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Background\udPsychotic experiences (PEs) are associated with an increased risk of future psychotic and non-psychotic mental disorders. The identification of biomarkers of PEs may provide insights regarding the underlying pathophysiology.\ud\udMethods\udThe current study applied targeted lipidomic approaches to compare plasma lipid profiles in participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who did (n = 206) or did not (n = 206) have PEs when aged approximately 24 years.\ud\udResults\udIn total, 202 lipids including 8 lipid classes were measured by using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Eight lipid clusters were generated. Thirteen individual lipids were nominally significantly higher in the PEs group compared to the control group. After correction for multiple comparisons, 9 lipids comprising 3 lysophosphatidylcholines (LPCs), 2 phosphatidylcholines (PCs) and 4 triacylglycerols (TGs) remained significant. In addition, PEs cases had increased levels of TGs and LPCs with a low double bond count.\ud\udConclusions\udThese findings indicate plasma lipidomic abnormalities in individuals experiencing PEs. The lipidomic profile measures could aid our understanding of the underlying pathophysiological mechanisms.

Current evidence suggests that chemical exposure alters gut microbiota composition, with higher exposure to environmental chemicals being associated with reduced microbiome diversity. However, not much is known about the impact of per- and polyfluoroalkyl substances (PFAS) on gut bacteria. Here we set out to identify the gut bacterial species that associate with chemical exposure before (maternal) and after (maternal, infant) birth in a mother-infant series. Paired blood and stool samples were collected from mother-infant dyads (n = 30) in a longitudinal setting. PFAS were quantified in maternal blood to examine their associations with the microbial compositions (determined by shotgun metagenomic sequencing) in mothers and infants. High maternal exposure to PFAS was persistently associated with increased abundance ofMethanobrevibacter smithiiin maternal stool. Among individual PFAS compounds, PFOS and PFHpS showed the strongest connection withM. smithii. However, maternal PFAS exposure associated only weakly with the infant microbiome. Our findings suggest that PFAS exposure contributes to the modulation of the adult gut microbiome composition.

Human blood is a self-regenerating lipid-rich biological fluid that is routinely collected in hospital settings. The inventory of lipid molecules found in blood plasma (plasma lipidome) offers insights into individual metabolism and physiology in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metabolism; therefore, plasma lipidomics based on MS is an emerging tool in an array of clinical diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clinical applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent laboratories as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.

Summary T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4+ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.

Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Lipids have many important biological roles, such as energy storage sources, structural components of plasma membranes and as intermediates in metabolic and signaling pathways. Lipid metabolism is under tight homeostatic control, exhibiting spatial and dynamic complexity at multiple levels. Consequently, lipid-related disturbances play important roles in the pathogenesis of most of the common diseases. Lipidomics, defined as the study of lipidomes in biological systems, has emerged as a rapidly-growing field. Due to the chemical and functional diversity of lipids, the application of a systems biology approach is essential if one is to address lipid functionality at different physiological levels. In parallel with analytical advances to measure lipids in biological matrices, the field of computational lipidomics has been rapidly advancing, enabling modeling of lipidomes in their pathway, spatial and dynamic contexts. This review focuses on recent progress in systems biology approaches to study lipids in health and disease, with specific emphasis on methodological advances and biomedical applications.

Background & Aims: Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. Methods: Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n = 62 and n = 63) or PNPLA3 genotype (PNPIA3(148MM/MI), n = 61 vs. PNPLA3(148II), n = 64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. Results: Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI) vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. Conclusions: Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Seroconversion to islet autoimmunity is preceded by metabolic disturbances in children who later progress to overt type 1 diabetes (T1D). The underlying metabolic pathways and the interaction of metabolic and immune system factors involved in progression to the disease are however poorly understood. There is a clear need for mathematical models which capture the temporal and spatial complexity of early pathogenesis of T1D. Here we review the early attempts to model the development of islet autoimmunity and T1D, including the models which emphasize the potential beneficial role of autoimmune response in specific circumstances, such as to 'correct' for the early metabolic disturbances. We also highlight the genome-scale metabolic modeling as a promising new avenue to study metabolism and its interactions with the immune system in T1D.

In this paper, we study fundamental properties of the Self-Organizing Map (SOM) and the Generative Topographic Mapping (GTM), ramifications of the initialization of the algorithms and properties of the algorithms in the presence of missing data. We show that the commonly used principal component analysis (PCA) initialization of the GTM does not guarantee good learning results with high-dimensional data. Initializing the GTM with the SOM is shown to yield improvements in self-organization with three high-dimensional data sets: commonly used MNIST and ISOLET data sets and epigenomic ENCODE data set. We also propose a revision of handling missing data to the batch SOM algorithm called the Imputation SOM and show that the new algorithm is more robust in the presence of missing data. We benchmark the performance of the topographic mappings in the missing value imputation task and conclude that there are better methods for this particular task. Finally, we announce a revised version of the SOM Toolbox for Matlab with added GTM functionality.

Background and aims Whole-grain cereals and diets with a low glycemic index may protect against the development of type 2 diabetes and heart disease, but the mechanisms are poorly understood. We studied the effect of carbohydrate modification on serum metabolic profiles, including lipids and branched chain amino acids, and dependencies between these and specific gene expression pathways in adipose tissue. Methods and results Twenty subjects with metabolic syndrome were selected from the larger FUNGENUT study population, randomized either to a diet high in oat and wheat bread and potato (OWP) or rye bread and pasta (RP). Serum metabolomics analyses were performed using ultra-performance liquid chromatography coupled to electrospray ionization mass spectrometry (UPLC/MS), gas chromatography (GC) and UPLC. In the OWP group multiple proinflammatory lysophosphatidylcholines increased, while in the RP group docosahexaenoic acid (DHA 22:6n-3) increased and isoleucine decreased. mRNA expression of stress reactions- and adipose tissue differentiation-related genes were up-regulated in adipose tissue in the OWP group. In the RP group, however, pathways related to stress reactions and insulin signaling and energy metabolism were down-regulated. The lipid profiles had the strongest association with the changes in the adipose tissue differentiation pathway when using the elastic net regression model of the lipidomic profiles on selected pathways. Conclusion Our results suggest that the dietary carbohydrate modification alters the serum metabolic profile, especially in lysoPC species, and may, thus, contribute to proinflammatory processes which in turn promote adverse changes in insulin and glucose metabolism.

The development of microarray technology allows the simultaneous measurement of the expression of many thousands of genes. The information gained offers an unprecedented opportunity to fully characterize biological processes. However, this challenge will only be successful if new tools for the efficient integration and interpretation of large datasets are available. One of these tools, pathway analysis, involves looking for consistent but subtle changes in gene expression by incorporating either pathway or functional annotations. We review several methods of pathway analysis and compare the performance of three, the binomial distribution, z scores, and gene set enrichment analysis, on two microarray datasets. Pathway analysis is a promising tool to identify the mechanisms that underlie diseases, adaptive physiological compensatory responses and new avenues for investigation.

We found significant species-specific correlations between the use of two synonymous codons and protein secondary structure units by comparing the three-dimensional structures of human and Escherichia coli proteins with their mRNA sequences. The correlations are not explained by codon-context, expression level, GC/AU content, or positional effects. The E. coli correlation is between Asn AAC and the C-terminal regions of beta-sheet segments; it may result from selection for translational accuracy, suggesting the hypothesis that downstream Asn residues are important for beta-sheet formation. The correlation in human proteins is between Asp GAU and the N termini of alpha-helices; it may be important for eukaryote-specific sequential, cotranslational folding. The kingdom-specific correlations may reflect kingdom-specific differences in translational mechanisms. The correlations may help identify residues that are important for secondary structure formation, be useful in secondary structure prediction algorithms, and have implications for recombinant gene expression.

A recently introduced model of a quasi one-dimensional spin glass by means of Monte Carlo simulations was studied. The model consists of linear chains of Ising spins with ferromagnetic nearest-neighbour interchain coupling of strength, K , in addition to infinite-range random interactions. The Edwards-Anderson order parameter and the field-cooled and zero-field-cooled susceptibilities are evaluated for various values of K .

Background & AimsAnimal studies suggest that endocannabinoids could contribute to the development of nonalcoholic fatty liver disease (NAFLD). In addition, NAFLD has been shown to be associated with multiple changes in lipid concentrations in liver biopsies. There are no data on splanchnic free fatty acid (FFA), glycerol, ketone body, endocannabinoid, and lipid fluxes in vivo in subjects with NAFLD.MethodsWe performed hepatic venous catheterization studies in combination with [2H2]palmitate infusion in the fasting state and during a low-dose insulin infusion in 9 subjects with various degrees of hepatic steatosis as determined using liver biopsy. Splanchnic balance of endocannabinoids and individual lipids was determined using ultra performance liquid chromatography coupled to mass spectrometry.ResultsConcentrations of the endocannabinoid 2-arachidonoylglycerol were higher in arterialized (91 ± 33 μg/L basally) than in hepatic venous (51 ± 19 μg/L; P < .05) plasma. Fasting arterial (r = 0.72; P = .031) and hepatic venous (r = 0.70; P = .037) concentrations of 2-arachidonoylglycerol were related positively to liver fat content. Analysis of fluxes of 85 different triglycerides showed that the fatty liver overproduces saturated triglycerides. In the plasma FFA fraction in the basal state, the relative amounts of palmitoleate and linoleate were lower and those of stearate and oleate were higher in the hepatic vein than in the artery. Absolute concentrations of all nontriglyceride lipids were comparable in arterialized venous plasma and the hepatic vein both in the basal and insulin-stimulated states.ConclusionsThe human fatty liver takes up 2-arachidonoylglycerol and overproduces triacylglycerols containing saturated fatty acids, which might reflect increased de novo lipogenesis.