfies, wat daarop dui dat hierdie kliere moontlik 'n meer belangrike rol by mannetjies as by wyfies speel. Lae geslagsdimorfisme inten minste twee spesies stel voor dat generasiekliere moontlik ewe belangrik in beide geslagte van hierdie spesies kan wees. In wyfies word die aanwesigheid van generasiekliere sterk deur klimaat gereguleer. Daar is geen aanduiding van verskille in generasieklierprofiel tussen grondbewonende en rotsbewonende spesies nie, behalwe dat generasiekliere reeds by geboorte teenwoordig is in ten minste drie grondbewonende spesies. In ander spesies ontwikkel hierdie kliere eers later. In mannetjies van die meeste spesies, begin generasiekliere voor oftydens geslagsrypheid ontwikkel, met 'n drastiese toename in aantal kliere wanneer asimptotiese liggaamsgrootte bereik word. Die aansienlike inter- en intrapopulasie variasie in aantal kliere in wyfies, maar nie in mannetjies nie, ondersteun die hipotese dat die teenwoordigheid van generasiekliere in wyfies aan energie gekoppel is en deur klimaat gereguleer word. 'n Teenoorgestelde geografiese patroon in die aantal generasiekliere in C. cataphractus, stel voor dat ander faktore as klimaat vir die verskil in aantal kliere verantwoordelik is en 'n verskil in populasiedigtheid word as verklaring voorgestel. Om vir verskille in aggressievlakke te toets, is wyfies met en wyfies sonder generasiekliere is teenoor mekaar getoets in twee eksperimente. In een eksperiment is wyfies van verskillende lokaliteite teenoor mekaar getoets, en in 'n ander eksperiment is wyfies van dieselfde lokaliteit teenoor mekaar getoets. Inbeide eksperimente is geen beduidende verskille is in die aggressievlakke van wyfies nie waargeneem nie. Daar word voorgestel dat generasiekliere nie uitsluitlik in gebiedsafbakening funksioneer nie, maar dat dit eerder as reukversterker vir die femorale kliere dien. Om die funksie van generasiekliere vas te stel, is die reaksie van 12 mannetjie C. cordylus op klierstimuli van wyfies getoets. Verskillende kliersekresies (femoraal, generasie, en femoraal en generasie gekombineerd) van wyfies is mannetjies voorgelê, en water is as 'n kontrole gebruik. Totale aantal tongskiete en aantal tongskiete wat na die sekresie gerig is, is getel. Geen beduidende verskil in die aantal tongskiete is tussen die verskillende groepe waargeneem nie. Mannetjies het egter beenwaai- en kopvryfgedrag getoon. Die rede vir die gedrag wat deur C. cordylus mannetjies in die teenwoordigheid van klierstimuli van wyfies vertoon word, is egter tans onduidelik. Die algemene afwesigheid van tongskiete na skuurpapier wat met klierstimuli van wyfies gemerk is, mag moontlik wees as gevolg van 'n fout in die eksperimentele ontwerp of omdat die eksperiment buite die paarseisoen uitgevoer is. Die vertoning van beenwaai- en kopvryfgedrag stel egter voor dat gordelakkedisse nie uitsluitlik op tongskiete staatmaak om lede van dieselfde spesie waar te neem nie. Die ware funksie van generasiekliere is dus steeds onopgelos en verdere studies word benodig om dit duidelikheid hieroor te kry.

Typescript (photocopy). / Digitized by Kansas Correctional Industries

Thesis (Ph.D.)--University of the Witwatersrand, Faculty of Science, 2000.

Ces travaux de thèse sont focalisés sur l’étude de trois adipocytokines (adiponectine, visfatine et chémérine) chez des espèces dont les anomalies du métabolisme énergétique sont associées à des désordres de la fonction de reproduction. Nos résultats montrent des effets du régime alimentaire sur le métabolisme lipidique et glucidique et de manière moins prononcée sur les fonctions de reproduction chez la vache laitière et la poule reproductrice de souche chair. Ces effets ont en partie été associés aux profils d’expression de l’adiponectine, la visfatine et la chémérine. De plus, nous avons mis en évidence une surexpression du système chémérine/CMKLR1 dans le liquide folliculaire et dans les cellules ovariennes de patientes atteintes du syndrome des ovaires polykystiques associé ou non à une obésité. D’une part, ces découvertes révèlent la possibilité de considérer ces adipocytokines comme de potentiels biomarqueurs de l’évaluation de la croissance, de l’état d’engraissement et de fertilité dans les élevages agricoles. D’autre part, elles suggèrent une potentielle implication de la chémérine dans la régulation des fonctions ovariennes chez la femme. / This thesis is focused on the study of three adipokines (adiponectin, visfatin and chemerin) in species that develop abnormalities of energy metabolism associated with reproductive disorders. Our results have shown some diet effects on the lipid and carbohydrate metabolisms and in a less extend, on the reproductive functions in dairy cows and broiler hens. These effects were partly associated with the expression profiles of adiponectin, visfatin and chemerin. In addition, we have demonstrated overexpression of the chemerin/CMKLR1 system in follicular fluid and in ovarian cells of patients with polycystic ovarian syndrome, with or without obesity. First, these findings reveal the possibility of considering these adipokines as potential biomarkers for evaluating growth, fattening status and fertility in agricultural farms. On the other hand, they suggest a potential involvement of chemerin in the regulation of ovarian functions in women.

Commercial gestational surrogacy, also called contract pregnancy, involves privately contracting a biogenetically curated pregnancy using IVF. It distinguishes itself from what is commonly considered 'natural' in procreation, in that the human fetuses it produces are formally entered into a legal unit other than the family of the gestator. My work here contends that this practice is best thought, not in isolation, but in the context of social reproduction more generally and as a central component of future geographies of fetal manufacture that would treat (all) pregnancy as work. This project demands, for me, a critical revisiting of theoretic texts like Mary O'Brien's The Politics of Reproduction (O'Brien 1981). But, in my reading, O'Brien's race-blind gynocentrism doomed her to miss the ensemble of practices - forms of surrogacy among them - that have already long been engaged in the sublation of reproductive labour she professes (yet defers until after the revolution). In geography as in O'Brien, the political horizon of reproductive justice theorised by Black and/or Marxist feminists since the 1970s (Davis 1981; Ross et al. 2016), has been neglected. In assembling materials for a future rewriting of "The Politics of Reproduction" in the context of geography -a trans-inclusive uterine geography- I draw on this canon of reproductive justice first. I question the assumption that there can ever be an absence of surrogacy (i.e. an absence of assistance, co-production, or "sym-poesis" (Haraway 2016)) in babymaking. Thus I explore the synthetic substance of surrogacy synthetically, using a lens I call 'gestational labour': a conceptual hybrid of the postwork perspective on care (Weeks 2011; Federici 1975), the Marxist-feminist concept 'clinical labour' (Cooper and Waldby 2014) and cyborgicity (Haraway 1991). Deploying 'gestational labour' together with a commitment to solidarity vis-à-vis surrogates, I analyse recent events, pro- and anti-surrogacy discourses (both clinical-capitalist and activist), and trends in critical literature that illuminate an immanent 'uterine geography' (or fail to). I aim to demonstrate that the technophobic anticommodification critique of surrogacy's detractors is ultimately as insufficient as the class-blind ('philanthrocapitalist') feminism of surrogacy's sales representatives. My point is that so-called natural forms of the family are themselves already 'technologies of reproductive assistance' differently mediated in the market. Our task is unfortunately neither a matter of simply saying 'stop', nor of pretending that the satisfaction people feel in "mutually advantageous exploitation" (Panitch 2013), on such an unequal playing-field, is somehow 'enough'.Surrogate gestators sometimes show us glimpses of 'mothering against motherhood'. They expose gestation as a cyborg form of labour-power, which is to say, collective human activity always already mixed up with 'technologies' on the one hand and strange more-than-human organisms on the other. Pitting surrogacy against surrogacy, I propose keeping our understanding of what surrogacy could mean radically open. On this basis, I point readers and potential future collaborators towards new kinds of sym-poetic geographical practice: surrogacies - or, engagements with reproductive politics in the broadest sense - which I think our historic moment urgently requires.

Experiments were conducted to determine whether endogenous progesterone regulates synthesis and/or secretion of luteal oxytocin (OT). In experiment 1, mature ewes (n=5 per group) were assigned randomly to control or mifepristone (RU 486) treatment groups. Ewes were injected twice daily s.c. with vehicle or 10 mg RU 486 from days 5-7 of the estrous cycle (estrus=day 0). On day 8, following an i.v. prostaglandin F₂α (250 μg cloprostenol) challenge, venous samples were collected at frequent intervals to determine plasma OT concentrations. Plasma OT in RU 486-treated animals did not differ significantly from those of the control animals (P>0.05). In Experiment 2, ewes were injected s.c. daily with vehicle or 175 mg RU 486 from days 2-5 of the estrous cycle followed by a prostaglandin F₂α (250 μg cloprostenol) challenge on day 6. Four of five RU 486-treated ewes exhibited "split-estrus" (estrous behavior through 36 hours and again 84 to 108 hours after the onset of initial estrus). There was no significant difference in mean plasma OT or progesterone levels between treatment groups (P>0.05). Mean mature corpus luteum (CL) weights of control and RU 486-treated ewes on day 6 did not differ (394.8 ± 28.8 vs. 319.5 ± 48.3 mg; P>0.05). Mifepristone-treated ewes contained mature CL, new CL (2 of 4 ewes), and/or preovulatory follicles (≥ 10 mm, 2 of 4 ewes). Average interestrous interval for RU 486-treated ewes was 9 days longer than that of control animals (26.2 ± 2.9 vs. 17 ± 0.5 days; P<0.025). A subsequent study was conducted to determine the effects of gonadotropin-releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) on luteal OT and progesterone production in beef heifers. Ten heifers with normal estrous cycles were assigned randomly in equal numbers to a control and treatment group. On day 2 of the estrous cycle (estrus=day 0) heifers were injected with either physiological saline or 100 pg GnRH every 4 hours for 56 hours. Samples were collected 0 min pre- and 180 min post-GnRH challenge for progesterone analysis. Sixty hours after the initial injection of GnRH or saline, heifers were challenged with an i.v. injection of 500 pg prostagland in F₂α (cloprostenol) and blood was collected at frequent intervals for OT analysis. Luteal OT synthesis was suppressed (P<0.01) in heifers receiving repeated injections of GnRH compared to saline-treated control animals. Progesterone secretion was significantly greater in saline-treated animals compared to GnRH-treated animals pre- and post-challenge (1.0 ± 0.06 vs. 0.93 ± 0.11 ng/ml and 1.16 ± 0.05 vs. 0.96 ± 0.13 ng/ml, respectively; P<0.05). / Graduation date: 2003