Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which ...harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.
► Glucose and fatty acids are differentially utilized in molecular subsets of DLBCL ► Mitochondria are predominant in the metabolic signature of BCR-independent DLBCLs ► Fatty acid oxidation and glutathione synthesis are relevant to OxPhos-DLBCL survival ► Fuel utilization pathways define additional levels of heterogeneity in DLBCL
Airway clearance therapy (ACT) is considered an important approach to improve airway clearance in children with cystic fibrosis (CF). Daily ACT administration requires substantial commitments of time ...and energy that complicate ACT and reduce its benefits. It is crucial to establish ACT as a positive routine. Music therapy (MT) is an aspect of integrative strategies to ameliorate the psycho-emotional consequences of chronic diseases, and a MT intervention could help children with CF between the ages of 2 and 17 develop a positive response. The aim of this randomized controlled trial was to evaluate the effects of specifically composed and recorded instrumental music as an adjunct to ACT. We compared the use of specifically composed music (Treated Group, TG), music that the patient liked (Placebo Group, PG), and no music (Control Group, CG) during the usual ACT routine in children with CF aged from 2 to 17. The primary outcomes, i.e., enjoyment and perception of time, were evaluated via validated questionnaires. The secondary outcome, i.e., efficiency, was evaluated in terms of avoided healthcare resources. Enjoyment increased after the use of the specifically composed music (children +0.9 units/parents +1.7 units; p<0.05) compared to enjoyment with no music (0 units) and familiar music (+0.5 units). Perception of time was 11.1 min (±3.9) less than the actual time in the TG (p<0.05), 3.9 min (±4.2) more than the actual time in the PG and unchanged in the CG. The potential cost saving related to respiratory exacerbations was €6,704.87, while the cost increased to €33,524.35 in the CG and to €13,409.74 in the PG. In conclusion, the specifically composed, played and compiled instrumental recorded music is an effective adjunct to ACT to establish a positive response and is an efficient option in terms of avoided costs. Trial registered as ISRCTN11161411. ISRCTN registry (www.isrctn.com).
Leaf senescence is a complex process, which has dramatic consequences on crop yield. In sunflower, gap between potential and actual yields reveals the economic impact of senescence. Indeed, sunflower ...plants are incapable of maintaining their green leaf area over sustained periods. This study characterizes the leaf senescence process in sunflower through a systems biology approach integrating transcriptomic and metabolomic analyses: plants being grown under both glasshouse and field conditions. Our results revealed a correspondence between profile changes detected at the molecular, biochemical and physiological level throughout the progression of leaf senescence measured at different plant developmental stages. Early metabolic changes were detected prior to anthesis and before the onset of the first senescence symptoms, with more pronounced changes observed when physiological and molecular variables were assessed under field conditions. During leaf development, photosynthetic activity and cell growth processes decreased, whereas sucrose, fatty acid, nucleotide and amino acid metabolisms increased. Pathways related to nutrient recycling processes were also up‐regulated. Members of the NAC, AP2‐EREBP, HB, bZIP and MYB transcription factor families showed high expression levels, and their expression level was highly correlated, suggesting their involvement in sunflower senescence. The results of this study thus contribute to the elucidation of the molecular mechanisms involved in the onset and progression of leaf senescence in sunflower leaves as well as to the identification of candidate genes involved in this process.
Summary
Acremonium strictum elicitor subtilisin (AsES) is a 34‐kDa serine‐protease secreted by the strawberry fungal pathogen A. strictum. On AsES perception, a set of defence reactions is induced, ...both locally and systemically, in a wide variety of plant species and against pathogens of alternative lifestyles. However, it is not clear whether AsES proteolytic activity is required for triggering a defence response or if the protein itself acts as an elicitor. To investigate the necessity of the protease activity to activate the defence response, AsES coding sequences of the wild‐type gene and a mutant on the active site (S226A) were cloned and expressed in Escherichia coli. Our data show that pretreatment of Arabidopsis plants with inactive proteins, i.e. inhibited with phenylmethylsulphonyl fluoride (PMSF) and mutant, resulted in an increased systemic resistance to Botrytis cinerea and expression of defence‐related genes in a temporal manner that mimics the effect already reported for the native AsES protein. The data presented in this study indicate that the defence‐eliciting property exhibited by AsES is not associated with its proteolytic activity. Moreover, the enhanced expression of some immune marker genes, seedling growth inhibition and the involvement of the co‐receptor BAK1 observed in plants treated with AsES suggests that AsES is being recognized as a pathogen‐associated molecular pattern by a leucine‐rich repeat receptor. The understanding of the mechanism of action of AsES will contribute to the development of new breeding strategies to confer durable resistance in plants.
Previous studies have consistently shown that caloric restriction (CR) decreases mitochondrial reactive oxygen species (ROS) (mitROS) generation and oxidative damage to mtDNA and mitochondrial ...proteins, and increases maximum longevity, although the mechanisms responsible for this are unknown. We recently found that protein restriction (PR) also produces these changes independent of energy restriction. Various facts link methionine to aging, and methionine restriction (MetR) without energy restriction increases, like CR, maximum longevity. We have thus hypothesized that MetR is responsible for the decrease in mitROS generation and oxidative stress in PR and CR. In this investigation we subjected male rats to exactly the same dietary protocol of MetR that is known to increase their longevity. We have found, for the first time, that MetR profoundly decreases mitROS production, decreases oxidative damage to mtDNA, lowers membrane unsaturation, and decreases all five markers of protein oxidation measured in rat heart and liver mitochondria. The concentration of complexes I and IV also decreases in MetR. The decrease in mitROS generation occurs in complexes I and III in liver and in complex I in heart mitochondria, and is due to an increase in efficiency of the respiratory chain in avoiding electron leak to oxygen. These changes are strikingly similar to those observed in CR and PR, suggesting that the decrease in methionine ingestion is responsible for the decrease in mitochondrial ROS production and oxidative stress, and possibly part of the decrease in aging rate, occurring during caloric restriction.--Sanz, A., Caro, P., Ayala, V., Portero-Otin, M., Pamplona, R., Barja, G. Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins.
Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in ...pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity.
•Anthracnose resistance in strawberry is characterized by early stomatal closure, callose and lignin accumulation.•Resistant strawberry plants accumulated high levels of carbohydrates while ...susceptible plants was characterized by accumulation of amino acids and their derivatives.•Activation of JA/ET pathways, and the up-regulation of defence-related genes help to effectively cope with C. acutatum infection.
Strawberry (Fragaria x ananassa Duch.) production is an important economic activity in Argentina. Anthracnose, caused by Colletotrichum spp., is the most destructive fungal disease for strawberry and causes a huge economic loss every year. The gene-regulatory networks and metabolic pathways involved in the interaction between Fragaria ananassa and Colletotrichum acutatum are poorly understood. Sixteen strawberry cultivars were characterized in a local strain, M11, of C. acutatum, and the results showed that the Camarosa and Pajaro cultivars were the most tolerant and susceptible, respectively. Metabolic, biochemical and molecular analyses were used to study pathogen and strawberry interaction. The results showed that (1) after being infected by the pathogen, the Camarosa cultivar showed early induction of stomatal closure, callose and lignin accumulation; (2) the metabolic profile of the Camarosa cv. infected by C. acutatum showed high levels of carbohydrate accumulation, while the Pajaro cv. was characterized by accumulation of amino acids and their derivatives; (3) the expression of defence-related genes was induced earlier in the Camarosa cv. The above results demonstrated that an early and complex network of defence responses is triggered in the tolerant cultivar (Camarosa cv.), when infected by C. acutatum. Altogether, these results led us to expand the boundaries of knowledge of the metabolic pathways and gene-regulatory networks involved in the interaction between strawberry and Colletotrichum acutatum.
SUMMARY
An important aspect of plant–virus interaction is the way viruses dynamically move over long distances and how plant immunity modulates viral systemic movement. Salicylic acid (SA), a ...well‐characterized hormone responsible for immune responses against virus, is activated through different transcription factors including TGA and WRKY. In tobamoviruses, evidence suggests that capsid protein (CP) is required for long‐distance movement, although its precise role has not been fully characterized yet. Previously, we showed that the CP of Tobacco Mosaic Virus (TMV)‐Cg negatively modulates the SA‐mediated defense. In this study, we analyzed the impact of SA‐defense mechanism on the long‐distance transport of a truncated version of TMV (TMV ∆CP virus) that cannot move to systemic tissues. The study showed that the negative modulation of NPR1 and TGA10 factors allows the long‐distance transport of TMV ∆CP virus. Moreover, we observed that the stabilization of DELLA proteins promotes TMV ∆CP systemic movement. We also characterized a group of genes, part of a network modulated by CP, involved in TMV ∆CP long‐distance transport. Altogether, our results indicate that CP‐mediated downregulation of SA signaling pathway is required for the virus systemic movement, and this role of CP may be linked to its ability to stabilize DELLA proteins.
Significance Statement
Tobacco mosaic virus capsid protein interferes with the immune system of plants, and this negative modulation allows the virus to move systemically. Specific signaling players (DELLA, NPR1 and TGA10) are involved in the regulation of tobacco mosaic virus systemic movement, indicating that this process is highly regulated.
Previous studies have shown that caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat organs, which can be linked to the slowing of aging rate induced ...by this regime. These two characteristics are also typical of long-lived animals. However, it has never been investigated if those decreases are linked to the decrease in the intake of calories themselves or to decreases in specific dietary components. In this study the possible role of the dietary protein was investigated. Using semipurified diets, the ingestion of proteins of Wistar rats was decreased by 40% below that of controls while the other dietary components were ingested at the same level as in animals fed ad libitum. After seven weeks in this regime the liver of the protein restricted animals showed 30-40% decreases in mitochondrial production of reactive oxygen species (ROS) and in oxidative damage to nuclear and mitochondrial DNA. The decreases in ROS generation occurred specifically at complex I. They also occurred without changes in mitochondrial oxygen consumption. Instead, there was a decrease in the percent free radical leak (the percentage of total electron flow leading to ROS generation in the respiratory chain). These results are strikingly similar to those previously obtained after 40% caloric restriction in the liver of Wistar rats. Thus, the results suggest that part of the decrease in aging rate induced by caloric restriction can be due to the decreased intake of proteins acting through decreases in mitochondrial ROS production and oxidative DNA damage. Interestingly, these tissue oxidative stress-linked parameters can be lowered by restricting only the intake of dietary protein, probably a more feasible option than caloric restriction for adult humans.
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