Mechanistic contributions of FBXO7 to Parkinson disease

Parkinson disease (PD) is, without doubt, a burden on modern society as the prevalence increases significantly with age. Owing to this growing number of PD cases, it is more critical than ever to understand the pathogenic mechanisms underlying PD to identify therapeutic targets. The discovery of genetic mutations associated with PD and parkinsonism paves the way toward this goal. Even though, familial forms of the disease represent the minority of PD cases and some forms are so rare that there are only a few affected families, the research on the associated genes is invaluable. Recent additions to PARK mutations are those in PARK15 that encodes the F‐box protein O‐type 7 (FBXO7). In this review, we highlight the recent research on FBXO7, which advances our knowledge of the etiopathological pathways and fills unexpected gaps therein, justifying the dedicated study of rare variants of PD.

     

Temperature-Dependent Estimation of Gibbs Energies Using an Updated Group-Contribution Method

Reaction-equilibrium constants determine the metabolite concentrations necessary to drive flux through metabolic pathways. Group-contribution methods offer a way to estimate reaction-equilibrium constants at wide coverage across the metabolic network. Here, we present an updated group-contribution method with 1) additional curated thermodynamic data used in fitting and 2) capabilities to calculate equilibrium constants as a function of temperature. We first collected and curated aqueous thermodynamic data, including reaction-equilibrium constants, enthalpies of reaction, Gibbs free energies of formation, enthalpies of formation, entropy changes of formation of compounds, and proton- and metal-ion-binding constants. Next, we formulated the calculation of equilibrium constants as a function of temperature and calculated the standard entropy change of formation $\left({\mathit{\Delta }}_{\text{f}}{S}^{°}\right)$ using a model based on molecular properties. The median absolute error in estimating ${\mathit{\Delta }}_{\text{f}}{S}^{°}$ was 0.013 kJ/K/mol. We also estimated magnesium binding constants for 618 compounds using a linear regression model validated against measured data. We demonstrate the improved performance of the current method (8.17 kJ/mol in median absolute residual) over the current state-of-the-art method (11.47 kJ/mol) in estimating the 185 new reactions added in this work. The efforts here fill in gaps for thermodynamic calculations under various conditions, specifically different temperatures and metal-ion concentrations. These, to our knowledge, new capabilities empower the study of thermodynamic driving forces underlying the metabolic function of organisms living under diverse conditions.     

Modelling the effects of temperature and wetness on the polycyclic phase of Stemphylium vesicarium,the pathogen causing purple spot on asparagus (Asparagus officinalis L.)

The polycyclic phase of Stemphylium vesicarium is the key factor for the forecast and integrated control of purple spot on asparagus. The annual dynamics of airborne conidia were determined under field conditions by conidia traps. From 2013 to 2015, conidia became airborne at the earliest at mid‐July, but the number trapped was considerably enhanced only after mid‐August, early September. The cumulative percentage of trapped conidia was best described using a logistic function depending on the daily temperature sum (base 0°C) accumulated only on days with >0.2 mm of rainfall (R² = .81). The germination of conidia was modelled by a generalized beta‐modified Chapman Richards function, and the germ tube length was modelled by a generalized beta‐power function. Conidia germinated in a wide temperature range, with an optimum at 23.3°C, whereas germ tube length had a narrow nearly optimum temperature range around 28.7°C, which indicates that infection by conidia is more restricted by germ tube growth than by germination. The effect of temperature on the number of lesions produced by two strains on green asparagus spears had the narrowest optimum range (optimum at 21.9°C) of all parts of the polycyclic phase. In plant tissue, the spread of the fungus depends on the mycelium growth. The mycelium growth of the four strains, which was modelled with data from a petri dish experiment, had an optimum temperature at 24.7°C.     

Effects of host larval stage preferences and diet on life history traits of Diadegma mollipla,an African parasitoid of the Diamondback Moth

Knowledge of the biological attributes of parasitoids plays a fundamental role in improved management of their pest hosts. Diadegma mollipla is a major indigenous parasitoid of the Diamondback Moth (DBM), Plutella xylostella (Linnaeus), in Eastern Africa. Two laboratory experiments were conducted to determine the DBM larval stage preferences of D. mollipla and their influence on life history traits and the effect of different diets (20% honey, 20% sugar solution, water or nothing) on adult parasitoid longevity. In the first study, 60 DBM larvae (15 each of larval stages L1–L4) were exposed to either one adult parasitoid female or four competing females in choice experiments. When DBM larvae were exposed to one parasitoid, in terms of parasitism, L1 and L2 were found to be the most preferred stages, followed by L3 and then L4. Sex ratio (females/males) increased with host larval stage from 1.3 to 3.1. Pre-imaginal development time was longer in L1 than in the other three stages. When exposed to four parasitoids, no significant differences in parasitism rates and progeny production were obtained between DBM larval stages. However, sex ratio increased from 0.8 in L1 to 4.1 in L4. Developmental time was longest in L4, intermediate in L1 and L3, and shortest in L2. In the diet experiment, honey and sugar were found to significantly increase longevity for D. mollipla adults of both sexes. Overall, combined adult male and female longevity was 24.5, 9.9, 2.2 and 1.9 days when fed on honey, sugar, water or nothing, respectively.     

Influence of macroclimate and local conservation measures on taxonomic,functional, and phylogenetic diversities of saproxylic beetles and wood-inhabiting fungi

Wood-inhabiting fungi and saproxylic beetles are threatened by habitat degradation. Our understanding of the importance of macroclimate and local factors determining their taxonomic diversity has increased, but determinants of functional and phylogenetic diversity are poorly understood. We investigated assemblages of wood-inhabiting fungi and saproxylic beetles along a 1000 m elevational gradient of a temperate low mountain range. We (i) tested the relative importance of macroclimate (i.e. elevation) and local variables (microclimate, i.e. canopy closure, amount and diversity of dead wood) in determining observed and rarefied diversities and (ii) explored whether determinants of observed functional and phylogenetic diversities match those of taxonomic diversity. For both taxa, the determinants of observed phylogenetic and functional diversities largely matched those of taxonomic diversity. The diversity of wood-inhabiting fungi was predominantly determined by local variables, whereas that of saproxylic beetles was determined by both local variables and elevation. Taxonomic and phylogenetic diversities of saproxylic beetles decreased with increasing elevation, but standardized functional richness and entropy of both groups increased with increasing elevation. Diversities of wood-inhabiting fungi increased with canopy closure, while diversities of saproxylic beetles decreased with increasing canopy closure. Microclimate and dead-wood amount and diversity affected the observed and rarefied diversity of both saproxylic taxa, which justifies conservation actions that focus on attributes of dead wood and canopy cover. The contrasting responses of fungi and beetles highlight the need for amounts of diverse dead wood in the various microclimates to preserve functional and phylogenetic diversities of saproxylic organisms.     

Design,synthesis, nuclear localization,and biological activity of a fluorescent duocarmycin analog,HxTfA

HxTfA 4 is a fluorescent analog of a potent cytotoxic and antimalarial agent, TfA 3, which is currently being investigated for the development of an antimalarial vaccine, PlasProtect®. HxTfA contains a p-anisylbenzimidazole or Hx moiety, which is endowed with a blue emission upon excitation at 318?nm; thus enabling it to be used as a surrogate for probing the cellular fate of TfA using confocal microscopy, and addressing the question of nuclear localization. HxTfA exhibits similar selectivity to TfA for A-tract sequences of DNA, alkylating adenine-N3, albeit at 10-fold higher concentrations. It also possesses in vitro cytotoxicity against A549 human lung carcinoma cells and Plasmodium falciparum. Confocal microscopy studies showed for the first time that HxTfA, and by inference TfA, entered A549 cells and localized in the nucleus to exert its biological activity. At biologically relevant concentrations, HxTfA elicits DNA damage response as evidenced by a marked increase in the levels of γH2AX observed by confocal microscopy and immunoblotting studies, and ultimately induces apoptosis.     

The Genomic Basis of Color Pattern Polymorphism in the Harlequin Ladybird

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Tyrosine phosphorylation of Munc18‐1 inhibits synaptic transmission by preventing SNARE assembly

Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18‐1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho‐proteomics abolished the stimulatory effect of Munc18‐1 on SNARE complex formation (“SNARE‐templating”) and membrane fusion in vitro. Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18‐1‐null neurons expressing Munc18‐1_Y473D. Synaptic transmission was temporarily restored by high‐frequency stimulation, as well as by a Munc18‐1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming. On the other hand, expression of non‐phosphorylatable Munc18‐1 supported normal synaptic transmission. We propose that SFK‐dependent Munc18‐1 phosphorylation may constitute a potent, previously unknown mechanism to shut down synaptic transmission, via direct occlusion of a Synaptobrevin/VAMP2 binding groove and subsequent hindrance of conformational changes in domain 3a responsible for vesicle priming. This would strongly interfere with the essential post‐docking SNARE‐templating role of Munc18‐1, resulting in a largely abolished pool of releasable synaptic vesicles.