Aspects of plant behaviour under anoxia and post-anoxia

All plants are able to survive anoxic periods, but the degree of tolerance shows large variation. The main injuries related to anoxia are eventually due to changes in energy metabolism. Low energy charge values indicate a cessation of many ATP consuming processes. Sugar starvation, lactic acid fermentation and proton release from leaky vacuoles are responsible for cell death. Long-term anoxia tolerance is dependent on storage products in the vicinity of sinks, on an adequate control of glycolysis, synthesis of essential proteins, and stability of membranes and organelles. However, no fundamental differences between the metabolic pathways of tolerant and non-tolerant tissues are known. It is rather a question of minor changes and the regulation of anaerobic metabolism. Re-exposure of anoxic tissues to air may even be more detrimental than anoxia itself. These injuries are mainly due to enhanced radical generation. Lipid peroxidation processes lead to membrane damage, disintegration, and leakage of solutes. Under natural conditions plants are equipped with radical-detoxifying systems (SOD, peroxidases and antioxidants). Natural detoxifying systems can be reduced in non-adapted plants under anoxia and they become more sensitive to post-anoxic damage. In addition, the rapid conversion of ethanol to extremely toxic acetaldehyde seems to be a cause of tissue injury and deat

Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Aspects of plant behaviour under anoxia and post-anoxia

All plants are able to survive anoxic periods, but the degree of tolerance shows large variation. The main injuries related to anoxia are eventually due to changes in energy metabolism. Low energy charge values indicate a cessation of many ATP consuming processes. Sugar starvation, lactic acid fermentation and proton release from leaky vacuoles are responsible for cell death. Long-term anoxia tolerance is dependent on storage products in the vicinity of sinks, on an adequate control of glycolysis, synthesis of essential proteins, and stability of membranes and organelles. However, no fundamental differences between the metabolic pathways of tolerant and non-tolerant tissues are known. It is rather a question of minor changes and the regulation of anaerobic metabolism. Re-exposure of anoxic tissues to air may even be more detrimental than anoxia itself. These injuries are mainly due to enhanced radical generation. Lipid peroxidation processes lead to membrane damage, disintegration, and leakage of solutes. Under natural conditions plants are equipped with radical-detoxifying systems (SOD, peroxidases and antioxidants). Natural detoxifying systems can be reduced in non-adapted plants under anoxia and they become more sensitive to post-anoxic damage. In addition, the rapid conversion of ethanol to extremely toxic acetaldehyde seems to be a cause of tissue injury and death

Anoxia tolerance in tobacco roots: effect of overexpression of pyruvate decarboxylase

Plant survival during flooding relies on ethanolic fermentation for energy production. The available literature indicates that the first enzyme of the ethanolic fermentation pathway, pyruvate decarboxylase (PDC), is expressed at very low levels and is likely to be rate-limiting during oxygen deprivation. The authors expressed high levels of bacterial PDC in tobacco to study the modulation of PDC activity in vivo, and assess its impact on the physiology of ethanolic fermentation and survival under oxygen stress. In contrast to leaves, wild-type normoxic roots contained considerable PDC activity, and overexpression of the bacterial PDC caused only a moderate increase in acetaldehyde and ethanol production under anoxia compared to wild-type roots. No significant lactate production could be measured at any time, making it unlikely that lactate-induced acidification (LDH/PDC pH-stat) triggers the onset of ethanol synthesis. Instead, the authors favour a model in which the flux through the pathway is regulated by substrate availability. The increased ethanolic flux in the transgenics compared to the wild-type did not enhance anoxia tolerance. On the contrary, rapid utilisation of carbohydrate reserves enhanced premature cell death in the transgenics while replenishment of carbohydrates improved survival under anoxia