Lung tumor progression is regulated by proangiogenic factors. Heat shock protein A12B (HSPA12B) is a recently identified regulator of expression of proangiogenic factors. However, whether HSPA12B plays a role in lung tumor growth is unknown. To address this question, transgenic mice overexpressing HSPA12B (Tg) and wildtype littermates (WT) were implanted with Lewis lung cancer cells to induce lung tumorigenesis. Tg mice showed significantly higher number and bigger size of tumors than WT mice. Tg tumors exhibited increased angiogenesis and proliferation while reduced apoptosis compared with WT tumors. Interestingly, a significantly enhanced upregulation of Cox-2 was detected in Tg tumors than in WT tumors. Also, Tg tumors demonstrated upregulation of VEGF and angiopoietin-1, downregulation of AKAP12, and increased eNOS phosphorylation compared with WT tumors. Celecoxib, a selective Cox-2 inhibitor, suppressed the HSPA12B-induced increase in lung tumor burden. Moreover, celecoxib decreased angiogenesis and proliferation whereas increased apoptosis in Tg tumors. Additionally, celecoxib reduced angiopoietin-1 expression and eNOS phosphorylation but increased AKAP12 levels in Tg tumors. Our results indicate that HSPA12B stimulates lung tumor growth via a Cox-2-dependent mechanism. The present study identified HSPA12B as a novel facilitator of lung tumor growth and a potential therapeutic target for the treatment of lung cancer.

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Serum lactate levels are traditionally interpreted as a marker of tissue hypoxia and often used clinically as an indicator of severity and outcome of sepsis/septic shock. Interestingly, recent studies involving the effects of tumor-derived lactate suggest that lactate itself may have an immunosuppressive effect in its local environment. This finding adds to the recent advances in immunometabolism that shed light on the importance of metabolism and metabolic intermediates in the regulation of innate immune and inflammatory responses in sepsis. In this article, we summarize recent studies, showing that the activation of immune cells requires aerobic glycolytic metabolism and that lactate produced by aerobic glycolysis may play an immunosuppressive role in sepsis.

Effective treatment of the acute systemic inflammatory response associated with sepsis is lacking, but likely will require new ways to rebalance dysregulated immune responses. One challenge is that human sepsis often is diagnosed too late to reduce the hyperinflammation of early sepsis. Another is that the sequential response to sepsis inflammation rapidly generates an adaptive and immunosuppressive state, which by epigenetic imprint may last for months or years. Emerging data support that the immunosuppressive phase of sepsis can both directly reprogram gene expression of circulating and tissue cells, and disrupt development and differentiation of myeloid precursor cells into competent immunocytes. We recently reported that adoptive transfer of bone marrow CD34+ cells into mice after sepsis induction by cecal ligation and puncture significantly improves late-sepsis survival by enhancing bacterial clearance through improved neutrophil and macrophage phagocytosis. That study, however, did not examine whether CD34+ transfer can modify noninfectious acute systemic inflammatory responses. Here, we report that CD34+ cell transfer mice that have survived late sepsis also resist lethal lipopolysaccharide (LPS)-induced inflammatory shock (88% lived vs 0% of naive mice). The CD34+ cell-recipient survivor mice administered LPS had globally reduced levels of circulating inflammatory mediators compared with naive mice, but their peritoneal and bone marrow-derived macrophages (BMDMs), unlike those from naïve mice, remained LPS responsive ex vivo. We further found that CD34+ cell transfer into LPS-challenged naïve mice had diminished immunosuppression, as assessed by ex vivo responses of peritoneal and BMDMs to LPS challenge. We conclude that CD34+ cell adoptive transfer rebalances dysregulated immune responses associated with sepsis and endotoxin shock.

Cardiac dysfunction is a major consequence of septic shock and may be responsible for the high mortality of sepsis. We have reported that transgenic mice with cardiac-specific overexpression of heat shock protein 27 (Hsp27 Tg) exhibited the protection against doxorubicin-induced cardiac dysfunction. We hypothesized that overexpression of Hsp27 will attenuate cardiac dysfunction during endotoxemia. Hsp27 Tg and age-matched wild-type (WT) mice were injected with LPS. Cardiac function was evaluated by echocardiography, survival rate was carefully monitored, and activities of signaling pathways were determined by immunoblot. LPS administration significantly decreased cardiac function in WT mice. In Hsp27 Tg mice, LPS-induced cardiac dysfunction was significantly attenuated as evidenced by increased ejection fraction (27.3%) and fractional shortening (37.1%), respectively, compared with LPS-treated WT mice. Heat shock protein 27 Tg mice were more resistant to LPS-induced mortality than WT. The levels of phospho-Akt and phospho-glycogen synthase kinase 3β (phospho-GSK-3β) in the myocardium were significantly increased in Hsp27 Tg mice compared with WT after LPS administration. Nuclear factor κB-binding activity was significantly decreased in Hsp27 Tg mice compared with WT mice after LPS challenge. Similar results were observed in in vitro studies using Hsp27-transfected rat cardiomyoblasts. Importantly, phosphoinositide 3-kinase inhibition abolished the protective effect of Hsp27 in LPS-induced cardiac dysfunction and mortality of endotoxemia. Our results suggest that Hsp27 plays an important role in attenuation of cardiac dysfunction and mortality in endotoxemia and that the mechanisms of the protection may involve activation of the PI3K/Akt signaling pathway.

Research has documented cultural adjustment as an important issue influencing international students and other sojourners in their success abroad (Foster, 1962; Lysgaard, 1955; Oberg, 1960; Smalley, 1963). Few studies, however, have investigated particular variables influencing the cultural adjustment process of ESL learners enrolled in intensive English programs (IEPs). This mixed method study was designed to better understand the individual complexity of IEP learners' cultural adjustment by looking for patterns of variables that aid or hinder these students' experiences. Using the Culture Shock Questionnaire (CSQ), Index of Social Sojourners Support Survey (ISSS), and language-specific focus groups, this study investigated the individual cultural adjustment experiences of Chinese, Korean, Portuguese, and Spanish-speaking students enrolled in an intensive English program attached to a large private university in the United States. Statistically significant results were found when comparing students' demographic variables with the survey results. Students who identified themselves as having high levels of social support were more likely to experience low levels of culture shock. While, female students were more likely to experience higher levels of culture shock compared to male students. Additionally, qualitative data gathered from the open-ended survey questions and focus groups revealed three common variables that appeared to aid as well as hinder the students' cultural adjustment process: social support, self, and environment. Findings from this research have implications for the development of cultural adjustment training materials which might aid ESL students attending intensive English programs in the United States in their cultural adjustment process.

Heat shock protein A12A (HSPA12A) is a newly discovered member of the Hsp70 family. The biological characteristics and functional roles of HSPA12A are poorly understood. This study investigated the effects of HSPA12A on ischaemic stroke in mice. Ischaemic stroke was induced by left middle cerebral artery occlusion for 1 h followed by blood reperfusion. We observed that HSPA12A was highly expressed in brain neurons, and neuronal HSPA12A expression was downregulated by ischaemic stroke and stroke-associated risk factors (aging, obesity and hyperglycaemia). To investigate the functional requirement of HSPA12A in protecting ischaemic brain injury, HSPA12A knockout mice (Hspa12a−/−) were generated. Hspa12a−/− mice exhibited an enlarged infarct volume and aggravated neurological deficits compared to their wild-type (WT) littermates after stroke. These aggravations in Hspa12a−/− mice were accompanied by more apoptosis and severer hippocampal morphological abnormalities in ischaemic hemispheres. Long-term examination revealed impaired motor function recovery and neurogenesis in stroke-affected Hspa12a−/− mice compared to stroke-affected WT controls. Significant reduced activation of GSK-3β/mTOR/p70S6K signalling was also observed in ischaemic hemispheres of Hspa12a−/− mice compared to WT controls. Administration with lithium (non-selective GSK-3β inhibitor) activated GSK-3β/mTOR/p70S6K signalling in stroke-affected Hspa12a−/− mice. Notably, lithium administration attenuated the HSPA12A deficiency-induced aggravation in infarct size, neurological deficits and neuronal death in Hspa12a−/− mice after stroke. Altogether, the findings suggest that HSPA12A expression encodes a critical novel prosurvival pathway during ischaemic stroke. We identified HSPA12A as a novel neuroprotective target for stroke patients.

Recent terrorist attacks on critical infrastructures using car bombs have heightened awareness on the needs for blast resistance of structures. Blast design of civilian buildings has not been a common practice in structural design. For this reason, there is now an urgent need to mitigate the potentially devastating effects of blast shock waves on existing structures. The current research project, the results of which are reported in this dissertation, aims to expand knowledge on blast resistance of reinforced concrete building columns, while developing a technology and design procedure for protecting critical buildings columns against the damaging effects of impulsive blast loads through the use of externally applied fibre-reinforced polymer (FRP) jackets of different material architecture. The research project has a significant experimental component, with analytical verifications. A total of thirty two reinforced concrete columns were experimentally investigated under the effects of simulated blast loads using the University of Ottawa Shock Tube. Column dimensions were 150 mm x 150 mm in cross section and 2438 mm in length. Each concrete column was reinforced longitudinally with four 10M rebars which were tied laterally with 6.3 mm closed steel hoops, spaced at 37.5 mm and 100 mm c/c, representing seismic and non-seismic column details, respectively. The experimental research had two phases. Phase-I (sub-study) included blast tests of eight as-built, seismically detailed columns. The behaviour of these columns was explored under single and multiple blast shots, with and without the application of pre-blast axial loads. Phase-II (main-study) included column tests of different carbon FRP (CFRP) designs to investigate the significance of the use of different CFRP column jacket designs on dynamic response of twenty four seismic and non-seismic RC columns. Analytical investigation was conducted to assess and verify the significance of experimentally investigated parameters on column response. These included the use of Single-Degree-of-Freedom (SDOF) dynamic inelastic analysis, generation of dynamic resistance functions, the effects of variable axial loads, different plastic hinge lengths and the influence of secondary moments (P- moments) on column behaviour. The results indicate that the loading history has effects on column response, with multiple shots reducing column stiffness, and affecting dynamic response of columns relative to single blast shots of equivalent magnitude. The effect of concrete strength within the normal-strength concrete range is to increase strength and decrease deformations. Columns with CFRP jackets have considerable improvements in column deformability, with additional increases in column strength. The CFRP laminate design influences performance, with jackets having fibres in ±45o orientation especially improving column ductility and increasing plastic hinge lengths, thereby permitting redistribution of stresses and dissipating blast energy. Axial gravity loads vary during blast loads and can affect column strength. It was shown that SDOF dynamic inelastic analysis does capture key structural performance parameters in blast analysis. The consideration of experimentally observed parameters in column analysis; including the influence of CFRP design and associated change in plastic hinge length, variable axial load during response, and secondary moment (P- moments) result in significant improvements in the accuracy of blast analysis. The experimental results and the suggested improvements to the SDOF analysis technique can be used to implement a performance-based design approach recommended as part of the current research project for design of CFRP protection systems for concrete columns.This research project was conducted jointly by the National Research Council Canada (NRC) and the University of Ottawa.

We examine wave propagation on thin liquid films subjected to gravity, fluid friction, surface tension, and Marangoni effects. The physical configuration is a thin liquid layer on a planar incline. Following previous studies, the Marangoni effect is incorporated by a constant surface tension gradient and yields a non-convex flux function in our thin film equation. We extend previous studies by deriving the thin film equation governing two-dimensional waves on the liquid layer. We then derive a simplified evolution equation governing weakly nonlinear, quasi-planar, and weakly dissipative waves on the layer. When the undisturbed state is in the vicinity of an inflection point in the streamwise component of the flux function, the mixed nonlinearity, fourth order dissipation and the transverse modulations interact over time scales on the order of the scaled amplitude to the negative second power. The effect the transverse modulations is found to be intrinsically nonlinear. / Master of Science

Induced attack was studied under three conditions: (1) paired experimentally naive rats were exposed to intense electrical shock; (2) experimental subjects, previously trained to respond on a fixed vii ratio of six responses for liquid food reinforcement, were paired with target animals with the reinforcement contingency in effect; (3) experimental subjects were given a history of responding on a fixed ratio of six responses for positive reinforcement in the presence of shock, and finally this group was paired with experimentally naive targets when both the reinforcement and shock variables were present. Pairing experimental animals without shock did not cause attack, nor was bar-pressing behavior appreciably disrupted. Only when electrical shock was imposed upon pairs did attack occur. Furthermore, attack behavior severely reduced operant responding and there appeared to be no recovery of response rates over several sessions.