Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

Acute myeloid leukaemia (AML) comprises a heterogeneous group of hematologic neoplasms characterized by diverse combinations of genetic, phenotypic and clinical features representing a major challenge for the development of targeted therapies. Metabolic reprogramming, mainly driven by deregulation of the nutrient‐sensing pathways as AMPK, mTOR and PI3K/AKT, has been associated with cancer cells, including AML cells, survival and proliferation. Nevertheless, the role of these metabolic adaptations on the AML pathogenesis is still controversial. In this work, the metabolic status and the respective metabolic networks operating in different AML cells (NB‐4, HL‐60 and KG‐1) and their impact on autophagy and survival was characterized. Data show that whereas KG‐1 cells exhibited preferential mitochondrial oxidative phosphorylation metabolism with constitutive co‐activation of AMPK and mTORC1 associated with increased autophagy, NB‐4 and HL‐60 cells displayed a dependent glycolytic profile mainly associated with AKT/mTORC1 activation and low autophagy flux. Inhibition of AKT is disclosed as a promising therapeutical target in some scenarios while inhibition of AMPK and mTORC1 has no major impact on KG‐1 cells’ survival. The results highlight an exclusive metabolic profile for each tested AML cells and its impact on determination of the anti‐leukaemia efficacy and on personalized combinatory therapy with conventional and targeted agents.     

Genetic rescue in a plant polyploid complex: Case study on the importance of genetic and trait data for conservation management

Knowledge of the biology of rare plant species is indispensable to aid their survival and to inform efficient conservation actions, but in many cases relevant data are lacking. In addition, while studies of conservation genetics have provided a wealth of information on the considerations arising from inbreeding, mate limitation, or local adaptation, the impact of intraspecific polyploidy remains understudied. In this study, we examined the breeding system of the rare Australian daisy Rutidosis lanata (Asteraceae) and screened ten of its populations for their ploidy level to develop recommendations for management actions, in particular, with regard to seed sourcing and genetic rescue. We found R. lanata to represent a polyploid complex, with tetraploid, pentaploid and hexaploid individuals coexisting in the same species. Crossing experiments confirmed R. lanata to be self‐incompatible. Mate availability varied from c. 49% to c. 76% across populations. Most populations showed mate availability of c. 50%–70%, suggesting that mate limitation resulting from a lack of local genetic diversity may cause or at least contribute to reduced seed set. Crossing between populations resulted in significantly higher reproductive success for all populations except one, suggesting the possibility of genetic rescue through population mixing. However, the crossing experiments also showed that pentaploids suffer from a severely reduced paternal reproductive fitness. Any additional hybrids between tetraploids and pentaploids, as would be created by mixing populations with different genome copy numbers during conservation work, would consequently exacerbate mate limitation and thus reduce population viability. We conclude that seed set and thus population viability can be maximized by mixing populations with the same number of genome copies, but that populations with different numbers should be kept spatially separated. The case of Rutidosis lanata provides an example and a potential template for examining the conservation genetics of other species that may constitute polyploid complexes.     

Analysis of the transformation effect in cytochrome b559 of photosystem II in terms of the model of the heme-quinone redox interaction

Transformation of three-component redox pattern of cytochrome (Cyt) b559 in PS II membrane fragments upon various treatments is manifested in decrease of the relative content (R) of the high potential (HP) redox form of Cyt b559 and concomitant increase in the fractions of the two lower potential forms. Redox titration of Cyt b559 in different types of PS II membrane preparations was performed and revealed that (1) alteration of redox titration curve of Cyt b559 upon treatment of a sample is not specific to the type of treatment; (2) each value of R_HP defines the individual shape of the redox titration curve; (3) population of Cyt b559 may exist in several stable forms with multicomponent redox pattern: three types of three-component redox pattern and one type of two-component redox pattern as well as in the form with a single E_m; (4) transformation of Cyt b559 proceeds as successive conversion between the stable forms with multicomponent redox pattern; (5) upon harsh treatments, Cyt b559 abruptly converts into the state with a single E_m which value is intermediate between the E_m values of the two lower potential forms. Analysis of the data using the model of Cyt b559-quinone redox interaction revealed that diminution of R_HP in a range from 80 to 10% reflects a shift in redox equilibrium between the heme group of Cyt b559 and the interacting quinone, due to a gradual decrease of 90?mV in E_m of the heme group at the virtually unchanged E_m of the quinone component.     

Life at extreme elevations on Atacama volcanoes: the closest thing to Mars on Earth?

Here we describe recent breakthroughs in our understanding of microbial life in dry volcanic tephra (“soil”) that covers much of the surface area of the highest elevation volcanoes on Earth. Dry tephra above 6000 m.a.s.l. is perhaps the best Earth analog for the surface of Mars because these “soils” are acidic, extremely oligotrophic, exposed to a thin atmosphere, high UV fluxes, and extreme temperature fluctuations across the freezing point. The simple microbial communities found in these extreme sites have among the lowest alpha diversity of any known earthly ecosystem and contain bacteria and eukaryotes that are uniquely adapted to these extreme conditions. The most abundant eukaryotic organism across the highest elevation sites is a Naganishia species that is metabolically versatile, can withstand high levels of UV radiation and can grow at sub-zero temperatures, and during extreme diurnal freeze–thaw cycles (e.g. ??10 to +?30 °C). The most abundant bacterial phylotype at the highest dry sites sampled (6330 m.a.s.l. on Volcán Llullaillaco) belongs to the enigmatic B12-WMSP1 clade which is related to the Ktedonobacter/Thermosporothrix clade that includes versatile organisms with the largest known bacterial genomes. Close relatives of B12-WMSP1 are also found in fumarolic soils on Volcán Socompa and in oligotrophic, fumarolic caves on Mt. Erebus in Antarctica. In contrast to the extremely low diversity of dry tephra, fumaroles found at over 6000 m.a.s.l. on Volcán Socompa support very diverse microbial communities with alpha diversity levels rivalling those of low elevation temperate soils. Overall, the high-elevation biome of the Atacama region provides perhaps the best “natural experiment” in which to study microbial life in both its most extreme setting (dry tephra) and in one of its least extreme settings (fumarolic soils).     

Models for assessing local‐scale co‐abundance of animal species while accounting for differential detectability and varied responses to the environment

We developed a new modeling framework to assess how the local abundance of one species influences the local abundance of a potential competitor while explicitly accounting for differential responses to environmental conditions. Our models also incorporate imperfect detection as well as abundance estimation error for both species. As a case study, we applied the model to four pairs of mammal species in Borneo, surveyed by extensive and spatially widespread camera trapping. We detected different responses to elevation gradients within civet, macaque, and muntjac deer species pairs. Muntjac and porcupine species varied in their response to terrain ruggedness, and the two muntjac responded different to river proximity. Bornean endemic species of civet and muntjac were more sensitive than their widespread counterparts to habitat disturbance (selective logging). Local abundance within several species pairs was positively correlated, but this is likely due to the species having similar responses to (unmodeled) environmental conditions or resources rather than representing facilitation. After accounting for environment and correcting for false absences in detection, negative correlations in local abundance appear rare in tropical mammals. Direct competition may be weak in these species, possibly because the ‘ghost of competition past’ or habitat filtering have already driven separation of the species in niche space. The analytical framework presented here could increase basic understanding of how ecological interactions shape patterns of abundance across the landscape for a range of taxa, and also provide a powerful tool for forecasting the impacts of global change.     

Synthesis,molecular docking,and biological activity of 2-vinyl chromones: Toward selective butyrylcholinesterase inhibitors for potential Alzheimer's disease therapeutics

We investigated the biological activity of a series of substituted chromeno[3,2-c]pyridines, including compounds previously synthesized by our group and novel compounds whose syntheses are reported here. Tandem transformation of their tetrahydropyridine ring under the action of activated alkynes yielding 2-vinylsubstituted chromones was used to prepare nitrogen-containing derivatives of a biologically active chromone system. The inhibitory activity of these chromone derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) was investigated using the methods of enzyme kinetics and molecular docking. Antioxidant (antiradical) activity of the compounds was assessed in the ABTS assay. The results demonstrated that a subset of the studied chromone derivatives selectively inhibit BChE but do not exhibit antiradical activity. In addition, the results of molecular docking effectively explained the observed features in the efficacy, selectivity, and mechanism of BChE inhibition by the chromone derivatives.