Yeast Creates a Niche for Symbiotic Lactic Acid Bacteria through Nitrogen Overflow.

Cell Syst. 2017 Sep 26;:

Authors: Ponomarova O, Gabrielli N, Sévin DC, Mülleder M, Zirngibl K, Bulyha K, Andrejev S, Kafkia E, Typas A, Sauer U, Ralser M, Patil KR

Abstract
Many microorganisms live in communities and depend on metabolites secreted by fellow community members for survival. Yet our knowledge of interspecies metabolic dependencies is limited to few communities with small number of exchanged metabolites, and even less is known about cellular regulation facilitating metabolic exchange. Here we show how yeast enables growth of lactic acid bacteria through endogenous, multi-component, cross-feeding in a readily established community. In nitrogen-rich environments, Saccharomyces cerevisiae adjusts its metabolism by secreting a pool of metabolites, especially amino acids, and thereby enables survival of Lactobacillus plantarum and Lactococcus lactis. Quantity of the available nitrogen sources and the status of nitrogen catabolite repression pathways jointly modulate this niche creation. We demonstrate how nitrogen overflow by yeast benefits L. plantarum in grape juice, and contributes to emergence of mutualism with L. lactis in a medium with lactose. Our results illustrate how metabolic decisions of an individual species can benefit others.

PMID: 28964698 [PubMed - as supplied by publisher]

Multitarget search on complex networks: A logarithmic growth of global mean random cover time.

Chaos. 2017 Sep;27(9):093103

Authors: Weng T, Zhang J, Small M, Yang J, Bijarbooneh FH, Hui P

Abstract
We investigate multitarget search on complex networks and derive an exact expression for the mean random cover time that quantifies the expected time a walker needs to visit multiple targets. Based on this, we recover and extend some interesting results of multitarget search on networks. Specifically, we observe the logarithmic increase of the global mean random cover time with the target number for a broad range of random search processes, including generic random walks, biased random walks, and maximal entropy random walks. We show that the logarithmic growth pattern is a universal feature of multi-target search on networks by using the annealed network approach and the Sherman-Morrison formula. Moreover, we find that for biased random walks, the global mean random cover time can be minimized, and that the corresponding optimal parameter also minimizes the global mean first passage time, pointing towards its robustness. Our findings further confirm that the logarithmic growth pattern is a universal law governing multitarget search in confined media.

PMID: 28964125 [PubMed - in process]

Herbicide glufosinate inhibits yeast growth and extends longevity during wine fermentation.

Sci Rep. 2017 Sep 29;7(1):12414

Authors: Vallejo B, Picazo C, Orozco H, Matallana E, Aranda A

Abstract
Glufosinate ammonium (GA) is a widely used herbicide that inhibits glutamine synthetase. This inhibition leads to internal amino acid starvation which, in turn, causes the activation of different nutrient sensing pathways. GA also inhibits the enzyme of the yeast Saccharomyces cerevisiae in such a way that, although it is not used as a fungicide, it may alter yeast performance in industrial processes like winemaking. We describe herein how GA indeed inhibits the yeast growth of a wine strain during the fermentation of grape juice. In turn, GA extends longevity in a variety of growth media. The biochemical analysis indicates that GA partially inhibits the nutrient sensing TORC1 pathway, which may explain these phenotypes. The GCN2 kinase mutant is hypersensitive to GA. Hence the control of translation and amino acid biosynthesis is required to also deal with the damaging effects of this pesticide. A global metabolomics analysis under winemaking conditions indicated that an increase in amino acid and in polyamines occurred. In conclusion, GA affects many different biochemical processes during winemaking, which provides us with some insights into both the effect of this herbicide on yeast physiology and into the relevance of the metabolic step for connecting nitrogen and carbon metabolism.

PMID: 28963559 [PubMed - in process]

Constrained vertebrate evolution by pleiotropic genes.

Nat Ecol Evol. 2017 Sep 25;:

Authors: Hu H, Uesaka M, Guo S, Shimai K, Lu TM, Li F, Fujimoto S, Ishikawa M, Liu S, Sasagawa Y, Zhang G, Kuratani S, Yu JK, Kusakabe TG, Khaitovich P, Irie N, EXPANDE Consortium

Abstract
Despite morphological diversification of chordates over 550 million years of evolution, their shared basic anatomical pattern (or 'bodyplan') remains conserved by unknown mechanisms. The developmental hourglass model attributes this to phylum-wide conserved, constrained organogenesis stages that pattern the bodyplan (the phylotype hypothesis); however, there has been no quantitative testing of this idea with a phylum-wide comparison of species. Here, based on data from early-to-late embryonic transcriptomes collected from eight chordates, we suggest that the phylotype hypothesis would be better applied to vertebrates than chordates. Furthermore, we found that vertebrates' conserved mid-embryonic developmental programmes are intensively recruited to other developmental processes, and the degree of the recruitment positively correlates with their evolutionary conservation and essentiality for normal development. Thus, we propose that the intensively recruited genetic system during vertebrates' organogenesis period imposed constraints on its diversification through pleiotropic constraints, which ultimately led to the common anatomical pattern observed in vertebrates.Basic anatomical patterns are conserved in chordates. Here, the authors show mid-embryonic conservation during vertebrates' development and evolutionary constraints introduced by recruitment of mid-embryonic programmes to later stages of development.

PMID: 28963548 [PubMed - as supplied by publisher]

Superresolution microscopy of the β-carboxysome reveals a homogeneous matrix.

Mol Biol Cell. 2017 Oct 01;28(20):2734-2745

Authors: Niederhuber MJ, Lambert TJ, Yapp C, Silver PA, Polka JK

Abstract
Carbon fixation in cyanobacteria makes a major contribution to the global carbon cycle. The cyanobacterial carboxysome is a proteinaceous microcompartment that protects and concentrates the carbon-fixing enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) in a paracrystalline lattice, making it possible for these organisms to fix CO2 from the atmosphere. The protein responsible for the organization of this lattice in beta-type carboxysomes of the freshwater cyanobacterium Synechococcus elongatus, CcmM, occurs in two isoforms thought to localize differentially within the carboxysome matrix. Here we use wide-field time-lapse and three-dimensional structured illumination microscopy (3D-SIM) to study the recruitment and localization of these two isoforms. We demonstrate that this superresolution technique is capable of distinguishing the localizations of the outer protein shell of the carboxysome and its internal cargo. We develop an automated analysis pipeline to analyze and quantify 3D-SIM images and generate a population-level description of the carboxysome shell protein, RuBisCO, and CcmM isoform localization. We find that both CcmM isoforms have similar spatial and temporal localization, prompting a revised model of the internal arrangement of the β-carboxysome.

PMID: 28963440 [PubMed - in process]

Protein complex assemblies in epithelial cell polarity and asymmetric cell division.

J Mol Biol. 2017 Sep 26;:

Authors: Wen W, Zhang M

Abstract
Asymmetric local concentration of protein complexes on distinct membrane regions is a fundamental property in numerous biological processes and is a hallmark of cell polarity. Evolutionarily conserved core polarity proteins form specific and dynamic networks to regulate the establishment and maintenance of cell polarity, as well as distinct polarity-driven cellular events. This review focuses on the molecular and structural basis governing regulated formation of several sets of core cell polarity regulatory complexes, as well as their functions in epithelial cell polarization and asymmetric cell division.

PMID: 28963071 [PubMed - as supplied by publisher]

Key components of COPI and COPII machineries are required for chikungunya virus replication.

Biochem Biophys Res Commun. 2017 Sep 26;:

Authors: Zhang N, Zhang L

Abstract
The infection of CHIKV is associated with cellular membranes; however whether early secretory pathways are involved in CHIKV replication remains unclear. In the present study, we have provided initial evidences that CHIKV requires both COPI and COPII for its replication. Small interfering RNAs against COPI components, including coatomer, ARFs or GBF1, suppress CHIKV replication. Moreover, CHIKV infection is abolished by the presence of ARF1 inhibitor brefeldin A or GBF1 inhibitor Golgicide A. In addition, perturbation of COPII by silencing key components of COPII pathways leads to a reduction in CHIKV replication. Collectively, these observations demonstrate the importance of functional secretory pathways in the infectivity of CHIKV.

PMID: 28962860 [PubMed - as supplied by publisher]

Hexokinases link DJ-1 to the PINK1/parkin pathway.

Mol Neurodegener. 2017 Sep 29;12(1):70

Authors: Hauser DN, Mamais A, Conti MM, Primiani CT, Kumaran R, Dillman AA, Langston RG, Beilina A, Garcia JH, Diaz-Ruiz A, Bernier M, Fiesel FC, Hou X, Springer W, Li Y, de Cabo R, Cookson MR

Abstract
BACKGROUND: Early onset Parkinson's disease is caused by variants in PINK1, parkin, and DJ-1. PINK1 and parkin operate in pathways that preserve mitochondrial integrity, but the function of DJ-1 and how it relates to PINK1 and parkin is poorly understood.
METHODS: A series of unbiased high-content screens were used to analyze changes at the protein, RNA, and metabolite level in rodent brains lacking DJ-1. Results were validated using targeted approaches, and cellular assays were performed to probe the mechanisms involved.
RESULTS: We find that in both rat and mouse brains, DJ-1 knockout results in an age-dependent accumulation of hexokinase 1 in the cytosol, away from its usual location at the mitochondria, with subsequent activation of the polyol pathway of glucose metabolism in vivo. Both in the brain and in cultured cells, DJ-1 deficiency is associated with accumulation of the phosphatase PTEN that antagonizes the kinase AKT. In cells, addition of an inhibitor of AKT (MK2206) or addition of a peptide to dissociate association of hexokinases from mitochondria both inhibit the PINK1/parkin pathway, which works to maintain mitochondrial integrity.
CONCLUSION: Hexokinases are an important link between three major genetic causes of early onset Parkinson's disease. Because aging is associated with deregulated nutrient sensing, these results help explain why DJ-1 is associated with age-dependent disease.

PMID: 28962651 [PubMed - in process]

Statistically controlled identification of differentially expressed genes in one-to-one cell line comparisons of the CMAP database for drug repositioning.

J Transl Med. 2017 Sep 29;15(1):198

Authors: He J, Yan H, Cai H, Li X, Guan Q, Zheng W, Chen R, Liu H, Song K, Guo Z, Wang X

Abstract
BACKGROUND: The Connectivity Map (CMAP) database, an important public data source for drug repositioning, archives gene expression profiles from cancer cell lines treated with and without bioactive small molecules. However, there are only one or two technical replicates for each cell line under one treatment condition. For such small-scale data, current fold-changes-based methods lack statistical control in identifying differentially expressed genes (DEGs) in treated cells. Especially, one-to-one comparison may result in too many drug-irrelevant DEGs due to random experimental factors. To tackle this problem, CMAP adopts a pattern-matching strategy to build "connection" between disease signatures and gene expression changes associated with drug treatments. However, many drug-irrelevant genes may blur the "connection" if all the genes are used instead of pre-selected DEGs induced by drug treatments.
METHODS: We applied OneComp, a customized version of RankComp, to identify DEGs in such small-scale cell line datasets. For a cell line, a list of gene pairs with stable relative expression orderings (REOs) were identified in a large collection of control cell samples measured in different experiments and they formed the background stable REOs. When applying OneComp to a small-scale cell line dataset, the background stable REOs were customized by filtering out the gene pairs with reversal REOs in the control samples of the analyzed dataset.
RESULTS: In simulated data, the consistency scores of overlapping genes between DEGs identified by OneComp and SAM were all higher than 99%, while the consistency score of the DEGs solely identified by OneComp was 96.85% according to the observed expression difference method. The usefulness of OneComp was exemplified in drug repositioning by identifying phenformin and metformin related genes using small-scale cell line datasets which helped to support them as a potential anti-tumor drug for non-small-cell lung carcinoma, while the pattern-matching strategy adopted by CMAP missed the two connections. The implementation of OneComp is available at https://github.com/pathint/reoa .
CONCLUSIONS: OneComp performed well in both the simulated and real data. It is useful in drug repositioning studies by helping to find hidden "connections" between drugs and diseases.

PMID: 28962576 [PubMed - in process]

pulver: an R package for parallel ultra-rapid p-value computation for linear regression interaction terms.

BMC Bioinformatics. 2017 Sep 29;18(1):429

Authors: Molnos S, Baumbach C, Wahl S, Müller-Nurasyid M, Strauch K, Wang-Sattler R, Waldenberger M, Meitinger T, Adamski J, Kastenmüller G, Suhre K, Peters A, Grallert H, Theis FJ, Gieger C

Abstract
BACKGROUND: Genome-wide association studies allow us to understand the genetics of complex diseases. Human metabolism provides information about the disease-causing mechanisms, so it is usual to investigate the associations between genetic variants and metabolite levels. However, only considering genetic variants and their effects on one trait ignores the possible interplay between different "omics" layers. Existing tools only consider single-nucleotide polymorphism (SNP)-SNP interactions, and no practical tool is available for large-scale investigations of the interactions between pairs of arbitrary quantitative variables.
RESULTS: We developed an R package called pulver to compute p-values for the interaction term in a very large number of linear regression models. Comparisons based on simulated data showed that pulver is much faster than the existing tools. This is achieved by using the correlation coefficient to test the null-hypothesis, which avoids the costly computation of inversions. Additional tricks are a rearrangement of the order, when iterating through the different "omics" layers, and implementing this algorithm in the fast programming language C++. Furthermore, we applied our algorithm to data from the German KORA study to investigate a real-world problem involving the interplay among DNA methylation, genetic variants, and metabolite levels.
CONCLUSIONS: The pulver package is a convenient and rapid tool for screening huge numbers of linear regression models for significant interaction terms in arbitrary pairs of quantitative variables. pulver is written in R and C++, and can be downloaded freely from CRAN at https://cran.r-project.org/web/packages/pulver/ .

PMID: 28962546 [PubMed - in process]

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