Sulfur sequestration promotes multicellularity during nutrient limitation

The behaviour of Dictyostelium discoideum depends on nutrients. When sufficient food is present these amoebae exist in a unicellular state, but upon starvation they aggregate into a multicellular organism. This biology makes D. discoideum an ideal model for investigating how fundamental metabolism commands cell differentiation and function. Here we show that reactive oxygen species-generated as a consequence of nutrient limitation-lead to the sequestration of cysteine in the antioxidant glutathione. This sequestration limits the use of the sulfur atom of cysteine in processes that contribute to mitochondrial metabolism and cellular proliferation, such as protein translation and the activity of enzymes that contain an iron-sulfur cluster. The regulated sequestration of sulfur maintains D. discoideum in a nonproliferating state that paves the way for multicellular development. This mechanism of signalling through reactive oxygen species highlights oxygen and sulfur as simple signalling molecules that dictate cell fate in an early eukaryote, with implications for responses to nutrient fluctuations in multicellular eukaryotes

Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1

Molecular chaperones such as heat-shock proteins (HSPs) help in protein folding. Their function in the cytosol has been well studied. Notably, chaperones are also present in the nucleus, a compartment where proteins enter after completing de novo folding in the cytosol, and this raises an important question about chaperone function in the nucleus. We performed a systematic analysis of the nuclear pool of heat-shock protein 90. Three orthogonal and independent analyses led us to the core functional interactome of HSP90. Computational and biochemical analyses identify host cell factor C1 (HCFC1) as a transcriptional regulator that depends on HSP90 for its stability. HSP90 was required to maintain the expression of HCFC1-targeted cell-cycle genes. The regulatory nexus between HSP90 and the HCFC1 module identified in this study sheds light on the relevance of chaperones in the transcription of cell-cycle genes. Our study also suggests a therapeutic avenue of combining chaperone and transcription inhibitors for cancer treatment

Effect of arsenic-phosphorus interaction on arsenic-induced oxidative stress in chickpea plants

Arsenic-induced oxidative stress in chickpea was investigated under glasshouse conditions in response to application of arsenic and phosphorus. Three levels of arsenic (0, 30 and 60 mg kg−1) and four levels of P (50, 100, 200, and 400 mg kg−1) were applied to soil-grown plants. Increasing levels of both arsenic and P significantly increased arsenic concentrations in the plants. Shoot growth was reduced with increased arsenic supply regardless of applied P levels. Applied arsenic induced oxidative stress in the plants, and the concentrations of H2O2 and lipid peroxidation were increased. Activity of superoxide dismutase (SOD) and concentrations of non-enzymatic antioxidants decreased in these plants, but activities of catalase (CAT) and ascorbate peroxidase (APX) were significantly increased under arsenic phytotoxicity. Increased supply of P decreased activities of CAT and APX, and decreased concentrations of non-enzymatic antioxidants, but the high-P plants had lowered lipid peroxidation. It can be concluded that P increased uptake of arsenic from the soil, probably by making it more available, but although plant growth was inhibited by arsenic the P may have partially protected the membranes from arsenic-induced oxidative stress

A Polyadenylation Factor Subunit Implicated in Regulating Oxidative Signaling in Arabidopsis thaliana

BACKGROUND: Plants respond to many unfavorable environmental conditions via signaling mediated by altered levels of various reactive oxygen species (ROS). To gain additional insight into oxidative signaling responses, Arabidopsis mutants that exhibited tolerance to oxidative stress were isolated. We describe herein the isolation and characterization of one such mutant, oxt6. METHODOLOGY/PRINCIPAL FINDINGS: The oxt6 mutation is due to the disruption of a complex gene (At1g30460) that encodes the Arabidopsis ortholog of the 30-kD subunit of the cleavage and polyadenylation specificity factor (CPSF30) as well as a larger, related 65-kD protein. Expression of mRNAs encoding Arabidopsis CPSF30 alone was able to restore wild-type growth and stress susceptibility to the oxt6 mutant. Transcriptional profiling and single gene expression studies show elevated constitutive expression of a subset of genes that encode proteins containing thioredoxin- and glutaredoxin-related domains in the oxt6 mutant, suggesting that stress can be ameliorated by these gene classes. Bulk poly(A) tail length was not seemingly affected in the oxt6 mutant, but poly(A) site selection was different, indicating a subtle effect on polyadenylation in the mutant. CONCLUSIONS/SIGNIFICANCE: These results implicate the Arabidopsis CPSF30 protein in the posttranscriptional control of the responses of plants to stress, and in particular to the expression of a set of genes that suffices to confer tolerance to oxidative stress

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation

How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome

The Cys-Arg/N-end rule pathway is a general sensor of abiotic stress in flowering plants

Abiotic stresses impact negatively on plant growth, profoundly affecting yield and quality of crops. Although much is known about plant responses, very little is understood at the molecular level about the initial sensing of environmental stress. In plants, hypoxia (low oxygen, which occurs during flooding) is directly sensed by the Cys-Arg/N-end rule pathway of ubiquitin-mediated proteolysis, through oxygen-dependent degradation of group VII Ethylene Response Factor transcription factors (ERFVIIs) via amino-terminal (Nt-) cysteine [1, 2]. Using Arabidopsis (Arabidopsis thaliana) and barley (Hordeum vulgare), we show that the pathway regulates plant responses to multiple abiotic stresses. In Arabidopsis, genetic analyses revealed that response to these stresses is controlled by N-end rule regulation of ERFVII function. Oxygen sensing via the Cys-Arg/N-end rule in higher eukaryotes is linked through a single mechanism to nitric oxide (NO) sensing [3, 4]. In plants, the major mechanism of NO synthesis is via NITRATE REDUCTASE (NR), an enzyme of nitrogen assimilation [5]. Here, we identify a negative relationship between NR activity and NO levels and stabilization of an artificial Nt-Cys substrate and ERFVII function in response to environmental changes. Furthermore, we show that ERFVIIs enhance abiotic stress responses via physical and genetic interactions with the chromatin-remodeling ATPase BRAHMA. We propose that plants sense multiple abiotic stresses through the Cys-Arg/N-end rule pathway either directly (via oxygen sensing) or indirectly (via NO sensing downstream of NR activity). This single mechanism can therefore integrate environment and response to enhance plant survival

Genetic influences in different aspects of language development: The etiology of language skills in 4.5 year-old twins

The genetic and environmental etiologies of diverse aspects of language ability and disability, including articulation, phonology, grammar, vocabulary, and verbal memory, were investigated in a U.K. sample of 787 pairs of 4.5-year-old same-sex and opposite-sex twins. Moderate genetic influence was found for all aspects of language in the normal range. A similar pattern was found at the low end of the distribution with the exception of two receptive measures. Environmental influence was mainly due to nonshared factors, unique to the individual, with little influence from shared environment for most measures. Genetic and environmental influences on language ability and disability are quantitatively and qualitatively similar for males and females

Connecting genes, coexpression modules, and molecular signatures to environmental stress phenotypes in plants

<p>Abstract</p> <p>Background</p> <p>One of the eminent opportunities afforded by modern genomic technologies is the potential to provide a mechanistic understanding of the processes by which genetic change translates to phenotypic variation and the resultant appearance of distinct physiological traits. Indeed much progress has been made in this area, particularly in biomedicine where functional genomic information can be used to determine the physiological state (e.g., diagnosis) and predict phenotypic outcome (e.g., patient survival). Ecology currently lacks an analogous approach where genomic information can be used to diagnose the presence of a given physiological state (e.g., stress response) and then predict likely phenotypic outcomes (e.g., stress duration and tolerance, fitness).</p> <p>Results</p> <p>Here, we demonstrate that a compendium of genomic signatures can be used to classify the plant abiotic stress phenotype in <it>Arabidopsis </it>according to the architecture of the transcriptome, and then be linked with gene coexpression network analysis to determine the underlying genes governing the phenotypic response. Using this approach, we confirm the existence of known stress responsive pathways and marker genes, report a common abiotic stress responsive transcriptome and relate phenotypic classification to stress duration.</p> <p>Conclusion</p> <p>Linking genomic signatures to gene coexpression analysis provides a unique method of relating an observed plant phenotype to changes in gene expression that underlie that phenotype. Such information is critical to current and future investigations in plant biology and, in particular, to evolutionary ecology, where a mechanistic understanding of adaptive physiological responses to abiotic stress can provide researchers with a tool of great predictive value in understanding species and population level adaptation to climate change.</p

Fluorescent dyes as a probe for the localized field of coupled surface plasmon-related resonances

M. Kreiter, T. Neumann, S. Mittler, W. Knoll, and J. Roy Sambles, Physical Review B, Vol. 64, article 075406 (2001). "Copyright © 2001 by the American Physical Society."The fluorescence light of Cy5 dye molecules in the vicinity of a metal grating is studied for varying directions of both the exciting and the emitted light. A different angular dependence of the intensity of the emitted light is observed for different directions of excitation. Model calculations that take into account the localization of the electrical field of grating-coupled surface plasmon-related resonances are in good agreement with the experimental observations. In addition, the spatially inhomogenous photobleaching of the dye in the field of the coupled resonances is experimentally observed. These results can be viewed both as a way to use chromophores as molecular probes for the localized electrical near field of coupled surface plasmon-related resonances and as a way to manipulate dye molecules on a submicron scale