Regulation of the H<Superscript>+</Superscript>-ATP synthase by IF1: a role in mitohormesis

The mitochondrial H⁺-ATP synthase is a primary hub of cellular homeostasis by providing the energy required to sustain cellular activity and regulating the production of signaling molecules that reprogram nuclear activity needed for adaption to changing cues. Herein, we summarize findings regarding the regulation of the activity of the H⁺-ATP synthase by its physiological inhibitor, the ATPase inhibitory factor 1 (IF1) and their functional role in cellular homeostasis. First, we outline the structure and the main molecular mechanisms that regulate the activity of the enzyme. Next, we describe the molecular biology of IF1 and summarize the regulation of IF1 expression and activity as an inhibitor of the H⁺-ATP synthase emphasizing the role of IF1 as a main driver of energy rewiring and cellular signaling in cancer. Findings in transgenic mice in vivo indicate that the overexpression of IF1 is sufficient to reprogram energy metabolism to an enhanced glycolysis and activate reactive oxygen species (ROS)-dependent signaling pathways that promote cell survival. These findings are placed in the context of mitohormesis, a program in which a mild mitochondrial stress triggers adaptive cytoprotective mechanisms that improve lifespan. In this regard, we emphasize the role played by the H⁺-ATP synthase in modulating signaling pathways that activate the mitohormetic response, namely ATP, ROS and target of rapamycin (TOR). Overall, we aim to highlight the relevant role of the H⁺-ATP synthase and of IF1 in cellular physiology and the need of additional studies to decipher their contributions to aging and age-related diseases.     

On the narrative form of simulations

Understanding complex physical systems through the use of simulations often takes on a narrative character. That is, scientists using simulations seek an understanding of processes occurring in time by generating them from a dynamic model, thereby producing something like a historical narrative. This paper focuses on simulations of the Diels-Alder reaction, which is widely used in organic chemistry. It calls on several well-known works on historical narrative to draw out the ways in which use of these simulations mirrors aspects of narrative understanding: Gallie for “followability” and “contingency”; Mink for “synoptic judgment”; Ricoeur for “temporal dialectic”; and Hawthorn for a related dialectic of the “actual and the possible”. Through these reflections on narrative, the paper aims for a better grasp of the role that temporal development sometimes plays in understanding physical processes and of how considerations of possibility enhance that understanding.     

Melatonin transport into mitochondria

Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole’s protective actions. Melatonin’s mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.     

Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins

Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.     

Development and pathologies of the arterial wall

Arteries consist of an inner single layer of endothelial cells surrounded by layers of smooth muscle and an outer adventitia. The majority of vascular developmental studies focus on the construction of endothelial networks through the process of angiogenesis. Although many devastating vascular diseases involve abnormalities in components of the smooth muscle and adventitia (i.e., the vascular wall), the morphogenesis of these layers has received relatively less attention. Here, we briefly review key elements underlying endothelial layer formation and then focus on vascular wall development, specifically on smooth muscle cell origins and differentiation, patterning of the vascular wall, and the role of extracellular matrix and adventitial progenitor cells. Finally, we discuss select human diseases characterized by marked vascular wall abnormalities. We propose that continuing to apply approaches from developmental biology to the study of vascular disease will stimulate important advancements in elucidating disease mechanism and devising novel therapeutic strategies.     

Duncan F. Gregory,William Walton and the development of British algebra: ‘algebraical geometry’, ‘geometrical algebra’, abstraction

This paper provides a detailed account of the period of the complex history of British algebra and geometry between the publication of George Peacock's Treatise on Algebra in 1830 and William Rowan Hamilton's paper on quaternions of 1843. During these years, Duncan Farquharson Gregory and William Walton published several contributions on ‘algebraical geometry’ and ‘geometrical algebra’ in the Cambridge Mathematical Journal. These contributions enabled them not only to generalize Peacock's symbolical algebra on the basis of geometrical considerations, but also to initiate the attempts to question the status of Euclidean space as the arbiter of valid geometrical interpretations. At the same time, Gregory and Walton were bound by the limits of symbolical algebra that they themselves made explicit; their work was not and could not be the ‘abstract algebra’ and ‘abstract geometry’ of figures such as Hamilton and Cayley. The central argument of the paper is that an understanding of the contributions to ‘algebraical geometry’ and ‘geometrical algebra’ of the second generation of ‘scientific’ symbolical algebraists is essential for a satisfactory explanation of the radical transition from symbolical to abstract algebra that took place in British mathematics in the 1830s–1840s.     

Butterflies (Lepidoptera: Papilionoidea) of Mount Kilimanjaro: Nymphalidae subfamilies Libytheinae,Danainae, Satyrinae and Charaxinae

This paper, which presents an annotated checklist of the ‘lower Nymphalidae’ (Libytheinae, Danainae, Satyrinae, Charaxinae), is the fourth in a series on the butterfly fauna of Mount Kilimanjaro. Four genera of lower Nymphalidae (Danaus, Amauris, Bicyclus, Charaxes), with a total of 11 included species, are known or believed to occur within the main forest zone, from c. 1800 to 2800 m. Of these, only three species of Charaxes (Charaxes berkeleyi, Charaxes ansorgei, Charaxes xiphares) may be restricted locally to this primary forest. The lower slopes fauna, below 1800 m, is considerably richer, with a total of 11 genera and 41 species listed (8 species of which extend into the forest zone). Possible additional species, dubious earlier records, problems with African subspecies of Danaus chrysippus, a need for more work on certain Satyrinae, and classification of the genus Charaxes are discussed. An identification key to the subfamilies of Nymphalidae, and the 19 genera of Libytheinae, Danainae, Satyrinae, Charaxinae that occur in Tanzania, together with a key to the adults of all the species of these four subfamilies considered to occur or have occurred on Kilimanjaro, with 206 colour images, are included as online Supplementary Information.     

A tale of tails: deciphering the contribution of terminal tails to the biochemical properties of two Dps proteins from Streptomyces coelicolor

Dps proteins are members of an extensive family of proteins that oxidise and deposit iron in the form of ferric oxide, and are also able to bind DNA. Ferroxidation centres are formed at the interface of anti-parallel dimers, which further assemble into dodecameric nanocages with a hollow core where ferric oxide is deposited. Streptomyces coelicolor encodes three Dps-like proteins (DpsA, B and C). Despite sharing the conserved four-helix bundle organisation observed in members of the Dps family, they display significant differences in the length of terminal extensions, or tails. DpsA possess both N- and C-terminal tails of different lengths, and their removal affects quaternary structure assembly to varying degrees. DpsC quaternary structure, on the other hand, is heavily dependent on its N-terminal tail as its removal abolishes correct protein folding. Analysis of the crystal structure of dodecamers from both proteins revealed remarkable differences in the position of tails and interface surface area; and provides insight to explain the differences in biochemical behaviour observed while comparing DpsA and DpsC.     

Feeding ecology of the common sun skink,Eutropis multifasciata (Reptilia: Squamata: Scincidae), in the plains of central Vietnam

We studied the feeding ecology of Eutropis multifasciata in the tropical plains of central Vietnam to understand better the foraging mode, spatiotemporal and sexual variation in dietary composition, and rarefaction curves of prey-taxon richness for males and females. Stomach contents (n = 161) were collected from October 2013 to May 2014 using a nonlethal stomach-flushing technique. A total of 680 food items (624 animal items and 56 plant items) was found in 161 stomachs of skinks, representing 19 unique animal categories. We found that the diet of E. multifasciata is composed mainly of small, sedentary and clumped prey and that this skink specialises on spiders, insect larvae, snails, grasshoppers and crickets (with a combined importance index of 60%). Dietary composition, prey size and total prey volume in E. multifasciata changed between dry and rainy seasons and among regions. The total volume of food items consumed by males was larger than that of females, and the diversity and evenness index of prey categories were larger in males than in females. However, using rarefaction curves revealed that females have the higher prey-taxon richness after points between 130 and 140 prey items for frequency, and between 160 and 170 prey items for number of items, and the differences were not statistically significant. The foraging behaviour of E. multifasciata best fits a ‘widely foraging’ model.