Ayse Bilgin

Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression

Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease. To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients. Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA). The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor. We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity. A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%. After validation in another independent cohort, sensitivity was maintained at 85%. Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers.

Relationship between central and peripheral fatty acids in humans

BackgroundIn recent years the physiological and pathological importance of fatty acids in both the periphery and central nervous system (CNS) has become increasingly apparent. However surprisingly limited research has been conducted comparing the fatty acid composition of central and peripheral lipid stores.MethodsThe present study compared the distribution of polyunsaturated (PUFA), as well as specific saturated (SFA) and monounsaturated (MUFA) fatty acids in the whole blood and cerebrospinal fluid (CSF) of humans. Gas chromatography with flame ionization detection was used to determine the fatty acid profiles of twenty-eight matched CSF and whole blood samples. Multiple linear regression modeling, controlling for age, was used to identify significant relationships.ResultsA significant positive relationship was seen between whole blood total omega-3 fatty acids and the CSF omega-3 subfractions, docosapentaenoic acid (DPA) (P = 0.019) and docosahexaenoic acid (DHA) (P = 0.015). A direct association was also observed between the whole blood and CSF omega-6 PUFA, arachidonic acid (AA) (P = 0.045). Interestingly an inverse association between central and peripheral oleic acid was also found (P = 0.045).ConclusionsThese findings indicate a relationship between central and peripheral fatty acids of varying degrees of unsaturation and chain length and support the view that some systemic fatty acids are likely to cross the human blood brain barrier (BBB) and thereby influence central fatty acid concentrations.

Age and circadian influences on picolinic acid concentrations in human cerebrospinal fluid

It has been suggested that picolinic acid (PIC), an endogenous metabolite of l‐tryptophan, possesses neuro‐protective and anti‐proliferative effects within the CNS. However, the literature surrounding PIC is limited, and its exact endogenous function is not known. Picolinic acid is produced via the kynurenine pathway which has been implicated in the pathogenesis of a range of neuro‐inflammatory diseases. Although not extensively studied, there have been reports of altered PIC production alongside other kynurenine metabolites in inflammatory disorders. In order to investigate whether PIC concentrations are altered with disease in the CNS, we analysed PIC levels in the CSF of 241 patients who underwent lumbar puncture as part of their standard clinical evaluation. In patients with no apparent CNS disease, CSF PIC levels were 10‐fold higher in samples taken between 20:00 and 16:00 h compared with those collected between 04:00 and 12:00 h. This result suggests a diurnal variation in PIC synthesis within the CNS. In addition, we observed a direct correlation between a patient’s age and their PIC concentration. No significant correlations were observed between CSF PIC levels and any specific disease state.

Altered kynurenine pathway metabolism in autism: Implication for immune‐induced glutamatergic activity

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross‐sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age‐matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621–631.

Novel relationships between B12, folate and markers of inflammation, oxidative stress and NAD(H) levels, systemically and in the CNS of a healthy human cohort.

Objective: To evaluate the relationship between folate, cobalamin (Cbl), and homocysteine (Hcy), and markers of inflammation and oxidative stress within the periphery and central nervous system (CNS) of a healthy human cohort. Methods: Thirty-five matched cerebrospinal fluid (CSF) and plasma samples were collected from consenting participants who required a spinal tap for the administration of anaesthetic. Plasma concentrations of Hcy and both plasma and CSF levels of folate, Cbl, nicotinamide adenine dinucleotide (NAD(H)) and markers of inflammation (interleukin-6, IL-6), and oxidative stress (F2-isoprostanes, 8-hydroxy-2′-deoxyguanosine (8-OHdG), and total antioxidant capacity (TAC)) were quantified. Results: In the peripheral circulation, positive associations were observed between plasma folate and Cbl, and plasma TAC (P ≤ 0.01; P ≤ 0.01) and plasma NAD(H) (P ≤ 0.05; P ≤ 0.05) levels, respectively. Plasma folate was inversely associated with plasma Hcy concentrations (P ≤ 0.05); however, no statistically significant relationships were observed between plasma Hcy and plasma markers of inflammation, oxidative stress, or [NAD(H)]. Within the CNS plasma Hcy correlated positively with CSF IL-6 (P ≤ 0.01) and negatively with CSF NAD(H) (P ≤ 0.05) concentrations. An inverse association was observed between CSF folate and CSF levels of IL-6 (P ≤ 0.05). Unexpectedly, a positive association between CSF Cbl and CSF 8-OHdG levels was also found (P ≤ 0.01). Discussion: These results indicate that folate and Cbl concentrations may influence the levels of oxidative damage, inflammation, and NAD(H), both systemically and within the CNS.

Predicting overall viability of cord blood harvests

BACKGROUND: Cord blood (CB) is a product rich in primitive adult stem cells used in hematopoietic stem cell transplantation. After collection, the CB is transported to a facility where the unit is processed and then frozen up to 48 hours later. These processes can lead to compromised white blood cell (WBC) viability. This study investigates the factors that affect WBC viability before freezing of the cells.

Postprandial oxidative stress is increased after a phytonutrient-poor food but not after a kilojoule-matched phytonutrient-rich food.

Research indicates that energy-dense foods increase inflammation and oxidative activity, thereby contributing to the development of vascular disease. However, it is not clear whether the high kilojoule load alone, irrespective of the nutritional content of the ingested food, produces the postprandial oxidative and inflammatory activity. This study investigated the hypothesis that ingestion of a high-fat, high-sugar, phytonutrient-reduced food (ice cream) would increase oxidative and inflammatory activity greater than a kilojoule-equivalent meal of a phytonutrient-rich whole food (avocado). The individual contributions of the fat/protein and sugar components of the ice cream meal to postprandial inflammation and oxidative stress were also quantified. Using a randomized, crossover design, 11 healthy participants ingested 4 test meals: ice cream, avocado, the fat/protein component in ice cream, and the sugar equivalent component in ice cream. Plasma glucose, cholesterol, triglycerides, and inflammatory and oxidative stress markers were measured at baseline and 1, 2, and 4 hours (t1, t2, t4) after ingestion. Lipid peroxidation was increased at 2 hours after eating fat/protein (t0-t2, P < .05) and sugar (t1-t2, P < .05; t1-t4, P < .05). Antioxidant capacity was decreased at 4 hours after eating ice cream (t0-t4, P < .01) and sugar (t0-t4, P < .01). Ingestion of a kilojoule-equivalent avocado meal did not produce any changes in either inflammatory or oxidative stress markers. These data indicate that the ingestion of a phytonutrient-poor food and its individual fat/protein or sugar components increase plasma oxidative activity. This is not observed after ingestion of a kilojoule-equivalent phytonutrient-rich food.

Cross‐cultural study into ICT student attitudes and behaviours concerning teams and project work

Purpose – The purpose of this paper is to describe a project involving information and communication technology (ICT) students in Australia and Singapore, working together as a virtual global team. The authors investigated the question: Can differences be found in the behaviours and attitudes of our two cohorts to working in teams? This would allow the authors to better manage the project and reflect on its success/failure.Design/methodology/approach – The authors ran a one semester cross‐cultural software development project. An anonymous online survey measured three temporal dimensions commonly used in time‐at‐work studies and seven cultural dimensions. The results are discussed in the context of cohort behaviours, project outcomes/outputs and related literature.Findings – Differences were found along the temporal dimensions of punctuality, time boundaries and awareness of time use. While conformance with national cultural stereotypes was evident, only selected statements in the cultural dimensions show...

Suboptimal Omega-3 Levels in Australian Adolescents

Objective: To quantitate the omega-3 status in a cohort of Australian adolescents. Design, Setting and Participants: A cross-sectional descriptive study of 251 apparently healthy adolescents (192 female, 59 male) aged 15-17 years, in year 11, from 10 schools within the Northern Sydney and Central Coast areas of New South Wales. Participants provided a morning non-fasting blood sample via finger-prick and written answers to specific demographic and lifestyle questions. Omega-3 index was calculated by adding %EPA and %DHA values in the whole blood. Equivalent erythrocyte omega-3 index values were obtained by using conversion factors (1.33 for EPA and 2.22 for DHA) from published erythrocyte/whole blood values. Main Outcome Measures: Quantitation of the individual, and estimation of the group average, blood omega-3 Index. Results: The blood omega-3 Index for this adolescent cohort ranged from 2.1-22.3 with a mean of 8.3±3.2, and median of 7.8. On average males had a higher omega-3 Index compared to females (10.5±3.7 vs 7.7±2.6, p 8. Three percent had an Index of <4, placing them in the high risk category for disease. On average, adolescents from low or medium socioeconomic communities had a significantly lower omega-3 Index compared to those from higher socioeconomic neighbourhoods (mean difference=1.4, p=0.018). Overall 20% of boys and 17% of girls reported regularly taking omega-3 supplements. Regular use of omega-3 supplements was associated with a higher average omega-3 Index (9.8±3.7, n=44 compared to 8.0±3.0, n=203, p=0.001 in those not taking supplements). Conclusion: This study indicates that Australian adolescents, even when from advantaged homes, have a high probability of below optimum omega-3 levels. As reduced omega-3 levels are linked to conditions of public health concern such as diabetes, asthma and depression, targeted strategies to improve the omega-3 status in the childhood population may be warranted.

Assuring graduate competency: a technology acceptance model for course guide tools

Abstract Higher education institutions typically express the quality of their degree programs by describing the qualities, skills, and understanding their students possess upon graduation. One promising instructional design approach to facilitate institutions’ efforts to deliver graduates with the appropriate knowledge and competencies is curriculum mapping. To support the complex activity of curriculum mapping and to address existing problems associated with current practices around unit guides, that many Australian higher education institutions are developing unit guide information systems (UGISs). This study examines factors influencing the acceptance and use of UGIS by unit conveners and academics. This study proposed a model for the acceptance of UGIS, which integrated key constructs from the technology acceptance model (TAM), social cognitive theory and model of PC utilization including seven main factors: perceived usefulness, perceived ease of use, attitude towards using the UGIS, intention to use the UGIS, social influence, unit guide specific self-efficacy, and unit guide specific anxiety. The model was tested on a sample of 134 unit guide users from 39 Australian universities and analyzed using structural equation modeling and partial least squares methods. Analysis showed that attitude, perceived usefulness, and perceived ease of use from the basic TAM model contributed significantly to explain the intention of academics and unit conveners to use UGIS. In addition, the integration of self-efficacy, anxiety and social influence as constructs were found to improve the fit of the model. Implications of the results are discussed within the context of unit guides and curriculum mapping.