Structure‐based design, synthesis and biological evaluation of bis‐tetrahydropyran furan acetogenin mimics targeting the trypanosomatid F1 component of ATP synthase

This work was funded by the Leverhulme Trust (G.J.F.), Wellcome Trust ISSF support (G.J.F./T.K.S.) and the European Community’s Seventh Framework Programme under grant agreement No. 602773 [Project KINDRED] (T.K.S.).The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the T. brucei FoF1‐ATP synthase as a target of our earlier triazole analogue series. Using computational docking studies we hypothesized that the central triazole heterocyclic spacer could be substituted for a central 2,5‐substituted furan moiety, thus diversifying the chemical framework for the generation of compounds with greater potency and/or selectivity. Here we report the design, docking, synthesis and biological evaluation of new series of trypanocidal compounds and demonstrate their on‐target inhibitory effects. Furthermore, the synthesis of furans by the modular coupling of alkyne‐ and aldehyde‐THPs to bis‐THP 1,4‐alkyne diols followed by ruthenium/xantphos‐catalysed heterocyclisation described here represents the most complex use of this method of heterocyclisation to date.Publisher PDFPeer reviewe

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.Peer reviewe

Elucidating the mechanism of action of copper heptagluconate on the plant immune system against Pseudomonas syringae in tomato (Solanum lycopersicum L)

BACKGROUND: Phytopathogenic problems caused by the bacterial pathogenPseudomonas syringaein tomato are becomingmore serious due to the emergence of strains resistant to classical pesticides. This has led to research into new formulationswith lower environmental problems. One of the most promising alternatives to the use of classical pesticides is the inductionof natural plant defences. New formulations based on Cu complexed with heptagluconic acid induce plant innate defencesand could be an alternative to classical treatments based on inorganic Cu against bacterial speck. To study the efficacy of thiscompound in tomato againstP. syringae, we tested its systemic effect Applying the treatments via radicular.RESULTS: Treated plants showed less infection development and lower number of viable bacteria in leaves. We also observedbetter performance of parameters involved in plant resistance such as the antioxidant response and the accumulation ofphenolic compounds.CONCLUSION: Results showed that soil drench applications can be highly effective for the prevention and control of bacterialspeck in tomato plants, showing a reduction in symptoms of∼50%. Moreover, application of Cu heptagluconate inducedaccumulation of the plant polyphenols caffeic and chlorogenic acids, and reduced the amount of reactive oxygen species ininfected plants

Interaction Between Convection and Pulsation

This article reviews our current understanding of modelling convection dynamics in stars. Several semi-analytical time-dependent convection models have been proposed for pulsating one-dimensional stellar structures with different formulations for how the convective turbulent velocity field couples with the global stellar oscillations. In this review we put emphasis on two, widely used, time-dependent convection formulations for estimating pulsation properties in one-dimensional stellar models. Applications to pulsating stars are presented with results for oscillation properties, such as the effects of convection dynamics on the oscillation frequencies, or the stability of pulsation modes, in classical pulsators and in stars supporting solar-type oscillations.Comment: Invited review article for Living Reviews in Solar Physics. 88 pages, 14 figure

Jerarca: Efficient Analysis of Complex Networks Using Hierarchical Clustering

Background: How to extract useful information from complex biological networks is a major goal in many fields, especially in genomics and proteomics. We have shown in several works that iterative hierarchical clustering, as implemented in the UVCluster program, is a powerful tool to analyze many of those networks. However, the amount of computation time required to perform UVCluster analyses imposed significant limitations to its use. Methodology/Principal Findings: We describe the suite Jerarca, designed to efficiently convert networks of interacting units into dendrograms by means of iterative hierarchical clustering. Jerarca is divided into three main sections. First, weighted distances among units are computed using up to three different approaches: a more efficient version of UVCluster and two new, related algorithms called RCluster and SCluster. Second, Jerarca builds dendrograms based on those distances, using well-known phylogenetic algorithms, such as UPGMA or Neighbor-Joining. Finally, Jerarca provides optimal partitions of the trees using statistical criteria based on the distribution of intra- and intercluster connections. Outputs compatible with the phylogenetic software MEGA and the Cytoscape package are generated, allowing the results to be easily visualized. Conclusions/Significance: The four main advantages of Jerarca in respect to UVCluster are: 1) Improved speed of a novel UVCluster algorithm; 2) Additional, alternative strategies to perform iterative hierarchical clustering; 3) Automatic evaluatio

Virtual histological assessment of the prenatal life history and age at death of the Upper Paleolithic fetus from Ostuni (Italy)

The fetal remains from the Ostuni 1 burial (Italy, ca 27 ka) represent a unique opportunity to explore the prenatal biological parameters, and to reconstruct the possible patho-biography, of a fetus (and its mother) in an Upper Paleolithic context. Phase-contrast synchrotron X-ray microtomography imaging of two deciduous tooth crowns and microfocus CT measurements of the right hemimandible of the Ostuni 1b fetus were performed at the SYRMEP beamline and at the TomoLab station of the Elettra - Sincrotrone laboratory (Trieste, Italy) in order to refne age at death and to report the enamel developmental history and dental tissue volumes for this fetal individual. The virtual histology allowed to estimate the age at death of the fetus at 31–33 gestational weeks. Three severe physiological stress episodes were also identifed in the prenatal enamel. These stress episodes occurred during the last two months and half of pregnancy and may relate to the death of both individuals. Compared with modern prenatal standards, Os1b’s skeletal development was advanced. This cautions against the use of modern skeletal and dental references for archaeological fnds and emphasizes the need for more studies on prenatal archaeological skeletal samples