This study examined the effect of resistance training proximity to failure on strength, muscle hypertrophy, and fatigue. Fourteen men were randomized into two groups (4-6 rating of perceived exertion-RPE per set or 7-9 RPE per set) and completed an eight-week program. Squat and bench press strength, muscle thickness, subjective fatigue, muscle soreness, and biomarkers (creatine kinase-CK and lactate dehydrogenase-LDH) were assessed. There were no significant differences (p>0.05) in the rate of strength gains and equivalence testing revealed hypertrophy was not statistically similar nor different. All results for indirect markers of muscle damage and fatigue indicated similar recovery between groups within 48 hours; however, a small between group effect size (g=0.39) existed indicating higher session RPE in the 7-9 RPE group across the entire training program. These results suggest that strength and possibly hypertrophy outcomes are similar when training each set to 4-6 RPE or 7-9 RPE in trained men. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

Gastro-esophageal adenocarcinomas (GEA) are among the fastest rising malignancies in North America. Despite advances in cancer prevention and treatment for other cancers, the number of GEA cases continues to rise and prognosis remains bleak with five-year survival rates of only 20%. Additionally, many GEA patients won’t respond to first line therapy, many may develop therapeutic resistance, or will show disease recurrence. Previous drug screen models failed clinical trials due to the failure of the model to adequately recapitulate the primary sample. A new model, the patient-derived organoid (PDO), has become the newest method of investigating and testing numerous characteristics of the in vivo tumor. Initial studies have demonstrated the organoid’s advantages: PDOs are highly heterogeneous, may be maintained in culture indefinitely, and have the capability to model carcinogenesis and therapeutic response. However, limitations exist and questions remain that have yet to be addressed. Indeed, one of the challenges of using organoids is knowing whether the organoids are recapitulating normal or tumor tissue. Additionally, there seem to be limits on immortality of the organoids and the heterogeneity. Finally, without the stroma and Tumor Microenvironment (TME) in culture, the model is limited in its ability to test the response to immunotherapy-based drugs. Current research aims to develop a clinical pipeline utilizing organoids regularly as a diagnostic tool to evaluate therapeutic response, identify emergence of chemoresistance and perform targeted drug screens. Overall, PDOs are a burgeoning method of investigating GEA and are a powerful translational tool from bench to bedside.

Fusarium head blight (FHB) is an important disease of small grain cereals including wheat that affects grain quality and yield. The fungus Fusarium graminearum (Fg) is the major agent of this disease. Lack of natural resistance has limited ability to control wheat losses to this disease. Developing new approaches is critical for increasing host plant resistance to this fungus. This work has identified four processes that can be targeted for enhancing host plant resistance to FHB. The first involves targeting the pattern-triggered immunity mechanism to promote host plant resistance. Two other approaches involved reducing activity of susceptibility factors in the host to enhance plant resistance. The susceptibility factors targeted include accumulation of the phytohormone jasmonic acid and the 9-lipoxygenase pathway that oxidizes fatty acids. Besides suppressing host defenses against Fg, jasmonic acid also directly acts on the fungus to promote fungal growth. 9- lipoxygenases similarly suppress host defenses to promote fungal pathogenicity. Another approach that was developed involved having the plant express double stranded RNA to target fungal virulence genes for silencing. This host-induced gene silencing approach was employed to target two fungal virulence genes, the lipase encoding FGL1 and salicylate hydroxylase encoding FgNahG, which the fungus secretes into the host to promote turnover of the plant defense signaling metabolite salicylic acid. FGL1 in contrast acts on host lipids to release fatty acids, which suppress the deposition of callose that provides a physical barrier to limit fungal spread.

Regions of HIV-1 gag between p2 and p6Gag/p6Pol, in addition to protease (PR), develop genetic diversity in HIV-1 infected individuals who fail to suppress virus replication by combination protease inhibitor (PI) therapy. To elucidate functional consequences for viral replication and PI susceptibility by changes in Gag that evolve in vivo during PI therapy, a panel of recombinant viruses was constructed. Residues in Gag p2/p7NC cleavage site and p7NC, combined with residues in the flap of PR, defined novel fitness determinants that restored replicative capacity to the posttherapy virus. Multiple determinants in Gag have a dominant effect on PR phenotype and increase susceptibility to inhibitors of drug-resistant or drug-sensitive PR genes. Gag determinants of drug sensitivity and replication alter the fitness landscape of the virus, and viral replicative capacity can be independent of drug sensitivity. The functional linkage between Gag and PR provides targets for novel therapeutics to inhibit drug-resistant viruses.

This study examined the accuracy of predicting back squat and bench press one repetition maximum (1RM) from submaximal average concentric velocity (ACV).Seventeen resistance trained men performed a warm-up and 1RM test on the squat and bench press, in which ACV was assessed on all repetitions. The ACVs during the warmup closest to 1.0 and 0.5 m.s-1 were used in a 2-point linear regression forecast of 1RM and the ACVs established at the loads closest to 20, 50, 70, and 80% of 1RM were used in a 4-point 1RM prediction. An ANOVA indicated significant differences between predicted and actual 1RM for all predictions (p<0.001). Both Bland-Altman and Mountain plots confirmed the findings of the ANOVA as data were not tightly conformed to the respective zero difference lines. Therefore, these results suggest that a linear regression forecast using submaximal ACV does not accurately predict 1RM in the ¬back squat and bench press. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

The struggle to achieve integration of public schools in Southampton County, Virginia, has been an ongoing process that has occurred through the years since the Brown v. Board of Education, 347 U.S. 483, 493, 74 S.Ct. 686, 691 (1954) and Brown v. Board of Education, 349 U.S. 294, 75 S.Ciit. 753 (1955), and Green v. County School Board of New Kent County, Virginia, 391 U.S. 430, 88 S.Ct. 1689, 20 L.Ed.2d 716 (1968). The time frame of 1954 until 1970 is particularly significant because of happenings that took place prior to the time that Judge Robert R. Merhige, federal judge of the Fourth Circuit Court of Appeals, ruled that all school divisions which operated dual school systems for Black and White students must fully integrate. Through the use of acceptable methods of historical research including personal interviews to record the oral history, school board minutes, personal correspondence, newspaper articles, books, and other such materials available to the writer, this dissertation records information regarding the desegregation of Southampton County Schools. The purpose of this study is to examine the roles of individuals and groups in the desegregation process that took place in the public schools of this rural, southside Virginia county during the years of 1954 to 1969. This study will provide a greater understanding of leadership, local governance, racial, and social class concerns of Southampton County citizens, as well as, a documentation of an important part of the history of Southampton County, Virginia. / Ed. D.

archives@tulane.edu / Androgen excess predisposes females to type 2 diabetes. Using mouse models, our lab reported that androgen excess causes insulin resistance via activation of the androgen receptor (AR) in the brain. Neurons of the arcuate nucleus of the hypothalamus (ARC) regulate hepatic glucose production (HGP). Thus, I hypothesized that in female mice, androgen excess in neurons of the ARC causes hepatic insulin resistance by increasing HGP. To test this, I injected AaV-Cre-GFP or AaV-GFP into the ARC of ARlox/lox female mice to generate ARC-specific AR knockout (ARC-ARKO) and control mice, respectively. When exposed to a Western diet, control female mice chronically treated with dihydrotestosterone (DHT) developed insulin resistance and fasting hyperglycemia compared to vehicle-treated control mice. In contrast, DHT-treated ARC-ARKO mice remained insulin sensitive and normoglycemic compared to vehicle-treated ARC-ARKO mice. During a hyperinsulinemic-euglycemic clamp, insulin’s ability to suppress HGP was blunted in DHT-treated control mice. In contrast, insulin was still able to suppress HGP in DHT-treated ARC-ARKO females. Additionally, during the clamp, DHT-treated control mice showed no alteration in hepatic activation of AKT, a marker of hepatocyte insulin sensitivity, but exhibited reduced activation of hepatic STAT3, a marker of hypothalamic insulin sensitivity. In contrast, in DHT-treated ARC-ARKO mice activation of hepatic STAT3 was increased. In a parallel study, estradiol treatment improved insulin sensitivity in control ovariectomized (OVX) mice. In contrast, in DHT-treated OVX mice, estradiol treatment did not improve insulin sensitivity. Together these results suggest that in female mice exposed to a Western diet, androgen excess causes hypothalamic estrogen resistance and insulin resistance in ARC neurons via action at the AR leading to impairments in the brain-IL6-pSTAT3 pathway which results in unsuppressed HGP. / 1 / Jamie Morford

Indiana University-Purdue University Indianapolis (IUPUI) / The Centers for Disease Control (CDC) and World Health Organizations (WHO) have highlighted six species of highly drug-resistant bacteria, commonly termed the ESKAPE pathogens, that new antibacterials are urgently needed to treat). The ESKAPE pathogens account for over two-million infections and have healthcare costs upwards of $20 billion dollars annually. Over the past several decades, pharmaceutical companies have drastically reduced their research programs for developing new antibacterial agents. As well, bacteria are predisposed to rapidly generate resistance against these “me too” drugs, making this strategy a temporary stop-gap in our ability to fight these pathogens. This has left the burden to identify new antibiotics that function through fundamentally unique mechanisms of action to academia. Towards this goal, we are developing a unique antibacterial strategy that functions through targeting the bacterial GroEL chaperonin systems. GroEL is a molecular chaperone that helps fold proteins into their functional states. Being an essential protein, inhibiting GroEL activity leads to global aggregation and bacterial cell death. We previously reported a high-throughput screening effort that identified 235 GroEL inhibitors. A subsequent study with a subset of these inhibitors identified several that kill bacteria. To follow-up, we have synthesized 43 analogs of a hit-to-lead molecule, compound 1, containing systematic deletions of substituents and substructures to determine the essential parts of the scaffold for inhibiting GroEL and killing bacteria. Along with inhibiting GroEL, several compound 1 analogs exhibit >50-fold therapeutic windows between antibacterial efficacy and cytotoxicity to human liver and kidney cells in cell culture. Evaluation of two lead candidates (1 and 11) in a gain-of-resistance assay indicated that MRSA bacteria were not able to easily generate resistance to this compound class. Compound 1 also exhibited the ability to permeate through already established S. aureus biofilms and maintain its bactericidal effects, whereas vancomycin could not. Having established initial structure-activity relationships for the compound 1 substituents and substructures in this study, future efforts will focus on optimizing the antibacterial effects of lead candidates and reducing their off-target toxicity to human cells.

M.Sc. (Med.), Faculty of Health Sciences, University of the Witwatersrand, 2009

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the field of Paediatrics. Johannesburg, 2015 / The introduction of combined antiretroviral treatment (cART) reduced HIV related mortality more than 70% and the rate of new infection in children continue to decrease considerably. However this benefit is threatened by the emergence of drug resistant strains of HIV. Studies exploring the patterns of drug resistance in the paediatric population are crucial for policy makers and for individual patients’ management. In sub-Saharan Africa where HIV-1 subtype C is more prevalent, there is a limited number of paediatric studies exploring the drug resistance patterns. To get more insight on this problem, we explored the drug resistance mutations (DRMs) patterns in a paediatric population attending a referral public paediatric HIV clinic. Methodology The study was a cross-sectional retrospective descriptive study. Convenience sampling method was used and all paediatric patients (0-14 years) who underwent genotypic HIV drug resistance testing at Empilweni Clinic between January 1st, 2004 and February 28th, 2012 were included. Demographic and clinical data were collected from the clinical electronic database and DRM frequencies related to treatment exposure were presented. Results During our study period, 63 patient samples were sent for HIV genotyping drug resistance testing. Eleven samples did not meet the inclusion criteria. Among the 52 patient samples retained, 44 patients (84.6%) had a successful HIV amplification and all were infected with HIV-1 subtype C. Ninety one percent (n=40) of the patients had at least one DRM isolated but in only 78% (n=34) did these mutations translate into genotypic drug resistance to at least one antiretroviral drug (ARV) used in South Africa. Nucleotide reverse transcriptase inhibitors (NRTI) mutations were the most commonly identified with M184V being the most prevalent (64.4%; n=29). This was associated with thymidine analogue mutations (TAMs) in 36.3% of the patients (n=16). TAMs were identified in 25% (n=11) of the patients. K65R and Q151M were rarely identified in our cohort. V106M and K103N were the most common non-nucleotide reverse transcriptase inhibitors (NNRTI) mutations and were both identified in 21.9% (n=7) of the patients exposed to NNRTI-based regimen. V82A was the most commonly identified protease gene (PR) mutation in 29.3% (n=12) of the cases. Forty eight percent of the patients (n=21) had a dual class resistance and 11.4% (n=5) had resistance to ARVs from all the three classes. Over a quarter (27.2%, n=12) of the patients in our cohort were still sensitive to all ARVs used in South Africa. The development of drug resistance was not associated with any clinical characteristic in our cohort. Conclusion The drug resistance mutations identified in paediatric patients failing cART show a complex pattern with some failing patients still sensitive to all ARVs while others harbour complex resistance mutations. Therefore, regular counselling to optimize adherence and regular viral load monitoring for early detection of failure may be important tools for continued cART success. Given the complexity of the DRMs patterns in paediatric patients, the HIV drug resistance test is warranted to guide the choice of appropriate cART regimens.