Iodine is an essential element for the production of thyroid hormone, which is required for fetal cognitive development during pregnancy. Changes in maternal metabolism and physiology increase iodine requirements, and even mild iodine deficiency may lead to adverse effects on fetal neurodevelopment. While overall iodine intake in the United States is considered to be sufficient, there have been recent concerns about mild deficiency among women of childbearing years. Potentially exacerbating this issue amongst Haitian-American women is the known occurrence of iodine deficiency in Haiti. Attempts to supplement iodized salt by UNICEF have been unsuccessful due to Haiti's current political climate. Haitian immigrant women living in the United States may be at particular risk for iodine deficiency during pregnancy due to their unique dietary patterns. We conducted a cross-sectional study of 21 pregnant Haitian women living in the Boston area in order to determine if they are ingesting adequate dietary iodine. Our subjects included women with singleton pregnancies, who were not taking any thyroid hormone or anti-thyroid medication, and who were recruited at the Antenatal Clinic at Boston Medical Center. We obtained spot urine iodine concentrations, as well as information pertaining to iodine-containing prenatal vitamin use. To date, this has been the only such study carried out in this particularly vulnerable ethnic group and this study provides information of public health importance.

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archives@tulane.edu / The relationship between behavior, hormones and the environment has long been of interest to evolutionary biologists and biological anthropologists. Hormone levels vary between individuals, seasonally, and affect behavior. Research in male mammals shows dominance rank is related to androgen and cortisol levels, both of which vary with breeding season. However, even though females also produce androgens and they play a crucial role in regulating the female reproductive system, the role of androgens in the behavior of females is not well understood. White-faced capuchins (Cebus capucinus imitator) are female philopatric, medium-sized Neotropical monkeys. We characterize dominance in female white-faced capuchins, examine how rates of agonism vary with social and environmental change, and investigate the hormonal underpinnings of behavior in Sector Santa Rosa, Área de Conservación Guanacaste, Costa Rica. We find that females demonstrate only moderately linear dominance hierarchies, likely due to high kin-relatedness between females. We determined nearly the same hierarchy despite the methodology used to determine the rank order. Rates of agonism varied with dominance rank and fruit availability and we suggest that females inherit their rank from their mother, but use agonism to maintain this rank throughout their lives. Females adjust their rates of agonism such that they exhibit greater rates of agonism when ripe fruit availability is low. We propose that females need to increase agonism in order to gain access to sufficient resources to sustain themselves and their reproductive requirements. We also suggest that higher fruit availability leads to fewer bouts of agonism because there is enough fruit to occupy most group members. Higher-ranking females exhibit higher androgen and cortisol levels. This is inconsistent with the dual-hormone hypothesis, which suggests that higher-ranking individuals have higher androgen, but lower cortisol levels. It is possible that the threat of male takeovers leads to higher stress and thus higher levels of cortisol as the threat of infanticide remains present. Androgen and cortisol levels did not vary seasonally with fruit availability. This work advances our understanding of the relationship of behavior, hormone levels and environmental changes and is especially important for a growing understanding of androgens in female primates. / 1 / Gillian Louisa King-Bailey

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As society adopts a sedentary lifestyle coupled with increased energy intake, obesity continues to spread pervasively throughout the world. It poses a strong public health threat due to the development of related comorbidities in individuals, such as diabetes, hypertension, dyslipidemia, and obstructive sleep apnea. Prior to the new millennium, treatment of obesity included lifestyle modifications or bariatric surgery. However, this alienated a large subset of the population who were unable to lose weight with behavioral changes alone but not obese enough to qualify for bariatric surgery. Thus, the need for an intermediate therapeutic method existed. Short-term pharmacotherapy, such as orlistat, was developed as a potential treatment option for weight loss. However, as the years passed, scientists began targeting the central nervous system (CNS) and gastrointestinal systems to develop long-term medications. As a result, liraglutide, lorcaserin, naltrexone/bupropion extended-release, and phentermine/ topiramate extended-release became FDA-approved for long-term treatment of obesity. Each drug acts on a specific part of the CNS to modulate appetite and cause decreased food intake in patients. Clinical trials conducted on these medications found phentermine/topiramate extended-release to cause the greatest weight loss. However, none of the medications emerged as a first-line treatment option for weight loss. With a myriad of side effects and contraindications, clinicians must practice personalized medicine to prescribe certain drugs for patients. Furthermore, because these medications have been relatively recently approved, research on long-term effects of these medications on the human body is not available. Despite this, the emergence of pharmacotherapy in conjunction with lifestyle modifications in treating obesity has been positive. It has created a necessary step in the direction of reducing obesity prevalence worldwide and thus a proactive step in promoting the health of individuals.

Age at pubertal initiation is associated with the risk of many severe health outcomes later in life. “Reactivation” of the hypothalamic-pituitary-gonadal axis, signified via an increase in the amplitude and frequency of gonadotropin-releasing hormone, (GnRH) marks the commencement of puberty. For decades, physicians and scientists have attempted to unravel the mysterious mechanisms underlying the onset of this transitional period of reproductive maturation. In 2013, loss-of-function mutations in maternally imprinted Makorin RING Finger 3 (MKRN3) were determined to be the one of the causes of central precocious puberty (CPP), establishing MKRN3 as the first inhibitory gene with mutations in humans indicated in the upstream regulation of GnRH. MKRN3 accomplishes this suppression through its function as an E3 ligase, marking components involved in the transcription of kisspeptin and neurokinin B, two stimulatory regulators of GnRH, for degradation by the proteasome. MKRN3 remains the most common genetic cause of CPP to date. As a maternally imprinted gene, loss-of-function mutations in MKRN3 have only been shown to produce a phenotype in patients when inherited paternally. However, the mechanisms conferring monoallelic expression of MKRN3 are not well understood – nor are the downstream implications of MKRN3 imprinting abnormalities on the development, or even simply, association, with pubertal disorders. It has been determined that differential methylation – a common epigenetic modification involved in the demarcation of imprinted genes – plays a role in the imprinting mechanism of MKRN3. The purpose of this study is to characterize the differentially methylated region (DMR) and to expand understanding of how this region may serve to mark the maternal allele for repression. This will set the foundation for subsequent studies into the potential contribution of methylation defects in the MKRN3 DMR toward the onset of pubertal disorders. Two potential regulatory sites decorated with CpG islands were identified: the proximal-promoter and a potential enhancer. In classical imprinting studies, differential methylation of the proximal-promoter has been shown to mark alleles on a parent-specific basis for transcriptional inhibition – subsequently silencing expression dependent on parental origin. Additionally, many studies describe a similar process with an upstream or downstream enhancer region being the site influencing transcriptional activity of the alleles on a parent-of-origin basis; preliminary studies indicate a region 3.7 kb upstream of the MKRN3 transcription start site which may act as an enhancer for MKRN3. In this study, DNA was extracted from whole, peripheral blood of individuals with normal pubertal development, followed by bisulfite conversion and PCR amplification, with clean-up and submission for next generation sequencing. Sequencing analysis allowed for the quantification of the methylation profile of each sample at its respective regulatory site. The proximal-promoter was found to be almost entirely methylated while the enhancer exhibited differential methylation, but with notable variability between samples. We identified this enhancer region as the presumptive DMR of MKRN3. Additional research is required to confirm the status of the proposed enhancer as the DMR regulating the paternal-specific expression of MKRN3.

BACKGROUND: P53 is a tumor suppressor protein that acts to regulate the cell cycle and, therefore, regulate cell division processes and cell death processes. P53 mutations are classified as either contact mutations, where changes are found in the residues that contact with DNA, or structural mutations, where changes cause either a full or partial distortion of the conformation. Certain “hotspot” mutations have been identified, and these abolish the functionality of p53 as a tumor suppressor. P53’s function as a tumor suppressor is two-fold. It induces cellular apoptosis and affects the cell cycle. The DREAM complex (dimerization partner, RB-like, E2F and multi-vulval Class B complex) works by repression of gene expression or activation of gene expression. Indirectly, p53 activates this DREAM complex to repress cell cycle genes by replacing the activating complex. Human pituitary adenomas, the second most common intracranial tumors, usually form from different cell types in the anterior pituitary. If these adenomas secrete a pituitary hormone (GH, PRL, ACTH, or TSH), they are termed clinically functioning. If not, they are deemed clinically nonfunctioning. Pituitary tumors have a diverse genetic background, which include germline genetic defects, tumor genetic defects, and somatic genetic changes. Human pituitary carcinomas are much more rare than pituitary adenomas, and they are only usually diagnosed due to the pituitary tumor being noncontiguous with the sella turcica region and/or metastasis of the pituitary tumor. Because of the rarity of these, the genetics of these tumors is not well-documented, and the plan of treatment is diverse. In particular, corticotropic tumors are pituitary adenomas or pituitary carcinomas that are either clinically functioning, which secrete adrenocorticotropin (ACTH), or silent, which do not secrete ACTH. If the tumor is functioning, many patients have symptoms of Cushing’s disease (CD) due to the hypersecretion of ACTH, which triggers an increase in hormone production downstream hormone production. OBJECTIVE: This thesis seeks to describe a cohort of patients with functional corticotropic tumors and patients with silent (nonfunctioning) corticotropic tumors. In this cohort of patients, this thesis strives to find the gene mutations in this cohort to find a correlation between TP53 gene mutations that would affect the functionality of the p53 protein and the formation of corticotropic adenomas. METHODS: A total of 38 tumor samples from 36 patients between the ages of 20 and 79 were studied for somatic mutations. By way of whole-exome sequencing with normal DNA pairs, somatic mutations for each of the samples were determined. Along with somatic mutations, some samples were sequenced for germline mutations. RNA sequencing was completed to find somatic mutations and check the gene expression and gene transcription to compare to the somatic mutations found by way of whole-exome sequencing. Each of the somatic mutations found for TP53 were verified by ClinVar and COSMIC databases. RESULTS: From whole-exome sequencing, three samples out of the 38 samples were found to contain somatic mutations in the TP53 gene. In sample 29, two missense somatic mutations were found. First, in codon 743 (c.943G>A), this mutation produced the variant p53 protein, R248Q, a “hotspot” mutation. Second, in codon 523 (c.523C>T), this mutation produced the variant p53 protein, R175C. In sample 30, a missense mutation was found in codon 641 (c.641A>G), which produced the variant p53 protein, H214R. Last, in sample 36, a splice donor mutation was found in nucleotide 993 (c.993+1G>A), the variant located on intron 9 altered the consensus splice donor site. This resulted in an inclusion on intron 9 between exon 9 and exon 10, which produces a disrupted p53 protein. CONCLUSION: No patients with Cushing’s disease were found to have TP53 mutations, and 3 out of the 14 patients classified as silent corticotrophs had somatic mutations in the TP53 gene. Due to finding three patients that have a somatic mutation in the TP53 gene, and that, in each of these cases, the pituitary adenomas are all silent and aggressive, we can conclude that there is a correlation between TP53 gene mutations that produce an ineffective p53 protein and the formation of aggressive corticotropic adenomas.

BACKGROUND: MKRN3 is a gene recently identified to encode the first known inhibitor of puberty initiation. MKRN3 mutations have been identified in children diagnosed with familial central precocious puberty. MKRN3 is a maternally imprinted gene; only the father’s allele is expressed by the child. Family studies and patterns of inheritance affirm that mutant alleles only result in CPP when the mutation was inherited from the father. Although mutations in MKRN3 were found to have implications in development of central precocious puberty, its mechanism of action remains a mystery. Previous studies in our laboratory have focused on MKRN3’s function as an E3 ubiquitin ligase and thus sought to investigate its potential targets in the cell. Because kisspeptin is the most potent known activator of GnRH neurons, it seemed to be the most likely candidate. Despite efforts to identify an association between kisspeptin levels and MKRN3 expression, little headway has been made. OBJECTIVE: Beyond the most common known function of E3 ubiquitin ligases in protein degradation, increasing evidence suggests that E3 ubiquitin ligases contribute to aiding human brain development throughout childhood and into adolescence. This proposed action of E3 ubiquitin ligases led us to propose a role for MKRN3 as a potential regulator of GnRH neuronal plasticity and maturation. I hypothesized that MKRN3 plays a role in delaying GnRH neuronal maturation and neuronal plasticity until puberty onset. Thus, MKRN3 deficiency would result in premature GnRH neuron maturation. METHODS: A mouse model of Mkrn3 knockout mice (Mkrn3 +/p-) was compared to wildtype mice (Mkrn3+/+). Using DAB IHC, GnRH neurons in the rostral pre-optic area (rPOA) area were labeled and morphologically analyzed. Additionally, Golgi staining of neurons in the arcuate nucleus was done to visualize details of neuronal synapses. Neurons were visualized under 40X and 100X magnification. To visualize spines, confocal images of dendrites from Mkrn3+/p- and Mkrn3+/+ mice were captured. Images were visualized and analyzed using both ImageJ and NeuronStudio software (for spine analysis only). RESULTS: Initial morphological analysis of GnRH neurons failed to show any significant effect of the Mkrn3 genotype on dendrite arrangement, varying among complex, bipolar, and unipolar. Similarly, Golgi staining analysis revealed that the Mkrn3 genotype did not have a measurable effect on dendritic spine type percentages. Mkrn3+/p- and Mkrn3+/+ mice showed no apparent difference in the percentage of stubby, thin, and mushroom shaped spines. However, Mkrn3 deficiency did show an effect on spine density, with neurons from the arcuate nucleus of the hypothalamus of Mkrn3+/p- mice having an increased total number of dendritic spines compared to neurons from wildtype mice. CONCLUSIONS: Mkrn3 does not appear to have an effect on dendrite architecture of GnRH neurons nor change in spine type of arcuate nucleus neurons. However, the Mkrn3 genotype does seem to affect neuronal spine density, at least in the population of neurons in the arcuate nucleus. Future research is needed to conclusively determine the mechanism of action of MKRN3 and its specific role in central precocious puberty.