Isomeric lipid signatures reveal compartmentalized fatty acid metabolism in cancer

The cellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular FAs and their de novo synthesis. Given that oxidation of de novo synthesized FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates; however, hitherto, all FAs have been considered part of a common pool. To probe potential metabolic partitioning of cellular FAs, cancer cells were supplemented with stable isotope-labeled FAs. Structural analysis of the resulting glycerophospholipids revealed that labeled FAs from uptake were largely incorporated to canonical (sn-) positions on the glycerol backbone. Surprisingly, labeled FA uptake also disrupted canonical isomer patterns of the unlabeled lipidome and induced repartitioning of n-3 and n-6 PUFAs into glycerophospholipid classes. These structural changes support the existence of differences in the metabolic fates of FAs derived from uptake or de novo sources and demonstrate unique signaling and remodeling behaviors usually hidden from conventional lipidomics.     

Identification of a four-gene metabolic signature predicting overall survival for hepatocellular carcinoma

While hundreds of consistently altered metabolic genes had been identified in hepatocellular carcinoma (HCC), the prognostic role of them remains to be further elucidated. Messenger RNA expression profiles and clinicopathological data were downloaded from The Cancer Genome Atlas—Liver Hepatocellular Carcinoma and GSE14520 data set from the Gene Expression Omnibus database. Univariate Cox regression analysis and lasso Cox regression model established a novel four-gene metabolic signature (including acetyl-CoA acetyltransferase 1, glutamic-oxaloacetic transaminase 2, phosphatidylserine synthase 2, and uridine-cytidine kinase 2) for HCC prognosis prediction. Patients in the high-risk group shown significantly poorer survival than patients in the low-risk group. The signature was significantly correlated with other negative prognostic factors such as higher α-fetoprotein. The signature was found to be an independent prognostic factor for HCC survival. Nomogram including the signature shown some clinical net benefit for overall survival prediction. Furthermore, gene set enrichment analyses revealed several significantly enriched pathways, which might help explain the underlying mechanisms. Our study identified a novel robust four-gene metabolic signature for HCC prognosis prediction. The signature might reflect the dysregulated metabolic microenvironment and provided potential biomarkers for metabolic therapy and treatment response prediction in HCC.     

Why on Earth: Self-assembly of the first bacterial cell to abundantand diverse bacterial species

About 80% of the evolutionary history of life on Earth is restricted to microorganisms which have had several billion years to speciate. The reasons for the origin (self-assembly) of life on Earth, bacterial cell division and why there are so many different bacteria and their global dispersal are discussed from an evolutionary perspective.     

Reversible coupling of individual phycobiliprotein isoforms during state transitions in the cyanobacterium Trichodesmium analysed by single-cell fluorescence kinetic measurements

In the non-heterocyst, marine cyanobacterium Trichodesmium nitrogen fixation is confined to the photoperiod and occurs coevally with oxygenic photosynthesis although nitrogenase is irreversibly inactivated by oxygen. In previous studies it was found that regulation of photosynthesis for nitrogen fixation involves Mehler reaction and various activity states with reversible coupling of photosynthetic components. We now investigated these activity states in more detail. Spectrally resolved fluorescence kinetic measurements of single cells revealed that they were related to alternate uncoupling and coupling of phycobilisomes from and to the photosystems, changing the effective cross-section of PSII. Therefore, we isolated and purified the phycobiliproteins of Trichodesmium via ion exchange chromatography and recorded their UV/VIS absorption, fluorescence excitation and fluorescence emission spectra. After describing these spectra by mathematical equations via the Gauss-Peak-Spectra method, we used them to deconvolute the in vivo fluorescence spectra of Trichodesmium cells. This revealed that the contribution of different parts of the phycobilisome antenna to fluorescence quenching changed during the daily activity cycle, and that individual phycobiliproteins can be reversibly coupled to the photosystems, while the expression levels of these proteins did not change much during the daily activity cycle. Thus we propose that variable phycobilisome coupling plays a key role in the regulation of photosynthesis for nitrogen fixation in Trichodesmium.     

Evidence for increases in vegetation species richness across UK Environmental Change Network sites linked to changes in air pollution and weather patterns

We analysed trends in vegetation monitored at regular intervals over the past two decades (1993–2012) at the twelve terrestrial Environmental Change Network (ECN) sites. We sought to determine the extent to which flora had changed and link any such changes to potential environmental drivers. We observed significant increases in species richness, both at a whole network level, and when data were analysed within Broad Habitat groupings representing the open uplands, open lowlands and woodlands. We also found comparable increases in an indicator of vegetation response to soil pH, Ellenberg R. Species characteristic of less acid soils tended to show more consistent increases in frequency across sites relative to species with a known tolerance for strongly acidic soils. These changes are, therefore, broadly consistent with a response to increases in soil solution pH observed for the majority of ECN sites that, in turn, are likely to be driven by large reductions in acid deposition in recent decades. Increases in species richness in certain habitat groupings could also be linked to increased soil moisture availability in drier lowland sites that are likely to have been influenced by a trend towards wetter summers in recent years, and possibly also to a reduction in soil nitrogen availability in some upland locations. Changes in site management are also likely to have influenced trends at certain sites, particularly with respect to agricultural practices. Our results are therefore indicative of widescale responses to major regional-scale changes in air pollution and recent weather patterns, modified by local management effects. The relative consistency of management of ECN sites over time is atypical of much of the wider countryside and it is therefore not appropriate to scale up these observations to infer national scale trends. Nevertheless the results provide an important insight into processes that may be operating nationally. It will now be necessary to test for the ubiquity of these changes using appropriate broader spatial scale survey data.     

Normal human adipose tissue functions and differentiation in patients with biallelic LPIN1 inactivating mutations

Lipin-1 is a Mg²⁺-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation. Mice carrying inactivating mutations in the Lpin1 gene display the characteristic features of human familial lipodystrophy. Very little is known about the roles of lipin-1 in human adipocyte physiology. Apparently, fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. In this study, we performed a systematic histopathological, biochemical, and gene expression analysis of adipose tissue biopsies from human patients harboring LPIN1 biallelic inactivating mutations and affected by recurrent episodes of severe rhabdomyolysis. We also explored the adipogenic differentiation potential of human mesenchymal cell populations derived from lipin-1 defective patients. White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal qualitative composition of storage lipids. The increased expression of key adipogenic determinants such as SREBP1, PPARG, and PGC1A shows that specific compensatory phenomena can be activated in vivo in human adipocytes with deficiency of functional lipin-1.     

SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway

Gastric cancer is a major cause of mortality worldwide. The glutamate/aspartate transporter SLC1A3 has been implicated in tumour metabolism and progression, but the roles of SLC1A3 in gastric cancer remain unclear. We used bioinformatics approaches to analyse the expression of SLC1A3 and its role in gastric cancer. The expression levels of SLC1A3 were examined using RT‐qPCR and Western bolting. SLC1A3 overexpressing and knock‐down cell lines were constructed, and the cell viability was evaluated. Glucose consumption, lactate excretion and ATP levels were determined. The roles of SLC1A3 in tumour growth were evaluated using a xenograft tumour growth model. SLC1A3 was found to be overexpressed in gastric cancer, and this overexpression was associated with poor prognosis. In vitro and in vivo assays showed that SLC1A3 affected glucose metabolism and promoted gastric cancer growth. GSEA analysis suggested that SLC1A3 was positively associated with the up‐regulation of the PI3K/AKT pathway. SLC1A3 overexpression activated the PI3K/AKT pathway and up‐regulated GLUT1, HK II and LDHA expression. The PI3K/AKT inhibitor LY294002 prevented SLC1A3‐induced glucose metabolism and cell proliferation. Our findings indicate that SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. SLC1A3 is therefore a potential therapeutic target in gastric cancer.     

Porphyrogenic effects and induction of heme oxygenase in vivo by δ-aminolevulinic acid

The effects of single large doses of the porphyrin-heme precursor ?d-aminolevulinic acid on tissue porphyrins and on δ-aminolevulinate synthase and heme oxygenase, the rate-living enzymes of liver heme synthesis and degradation respectively, were studied in the chick embryo in ovo, in the mouse and in the rat. δ-Aminolevulinic acid treatment produced a distinctive pattern characterized by extensive tissue porphyrin accumulation and alterations in these rate-limiting enzymes in the liver. Repression of basal or allylisopropylacetamide-induced liver δ-aminolevulinate synthase was observed and, in the mouse and the rat, induction of liver heme oxygenase after δ-aminolevulinic acid treatment, in a manner similar to the known effects of hemin on these enzymes. In the chick embryo liver in ovo heme oxygenase was substantially higher than in rat and mouse liver, and was not significantly induced by δ-aminolevulinic acid or other compounds, including hemin, CS₂ and CoCl₂. Levulinic acid, an analogue of δ-aminolevulinic acid, did not induce heme oxygenase in mouse liver. δ-Aminolevunilic acid treatment did not impair ferrochelatase activity but was associated with slight and variable decreases in liver cytochrome P-450. Treatment of chick embryos with a small ‘priming’ dose of 1,4-dihydro-3,5-dicarbethoxycollidine, which impairs liver ferrochelatase activity, accentuated porphyrin accumulation after δ-aminolevulinic acid in the liver. These observations indicate that exogenous δ-aminolevulinic acid is metabolized to porphyrins in a number of tissues and, at least in the liver, to a physiologically significant amount of heme, thereby producing an increase in the size of one or more of the heme pools that regulate both heme systhesis and degradation. It is also possible than when δ-aminolevulinic acid is markedly overproduced in vivo it may be transported to many tissues and re-enter the heme pathway and alter porphyrin-heme metabolism in cells and tissues other than those in which its overproduction primarily occurs.     

Utilization of Serine, Leucine, Isoleucine, and Valine byThermoanaerobacter brockiiin the Presence of Thiosulfate orMethanobacteriumsp. as Electron Acceptors

Thermoanaerobacter brockiifermented serine to acetate and ethanol. It oxidized leucine to isovalerate, isoleucine to 2-methylbutyrate, and valine to isobutyrate only in the presence of thiosulfate, or when co-cultured withMethanobacteriumsp. This oxidative deamination was rendered thermodynamically possible by the ability ofT. brockiito reduce thiosulfate to sulfide or the transfer of reducing equivalents to the hydrogenotrophic methanogen. The results suggest thatT. brockiimay be of ecological significance in thermal environments in the turnover of amino acids, especially with thiosulfate or H₂-utilizing methanogens are present.