Post‐fire development of faunal habitat depends on plant regeneration traits

The concept that vegetation structure (and faunal habitat) develops predictably with time since fire has been central to understanding the relationship between fire and fauna. However, because plants regenerate after fire in different ways (e.g. resprouting from above‐ground stems vs. underground lignotubers), use of simple categories based on time since fire might not adequately represent post‐fire habitat development in all ecosystems. We tested the hypothesis that the post‐fire development of faunal habitat structure differs between ecosystems, depending on fire regeneration traits of the dominant canopy trees. We measured 12 habitat components at sites in foothill forests (n = 38), heathy woodlands (n = 38) and mallee woodlands (n = 98) in Victoria, Australia, and used generalised additive models to predict changes in each variable with time since fire. A greater percentage of faunal habitat variables responded significantly to time since fire in mallee woodlands, where fires typically are stand‐replacing, than in foothill forests and heathy woodlands, where canopy tree stems generally persist through fire. In the ecosystem with the highest proportion of epicormic resprouters (foothill forests), only ground cover and understorey vegetation responded significantly to time since fire, compared with all but one variable in the ecosystem dominated by basal resprouters (mallee woodlands). These differences between ecosystems in the post‐fire development of key habitat components suggest there may also be fundamental differences in the role of fire in shaping the distribution of fauna. If so, this challenges the way in which many fire‐prone ecosystems currently are categorised and managed, especially the level of dependence on time since fire and other temporal surrogates such as age‐classes and successional states. Where time since fire is a poor surrogate for habitat structural development, additional complexity (e.g. fire severity, topography and prior land‐use history) could better capture processes that determine faunal occurrence in fire‐prone ecosystems.     

PEtab—Interoperable specification of parameter estimation problems in systems biology

Reproducibility and reusability of the results of data-based modeling studies are essential. Yet, there has been—so far—no broadly supported format for the specification of parameter estimation problems in systems biology. Here, we introduce PEtab, a format which facilitates the specification of parameter estimation problems using Systems Biology Markup Language (SBML) models and a set of tab-separated value files describing the observation model and experimental data as well as parameters to be estimated. We already implemented PEtab support into eight well-established model simulation and parameter estimation toolboxes with hundreds of users in total. We provide a Python library for validation and modification of a PEtab problem and currently 20 example parameter estimation problems based on recent studies.     

Sirtuins and ageing—new findings

Sirtuins are a promising avenue for orally administered drugs that might deliver the anti-aging benefits normally provided by calorie restriction.Calorie (or dietary) restriction was first shown to extend rodent lifespan almost 80 years ago, and remains the most robust longevity-promoting intervention in mammals, genetic or dietary. Sirtuins are NAD-dependent deacylases homologous to yeast Sir2p and were first shown to extend replicative lifespan in budding yeast [1]. Because of their NAD requirement, sirtuins were proposed as mediators of the anti-ageing effects of calorie restriction [1]. Indeed, many studies in yeast, Caenorhabditis elegans, Drosophila melanogaster and mice have supported these ideas [2]. However, a 2011 paper posed a challenge: transgenic strains of C. elegans and Drosophila that overexpress SIR2 were found not to be long-lived [3].Rather than review the extensive sirtuin literature previous to that paper, I focus on a few key studies that have followed it, which underscore a conserved role of sirtuins in slowing ageing. In the first study, two highly divergent budding yeast strains—a lab strain and a clinical isolate—were crossed. A genome-wide quantitative trait locus analysis was then performed to map genes that determine differences in replicative lifespan [4]. The top hit was SIR2, explaining more than one-half of the difference in replicative lifespan between the two strains (due to five codon differences between the SIR2 alleles). In Drosophila, overexpression of dSIR2 in the fat body extended the lifespan of flies on the normal diet, whereas deletion of dSIR2 in the fat body abolished the extension of lifespan by a calorie-restriction-like protocol [5]. This example illustrates the key role of dSIR2 in lifespan determination and its central role in mediating dietary effects on longevity, discussed further below. Another study showed that two transgenic mouse lines that overexpress the mammalian SIRT6—mammals have seven sirtuins—had significantly extended lifespans [6]. Finally, a recent study clearly showed that worm sir2.1 could extend lifespan by regulating two distinct longevity pathways involving insulin-like signalling and the mitochondrial unfolded protein response [7]. All told, this body of work supports the original proposal that sirtuins are conserved mediators of longevity.Many other studies also illustrate that sirtuins can mediate the effects of diet. As an example, calorie restriction completely protected against ageing-induced hearing loss in wild type but not SIRT3^−/− mice [8]. The mitochondrial sirtuin SIRT3 thus helps to protect the neurons of the inner ear against oxidative damage during calorie restriction. Of course, these studies do not imply that sirtuins are the only mediators of calorie restriction effects, but they do indicate that they must be central components.Finally, what about the translational potential of this research, namely using putative SIRT1-activating compounds—resveratrol and newer, synthetic STACs? Two new studies provide strong evidence that the effects of these compounds really do occur through SIRT1. First, acute deletion of SIRT1 in adult mice prevented many of the physiological effects of resveratrol and other STACs [9]. Second, a single mutation adjacent to the SIRT1 catalytic domain abolished the ability of STACs to activate the enzyme in vitro, or to promote the canonical physiological changes in vivo [10].In summary, sirtuins seem to represent a promising avenue by which orally available drugs might deliver anti-ageing benefits normally triggered by calorie restriction. Indeed, the biology of sirtuins is complex and diverse, but this is an indication of their deep reach into key disease processes. Connections between sirtuins and cancer metabolism are but one new example of this. The future path of discovery promises to be exciting and might lead to new drugs that maintain robust health.     

Oligonucleotides With Purine Nitrogen-7 as Glycosylation Site

Abstract

The synthesis of phosphoramidites (2 and 3) derived from hypoxanthine and isoguanine N⁷-2¹-deoxyribonucleosides is described. Solid-phase synthesis furnishes oligonucleotides containing N⁷-glycosylated purines. New base pairs between purine N⁷- and N9-nucleosides are proposed.     

Synthesis of Iodoaminoimidazole Arabinoside (IAIA): A Potential Reductive Metabolite of the Spect Imaging Agent,Iodoazomycin Arabinoside (IAZA)

Abstract

The stereospecific synthesis of 1-(5-deoxy-5-iodo-α-D-arabino-furanosyl)-2-aminoimidazole (iodoaminoimidazole arabinoside: IAIA, 2) is described. The reaction of the protected sugar bromide (8) and trifluoroacetamidoimidazole (10B) gave the coupled product (11B), which gave the free nucleoside (4) on deblocking. It was identical with AIA obtained by reduction of AZA (azomycin arabinoside), whose anomeric configuration was found to be a by the X-ray crystallography.     

Synthesis,In Vitro Biological Stability,and Anti-HIV Activity of 5-Halo (or Methoxy)-6-Alkoxy (Azido or Hydroxy)-5,6-Dihydro-2′,3′-Didehydro-3′-Deoxythymidine Diastereomers as Potential Prodrugs of 2′,3′-Didehydro-3′-deoxythymidine (D4T)

Abstract

A new class of 5-halo (or methoxy)-6-alkoxy (azido or hydroxy)-5,6-dihydro-2′,3′-didehydro-3′-deoxythymidines (4–17) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodmgs of 2′,3′-didehydro-3′-deoxythymidine (D4T) were designed to have properties which would enhance their duration of action, lipophilicity and cephalic delivery to the central nervous system. The 5,6-dihydro derivatives of D4T (4–15), which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, OEt, N₃, OH) to the 5,6-olefinic bond of D4T. These 5,6-disubstituted-5,6-dihydro analogs of D4T are more lipophilic (P = 0.70 – 4.0 range) than D4T (P = 0.12) and are stable to E. coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give D4T, upon incubation of the 5-bromo- and 5-iodo-6-methoxy-5,6-dihydro derivatives (6, 7, 10, 11) with glutathione or a mouse liver soluble enzyme fraction, was extensive (50–95%). The most potent anti-HIV-1 agents, 5-iodo-6-methoxy (10, 11), 5-bromo-6-azido (14, 15) and 5-methoxy-6-hydroxy (16, 17) derivatives of D4T, exhibited anti-HIV activities comparable to D4T.

     

Oligonucleotides Containing Pyrazolo[3,4-d]Pyrimidines: 8-Aza-7-deazaadenines With Bulky Substituents in the 2- or 7-Position

The synthesis of the 2′-deoxyadenosine analogues 1b, 2b, and 3c modified at the 7- and/or 2-position is described. The effect of 7-chloro and 2-methylthio groups on the duplex stability is evaluated. For that, the nucleosides 1b, 2b, and 3c were converted to the corresponding phosphoramidites 15, 19, and 22, which were employed in the solid-phase oligonucleotide synthesis. In oligonucleotide duplexes, compound 1b forms stable base pairs with dT, of which the separated 1b- dT base pairs contribute stronger than that of the consecutive base pairs. Compound 2b shows universal base pairing properties while its N8 isomer 3c forms duplexes with lower stability.     

Acute toxicity,critical body residues,Michaelis–Menten analysis of bioaccumulation,and ionoregulatory disturbance in response to waterborne nickel in four invertebrates: Chironomus riparius, Lymnaea stagnalis, Lumbriculus variegatus and Daphnia pulex

We investigated the bioaccumulation and acute toxicity (48 h or 96 h) of Ni in four freshwater invertebrate species in two waters with hardness of 40 (soft water) and 140 mg L^− 1 as CaCO₃ (hard water). Sensitivity order (most to least) was Lymnaea stagnalis > Daphnia pulex > Lumbriculus variegatus > Chironomus riparius. In all cases water hardness was protective against acute Ni toxicity with LC50 values 3–3.5 × higher in the hard water vs. soft water. In addition, higher water hardness significantly reduced Ni bioaccumulation in these organisms suggesting that competition by Ca and Mg for uptake at the biotic ligand may contribute to higher metal resistance. CBR50 values (Critical Body Residues) were less dependent on water chemistry (i.e. more consistent) than LC50 values within and across species by ~ 2 fold. These data support one of the main advantages of the Tissue Residue Approach (TRA) where tissue concentrations are generally less variable than exposure concentrations with respect to toxicity. Whole body Ni bioaccumulation followed Michaelis–Menten kinetics in all organisms, with greater hardness tending to decrease B_max with no consistent effect on K_d. Across species, acute Ni LC50 values tended to increase with both K_d and B_max values — i.e. more sensitive species exhibited higher binding affinity and lower binding capacity for Ni, but there was no correlation with body size. With respect to biotic ligand modeling, log K_NiBL values derived from Ni bioaccumulation correlated well with log K_NiBL values derived from toxicity testing. Both whole body Na and Mg levels were disturbed, suggesting that disruption of ionoregulatory homeostasis is a mechanism of acute Ni toxicity. In L. stagnalis, Na depletion was a more sensitive endpoint than mortality, however, the opposite was true for the other organisms. This is the first study to show the relationship between Na and Ni.