Gerometabolites: The pseudohypoxic aging side of cancer oncometabolites

Oncometabolites are defined as small-molecule components (or enantiomers) of normal metabolism whose accumulation causes signaling dysregulation to establish a milieu that initiates carcinogenesis. In a similar manner, we propose the term “gerometabolites” to refer to small-molecule components of normal metabolism whose depletion causes signaling dysregulation to establish a milieu that drives aging. In an investigation of the pathogenic activities of the currently recognized oncometabolites R(-)-2-hydroxyglutarate (2-HG), fumarate, and succinate, which accumulate due to mutations in isocitrate dehydrogenases (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), respectively, we illustrate the fact that metabolic pseudohypoxia, the accumulation of hypoxia-inducible factor (HIFα) under normoxic conditions, and the subsequent Warburg-like reprogramming that shifts glucose metabolism from the oxidative pathway to aerobic glycolysis are the same mechanisms through which the decline of the “gerometabolite” nicotinamide adenine dinucleotide (NAD)⁺ reversibly disrupts nuclear–mitochondrial communication and contributes to the decline in mitochondrial function with age. From an evolutionary perspective, it is reasonable to view NAD⁺-driven mitochondrial homeostasis as a conserved response to changes in energy supplies and oxygen levels. Similarly, the natural ability of 2-HG to significantly alter epigenetics might reflect an evolutionarily ancient role of certain metabolites to signal for elevated glutamine/glutamate metabolism and/or oxygen deficiency. However, when chronically altered, these responses become conserved causes of aging and cancer. Because HIFα-driven pseudohypoxia might drive the overproduction of 2-HG, the intriguing possibility exists that the decline of gerometabolites such as NAD⁺ could promote the chronic accumulation of oncometabolites in normal cells during aging. If the sole activation of a Warburg-like metabolic reprogramming in normal tissues might be able to significantly increase the endogenous production of bona fide etiological determinants in cancer, such as oncometabolites, this undesirable trade-off between mitochondrial dysfunction and activation of oncometabolites production might then pave the way for the epigenetic initiation of carcinogenesis in a strictly metabolic-dependent manner. Perhaps it is time to definitely adopt the view that aging and aging diseases including cancer are governed by a pivotal regulatory role of metabolic reprogramming in cell fate decisions.     

A select panel of polymorphic microsatellite loci for individual identification of snow leopards (Panthera uncia)

Snow leopards (Panthera uncia) are elusive endangered carnivores found in remote mountain regions of Central Asia. New methods for identifying and counting snow leopards are needed for conservation and management efforts. To develop molecular genetic tools for individual identification of hair and faecal samples, we screened 50 microsatellite loci developed for the domestic cat (Felis catus) in 19 captive snow leopards. Forty‐eight loci were polymorphic with numbers of alleles per locus ranging from two to 11. The probability of observing matching genotypes for unrelated individuals (2.1 × 10^?11) and siblings (7.5 × 10^?5) using the 10 most polymorphic loci was low, suggesting that this panel would easily discriminate among individuals in the wild.     

Genetic structure of Eurasian badgers Meles meles (Carnivora: Mustelidae) and the colonization history of Ireland

The present study examined the contemporary genetic composition of the Eurasian badger, Meles meles, in Ireland, Britain and Western Europe, using six nuclear microsatellite loci and a 215‐bp fragment of the mitochondrial DNA control region. Significant population structure was evident within Europe (global multilocus microsatellite F_ST = 0.205, P < 0.001; global mitochondrial control region Φ_ST = 0.399, P < 0.001). Microsatellite‐based cluster analyses detected one population in Ireland, whereas badgers from Britain could be subdivided into several populations. Excluding the island populations of Ireland and Britain, badgers from Western Europe showed further structuring, with evidence of discrete Scandinavian, Central European, and Spanish populations. Mitochondrial DNA cluster analysis grouped the Irish population with Scandinavia and Spain, whereas the majority of British haplotypes grouped with those from Central Europe. The findings of the present study suggest that British and Irish badger populations colonized from different refugial areas, or that there were different waves of colonization from the source population. There are indications for the presence of an Atlantic fringe element, which has been seen in other Irish species. We discuss the results in light of the controversy about natural versus human‐mediated introductions. © 2012 The Linnean Society of London, Biological Journal of the Linnean Society, 2012, ?? , ??–??.     

Extensive expression regulation and lack of heterologous enzymatic activity of the Class II trehalose metabolism proteins from Arabidopsis thaliana

Trehalose metabolism has profound effects on plant growth and metabolism, but the mechanisms involved are unclear. In Arabidopsis , 21 putative trehalose biosynthesis genes are classified in three subfamilies based on their similarity with yeast TPS1 (encoding a trehalose-6-phosphate synthase, TPS) or TPS2 (encoding a trehalose-6-phosphate phosphatase, TPP). Although TPS1 (Class I) and TPPA and TPPB (Class III) proteins have established TPS and TPP activity, respectively, the function of the Class II proteins (AtTPS5-AtTPS11) remains elusive. A complete set of promoter- β -glucurinidase/green fluorescent protein reporters demonstrates their remarkably differential tissue-specific expression and responsiveness to carbon availability and hormones. Heterologous expression in yeast furthermore suggests that none of the encoded enzymes displays significant TPS or TPP activity, consistent with a regulatory rather than metabolic function for this remarkable class of proteins.     

Influence of simulated climate change and eutrophication on three‐spined stickleback populations: a large scale mesocosm experiment

1. Shallow lakes and their ectothermic inhabitants are particularly vulnerable to the effects of climatic warming. These impacts are likely to depend on nutrient loading, especially if the combination of warming and eutrophication leads to severe hypoxia. 2. To investigate effects of realistic warming and nutrient loading on a fish species with high tolerance of warming and hypoxia, we observed population changes and timing of reproduction of three‐spined sticklebacks in 24 outdoor shallow freshwater ecosystems with combinations of temperature (ambient and ambient +4 °C) and three nutrient treatments over 16 months. 3. Warming reduced stickleback population biomass by 60% (population size by 76%) and nutrient‐addition reduced biomass by about 80% (population size 95%). Nutrients and warming together resulted in extinction of the stickleback populations. These losses were mainly attributed to the increased likelihood of severe hypoxia in heated and nutrient‐addition mesocosms. 4. Warming of nutrient‐rich waters can thus have dire consequences for freshwater ectotherm populations. The loss even of a hardy fish suggests a precarious future for many less tolerant species in such eutrophic systems under current climate change predictions.     

Detectability of American Mink Using Rafts to Solicit Field Signs in a Population Control Context

Abstract: American mink (Neovison vison) are an ecologically damaging invasive species where they have been introduced in Europe. Effectiveness of mink population control by trapping has been difficult to assess, without knowing how efficiently mink are caught by traps or detected by other methods. Use of track-recording rafts to detect mink and guide trapping effort has proved efficient and leads to a supposition that no detection indicates absence of mink. To draw this conclusion with any confidence requires a measure of detectability. We applied occupancy models to data from an earlier study to estimate detectability of individual American mink on track-recording rafts. Estimated detectability of individual mink, per raft, and 2-week check period varied between 0.4 in late summer and 0.6 in late autumn. By inference, risk of failing to detect a mink that was present would be <5% given 4–6 independent opportunities to detect it. These opportunities could be created either by using a raft spacing that ensured multiple detections of each mink or by monitoring rafts through a succession of check intervals. Within certain simple constraints, raft location did not contribute substantially to detection probability. These findings will allow field operators, strategists, and funders to assess with confidence the success of efforts to control mink density. We expect the estimation of individual detectability to be similarly valuable in population control or eradication of other species.     

Phylogenetic diversity of Sri Lankan freshwater crabs and its implications for conservation

As part of a Global Biodiversity Hotspot, the conservation of Sri Lanka's endemic biodiversity warrants special attention. With 51 species (50 of them endemic) occurring in the island, the biodiversity of freshwater crabs is unusually high for such a small area (65 600 km²). Freshwater crabs have successfully colonized most moist habitats and all climatic and elevational zones in Sri Lanka. We assessed the biodiversity of these crabs in relation to the different elevational zones (lowland, upland and highland) based on both species richness and phylogenetic diversity. Three different lineages appear to have radiated simultaneously, each within a specific elevational zone, with little interchange thereafter. The lowland and upland zones show a higher species richness than the highland zone while – unexpectedly – phylogenetic diversity is highest in the lowland zone, illustrating the importance of considering both these measures in conservation planning. The diversity indices for the species in the various IUCN Red List categories in each of the three zones suggest that risk of extinction may be related to elevational zone. Our results also show that overall more than 50% of Sri Lanka's freshwater crab species (including several as yet undescribed ones), or approximately 72 million years of evolutionary history, are threatened with extinction.     

Impacts of ozone on Plantago major: apoplastic and symplastic antioxidant status

The aim of this work was to examine the correspondence between apoplastic/symplastic antioxidant status and previously reported plant age-related shifts in the ozone (O₃) resistance of Plantago major L. Seed-grown plants were fumigated in duplicate controlled environment chambers with charcoal/Purafil®-filtered air (CFA) or CFA plus 70 nmol mol⁻¹ O₃ for 7 h d⁻¹ over a 42 d period. Measurements of stomatal conductance and antioxidants were made after 14, 28 and 42 d fumigation, on leaves at an equivalent stage of development (youngest fully expanded leaf, measured c . 9 d after emergence). Ozone exposure resulted in a similar decline in stomatal conductance across plant ages, indicating that increases in O₃ resistance with plant age were mediated through changes in the tolerance of leaf tissue rather than enhanced pollutant exclusion. Leaf apoplastic washing fluid was found to contain 'unspecific' peroxidase, ascorbate peroxidase, superoxide dismutase and ascorbate, but not glutathione and the enzymes required to facilitate the regeneration of ascorbate from its oxidized forms. A weak induction in the activity of certain symplastic antioxidants was found after 14 d O₃ fumigation, despite a lack of visible symptoms of injury, but shifts in symplastic antioxidant enzyme activity were not consistent with previously observed increases in resistance to O₃ with plant age. By contrast, changes in 'unspecific' peroxidase activity and in the small pool of ascorbate in the leaf apoplast were found to accompany age-related shifts in O₃ resistance. It is concluded that constituents of the leaf apoplast may constitute a potentially important front line defence against O₃.     

Evaluation of Turtle Exclusion and Escapement Devices for Hoop-Nets

Abstract Baited and unbaited hoop-nets commonly are used to capture catfish in lotic and lentic systems. Turtle bycatch and post-capture mortality has been problematic during catfish surveys in Missouri, USA, most recently in the Gasconade River, Gasconade and Osage counties. We evaluated 3 modified hoop-net designs that would reduce turtle bycatch without reducing catfish capture in the Gasconade River during 15 May-15 July 2006 after pilot study evaluation of 5 hoop-net designs in April 2006. We deployed modified and control-nets in blocks for 48 hours to evaluate differences in turtle and catfish catch rate, as well as abundance, size, and mortality rate of turtle bycatch. The chimney design reduced turtle bycatch by 84% when compared to the control, without decreasing the number or average size of captured flathead catfish (Pylodictis olivaris). Environmental conditions that affected turtle mortality included Secchi disc transparency, temperature, dissolved oxygen, and stream river depth. This is the first known attempt to create turtle exclusion or escapement devices for hoop-nets deployed in freshwater systems. Biologists using hoop-nets to sample aquatic vertebrates in moderate to large river systems will benefit from our study. The application of this methodology will reduce turtle bycatch mortality, especially when sampling is conducted in high water temperatures.