A common strategy employed to destroy harmful bacteria is to disrupt the bacterial membrane through the action of pore-forming anti-microbial peptides. The manner in which the peptides arrange themselves spatially to form a pore in the membrane, which is important for understanding both the mechanism of pore formation and pore function, is a topic of current debate. We contrast the response of a model membrane bilayer to the presence of solid, cylindrical nanoparticle insertions, when the bilayer is composed of persistent worm-like chains and when it is composed of flexible Gaussian chains. We use self-consistent field theory, with the appropriate single-chain propagator, to describe the amphiphilic star-like triblock copolymers composing the membrane and the solvent. The nanoparticle surfaces are designed to have patches that prefer either the solvent or the tail groups of the copolymers, and the nanoparticles are fixed in space. Using this model with polymers in the lamellar phase, we investigate the question of pore-formation, nanoparticle insertion and hydrophobic mismatch in lipid bilayers and the effect that chain rigidity has on these particular interactions. We find that the main effect of increased chain rigidity is that it increases the free energy scaling and the significance of the energy barriers associated with these pore-forming processes. These results demonstrate the importance of using a more realistic persistent chain when modelling pore formation. / NSERC, CFI, SHARCNET

No description available.

<p>Several abnormal conditions, including some cancers, have been associated with changes in the membrane lipid and FA composition. Dietary fat serves as a major source of lipids and FA, particularly the polyunsaturated fatty acids (PUFA), n-6 and n-3. High intakes of n-6 PUFA have been linked to the development of colon cancer in association with low n-3 PUFA intake. Therefore understanding the differences in the lipid and FA profiles between cancer and normal cells in the colon, and the role diet plays in these factors may be invaluable in understanding their role in carcinogenesis. This study compares the lipid profile of azoxymethane (AOM) induced colon polyps to that of the surrounding mucosa tissue in rats fed a diet high in n-6 PUFA. Male Fischer rats were fed the AIN-76A diet containing sunflower oil that has high n-6 PUFA content for a period of nine months. Results indicate that the lipid and FA content of the colon polyps differs significantly from the surrounding mucosa. Colon polyps had an increase in membrane phopholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Changes in membrane fluidity were indicated by the decrease (p&lt / 0.05) in the PC/PE and cholesterol/phospholipids (chol/PL) ratios, and increase (p&lt / 0.05) in the polyunsaturated FA/saturated FA (P/S) ratio. Metabolism of FA was significantly altered in the polyps favouring n-6 FA metabolism and the production of prostaglandin E2. No clear indication of impaired &Delta / 6-desauturase enzyme activity was noticed. Increases in the n-6 PUFA content could be a reflection of the dietary FA intake that increases FA incorporation in the polyps. Changes in the FA parameters of the polyps, particularly an increase in C20:4n-6 and the n6/n3 ratio have been shown to contribute to the rapid growth of cancer tissue. These lipid changes associated with the development of colon polyps could provide unique targets for developing strategies in chemoprevention by dietary manipulation.</p>

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

BACKGROUND: Diaclyglycerol (DAG) oil has the potential as an effective weight control agent as well as an agent to modify overweight related complications. OBJECTIVE: We aim to examine the efficacy of DAG oil (Enova oilTM) on regulating energy expenditure (EE), fat oxidation, body composition, lipid profiles and hepatic lipogenesis in comparison with conventional oils. DESIGN: Twenty-six overweight hypertriglyceridemic women consumed DAG or control oil for 28 days separated by a 4-week washout period using a randomized crossover design. Forty grams of either DAG or control oil were consumed daily by each study subject. RESULTS: DAG oil consumption for a period of 4-week does not alter total EE, fat oxidation, lean mass, fasting lipid profile or fatty acids synthesis rate, but effectively reduces (p<0.05) body weight and adiposity. CONCLUSION: DAG oil maybe an useful agent in the battle against obesity. However, its body weight/composition control effects are not from increasing of lean mass, or postprandial EE and fat oxidation. The consumption of DAG oil for a period of 4-week does not necessarily modify fasting lipid profiles or hepatic lipogenesis to reduce risk of coronary heart diseases in overweight hypertriglyceridemic subjects.

The objectives of this study was to examine the efficacy and safety of graded doses of c9, t11, t10, c12 CLA isomers on body composition, energy expenditure, lipid profile and hepatic biomarkers in hamsters. Male Golden Syrian hamsters (n=105) were randomized to seven treatments (control; 1, 2, 3% of c9, t11; 1, 2, 3% of t10, c12) for 28 days. Compared with control, 1% and 3% t10, c12 had lowered food intake with all three doses of t10, c12 lowering (p<0.0001) body fat mass (g). Groups fed with 1, 2, 3% t10, c12 and 3% c9, t11 treatments showed higher lean mass compared to control and other treatment groups. However, neither body weights, nor serum HDL or triglyceride levels differed across treatment groups. The 3% t10, c12 groups exhibited higher (p<0.0001) cholesterol and LDL-C levels compared to control or other treatment groups. The 2% and 3% t10, c12 groups also presented elevated ALT level (p<0.05). The present data suggest that 3% t10, c12 possess potential adverse effects on liver and posing unfavorable change in lipid profile.

Individuals with abdominal obesity are at higher risk for developing type 2 diabetes, predisposing cardiovascular events and insulin resistance. Low glycemic index (GI) diets may be beneficial in the management of insulin resistance. Insulin resistance is associated with increased intramyocellular lipid (IMCL) content as measured by proton nuclear magnetic resonance spectroscopy (1H-MRS). The primary objective of this thesis was to determine whether a low GI diet can improve insulin sensitivity by reducing IMCL of skeletal muscle. One hundred and twenty-one male and female participants aged 30 to 70 years (mean+SD, 53+10)) with abdominal obesity, entered a 4 to 6 week weight-maintaining, low-fat dietary advice run-in phase. Of the 121 eligible participants, 95 completed the run-in phase and were randomly assigned to either a low-GI (LGID, n=48) or high-GI diet (HGID, n=47) for 24 weeks. Participants underwent a 75g oral glucose tolerance test (OGTT) and had soleus-muscle IMCL measured by 1H-MRS at the beginning and end of the intervention period. Insulin sensitivity was assessed by the homeostatic model assessment index (HOMA) and the insulinogenic index (ISI) was calculated for insulin secretion. At the end of the run-in phase, there were significant reductions in serum total-, LDL-, and HDL-cholesterol (all, p<0.0001) and an increase in fasting plasma glucose (p<0.05). In 57 participants who wore a continuous glucose monitoring system for 24 hours during the run-in period, a total of 30% (p<0.001) of the variation in the incremental area under the blood glucose curve after self-selected breakfast meals was explained by GI. After 24 weeks, diet GI was significantly lower in the LGID than HGID group (55.5+3.1 vs 63.9+3.1, p<0.0001). Plasma glucose 60 minutes after the OGTT was significantly lower on the LGID than at baseline (p<0.05) and there was a non-significant trend towards an increase in ISI (p=0.07). On the HGID, ISI increased significantly from baseline (p<0.01). It is concluded that the LGID reduced 60 minute plasma glucose but did not significantly affect IMCL or insulin sensitivity in individuals with abdominal obesity.

<p>The incessant increase of antibiotic resistance among Gram-negative pathogens is a serious threat to public health worldwide. A lack of new antimicrobial agents, particularly those against multidrug-resistant Gram-negative bacteria further aggravates the situation, highlighting an urgent need for development of effective antibiotics to treat multidrug-resistant Gram-negative infections. Past efforts to improve existing classes of antimicrobial agents against drug-resistant Gram-negative bacteria have suffered from established (intrinsic or acquired) resistance mechanisms. Consequently, the essential LpxC enzyme in the lipid A biosynthesis, which has never been exploited by existing antibiotics, has emerged as a promising antibiotic target for developing novel therapeutics against multidrug-resistant Gram-negative pathogens. </p><p>In Chapter I, I survey the medically significant Gram-negative pathogens, the molecular basis of different resistance mechanisms and highlight the benefits of novel antibiotics targeting LpxC. In Chapter II, I discuss a structure-based strategy to optimize lead compounds for LpxC inhibition, revealing diacetylene-based compounds that potently inhibit a wide range of LpxC enzymes. The elastic diacetylene scaffold of the inhibitors overcomes the resistance mechanism caused by sequence and conformational heterogeneity in the LpxC substrate-binding passage that is largely defined by Insert II of LpxC. In Chapter III, I describe the structural basis of inhibitor specificity of first-generation LpxC inhibitors, including L-161,240 and BB-78485 and show that bulky moieties of early inhibitors create potential clashes with the &#61538;a-&#61538;b loop of Insert I of non-susceptible LpxC species such as P. aeruginosa LpxC, while these moieties are tolerated by E. coli LpxC containing long and flexible Insert I regions. These studies reveal large, inherent conformational variation of distinct LpxC enzymes, providing a molecular explanation for the limited efficacy of existing compounds and a rationale to exploit more flexible scaffolds for further optimization of LpxC-targeting antibiotics to treat a wide range of Gram-negative infections. </p><p>In Chapters IV and V, a fragment-based screening and structure-guided ligand optimization approach is presented, which has resulted in the discovery of a difluoro biphenyl diacetylene hydroxamate compound LPC-058 with superior activity in antibacterial spectrum and potency over all existing LpxC inhibitors. In Chapter VI, I describe our efforts to improve the cellular efficacy of LPC-058 by reducing its interaction with plasma proteins, such as human serum albumin (HSA). The binding mode of LPC-058 was captured in the crystal structure of HSA/LPC-058 complex. The acquired structural information facilitated the development of the dimethyl amine substituted compound LPC-088 that displays significantly improved cellular potency in presence of HSA.</p> / Dissertation

The reconstruction of past environmental conditions is a fascinating research area that attracts the interest of many individuals in various geological disciplines. Paleoenvironmental reconstruction studies can shed light on the understanding of past climates and are a key to the prediction of future climate changes and their consequences. These studies take on special significance when focused on areas sensitive to climate change. The Arctic region, which is experiencing dramatic changes today in its peatlands and in its ocean, is prime example. The entire region plays a major role in global climate changes and has recently received considerable interest because of the potential feedbacks to climate change and its importance in the global carbon cycle. For a better understanding of the role of Arctic peatlands and the Arctic Ocean to global climate changes, more records of past conditions and changes in the region are needed. This work applies different geochemical proxies, with special emphasis on lipid biomarkers, to the study of a permafrost peat deposit collected from the Eastern European Russian Arctic and a marine core retrieved from the Lomonosov Ridge in the central Arctic Ocean. The results reported of this study show that molecular stratigraphy obtained from the analysis of lipid biomarkers in both peat and marine profiles, combined with other environmental proxies, can contribute significantly to the study of Arctic ecosystems of the past. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.</p>

The glycosylation pattern of a chimeric heavy chain antibody (EG2) produced from CHO cells was affected by the glucose concentration (0-25 mM) of cultures established at high density (>106 cells/ml) over 24 h. The resulting proportion of non-glycosylated Mab was directly correlated to the exposure time of cells to media depleted of glucose. Deprivation of glucose for the full 24 h resulted in a 52% non-glycosylated Mab fraction. Analysis of steady state levels of intracellular lipid-linked oligosaccharides (LLOs) showed that under glucose limitation there was a reduction in the amount of full length LLO (Glc3Man9GlcNac2), with a concomitant increase in the smaller mannosyl-glycans (Man2-5GlcNAc2). Glycan microheterogeneity was quantified by galactosylation and sialylation indices (GI and SI), which showed a direct correlation to the cell specific glucose uptake. These findings are important in relation to the low substrate that may occur in fed-batch cultures for Mab production.