Biology

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Open Access
Characterization of PRD-1 Mutation in Neurospora crassa
(2014-07-09) Firoozi, Ghazaleh; Lakin-Thomas, Patricia
In Neurospora crassa, rhythmic conidiation is controlled by several oscillators such as FRQ/WCC and FLO. The frequency (frq) gene and white collar genes (WC-1 and WC-2) are the most important components of the FRQ/WCC oscillator and prd-1 and prd-2 genes could be important components of the FLO. This project aims to characterize the prd-1 mutation. This involved mapping the mutation using PCR analyses based on single nucleotide polymorphism (SNP) markers. After determining a minimal interval, candidate genes were sequenced, and knockout mutants were screened in this interval for prd-1 phenotype. A candidate gene was found to have a mutation that affects the splicing of the mRNA. The identity of the gene was confirmed by complementing the prd-1 mutant with a wild type copy of the identified candidate gene. The prd-1 gene is identified as an RNA helicase.
Open Access
Manipulation of Endogenous and Exogenous Sources of Cholesterol and its Effects on Beta Cell Function.
(2014-07-09) Bacani, Joseph Gerard; Tsushima, Robert
Type 2 diabetes mellitus (T2DM) prevalence continues to increase worldwide. Changes in β-cell function and mechanisms behind the aberrant insulin secretion found in T2DM patients are still poorly understood. Cholesterol is a vital molecule to all cellular systems, being an important factor regulating membrane fluidity and a number of signalling pathways. In this study, a series of experiments are conducted on the mouse insulinoma cell line, MIN6, limiting exogenous cholesterol through use of lipid free serum, as well as limiting endogenous cholesterol sources through the use of 3-hydroxy-3-methyl-glutaryl-CoA reductase and 7-dehydrocholesteral reductase inhibitors. The results show a marked decrease in both cholesterol content as well glucose stimulated insulin secretion in the drug-treated groups. A series of promoter assays, RT-PCR experiments and western blot analysis determined disruption in site-directed surface expression of important channel proteins involved in insulin secretion, and potentially a change in insulin degradation enzyme activity.
Open Access
A Steroid Driven Peripheral Oscillator in Fat Body Cells of Rhodnius prolixus (Hemiptera)
(2014-07-09) Saroiu, Tudor; Steel, Colin G.
Circadian clocks are central to physiology. In animals, clocks are distributed in cells and tissues throughout the organism. The specific role of these clocks in the tissues within which they reside as well as the way they communicate and interact with each other is unclear. Using immunohistochemistry and laser confocal microscopy I have investigated whether the fat body in the insect Rhodnius prolixus contains an autonomous circadian clock. Fat body was found to express the canonical clock protein PER in a circadian fashion in vivo. However, when fat body was incubated in vitro, PER rapidly became undetectable. A pulse of ecdysteroid, but not brain neuropeptide extract, successfully induced PER expression but not cycling. Therefore, Rhodnius fat body does not seem to possess a local clock. It is inferred that PER cycling in the fat body is driven by the known rhythm of ecdysteroid concentration in the haemolymph.
Open Access
Anterior Cingulate Cortex Cells Identify Errors of Attentional Control Prior to Prefrontal Disengagement
(2014-07-09) Shen, Chen; Womelsdorf, Thilo
The anterior cingulate cortex (ACC) is implicated in the detection of errors and the allocation of correctional adjustments. However, error detection alone is not sufficient to resolve and prevent future mistakes since errors can occur in various ways, subsequently requiring different adjustments. I therefore investigated whether the ACC tracks specific processing states that give rise to errors in order to identify which specific processing aspects need readjustment. To do this, my lab recorded from cells in the prefrontal cortex (PFC) of macaques while they were performing a selective-attention task that elicited three types of error. My study provides support for the functional role of the ACC in performance monitoring and specifying correctional adjustments through the tracking of specific sources of erroneous task outcomes.
Open Access
Identifying Substrates, Interacting Partners and Cofactors of Pirh2: Characterizing the Pirh2-PKCdelta Interaction
(2014-07-09) Nuaaman, Mais M.; Benchimol, Samuel
p53 is a central player in the cellular response to stress, allowing cells to cope in the presence of diverse stress signals including DNA damage and oncogene activation. In response to stress, p53 acts as a transcription factor to regulate the expression of protein-coding and non-coding RNA genes that collectively result in cell cycle arrest, senescence or apoptosis. One such p53-regulated gene encodes the Pirh2 protein, an E3 ubiquitin ligase known to ubiquitinate many substrates including p53, p27/Kip1 cell cycle inhibitor and DNA polymerase η. The objective of this project was to validate a putative interaction between Pirh2 and Protein Kinase Cδ and determine if the latter was a substrate for Pirh2-mediated ubiquitination. While data suggest that Pirh2 protein expression negatively correlates with PKCδ protein levels, it could not be confirmed that Pirh2 mediates ubiquitin-dependent degradation of PKCδ protein.
Open Access
Circadian Organization of the Neuroendocrine System of an Adult Insect, Rhodnius Prolixus (STÄL) (HEMIPTERA)
(2015-01-26) Cardinal-Aucoin, Michael David; Steel, Colin G.
Circadian clocks synchronize with external environmental cycles and regulate rhythms throughout the organism, creating an internal temporal organization of cellular and physiological processes. In the model insect Rhodnius prolixus the prothoracicotropic hormone (PTTH)-ecdysteroid axis is a central component of the larval circadian system. However, PTTH is considered a larval hormone and its only known target, the ecdysteroid-producing prothoracic glands, are absent in adults. Here, PTTH is demonstrated to be present in adult female Rhodnius and its synthesis and release during the period of egg development and oviposition were shown to fluctuate with a daily rhythm that is controlled by the circadian clock in the brain. Ecdysteroids are also present during this time and their levels in hemolymph and ovaries undergo synchronous daily variations that are likewise under clock control. Ovaries are the only adult tissue examined that both contained and released ecdysteroids. It is inferred that the ovaries generate the rhythm of ecdysteroids in the hemolymph. The parallel patterns of PTTH and ecdysteroid release suggest these processes are related and it is tempting to speculate that the PTTH-ecdysteroid axis persists in the adult leading to the orchestration of complex adult-specific processes, such as egg development and oviposition.
Open Access
Role of SNARE Proteins in Natriuretic Peptide Secretion by the Heart
(2015-01-26) Natividad, Nikki; Tsushima, Robert
The hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are stored and secreted by cardiac myocytes. To date, there is little information reported regarding the cellular mechanisms regulating the release of these hormones. Recent studies have identified soluble N-ethyl-maleimide-sensitive-fusion attachment protein receptors (SNAREs) in the trafficking, docking and fusion of ANP and BNP secretory vesicles. In this study, I characterized the expression profiles of the three SNARE proteins (syntaxin 5A, syntaxin 18, and SNAP29), implicated in constitutive exocytosis, in atrial and ventricular cardiac myocytes. My results suggest that syntaxin 5A, syntaxin 18 and SNAP29 are not important in the constitutive secretion of ANP and may play a role in another protein trafficking pathway. Syntaxin 1A and SNAP25, two SNARE proteins previously characterized in atrial cardiac myocytes, form a complex in adults that has been implicated in the exocytosis of ANP. I investigated the protein expression and promoter activity of these two SNARE proteins in neonatal and adult atrial and ventricular cardiac myocytes. The functional role of syntaxin 1A and SNAP25 was assessed using botulinum neurotoxin C (BoNT/C) and BoNT/A which cleave these SNARE proteins, respectively. Treatment of cardiac myocytes with BoNT/A and BoNT/C suggest that syntaxin 1A and SNAP25 regulate ANP secretion in neonatal cardiac myocytes, albeit low levels. Lastly, I examined the influence of forskolin and phorbol myristate acetate (PMA) on the syntaxin 1A and SNAP25 promoter. The lack of effect of these agents on gene reporter activity suggests that the CRE element in the syntaxin 1A and SNAP25 promoter do not significantly affect transcriptional activity. Overall, my studies demonstrate the developmental changes in SNARE protein expression in the heart, and their potential role in ANP secretion.
Open Access
Structural and Functional Analyses of the Interaction Between the USP7-NTD and the E2-Conjugating Enzymes, UbE2E2 and UbE2E3
(2015-01-26) Ashurov, Leila; Saridakis, Vivian
Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that regulates the turnover of proteins in a cell. To date several interacting partners that are involved in various cellular processes have been identified for USP7. Many of the interacting partners of USP7 contain a P/AxxS motif. We have identified two E2 ubiquitin-conjugating enzymes, UbE2E2 and UbE2E3, which contain the P/AxxS motif. Using a co-immunoprecipitation assay we have shown that these E2 proteins interact with USP7 through their P/AxxS motif. Co-crystal structures of the N-terminal domain of USP7 (USP7-NTD) and the E2 peptides reveal that the interactions are formed between USP7-NTD residues 164DWGF167 and the E2 P/AxxS motifs. It has also been established that USP7 may be involved in regulating the cellular levels of UbE2E2. Overall, our findings suggest USP7, a de-ubiquitinating enzyme, is a regulator of ubiquitin-conjugating enzymes, which are involved in the ubiquitination cascade.
Open Access
Variability in the Foraging Patterns of Polar Bears (Ursus Maritimus) in the Canadian High Arctic and Foxe Basin
(2015-01-26) Galicia, Melissa Paula; Thiemann, Gregory; Canadian Arctic
Ongoing climate warming is projected to cause further declines in sea ice across the Arctic; as a result the foraging ecology of marine species will change. This thesis aimed to investigate the ecological patterns associated with polar bear diet selection. I characterized polar bear diet in the High Arctic, an area that supports a high density of bears and Foxe Basin, a subpopulation that has remained stable despite shifts in sea ice habitat. I used adipose tissue samples and quantitative fatty acid signature analysis to quantify diet composition. Lipid content was used as an indicator of body condition and decreased from fall to spring in bears when prey are less available. Diet estimates revealed spatial differences in polar bear foraging and identified the importance of locally and seasonally abundant prey. The ability of some individuals to alternate between prey species may help mitigate the effects of a declining sea ice habitat.
Open Access
Determination of VraR Binding Activity on Promoters of fmtA, murZ, sgtB and pbp2
(2015-01-26) Yang, Zhifeng; Golemi-Kotra, Dasantila
VraSR two-component system rapidly senses the cell wall damage by antibiotics and positively modulates a set of genes (VraSR Regulon) to enhance the resistance phenotype in S. aureus. fmtA, murZ, sgtB and pbp2 are members of VraSR Regulon, and they are involved in cell wall peptidoglycan synthesis in response to cell wall inhibitors such as β-lactams. We investigated VraR binding activity on fmtA promoter/its mutants by in vitro and in vivo experiments. We found VraR can bind to two conserved motifs on fmtA promoter in the formation of a dimer and up-regulate the transcription of fmtA under oxacillin conditions. We also found fmtA had two transcription start sites: -157G was responsible for maintenance of a basal level expression, and -195G was induced by oxacillin treatment. We reported VraR/phosphorylated-VraR binding sequences on promoters of murZ, sgtB and pbp2. Putative transcription start sites of murZ, sgtB and pbp2 were also identified.
Open Access
Role and Regulation of FRA-2 During Skeletal Muscle Development
(2015-01-26) Alli, Nezeka Sultana; McDermott, John Charles
Regulation of skeletal muscle development and regeneration is critical to all metazoans and also of clinical relevance as muscle wasting is manifested in a variety of disorders. The events contributing to development and regeneration of skeletal muscle are primarily controlled by members of the myogenic regulatory factors (MRF) and myocyte enhancer factor 2 (MEF2) transcription factor families. Secondary factors also exert effects on myogenesis such as the activator protein 1 (AP-1) transcription factor which has a complex role in the differentiation process. The AP-1 subunit Fra-2 has a role in skeletal muscle development and regeneration but it is less defined. Here, the role of Fra-2 in skeletal myogenesis was investigated thereby extending the study of AP-1 in muscle. It was determined that Fra-2 is regulated by the ERK 1/2 MAPK pathway via phosphorylation at S320 which is important for Fra-2 protein stability. Gain of function studies exploiting stability of Fra-2 achieved by phosphomimetic mutations impacted differentiation negatively. Conversely, loss of function using siRNAs resulted in precocious differentiation suggesting an overall inhibitory role for Fra-2 in myogenic cells. Intriguingly, it was observed that AP-1 is differentially expressed in a differentiated culture of C2C12 myogenic cells in that Fra-2 expression is restricted to monomucleated reserve cells and not in the differentiated myotubes. Furthermore, it was determined that Fra-2 is expressed in Pax7 positive satellite cells in a single muscle fibre culture model and that it binds to the promoter of the mustn1 gene which, in turn, is also a novel satellite cell marker. In conclusion, Fra-2 protein stability is regulated by phosphorylation of ERK 1/2 in myogenic cells and its expression in quiescent reserve cells and in satellite cells suggests a possible role for Fra-2 in maintaining the undifferentiated state in myogenic progenitor cells.
Open Access
The Effects of Daytime Melatonin Administration on Sleep, Higher Cognitive Function, and Changes in the Brain
(2015-01-26) Leung, Samantha Eve; Steel, Colin G.H.; De Souza, Joseph F. X.
This study investigated the effects of exogenous melatonin on people’s sleep, ability to perform an emotional Stroop task, and underlying brain architecture. 10 healthy adults (age = 26.8 ± 6.25 years) underwent a baseline period followed by an experimental period whereby melatonin was administered at inappropriate times, with daily activity logs kept throughout. The emotional Stroop task was performed four times during each period, followed by an MRI scan. Following melatonin administration, sleep and wake times were significantly shifted and sleep quality ratings were significantly decreased compared to baseline values. Additionally, processing of emotional words but not faces was negatively affected by the melatonin treatment. Fractional anisotropy and mean diffusivity values were also significantly altered in the inferior frontal gyrus. It is inferred that the melatonin treatment induced circadian desynchronization, resulting in behavioural changes and structural alterations in brain regions involved in performance of the emotional Stroop task.
Open Access
Measuring Memory in an Alzheimer's Treatment Trial Using a Visual Search Task
(2015-01-26) Dragan, Michelle; Hoffman, Kari
Alzheimer’s Disease (AD) is characterized by episodic memory deficits attributed to damage to the hippocampal formation. AD therapies specifically targeting hippocampal function may be best evaluated through the use of selective hippocampal tasks. I used a nonverbal hippocampal-dependent target-in-scene detection task to determine if task performance shows age-related decline and/or AD-related impairments. Participants located objects (‘targets’) that appeared/disappeared in flickering natural scenes, yielding faster search times for remembered targets than for forgotten ones. AD patients took longer and required more fixations to detect targets, indicating impaired memory. Furthermore, the AD and aged populations exhibited slower pupillary responses. As part of a clinical trial, I next asked whether deep-brain stimulation of the extended hippocampal circuit would modify memory performance in patients with early AD. The double-blind treatment trial is still underway, thus treatment efficacy is yet to be evaluated, however, trial participants showed a measurable, progressive memory impairment in this task.
Open Access
Migration and Winter Ecology of a Declining Forest Songbird
(2015-01-26) Mckinnon, Emily Anne; Stutchbury, Bridget J.
Fundamental gaps in understanding of the year-round biology of migratory songbirds are hampering conservation of dozens of at-risk species. Until recently, determining where and when during their annual cycle migratory songbirds are most limited was not possible, because linking an individual’s survival and condition across seasons and over thousands of kilometres was extremely difficult. With miniaturized tracking devices, I followed a declining migratory songbird, the Wood Thrush (Hylocichla mustelina) over its entire annual cycle, from well-studied breeding sites in temperate forests of eastern North America to its overwintering range in the Neotropics. As with most migratory birds, information on non-breeding ecology and habitat use is lacking for Wood Thrushes. In this dissertation, I examined demographic patterns in migration behaviour, and quantified effects of habitat occupancy in winter on condition of the birds and on spring migration performance. I found that Wood Thrush spring migration shows a distinct age-related switch from late timing and more stopovers as juveniles to earlier timing and fewer stopovers as adults. I also show, at a study site in Belize, that winter habitat quality (abundance of food and moisture) declines over the non-breeding season, and that Wood Thrushes are in the lowest body condition of the winter immediately prior to initiation of spring migration. Finally I show that despite variation in pre-migration body condition and habitat moisture, there were no carry-over effects of winter habitat occupancy to spring migration. Overall this work supports the hypothesis that Wood Thrush spring migration is primarily under genetic control, rather than condition-dependent, since winter conditions do not appear to limit migratory performance. Climate change models predict more droughts in Central America, which could decrease the condition of overwintering Wood Thrushes, and may result in detectable carry-over effects on migration in the future.
Open Access
The Role and Regulation of Cyclin G2 in Human Ovarian Cancer Cells
(2015-08-28) Bernaudo, Stephanie; Peng, Chun
Epithelial Ovarian Cancer (EOC) is the leading cause of cancer related death associated with gynecological malignancies. Survival is greatly impeded by poor screening methods, non-specific symptoms, and limited knowledge of the cellular targets that contribute to disease. Cell division is under direct regulation of the cyclin family. Typical cyclins will accumulate periodically to activate cyclin-dependent kinases (CDKs) leading to the unidirectional flow of the cell cycle, whereas the unconventional G-type cyclins (cyclin G1, G2, and I) act to oppose cell cycle progression. Indeed, dysregulation of the cycle cell is an important molecular mechanism that is frequently altered in cancers, including EOC. Interestingly, recent evidence has suggested that the loss of cyclin G2 is associated with cancer progression and poor survival. In this study, we have investigated the role and regulation of cyclin G2 in EOC cells. We found that cyclin G2 overexpression decreases the overall tumor burden by reducing proliferation, migration, and invasion. Interestingly, these anti-tumorigenic effects are mediated, at least in part, by enhancement the epithelial phenotype via attenuation of β-catenin signaling. Cyclin G2 promotes the degradation of β-catenin and directs its sub-cellular localization to the membrane, possibly through up-regulation of E-cadherin. In addition, we have previously shown that cyclin G2 is highly unstable, and degraded very quickly by the ubiquitin-proteasome pathway. This study also suggests the calpain-mediated proteolysis is a major factor that contributes to the degradation of cyclin G2. This process is dependent on the presence of the cyclin G2 C-terminal PEST motif, as well as epidermal growth factor signalling. Together, these data suggest that the loss of cyclin G2 in human malignancies, possibly through growth factor signaling and multiple downstream degradation processes, may contribute to the increased tumorgenicity of ovarian cancer cells.
Open Access
Molecular Evolution of the Brain Transcription Regulatory Network Affecting Worker Behaviour of Honey Bees (Apis Mellifera)
(2015-08-28) Molodtsova, Daria; Zayed, Amro
The brain transcription regulatory network drives the behavioural states of honey bee workers. It is paradoxical that labile behaviour is guided by a network of evolutionary conserved pleiotropic transcription factors. So how does adaptive change in behaviour arise? I used a population genomics approach to estimate the strength of selection on coding and cis-regulatory mutations of transcription factors and their target genes in the honey bee brain transcription regulatory network. I found that replacement mutations in highly connected transcription factors and target genes experience significantly stronger negative selection relative to weakly connected transcription factors and targets. Interestingly, connectedness and network structure had minimal influence on the strength of selection on putative regulatory sequences for both transcription factors and their targets. This study suggests that adaptive evolution of complex behaviour can arise because of positive selection on protein-coding mutations in peripheral genes, and on regulatory sequence mutations in both transcription factors and their targets throughout the network.
Open Access
Regulation of Cardiac Remodelling by Adiponectin in Response to Pressure Overload and Unloading: A Focus on the Extracellular Matrix
(2015-08-28) Dadson, John Keith Essien; Sweeney, Gary
Cardiac remodelling, the reorganization of the heart which occurs in response to factors impacting its function, includes remodelling of the extracellular matrix (ECM) and hypertrophic cardiomyocyte growth. Pressure overload (PO) induced remodelling of the ECM is initially considered a compensatory mechanism to maintain myocardial integrity, but is also considered a progressive, negative event increasing myocardial stiffness. Adiponectin, an adipokine inversely correlated with type 2 diabetes and obesity, plays an important role in the adaptive response of the heart in various cardiomyopathies, however, adiponectin signalling leading to ECM regulation remains unclear. The studies presented here investigate the role of adiponectin in regulating cardiac remodelling with a particular focus on the ECM from a physiological and mechanistic perspective. Studies using wild-type (WT) and adiponectin deficient (AdKO) mice showed that PO induced left ventricular (LV) cardiac remodelling is delayed by adiponectin deficiency. The appearance of thick collagen fibres and activation of pro-fibrotic genes (MMPs and TIMPs) is delayed in AdKO mice subjected to PO when compared to WT mice. Cardiac hypertrophy and dysfunction, measured by echocardiography, is similarly delayed in AdKO mice. Furthermore, MEF2 activation determined using MEF2-lacZ reporter mice, is decreased in AdKO mice compared to WT mice following PO. Studies in primary neonatal cardiac fibroblasts identified the APPL1-AMPK signalling axis as the mediator of adiponectin stimulated ECM remodelling through membrane localization of APPL1 and subsequent phosphorylation of AMPK, leading to MT1-MMP re-localization, MMP2 activation, and fibroblast migration. Also, adiponectin pre-treatment inhibited angiotensin II induced fibroblast to myofibroblast differentiation. Furthermore, in primary neonatal cardiomyocytes we identify the hypertrophic regulators Myocyte Enhancing Factor-2 (MEF2) and Atrial Natriuretic Factor (ANF) as downstream targets of adiponectin signalling. Lastly, using an in vivo model of reverse remodeling, we show that myocardial strain and cardiac hypertrophy are regressed following LV unloading. However, regression of cardiac fibrosis was incomplete leading to persistent small fibre fibrosis. Together these studies establish adiponectin as an important regulator of cardiac remodelling via the APPL1-AMPK signalling axis and MEF2 activation. Furthermore, we show that adiponectin deficiency confers protection against PO induced remodelling.
Open Access
The Effects of Social Interactions on Learning and Memory in the Honey Bee Apis Mellifera
(2015-08-28) Tsvetkov, Nadejda; Zayed, Amro
The honey bee Apis mellifera has been used to study the genetics of learning and memory for several decades. In Chapter 2, a literature review revealed that learning and memory phenotypes are highly heritable. Several quantitative trait loci and specific genes which code for neurotransmitter receptors were identified. Whereas transcriptomic approaches showed that the process of learning and memory involves hundreds of genes. Although understanding the genetic components is crucial, it is also important to understand how environmental factors affect learning and memory. In Chapter 3, I investigate the effect of social interactions on discrimination learning by randomly assigning bees into three different social groups: 1 bee, 8 bees, and 32 bees. Using the proboscis extension conditioned response test, I found that the fewer social interactions a bee experiences, the more responsive she is to sucrose. Bees raised in groups of 32 had the best performance in discrimination learning.
Open Access
Salinity Responsive Aquaporins in the Larval Mosquito Aedes Aegypti
(2015-08-28) Akhter, Hina; Andrew Donini, Andrew
The anal papillae (AP) of the mosquito larva, Aedes aegypti are important sites for ionoregulation because they actively take up ions from a dilute external environment to help maintain appropriate ion levels in the hemolymph. An apparent paradox is that these structures are also permeable to water and because of the syncytial nature of the epithelium, aquaporins (AQPs) are likely to be involved. A previous study has revealed expression of AQP homologs in the anal papillae of freshwater reared larvae. In the present study, transcript expression levels of six AQP homologs in the AP were examined in larvae reared in ion poor water and 7.5 g L-1 Instant Ocean® salts (~ 30% seawater). The mRNA expression of four of these AQP homologs (AaAQP2, AaAQP3a, AaAQP3b, AaAQP4) was salinity responsive suggesting the importance of these homologs in salinity acclimation. In addition, western blot analysis of AaAQP3a and AaAQP3b confirmed the salinity responsive nature of these two proteins. Immunohistochemistry also confirmed the presence of AaAQP3a and AaAQP3b in both the apical and basal membranes of the AP.
Open Access
Effect of Lipotoxicity on ER Stress, Autophagy and Apoptosis in Skeletal Muscle and Regulation by Adiponectin
(2015-08-28) Rai, Esther Priyanka; Sweeney, Gary
Obesity is a key factor contributing to the “metabolic syndrome” which increases the risk for type 2 diabetes, cardiovascular disease and liver complications. In obese conditions, lipotoxicity is a serious concern as the accumulation of lipids and lipid-intermediates in non-adipose tissue such as skeletal muscle, heart, liver and pancreas, leads to cellular dysfunction and activation of stress responses. In this study, I have examined how palmitate-induced lipotoxicity, effects the cellular processes ER stress, autophagy and apoptosis, in L6 rat skeletal muscle cells. I have elucidated cross-talk mechanisms between these processes, and have demonstrated that palmitate induces excessive protein accumulation, thereby stimulating ER stress, activation of the UPR and subsequent apoptosis. Autophagy may be recruited as a compensatory mechanism to help the cell cope with the stress of protein overload through its degradative pathway. Additionally, adiponectin may increase autophagic flux, thereby contributing to cytoprotective effects of reducing ER stress and apoptosis.