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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.
321

Gene modifiers and novel therapies for multiple endocrine neoplasia type 1

Javid, Mahsa January 2012 (has links)
Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of pituitary, pancreatic islet and parathyroid tumours. MEN1-associated tumours show loss of heterozygosity and the MEN1 gene encodes a putative tumour-suppressor, menin, whose over-expression in vitro inhibits cell proliferation. MEN1-associated tumours present earlier, are more aggressive and more difficult to treat than sporadic endocrine tumours. Strategies for earlier identification of index cases and novel therapies may contribute towards reduced morbidity and mortality from the condition. In this study, I first investigated the safety and efficacy of MEN1 gene replacement therapy using a modified adenoviral vector in pituitary tumours of heterozygous Men1 knockout mice. This revealed that MEN1 gene replacement was safe, effective and induced reduction of tumour cell proliferation. I also performed an in vivo phage-displayed peptide library screening study in heterozygous Men1 knockout mice to identify novel peptides that specifically bind pancreatic islet tumours. This identified one peptide sequence that likely targets pancreatic islet tumours. To further elucidate the role of menin I carried out phenotypic characterization of the mouse model for MEN1 in two mouse strains to investigate the effect of different genetic backgrounds and the potential for genetic modifiers on tumour phenotype. The frequency of pituitary and adrenal tumours was significantly influenced by the mouse strain, demonstrating the importance of genetic background on MEN1 tumour occurrence, implicating the role of genetic modifiers. Finally, I investigated the prevalence of MEN1 mutations in a cohort of patients presenting with primary hyperparathyroidism under 40 years of age. This revealed that 6% of under 40 year-olds with apparently sporadic parathyroid tumours have MEN1 mutations, and are likely to present with multiple parathyroid tumours. Pre-operative genetic screening of under 40 year-old patients with multiglandular parathyroid disease may reduce post-operative recurrence of hyperparathyroidism in those patients with MEN1 mutations.
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322

The role of the G-protein subunit, G-α-11, and the adaptor protein 2 sigma subunit, ap2-σ-2, in the regulation of calcium homeostasis

Howles, Sarah Anne January 2015 (has links)
The calcium sensing receptor (CaSR) is a G-protein coupled receptor (GPCR) that plays a central role in calcium homeostasis. Loss-of-function mutations of the CaSR cause familial hypocalciuric hypercalcaemia type 1 (FHH1), whilst gain-of-function mutations are associated with autosomal dominant hypocalcaemia (ADH). However, 35% of cases of FHH and 60% of cases of ADH are not due to CaSR mutations. This thesis demonstrates that FHH type 2 (FHH2) and the new clinical disorder, ADH type 2 (ADH2), are due to loss- and gain-of-function mutations in the G-protein subunit, Gα11, respectively. The CaSR signals through Gα11 and FHH2-associated mutations are shown to exert their effects through haploinsufficiency. Three-dimensional modelling of ADH2-associated Gα11 mutations predicts impaired GTPase activity and increases in the rate of GDP/GTP exchange. Furthermore, mouse models of FHH2 and ADH2 have been identified and re-derived to enable in vivo studies of the role of Gα11 in calcium homeostasis. I also demonstrate that FHH3 is due to loss-of-function mutations in the adaptor protein 2 sigma subunit, AP2σ2, which exert dominant-negative effects. AP2σ2 is a component of the adaptor protein 2 (AP2), which is a crucial component of clathrin-coated vesicles (CCV) and facilitates clathrin-mediated endocytosis of plasma membrane components such as GPCRs. All of the identified FHH3-associated mutations affect the Arg15 residue of AP2σ2, which forms key polar contacts with CCV cargo proteins. This thesis proposes that FHH3-associated AP2σ2 mutations impair CaSR internalisation and thus negatively impact on CaSR signalling. In addition, these studies show that these signalling defects can be rectified by the use of the CaSR allosteric modulator cinacalcet, which may represent a useful therapeutic modality for FHH3 patients. In summary, FHH2 is due to loss-of-function mutations in Gα11 causing haploinsufficiency, whilst FHH3 is due to loss-of-function mutations in AP2σ2, which exert dominant-negative effects. In contrast, ADH2 is due to gain-of-function mutations in Gα11.
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323

Functional Neural Toxicity and Endocrine Responses in Mice Following Naphthalene Exposure

Colbert, Crystal 08 1900 (has links)
Polycyclic aromatic hydrocarbons (PAHs) are a well studied and diverse class of environmental toxicants. PAHs act via the aryl hydrocarbon receptor (AhR), and studies have suggested that PAHs may elicit neurological and estrogenic effects. Doses of PAHs between 50 to 150 ppm may elicit neurotoxicity in rodent models. The present study investigated the effects of naphthalene on in vivo steroidogenesis in Swiss Webster male mice, and in vitro neural function of Balb-C/ICR mice frontal cortex neurons. These data suggest that naphthalene may not elicit steroidogenic effects at concentrations ranging from 0.2 to 25 mg/kg/day, following a 7 day subcutaneous dosing regime. In addition, naphthalene may cause functional toxicity of frontal cortex neurons at concentrations of 32 to 160 ppm naphthalene.
324

The Effect of Alcohol Consumption on Adipokine Secretion

DeGroat, Ashley 01 May 2018 (has links)
Alcoholic Fatty Liver Disease (AFLD) is caused by excessive alcohol consumption and is a leading cause of liver related mortalities, with currently no treatments available. The goal of this project was to establish the effect of alcohol consumption on adipose tissue-derived secreted factors, adiponectin and C1q TNF Related Proteins 1-3 (CTRP1-3). We propose that excessive alcohol consumption will reduce circulating levels of adiponectin and CTRPs 1-3. Mice were fed a Lieber-Decarli control or alcohol diet for 10-days with a gavage (NIAAA model) or 6-weeks with no gavage (chronic model). Serum and adipose tissue were collected and CTRPs 1-3 and adiponectin levels were examined by immunoblot analysis. Our results indicate that long-term alcohol consumption effects adipokine secretion in a sex specific manner. Further research will be needed to explore the physiological relevance of these findings, to determine if these changes are beneficial to combat the negative effects of excessive alcohol consumption.
325

Avaliação da eficiência da eletroforese capilar como técnica analítica na prospecção de metabólitos de esteróides em extratos fecais de onça-pintada (Panthera onca) / Evaluation of the efficiency of the capillary electrophoresis as analytical technique in the research of steroids metabolites in jaguar fecal extracts (Panthera onca)

Guião-Leite, Flaviana Lima 12 June 2006 (has links)
O objetivo deste trabalho foi desenvolver um protocolo de extração hormonal à partir de fezes de onça-pintada (Panthera onca) e validar uma metodologia de análise destes extratos por eletroforese capilar, verificando a eficiência analítica desta técnica no estudo dos metabólitos de esteróides sexuais em fezes, com o intuito de utilização futura desta metodologia na rotina dos laboratórios de endocrinologia. Foram testados sete tratamentos para as amostras de fezes liofilizadas: quatro protocolos de extração em diferentes solventes, um de hidrólise ácida e dois protocolos de extração em fase sólida (SPE). O protocolo de extração em acetonitrila foi satisfatório como pré-tratamento da amostra e aliado à SPE C-18 apresentou bons resultados no que diz respeito à sensibilidade, precisão, recuperação e tempo de análise. Com base nos resultados obtidos, a eletroforese capilar pode ser considerada uma ótima alternativa para a prospecção de metabólitos de hormônios, podendo ser utilizada em análises de rotina nos laboratórios de endocrinologia animal, sobretudo naqueles que se dedicam às metodologias não-invasivas de avaliação da função reprodutiva em animais selvagens. / The objective of this work was to develop a protocol of hormonal extraction from jaguar feces (Panthera onca) and validate a methodology of analysis of these extracts with capillary electrophoresis, verifying the analytical efficiency of this technique in the study of the steroids metabolites in feces, with the objective of future use of this methodology in the routine of the endocrinology laboratories. Seven treatments were tested for the samples: four extraction protocols in different solvents, one of acid hydrolysis and two extraction protocols in solid phase (SPE). The extraction protocol in acetonitrila was satisfactory as pre-treatment of the samples and ally to SPE C-18, it presented good results with respect to the sensibility, precision, recovery and time of analysis. Based on the obtained results, the capillary electrophoresis can be considered a great alternative for the research of metabolites of hormones, it could also be used in routine analyses in the endocrinology laboratories, mainly in those that are devoted to the non-invasive evaluation methodologies of the reproductive function in wild animals.
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326

Perda clínica de inserção periodontal em uma população brasileira com deficiência isolada do hormônio do crescimento / Periodontal Clinical Attachment Loss in an Isolated Growth Hormone Deficiency Brazilian population

Britto, Isabella Maria Porto de Araujo 01 December 2010 (has links)
Não existe relato da condição periodontal em indivíduos com Deficiência Isolada do Hormônio do Crescimento (IGHD). O objetivo deste estudo foi investigar possíveis associações entre IGHD e a perda clínica de inserção periodontal (PCI) em uma população com IGHD congênita, presente no Nordeste do Brasil. Material e Métodos: Todos os indivíduos previamente identificados com IGHD e com idade 12 anos foram elegíveis para participar do estudo (n=46). A amostra final ficou composta por 33 casos (IGHD) e 33 controles (não - IGHD) após a exclusão dos edêntulos (n=5) e dos que haviam recebido previamente tratamento com reposição do Hormônio do Crescimento (n=8). Eles foram pareados por idade, gênero, condição sócio-econômica, hábito de fumo e diabetes. Todos foram submetidos a exame periodontal completo em 6 sítios por dente, e entrevistados por meio de um questionário estruturado. Resultados: Indivíduos com IGHD apresentaram quantidade semelhante de biofilme (p=0,32), menos cálculo supragengival (p=0,01), e mais sangramento à sondagem (p<0,01) em comparação com os controles. Após uma série de análises de regressão logística múltipla condicional, ajustada para cálculo supragengival, indivíduos com IGHD mostraram maior chance de apresentar Perda Clínica de Inserção Periodontal 7mm (OR= 18,1; IC 95% = 2,4 - 137,2). Conclusão: Indivíduos com IGHD severa e congênita possuem maior chance de apresentar Perda Clínica de Inserção Periodontal. / There are no reports of periodontal status in subjects with Isolated Growth Hormone Deficiency (IGHD). The aim of this study was to investigate possible associations between IGHD and periodontal clinical attachment loss (CAL) in a population affected by congenital IGHD, residing in Northeastern Brazil. Material and Methods: All previously identified IGHD subjects age 12 years were eligible for this study (n=46). The final study sample comprised 33 cases (IGHD) and 33 controls (non - IGHD) after excluding edentulous (n = 5) and subjects previously treated with GH replacement (n = 8). They were matched by age, gender, socioeconomic status, smoking and diabetes status. Subjects were submitted to a full-mouth clinical examination of six sites per tooth and were interviewed using a structured, written questionnaire. Results: IGHD subjects had same amount visible plaque (p=0.32), less supragingival calculus (p = 0.01), and more bleeding on probing (p < 0.01) than controls. After performance of conditional multiple regression analyses adjusted by supragingival calculus, IGHD subjects had a higher likelihood of having CAL 7 mm (OR = 18.1; 95% Cl = 2.4 - 137.2). Conclusion: Severe congenital IGHD subjects have a greater chance of having Periodontal Clinical Attachment Loss.
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327

Níveis séricos de progesterona, estrógenos e seus metabólitos fecais durante o ciclo estral de cabras (Capra hircus, Linnaeus, 1758) / Serum levels of progesterone, estrogens and their faecal metabolites along the estrous cycle in goats (Capra hircus, Linnaeus, 1758)

Faria Junior, Sebastião Pereira de 13 December 2006 (has links)
Cabras leiteiras das raças Saanen e Toggenburg (n=10) mantidas num rebanho particular no Estado de São Paulo tiveram seus níveis séricos de progesterona e estradiol comparados às concentrações fecais, durante o período correspondente a três ciclos estrais. O perfil hormonal foi confrontado com as manifestações comportamentais de estro visando uma contribuição ao conhecimento do ciclo das cabras destas raças em condições brasileiras, que leve a um manejo reprodutivo mais eficiente. As correlações entre níveis séricos e fecais foram calculadas, sugerindo a validade do modelo de dosagem hormonal nas fezes em cervídeos. Foi verificada correlação extremamente significante entre as concentrações séricas de progesterona e as de progestinas fecais, com r=0,83 e p<0,0001. Entre as concentrações séricas de estradiol e as de seus metabólitos nas fezes não foi verificada correlação significante, com r=-0,16 e p<0,3916. A partir da observação dos resultados e sua análise estatística, pode-se concluir que, dentro das condições deste trabalho, as concentrações de progestinas fecais apresentam variação correspondente à da progesterona sérica ao longo do ciclo estral das cabras; por outro lado, diferentemente das observações de outros autores, o mesmo não ocorre com os metabólitos fecais do estradiol em relação ao estradiol sérico. / Saanen e Toggenburg dairy goats (n=10) kept in a private flock in São Paulo State had their serum levels of progesterone and estradiol compared to faecal concentrations of the respective metabolites, through an interval corresponding to 3 estrous cycles. Hormonal profile was checked with behavioural manifestations of estrous searching for a better knowledge of the cycle of these breeds in brazilian environment, leading to a more efficient reproductive management. Correlations between serum and faecal levels were calculated, suggesting that the model of faecal hormone measurements could be valuable in cervidae. It was found an extremely significant correlation between progesterone serum concentration and progestin faecal concentration, with r=0,83 and p<0,0001. Between estradiol serum concentrations and its faecal metabolites? concentrations no significant correlation was found, with r=-0,16 and p<0,3916. Based on results observation and statistical analysis, we can assume that, in the circumstances of this trial, progestin faecal concentrations show a variation profile similar to that one of serum progesterone, through estrous cycle of goats; however, this fact could not be observed for estradiol metabolites, compared to serum estradiol concentrations.
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328

Avaliação endocrinológica do ciclo ovariano de macaco bugio (Alouatta caraya - HUMBOLDT, 1812) por meio de extração e dosagem de metabólitos de esteróides fecais / Endocrinological evaluation of ovarian cycle in howler monkeys (Alouatta caraya - HUMBOLDT, 1812) by extraction and measurement of fecal steroids

Kugelmeier, Tatiana 26 April 2005 (has links)
A endocrinologia ovariana de cinco fêmeas de bugio da espécie Alouatta caraya foi estudada por meio de extração e dosagem de metabólitos fecais de estrógenos e progestinas durante um período de cinco meses. Adicionalmente observou-se a presença de eritrócitos por meio de citologia vaginal em três das fêmeas estudadas. Duas fêmeas, uma em condição nutricional desfavorável e outra pré-púbere, apresentaram concentrações basais de estrógenos com mediana menor que 3,7 ng/g e de progestinas menor que 29,7 ng/g de fezes úmidas. Nas outras três fêmeas a mediana dos valores de pico de estrógenos fecais foi 711,55 ng/g e dos valores basais 130,51 ng/g de fezes úmidas. Para as progestinas fecais a mediana dos valores de pico foi 2653,54 ng/g e dos valores basais foi 149,88 ng/g de fezes úmidas. Nestes três animais as concentrações de ambos os metabólitos apresentaram uma variação cíclica e o intervalo entre picos de estrógenos fecais foi 19,6&plusmn;1,9 dias (média&plusmn;EPM). Estes metabólitos permaneceram elevados durante 9,1&plusmn;0,9 dias. Elevações sustentadas de metabólitos fecais de progestinas acompanhadas de pico e elevações de metabólitos fecais de estrógenos foram observadas em apenas quatro períodos. Nestes casos ambos os metabólitos elevaram-se aproximadamente ao mesmo tempo e estimou-se que a ovulação tivesse ocorrido antes do início destas elevações. Os períodos de sangramento coincidiram com a queda nas concentrações de estrógenos e progestinas fecais. / The ovarian endocrinology was assessed in five female howler monkeys (Alouatta caraya) by means of estrogen and progestogen metabolites extracted from fecal samples. Measurements were conducted for a period of five months, and erythrocytes were observed by vaginal cytology, in three females. In one subadult and in one undernourished female, estrogen concentrations remained at median basal levels &lt;3.7ng/g, and the progestogen concentrations were &lt;29.7ng/g of wet feces for almost the entire period of the experiment. For the other three females, median fecal estrogen peak concentration was 711.55ng/g and basal concentration was 130.51ng/g of wet feces. Median fecal progestogen concentration was 2653.54ng/g and for basal concentration was 149.88 ng/g of wet feces. The three females were found with a cyclical pattern for both metabolites concentrations, with fecal estrogen peak intervals of 19.6&plusmn;1.9 (mean&plusmn;SEM) days and the estrogen metabolites remained elevated for 9.1&plusmn;0.9 days. Fecal progestogen showed sustained elevations concurrently with fecal estrogen increase only in four periods and it was presumed that ovulation had occurred before the onset of those elevations. Bleeding periods occurred with the falling of both steroid metabolites.
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329

Monitoramento das oscilações anuais nos níveis de testosterona plasmática e andrógenos fecais de machos de jararaca-ilhoa (Bothrops insularis) mantidos em cativeiro / Annual fluctuations monitoring of plasma testosterone and fecal androgen levels in males of golden lancehead pitviper (Bothrops insularis) kept in captivity

Stein, Ingrid Vera 01 September 2016 (has links)
A jararaca-ilhoa (Bothrops insularis) é uma serpente criticamente ameaçada, endêmica da Ilha da Queimada Grande (IQG), litoral sul de São Paulo. Com a sua população em declínio, foi estabelecido um programa de reprodução em cativeiro, porém o conhecimento da sua biologia reprodutiva ainda é incipiente. Até o momento considera-se essa espécie como sazonal, com período de espermatogênese e cópulas associado, ocorrendo do outono até início da primavera, porém não existem estudos a cerca da endocrinologia reprodutiva. O objetivo desse trabalho foi validar um método de avaliação hormonal não invasiva por meio das fezes e realizar o monitoramento dos metabólitos fecais de testosterona em conjunto com avaliação plasmática de testosterona. Ao longo de 36 meses foram coletadas 156 amostras de fezes e 30 amostras de sangue de oito machos cativos. As concentrações de metabólitos fecais de testosterona variaram entre 10,9 à 249,3 ng/g de fezes, enquanto as concentrações de testosterona plasmática variaram de 0,07 à 0,30 ng/mL de plasma. Não houve diferença significativa entre as concentrações plasmáticas de testosterona e de metabólitos fecais de testosterona ao longo do ano, apesar dos machos demonstrarem comportamento reprodutivo durante esse período. Os dados corroboram com outros estudos de estocagem espermática, qualidade seminal e volume gonadal, porém vão de encontro à resultados de histologia testicular. São discutidas a possibilidade da espécie ser assazonal ou desses resultados serem uma consequência das condições do cativeiro. Esse estudo contribui com a validação de um novo método de avaliação longitudinal de esteroides sexuais em B. insularis, com o conhecimento da biologia reprodutiva de serpentes tropicais e com a conservação de animais ameaçados de extinção / The golden lancehead pitviper (Bothrops insularis) is a critically endangered snake, endemic of the Queimada Grande Island, southeastern Brazil. With its declining population, a captive breeding program was established, but the knowledge of its reproductive biology is incipient. By the time this species is considered as seasonal, with spermatogenesis period and matting associated, occurring from autumn until early spring, but there are no studies about their reproductive endocrinology. The aim of this study was to validate a noninvasively hormonal evaluation method through feces and carry out the monitoring of androgens in conjunction with plasma testosterone evaluation. Over 36 months 156 stool samples and 30 blood samples were collected from eight captive males. The fecal androgen concentrations ranged from 10.9 to 249.3 ng / g of feces and the plasma testosterone concentrations ranged from 0.07 to 0.30 ng / mL of plasma. There was no significant difference between the concentrations of fecal androgens and plasma throughout the year, although the males had shown successfully reproductive behavior during this period. The data corroborate whith other studies of sperm storage, sperm quality and gonadal volume, but disagreeded of the results of testicular histology. We discuss the possibility of the species be assazonal or these results are a consequence of the captivity conditions. This study contributes to the validation of a new longitudinal evaluation method of sex steroids in B. insularis, with the knowledge of the reproductive biology of tropical snakes and the conservation of endangered animals
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330

Perfil analítico de estrógenos e progestinas em diferentes matrizes biológicas na espécie ovina (Ovis aires) / Analytic profile of estrogens and progestins in different biological matrixes in the ovine (Ovis aires)

Furtado, Priscila Viau 09 November 2007 (has links)
O objetivo deste trabalho foi avaliar de maneira detalhada e sistemática os perfis hormonais sanguíneos, fecais, urinários e salivares das progestinas e estrógenos durante o ciclo estral induzido de ovinos. Foram colhidas amostras diárias durante um período de 60 dias de sete fêmeas adultas (n=8) saudáveis e sexualmente maduras. Antes do início da fase de colheita das amostras, todos os animais foram submetidos ao protocolo de tratamento hormonal para indução e sincronização do cio durante dozes dias. O primeiro ciclo ovariano de cada animal desse experimento, detectado logo após a indução do cio foi descartado e seus valores não foram utilizados nas análises hormonais, pois poderiam estar sob o efeito dos hormônios exógenos. A concentração dos progestágenos foi determinada pelas técnicas analíticas de Radioimunoensaio (RIE) e Enzimaimunoensaio (EIE) e os estrógenos por RIE. Houve correlações entre as concentrações de progesterona medidas nas matrizes sérica e fecal, sérica e salivar, fecal e salivar (r=0,90, p<0,0001; r=0,90, p<0,0001; r=0,92, p<0,0001, respectivamente) durante os ciclos estrais observados (n=15). Obtivemos correlação (r=0,74, p<0,0001) entre as concentrações dos estrógenos quantificados nas matrizes sérica e fecal, mas não entre estas concentrações e aquelas medidas na matriz salivar. Não obtivemos nenhuma correlação entre as concentrações medidas na matriz urinária com as quantificadas nas outras matrizes para nenhum dos hormônios estudados. Obtivemos correlação entre as concentrações de progesterona medidas na matriz fecal pelos métodos de RIE e EIE (r=0,78, p<0,0001) e também na matriz salivar pelos dois métodos empregados (r=0,81, p<0,0001). Os resultados do presente experimento indicam que os imunoensaios utilizados podem ser utilizados para a avaliação das concentrações de progestágenos nas matrizes fecal e salivar durante o ciclo estral em ovinos. / The aim of the present work was evaluate the hormonal profiles of progestins and estrogens in blood, feces, urine and saliva during the induced estral cycle in ovine. Samples were collected daily a 60-day period from eight adult (n=8) cycling ewes. The animals were previously submitted to a protocol of estrus induction and synchronization for twelve days. In order to avoid the effect of exogenous hormones, the first cycle immediately after the synchronization was not considered for hormonal analysis. Progestagen concentrations were quantified by two analytical techniques, radioimmunoassay (RIA) and enzyme immunoassay (EIA). Estrogen concentrations were assessed by radioimmunoassay. Correlations in progesterone concentrations were found to be significant for serum and feces, serum and saliva and feces and saliva (r=0.90, p<0.0001; r=0.90, p<0.0001; r=0.92, p<0.0001, respectively) during the estrous cycles (n=15). Estrogen concentrations in the serum and feces were also positively correlated (r=0.74, p<0.0001). Salivary concentrations of estrogens were not correlated with fecal or serum concentrations of the same hormone. No correlation was found between urinary concentrations and concentrations found in other matrixes for both progestagens and estrogens. Concentrations of progestagens obtained using RIA and EIA were correlated on feces (r=0.78, p<0.0001) and saliva (r=0.81, p<0.0001). Results indicate that both immunoassays used in the present experiment can be used to evaluate progestagen concentrations on fecal and salivary matrixes during the estrous cycle of sheep.
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