Abstract Introduction & Background The role of dietary fiber in breast cancer etiology remains unclear. A negative correlation may be due to fiber’s ability to stave off obesity and aid in the extraction of serum estrogen, two known risk factors for the disease. Effects may differ by source, and type, of fiber. Most of the data available is from research with non-Hispanic white women. However, fiber intake may vary significantly across cultures. Purpose Statement & Question The research sought to investigate whether an increased intake of dietary fiber was associated with a corresponding decrease in the incidence of breast cancer. The question posed was: Among post-menopausal women of various cultures, what is the effect of high dietary fiber intake compared to low intake on the risk of developing breast cancer? Literature Review The search was for specific studies examining the effect of dietary fiber on breast cancer development. The university’s scholarly search engine was utilized to find five studies using key terms such as “dietary fiber” and “breast cancer”. Findings Results showed an overall protective effect from high (> 25 grams/day) total dietary fiber intake on developing breast cancer. Findings for soluble versus insoluble fiber were inconsistent, but evidence suggests that fiber from beans, vegetables, and fruit may have a greater effect than fiber from whole grains. Conclusion High total fiber consumption may reduce the risk of developing breast cancer. Future research should investigate whether results hold true across more diverse populations.

Chlamydia trachomatiscauses a bacterial sexually transmitted infection, Chlamydia, that is often chronic and casues reproductive complications in women. We hypothesized that Chlamydia infection increases local acetylcholine (ACh) production, which regulates the host’s inflammatory response to the infection. Female mice infected with C. muridarumwere sacrificed at days 3, 9, 15, and 21 post-infection, genital tract tissues harvested, and immunohistochemistry performed to enumerate ACh-producing cells. Infection increased the number of ACh-producing cells in cervical tissue at days 3,15, and 21 post-infection (pi), uterine tissue at day 3 and 9 pi, and ovarian tissue day 3, 15, and 21 pi. These findings suggest that C. trachomatis increases ACh production, which may suppress the host’s immunity and aid in establishing chronic infection.

<p>Sexually transmitted infections (STIs), especially HIV/AIDS and HSV-2, continue to be a devastating burden on societies around the world. The close link between HSV-2 and HIV-1, the role of inflammation in driving these infections, and the limited success and availability of prophylactic and therapeutic measures underscore the need for continued search of alternative means of protection. Characterization of endogenous antimicrobials, especially those local to the female genital tract and actively regulating inflammatory and antiviral responses, could be beneficial for microbicidal trials. Although regulators of mucosal immunity, such as serine antiproteases, trappin-2 and elafin (Tr/E), have been associated with resistance to HIV-1, their antiviral activity remains poorly understood. Thus, the research presented in this thesis centers on characterization of antiviral properties of Tr and E individually and their potential mechanisms in defense against HSV-2 and HIV-1 in the female genital mucosa. Chapter 2 examines Tr/E contribution to antiviral host defense responses elicited by a synthetic mimic of viral dsRNA, polyI:C. Chapter 3 documents the presence and characteristics, including potential mechanisms, of antiviral activity of Tr/E against in vitro and in vivo HSV-2 infection. Chapters 4 and 5 determine the contribution of Tr/E to the natural anti-HIV-1 protection of CVL and structural characteristics, mode(s) of action, and cellular distribution/localization of antiviral Tr/E proteins. Therein, we present novel properties of each Tr/E by demonstrating their inhibitory and multiple effects against both HSV-2 and HIV-1. These effects appear to be mediated either through virus or cells and be associated with altered viral attachment/entry, transcytosis and infection, innate viral recognition, modulated inflammation and increased antiviral protection of cells. Reported antiviral activity of Tr/E was also contextual and exerted, at least in HEC-1A cells, via autocrine/paracrine mode and depended on elafin’s nuclear localization and its unmodified N-terminus. Tr/E may represent viable candidates for further studies in the field of STIs.</p> / Doctor of Philosophy (PhD)

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive neurodegenerative disease that causes degeneration in both upper and lower motor neurons. ALS progresses relentlessly after the onset of the disease, with most patients die within 3-5 years of diagnosis, largely due to respiratory failure. Since SOD1 became the first gene whose mutations were associated with ALS in 1993, more than 17 ALS causative genes have been identified. Among them, TAR DNA-binding protein (TARDBP) lies in the central of ALS pathology mechanism study, because TDP43 proteinopathy is observed not only in familial ALS cases carrying TARDBP mutations, but also in most of the sporadic ALS cases, which account for 90% of the whole ALS population. Several TDP43 overexpression mouse models have been successfully generated to study the gain-of-toxicity mechanism of TDP43 in ALS development, while the investigation of loss-of-function mechanism which could also contribute to ALS still awaits a proper mouse model. The major difficulty in generating TARDBP knock out mouse model lies in the fact that TARDBP is a development essential gene and complete depletion of TDP43 function causes embryonic lethality. In chapter I, I reviewed the recent advances in ALS study. Emphasis was given to ALS mouse models, especially TARDBP ALS mouse model. In Chapter II, I made a Tet-responsive construct that contains mCherry, a fluorescent protein, as an indicator for the expression of the artificial miRNA (amiTDP) residing in the 3’UTR of mCherry and targeting TARDBP. The construct was tested in NSC34 cells and TRE-mCherry-amiTDP43 transgenic mouse was generated with this construct. Crossing TRE-mCherry-amiTDP43 mouse with mPrp-tTA mouse, mCherry expression was successfully induced in mouse forebrain and cerebellum, but not in other tissues including spinal cord. By quantitative real-time PCR, amiTDP43 expression was confirmed to be coupled with mCherry expression. Fluorescent immunostaining revealed that mCherry was expressed in neurons, but not in astrocytes or microglia cells, and that in mCherry positive cells, TDP43 was significantly knocked down. Results from Nissl staining and GFAP immunostaining suggested that decrease of TDP43 in forebrain neuron only was not sufficient to cause neurodegeneration and neuron loss. In chapter III, I investigated the function of Armadillo Containing Protein 4 (ARMC4), which was originally considered ALS causative gene. Our study of the function of CG5155, the possible homolog of ARMC4 in Drosophila, indicated that CG5155 is a male fertility gene that is involved in spermatogenesis. Therefore, we have named this gene Gudu. The transcript of Gudu is highly enriched in adult testes. Knockdown of Gudu by a ubiquitous driver leads to defects in the formation of the individualization complex that is required for spermatid maturation, thereby impairing spermatogenesis. Furthermore, testis-specific knockdown of Gudu by crossing the RNAi lines with Bam-Gal4 driver is sufficient to cause the infertility and defective spermatogenesis. Since Gudu is highly homologous to vertebrate ARMC4, also an Armadillo-repeat-containing protein enriched in testes, our results suggest that Gudu and ARMC4 is a subfamily of Armadillo-repeat containing proteins with an evolutionarily conserved function in spermatogenesis.

Women can face a wide range of pelvic floor dysfunctions following pregnancy, ranging from urinary incontinence to pelvic pain. Unfortunately, these problems are not routinely checked for in postpartum check-ups and women do not always bring it to the physician’s attention. Strengthening of the pelvic floor muscles may be able to help women prevent these disorders and improve these women’s lifestyles. The purpose of this thesis was to review and analyze different trials to determine if different pelvic floor dysfunctions (urinary incontinence, sexual dysfunction, and pelvic girdle pain) can be treated using pelvic floor muscle training in the postpartum. After reviewing the literature, it was determined that Pelvic floor muscle training may be effective in treating Urinary incontinence, but there is a lack of research to state that it helps treat sexual dysfunction and pelvic pain. Pelvic floor muscle training is a conservative non-invasive treatment and very simple for women to do on their own, therefore more research should be performed to see if this can be a simple fix to a plethora of problems women face in the postpartum.

Chronic kidney disease (CKD) progresses faster in males than females; however, the underlying mechanisms remain poorly understood. Sex differences in glomerular capillary morphology has been hypothesized to contribute, in part, to the increased susceptibility to hypertension-induced renal injury and CKD progression in males, but this has not been investigated. The goal of the present study was to assess glomerular capillary morphology in male vs. female rats with intact kidneys and after uninephrectomy (UNX). We hypothesized that glomerular capillary radii (RCAP) and length (LCAP) would be greater in male rats. Male (n=4) and female (n=4) with intact kidneys and UNX (n=4 males, n=4 females) provided a 0.4% NaCl diet and water ad libitum. Kidneys were perfusion-fixed, the left kidney was excised, and a 3 mm transverse section through the midline of the kidney was selected for further processing. Multiple 1 mm3 cubes were randomly excised from the left, middle, and right regions of the outer cortex, embedded in EPONTM, sectioned (1 μm), and stained with toluidine blue. Four glomeruli from each region were randomly selected for stereological analysis. Glomerular tuft volume (VG), RCAP, and LCAP were assessed. In rats with intact kidneys, no significant sex differences were observed in VG, RCAP, or LCAP. VG, RCAP, and LCAP were significant greater in both male and female rats with UNX vs. respective rats with intact kidneys. In rats with UNX, males exhibited a significantly greater VG and LCAP, but not RCAP, as compared to females despite no significant differences in relative kidney weight. These data indicate that males exhibit greater compensatory increases in LCAP following UNX. The greater capillary length may lead to reduced podocyte density, a well-known mechanism that increases the susceptibility to CKD progression.