Call number: LD2668 .T4 1964 D57 / Master of Science

Sepsis-related multiple organ dysfunction syndrome is a leading cause of death in intensive care units. There is overwhelming evidence that oxidative stress plays a significant role in the pathogenesis of sepsis-associated multiple organ failure; however, reactive oxygen species (ROS)-associated biomarkers and/or diagnostics that define mortality or predict survival in sepsis are lacking. Lung or peripheral blood gene expression analysis has gained increasing recognition as a potential prognostic and/or diagnostic tool. The objective of this study was to identify ROS-associated biomarkers predictive of survival in patients with sepsis. In-silico analyses of expression profiles allowed the identification of a 21-gene ROS-associated molecular signature that predicts survival in sepsis patients. Importantly, this signature performed well in a validation cohort consisting of sepsis patients aggregated from distinct patient populations recruited from different sites. Our signature outperforms randomly generated signatures of the same signature gene size. Our findings further validate the critical role of ROSs in the pathogenesis of sepsis and provide a novel gene signature that predicts survival in sepsis patients. These results also highlight the utility of peripheral blood molecular signatures as biomarkers for predicting mortality risk in patients with sepsis, which could facilitate the development of personalized therapies.

Aggression studies in laboratory animals have largely focused on natural species-specific forms of aggression that poorly reflect pathological types of aggression in humans. The primary goal of this dissertation was to identify and characterize a subtype of aggression in support for a congenital animal model of reactive/impulsive-aggression in humans. Experiments using novel second-by-second analyses to investigate for individual differences in aggression and impulsive choice showed detailed quantitative and qualitative differences, and identified a convergence of behaviors to one distinct impulsive-aggressive profile in high-attack frequency (HAF) hamsters. As aggression and impulsivity widely implicate the serotonin (5HT) system, and previous studies have similarly characterized the neural control of aggression in hamsters, it was hypothesized that impulsive-aggression in HAF individuals was associated to common neurobiology. While 5HT does play a role, immunocytochemical experiments and pharmacological manipulations showed a distinct neurobiological profile of decreased 5HT availability, increased densities of 5HT1A and 5HT3 receptor subtypes, and drastically differential and opposite phenotypic-dependent reactivity to 5HT3 receptor blockade. Moreover, the current studies also showed that while 5HT3 receptor activity has broad effects, attenuating all behavioral aspects of the impulsive-aggressive phenotype (i.e. aggression, repetitiveness, fragmentation, and impulsive choice), 5HT1A receptor activity seems to have more limited effects. Additional retrospective studies investigated developmental and etiological differences between the phenotypes. HAF adults were associated with low agonistic activity in early puberty and an early emergence of impulsivity-related characteristics. These data indicate a differential developmental trajectory of behavior and accelerated maturation, consisting of a lack of play fighting during early puberty. The HAF phenotype was additionally associated with paternal, but not maternal influence, suggesting male genetic contribution. Together, these data support a congenital animal model that better reflects reactive forms of aggression in humans through the behavioral, neurobiological, and developmental characterization of HAF hamsters described herein. These data have pre-clinical and clinical significance and can be applied to diagnostic and preventative measures, as they illustrate the importance of distinguishing predictions about extreme fringe populations from that of normal populations, point towards more specific pharmacological therapeutic applications, identify early predictive behaviors of impulsive-aggression, and suggest heritability. / text

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The control of object manipulation tasks involves the close interplay of predictive and reactive control mechanisms. For example, when lifting an object, people typically predict the weight based on object size and material as well as sensorimotor memory obtained from previous lifts of the object. When lifting objects with a precision grip, people increase vertical load force to a target level that slightly exceeds the predicted weight. When the object is heavier than expected, the mismatch between expected and actual tactile signals associated with lift-off triggers a corrective action within ~100 ms, that involves probing increases in load force that continue until the object is lifted. Here we investigated whether this correction action can be adaptively influenced by experience. Participants repeatedly lifted an object that was instrumented with force sensors to measure the forces applied by the fingertips, with weight that could be varied without the knowledge of the participant. In 80% of trials, the weight was set to 2 N and, in different blocks of 110 trials, the remaining 20 % of trials (2 trials randomly selected from each successive 10 trials) was set to either 4 or 6 N. We found that the rate of change of the reflexively triggered increase in load force that occurred in the 4 or 6 N trials, scaled with the additional weight. That is, following the initial increase in load force to ~2 N, the subsequent increase in load force was more rapid for the 6 N object than the 4 N object. In contrast, the onset time of the reactive increase in load force was independent of the additional weight. Finally, this adaptation of reactive load force control took place quickly and was evident after only a few lifts of the heavier weight. These results indicate that the reactive increases in load force that occur when a lifted object is heavier than expected can be adapted and tuned, to refine behavior. This further suggests that multiple predictions can be generated about object weight when lifting. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2013-02-02 13:34:20.533

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Thesis advisor: Jianmin Gao / Thesis advisor: Eranthie Weerapana / Cysteine residues are known to perform an array of functional roles in proteins, including nucleophilic and redox catalysis, regulation, metal binding, and structural stabilization, on proteins across diverse functional classes. These functional cysteine residues often display hyperreactivity, and electrophilic chemical probes can be utilized to modify reactive cysteines and modulate their protein functions. A particular focus was placed on three peptide-based cysteine-reactive chemical probes (NJP2, NJP14. and NJP15) and their particular biological applications. NJP2 was discovered to be an apoptotic cell-selective inhibitor of glutathione S-transferase omega 1 and shows additional utility as an imaging agent of apoptosis. NJP14 aided in the development of a chemical-proteomic platform to detect Zn2+-cysteine complexes. This platform identified both known and unknown Zn2+-cysteine complexes across diverse protein classes and should serve as a valuable complement to existing methods to characterize functional Zn2+-cysteine complexes. Finally, NJP15 was part of a panel of site-selective cysteine-reactive inhibitors of protein disulfide isomerase A1 (PDIA1). These inhibitors show promise in clarifying the unique and redundant properties of PDIA1's dual active-sites, as well as interrogating the protein's role in cancer. Together, these case studies illustrate the potential of cysteine-reactive chemical probes to modulate protein activities, interrogate biological systems, and aid in the development of powerful therapeutic drugs. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Cassava ranks seventh in terms of worldwide crop production, providing a staple for over half a billion people. The production of cassava is limited by several factors, with post-harvest physiological deterioration (PPD) of storage roots a major constraint. PPD is a process initiated on harvesting and mediated by reactive oxygen species (ROS) that ultimately renders storage roots unpalatable and unmarketable. It is similar to a conventional plant wound response, but crucially lacks efficient wound repair and down-regulation of stress signalling. Therefore, the strategy utilised here to modulate PPD focussed on increasing the ROS scavenging ability of storage root tissue through a biotechnological approach. Three expression plasmids were produced, harbouring cassava genes encoding the antioxidant enzymes APX, CAT and SOD under the control of the storage rootspecific StPAT promoter. In addition, a reporter expression plasmid was created, with StPAT driving the expression of GusP. Transgenic Arabidopsis plants containing the StPAT::GusP cassette demonstrated root-specific GusP staining. Non-root tissue also showed wound-inducible GusP activity conferred by the StPAT promoter. This novel activity was detected almost immediately after wounding and occurred independently of ethylene, MeJa and ROS. The 3’ 261 bp of the StPAT promoter was sufficient to confer wound-inducible expression and contained putative wound responsive cis regulatory motifs. Analysis of PATATIN function indicated a role during early responses to wounding in the liberation of free fatty acids from cell membranes. Over-expression of the target genes in the model plant Arabidopsis increased the antioxidant enzyme activity in the roots of selected lines. Transgenic plants generally exhibited similar levels of oxidative stress resistance to wild-type plants, a result due in part to the efficient nature of the oxidative stress response of Arabidopsis – the APX activity of wild-type plants increased to transgenic levels under H2O2 stress. However, PPD in cassava is at least partially the result of a poor antioxidant response to harvesting, and so transformation of cassava with the expression plasmids remained a viable strategy. Transgenic cassava plants harbouring the expression cassettes are being generated and will soon be assessed for PPD resistance.

Artemisinin (AN), a sesquiterpene, derived from the herb, Artemisia annua is the most widely used anti-malarial compound. Current production is insufficient to meet the growing demand for this important drug. Many experiments have been done to try and deduce what factors may be important to increased yield. Here is is shown that many disparate phenomena known to induce AN production may be linked under the umbrella of reactive oxygen species (ROS). To that end, the metabolite and transcriptional changes associated with the transition from vegetative growth to flowering have been investigated. In addition, the role that exogenous sugars play in modulating these same factors has been explored in young seedlings. Lastly, exposure to DMSO was shown to increase AN production and that it may be linked to ROS. These combined results wered further explored to determine the effects of direct ROS elicitation and subsequent quenching on the production of AN and related metabolites. Information gained here supported a new alternative hypothesis for the role of ROS in AN production, one in which hydrogen peroxide may be controlling the balance of deoxyartemisinin (deoxyAN) and AN.