Doctor of Philosophy

dissertationDrug-free macromolecular therapeutics are a new paradigm in polymer-based nanomedicines. Instead of carrying cytotoxic small molecular weight drugs, drug-free macromolecular therapeutics crosslink proteins in the cell membrane through hybridization of oligonucleotides to initiate apoptosis signaling. However, the mechanism of the nanomedicines was not fully understood. To study the mechanism and to better understand the interactions between the therapeutics and the cell membrane, super-resolution optical microscopy was used. Super-resolution imaging was performed on Raji B cells treated with the drug-free conjugates. The clustering of CD20 and lipid rafts was quantified. Lipid raft cluster size increased after treatment with drug-free conjugates. Drug-free conjugates induced apoptosis in a lipid raft-dependent mechanism where stable lipid rafts are needed for proper initiation of apoptosis. Direct stochastic optical reconstruction microscopy revealed nanoscale differences in membrane distribution of CD20 and lipid rafts. Pair-correlation analysis of super-resolution images showed lipid raft sizes of ~200 nm in cells treated with drug-free conjugates. General applicability of direct stochastic optical reconstruction microscopy to studying drug-delivery systems was also demonstrated. Two conceptually different polymer-based therapeutics were labeled with 4 different synthetic fluorophores, and three-dimensional (3D) direct stochastic optical reconstruction microscopy was conducted at different time points to track localization of the therapeutic components. An internalized polymer conjugate was localized in clusters at 4 h, but after 24 h, the polymer released into the cytosol a fluorophore attached via an enzymatically degradable peptide. Pair-correlation functions of the dye attached to the polymer and the released dye showed changes in their decay lengths between 4 h and 24 h. The pair-correlation function of the released dye showed random distribution after 24 h. Using reversible addition?fragmentation chain-transfer (RAFT) polymerization, branched and star polymers were synthesized to study the effect of architecture on apoptosis induction in Raji B cells. A new chain transfer monomer was synthesized in order to produce controlled branched polymers in RAFT polymerization. A degradable tetra-functional chain transfer agent was also synthesized. The star chain transfer agent produced degradable star polymers of high molecular weight (~170 kDa). Drug-free conjugates were synthesized to produce linear, branched, and star polymer-MORF2 conjugates. Apoptosis in Raji B cells was measured but the three different architectures induced the same levels of apoptosis as measure by annexin V and caspase 3

Cheryl's Birthday

We present four logic puzzles and after that their solutions. Joseph Yeo designed 'Cheryl's Birthday'. Mike Hartley came up with a novel solution for 'One Hundred Prisoners and a Light Bulb'. Jonathan Welton designed 'A Blind Guess' and 'Abby's Birthday'. Hans van Ditmarsch and Barteld Kooi authored the puzzlebook 'One Hundred Prisoners and a Light Bulb' that contains other knowledge puzzles, and that can also be found on the webpage http://personal.us.es/hvd/lightbulb.html dedicated to the book.Comment: In Proceedings TARK 2017, arXiv:1707.0825

Oritavancin vs Standard of Care for Treatment of Nonendovascular Gram-Positive Bloodstream Infections

BACKGROUND: Data is limited comparing oritavancin (ORT) to the standard-of-care (SOC) for the treatment gram-positive blood stream infections (BSI). METHODS: This was a retrospective study of all patients in the Veteran\u27s Affairs Health Care System treated with at least 1 dose of oritavancin or at least 5 days of vancomycin, daptomycin, ceftaroline, ampicillin, ampicillin-sulbactam, nafcillin, oxacillin, or cefazolin for a documented gram-positive BSI from 1 January 2015 to 30 June 2021. Patients with polymicrobial blood cultures or positive cultures from other sites were included if the organisms were sensitive to the incident antimicrobial; no concomitant antimicrobials could be used once the incident agent was started. Individuals were also excluded if they were diagnosed with endocarditis, had a neutrophil count 96-hours of treatment before the incident antimicrobial was started.The primary composite outcome was clinical failure, defined as all-cause mortality within 30-days from the end of therapy, or blood cultures positive for the incident organisms ≥72 hours after administration of the first dose and ≤30 days after the administration of the final dose of the study antimicrobial, or any drug or line-related readmissions within 30-days of hospital discharge. RESULTS: Two hundred-forty patients were identified for screening with 96 meeting criteria (27 in ORT and 69 in SOC groups). Baseline characteristics were generally balanced between groups except more patients in the ORT group received \u3e96-hours of treatment before the incident antimicrobial was started (70.3% (19/27) vs 13.04% 9/69); CONCLUSIONS: ORT appears to be a safe and effective option when directly compared to the SOC for non-endocarditis BSIs

The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain

The plant cytotoxin ricin enters mammalian cells by receptor-mediated endocytosis, undergoing retrograde transport to the endoplasmic reticulum (ER) where its catalytic A chain (RTA) is reductively separated from the holotoxin to enter the cytosol and inactivate ribosomes. The currently accepted model is that the bulk of ER-dislocated RTA is degraded by proteasomes. We show here that the proteasome has a more complex role in ricin intoxication than previously recognised, that the previously reported increase in sensitivity of mammalian cells to ricin in the presence of proteasome inhibitors simply reflects toxicity of the inhibitors themselves, and that RTA is a very poor substrate for proteasomal degradation. Denatured RTA and casein compete for a binding site on the regulatory particle of the 26S proteasome, but their fates differ. Casein is degraded, but the mammalian 26S proteasome AAA-ATPase subunit RPT5 acts as a chaperone that prevents aggregation of denatured RTA and stimulates recovery of catalytic RTA activity in vitro. Furthermore, in vivo, the ATPase activity of Rpt5p is required for maximal toxicity of RTA dislocated from the Saccharomyces cerevisiae ER. Our results implicate RPT5/Rpt5p in the triage of substrates in which either activation (folding) or inactivation (degradation) pathways may be initiated

Dr. Bobbie Bailey & Family Performance Center Anniversary Celebration

The School of Music is proud to welcome back to campus several of our esteemed alumni for a special recital as part of the Bailey Performance Center 10th anniversary celebration! The School of Music celebrates the opening of the Bailey Performance Center with featured performances by the KSU Wind Ensemble Brass and Percussion, Symphony Orchestra, Chamber Singers, University Chorale and Chamber Singers Alumni Choir, along with pianist Robert Henry, soprano Jana Young, and more!https://digitalcommons.kennesaw.edu/musicprograms/1969/thumbnail.jp

Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization

OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors

How Important is Variability in Consumer Credit Limits?

Credit limit variability is a crucial aspect of the consumption, savings, and debt decisions of households in the United States. Using a large panel, this paper first demonstrates that individuals gain and lose access to credit frequently and often have their credit limits reduced unexpectedly. Credit limit volatility is larger than most estimates of income volatility and varies over the business cycle. While typical models of intertemporal consumption fix the credit limit, I introduce a model with variable credit limits. Variable credit limits create a reason for households to hold both high interest debts and low interest savings at the same time, since the savings act as insurance. Simulating the model using the estimates of credit limit volatility, I show that it explains all of the credit card puzzle: why around a third of households in the United States hold both debt and liquid savings at the same time. The approach also offers an important new channel through which financial system uncertainty affects household decisions

Kinetoplastid Phylogenomics Reveals the Evolutionary Innovations Associated with the Origins of Parasitism

The evolution of parasitism is a recurrent event in the history of life and a core problem in evolutionary biology. Trypanosomatids are important parasites and include the human pathogens Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp., which in humans cause African trypanosomiasis, Chagas disease, and leishmaniasis, respectively. Genome comparison between trypanosomatids reveals that these parasites have evolved specialized cell-surface protein families, overlaid on a well-conserved cell template. Understanding how these features evolved and which ones are specifically associated with parasitism requires comparison with related non-parasites. We have produced genome sequences for Bodo saltans, the closest known non-parasitic relative of trypanosomatids, and a second bodonid, Trypanoplasma borreli. Here we show how genomic reduction and innovation contributed to the character of trypanosomatid genomes. We show that gene loss has “streamlined” trypanosomatid genomes, particularly with respect to macromolecular degradation and ion transport, but consistent with a widespread loss of functional redundancy, while adaptive radiations of gene families involved in membrane function provide the principal innovations in trypanosomatid evolution. Gene gain and loss continued during trypanosomatid diversification, resulting in the asymmetric assortment of ancestral characters such as peptidases between Trypanosoma and Leishmania, genomic differences that were subsequently amplified by lineage-specific innovations after divergence. Finally, we show how species-specific, cell-surface gene families (DGF-1 and PSA) with no apparent structural similarity are independent derivations of a common ancestral form, which we call “bodonin.” This new evidence defines the parasitic innovations of trypanosomatid genomes, revealing how a free-living phagotroph became adapted to exploiting hostile host environments

Bostonia: v. 62, no. 2, 5-6

Founded in 1900, Bostonia magazine is Boston University's main alumni publication, which covers alumni and student life, as well as university activities, events, and programs