Parkinson Disease Protein DJ-1 Binds Metals and Protects against Metal-induced Cytotoxicity

The progressive loss of motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels are the classically described features of Parkinson disease (PD). Neuronal damage also progresses to other regions of the brain, and additional non-motor dysfunctions are common. Accumulation of environmental toxins, such as pesticides and metals, are suggested risk factors for the development of typical late onset PD, although genetic factors seem to be substantial in early onset cases. Mutations of DJ-1 are known to cause a form of recessive early onset Parkinson disease, highlighting an important functional role for DJ-1 in early disease prevention. This study identifies human DJ-1 as a metal-binding protein able to evidently bind copper as well as toxic mercury ions in vitro. The study further characterizes the cytoprotective function of DJ-1 and PD-mutated variants of DJ-1 with respect to induced metal cytotoxicity. The results show that expression of DJ-1 enhances the cells'' protective mechanisms against induced metal toxicity and that this protection is lost for DJ-1 PD mutations A104T and D149A. The study also shows that oxidation site-mutated DJ-1 C106A retains its ability to protect cells. We also show that concomitant addition of dopamine exposure sensitizes cells to metal-induced cytotoxicity. We also confirm that redox-active dopamine adducts enhance metal-catalyzed oxidation of intracellular proteins in vivo by use of live cell imaging of redox-sensitive S3roGFP. The study indicates that even a small genetic alteration can sensitize cells to metal-induced cell death, a finding that may revive the interest in exogenous factors in the etiology of PD.     

Catalytic Turnover Triggers Exchange of Subunits of the Magnesium Chelatase AAA+ Motor Unit

The ATP-dependent insertion of Mg²⁺ into protoporphyrin IX is the first committed step in the chlorophyll biosynthetic pathway. The reaction is catalyzed by magnesium chelatase, which consists of three gene products: BchI, BchD, and BchH. The BchI and BchD subunits belong to the family of AAA+ proteins (ATPases associated with various cellular activities) and form a two-ring complex with six BchI subunits in one layer and six BchD subunits in the other layer. This BchID complex is a two-layered trimer of dimers with the ATP binding site located at the interface between two neighboring BchI subunits. ATP hydrolysis by the BchID motor unit fuels the insertion of Mg²⁺ into the porphyrin by the BchH subunit. In the present study, we explored mutations that were originally identified in semidominant barley (Hordeum vulgare L.) mutants. The resulting recombinant BchI proteins have marginal ATPase activity and cannot contribute to magnesium chelatase activity although they apparently form structurally correct complexes with BchD. Mixing experiments with modified and wild-type BchI in various combinations showed that an exchange of BchI subunits in magnesium chelatase occurs during the catalytic cycle, which indicates that dissociation of the complex may be part of the reaction mechanism related to product release. Mixing experiments also showed that more than three functional interfaces in the BchI ring structure are required for magnesium chelatase activity.     

Dynamics and Management of Stage-Structured Fish Stocks

With increasing fishing pressures having brought several stocks to the brink of collapse, there is a need for developing efficient harvesting methods that account for factors beyond merely yield or profit. We consider the dynamics and management of a stage-structured fish stock. Our work is based on a consumer-resource model which De Roos et al. (in Theor. Popul. Biol. 73, 47–62, 2008) have derived as an approximation of a physiologically-structured counterpart. First, we rigorously prove the existence of steady states in both models, that the models share the same steady states, and that there exists at most one positive steady state. Furthermore, we carry out numerical investigations which suggest that a steady state is globally stable if it is locally stable. Second, we consider multiobjective harvesting strategies which account for yield, profit, and the recovery potential of the fish stock. The recovery potential is a measure of how quickly a fish stock can recover from a major disturbance and serves as an indication of the extinction risk associated with a harvesting strategy. Our analysis reveals that a small reduction in yield or profit allows for a disproportional increase in recovery potential. We also show that there exists a harvesting strategy with yield close to the maximum sustainable yield (MSY) and profit close to that associated with the maximum economic yield (MEY). In offering a good compromise between MSY and MEY, we believe that this harvesting strategy is preferable in most instances. Third, we consider the impact of harvesting on population size structure and analytically determine the most and least harmful harvesting strategies. We conclude that the most harmful harvesting strategy consists of harvesting both adults and juveniles, while harvesting only adults is the least harmful strategy. Finally, we find that a high percentage of juvenile biomass indicates elevated extinction risk and might therefore serve as an early-warning signal of impending stock collapse.     

PINT: a software for integration of peak volumes and extraction of relaxation rates

We present the software Peak INTegration (PINT), designed to perform integration of peaks in NMR spectra. The program is very simple to run, yet powerful enough to handle complicated spectra. Peaks are integrated by fitting predefined line shapes to experimental data and the fitting can be customized to deal with, for instance, heavily overlapped peaks. The results can be inspected visually, which facilitates systematic optimization of the line shape fitting. Finally, integrated peak volumes can be used to extract parameters such as relaxation rates and information about low populated states. The utility of PINT is demonstrated by applications to the 59 residue SH3 domain of the yeast protein Abp1p and the 289 residue kinase domain of murine EphB2.     

Lichenicolous fungi show population subdivision by host species but do not share population history with their hosts

Lichenicolous fungi are a species-rich biological group growing on lichen thalli. Here, we analyze the genetic structure of the lichenicolous basidiomycete Tremella lobariacearum and three host species (Lobaria pulmonaria, Lobaria macaronesica, and Lobaria immixta) in Macaronesia. We used ordination and analysis of molecular variance to investigate the structuring of genetic variation, and a simulation test to investigate whether rDNA haplotypes of T. lobariacearum were significantly associated with host species. To investigate the evolutionary and demographic history of the lichenicolous fungus and its hosts, we used coalescent samplers to generate trees, and Bayesian skyline plots. We found that the hosts were most important in structuring populations of the lichenicolous species. Despite their wide geographic distribution, the same haplotypes of T. lobariacearum consistently associated with a given host species. Our results suggest that the Lobaria hosts create a selective environment for the lichenicolous fungus. Both the pathogen and the host populations exhibited substantial genetic structure. However, evolutionary and demographic histories differed between the parasite and its hosts, as evidenced by different divergence times and tree topologies.     

Variance Heterogeneity in Saccharomyces cerevisiae Expression Data: Trans-Regulation and Epistasis

Here, we describe the results from the first variance heterogeneity Genome Wide Association Study (VGWAS) on yeast expression data. Using this forward genetics approach, we show that the genetic regulation of gene-expression in the budding yeast, Saccharomyces cerevisiae, includes mechanisms that can lead to variance heterogeneity in the expression between genotypes. Additionally, we performed a mean effect association study (GWAS). Comparing the mean and variance heterogeneity analyses, we find that the mean expression level is under genetic regulation from a larger absolute number of loci but that a higher proportion of the variance controlling loci were trans-regulated. Both mean and variance regulating loci cluster in regulatory hotspots that affect a large number of phenotypes; a single variance-controlling locus, mapping close to DIA2, was found to be involved in more than 10% of the significant associations. It has been suggested in the literature that variance-heterogeneity between the genotypes might be due to genetic interactions. We therefore screened the multi-locus genotype-phenotype maps for several traits where multiple associations were found, for indications of epistasis. Several examples of two and three locus genetic interactions were found to involve variance-controlling loci, with reports from the literature corroborating the functional connections between the loci. By using a new analytical approach to re-analyze a powerful existing dataset, we are thus able to both provide novel insights to the genetic mechanisms involved in the regulation of gene-expression in budding yeast and experimentally validate epistasis as an important mechanism underlying genetic variance-heterogeneity between genotypes.     

Four decades of functional community change reveals gradual trends and low interlinkage across trophic groups in a large marine ecosystem

The rate at which biological diversity is altered on both land and in the sea, makes temporal community development a critical and fundamental part of understanding global change. With advancements in trait‐based approaches, the focus on the impact of temporal change has shifted towards its potential effects on the functioning of the ecosystems. Our mechanistic understanding of and ability to predict community change is still impeded by the lack of knowledge in long‐term functional dynamics that span several trophic levels. To address this, we assessed species richness and multiple dimensions of functional diversity and dynamics of two interacting key organism groups in the marine food web: fish and zoobenthos. We utilized unique time series‐data spanning four decades, from three environmentally distinct coastal areas in the Baltic Sea, and assembled trait information on six traits per organism group covering aspects of feeding, living habit, reproduction and life history. We identified gradual long‐term trends, rather than abrupt changes in functional diversity (trait richness, evenness, dispersion) trait turnover, and overall multi‐trait community composition. The linkage between fish and zoobenthic functional community change, in terms of correlation in long‐term trends, was weak, with timing of changes being area and trophic group specific. Developments of fish and zoobenthos traits, particularly size (increase in small size for both groups) and feeding habits (e.g. increase in generalist feeding for fish and scavenging or predation for zoobenthos), suggest changes in trophic pathways. We summarize our findings by highlighting three key aspects for understanding functional change across trophic groups: (a) decoupling of species from trait richness, (b) decoupling of richness from density and (c) determining of turnover and multi‐trait dynamics. We therefore argue for quantifying change in multiple functional measures to help assessments of biodiversity change move beyond taxonomy and single trophic groups.     

Involvement of lipid transfer proteins in resistance against a non-host powdery mildew in Arabidopsis thaliana

Non-specific lipid transfer proteins (LTPs) are involved in the transport of lipophilic compounds to the cuticular surface in epidermal cells and in the defence against pathogens. The role of glycophosphatidylinositol (GPI)-anchored LTPs (LTPGs) in resistance against non-host mildews in Arabidopsis thaliana was investigated using reverse genetics. Loss of either LTPG1, LTPG2, LTPG5 or LTPG6 increased the susceptibility to penetration of the epidermal cell wall by Blumeria graminis f. sp. hordei (Bgh). However, no impact on pre-penetration defence against another non-host mildew, Erysiphe pisi (Ep), was observed. LTPG1 was localized to papillae at the sites of Bgh penetration. This study shows that, in addition to the previously known functions, LTPGs contribute to pre-invasive defence against certain non-host powdery mildew pathogens.