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A GATA Transcription Factor Recruits Hda1 in Response to Reduced Tor1 Signaling to Establish a Hyphal Chromatin State in Candida albicans
Lu, Yang
Su, Chang
Liu, Haoping
PLoS Pathogens
Candida albicans is an important opportunistic fungal pathogen of immunocompromised individuals. One critical virulence attribute is its morphogenetic plasticity. Hyphal development requires two temporally linked changes in promoter chromatin, which is sequentially regulated by temporarily clearing the transcription inhibitor Nrg1 upon activation of the cAMP/PKA pathway and promoter recruitment of the histone deacetylase Hda1 under reduced Tor1 signaling. Molecular mechanisms for the temporal connection and the link to Tor1 signaling are not clear. Here, through a forward genetic screen, we report the identification of the GATA family transcription factor Brg1 as the factor that recruits Hda1 to promoters of hypha-specific genes during hyphal elongation. BRG1 expression requires both the removal of Nrg1 and a sub-growth inhibitory level of rapamycin; therefore, it is a sensitive readout of Tor1 signaling. Interestingly, promoters of hypha-specific genes are not accessible to Brg1 in yeast cells. Furthermore, ectopic expression of Brg1 cannot induce hyphae, but can sustain hyphal development. Nucleosome mapping of a hypha-specific promoter shows that Nrg1 binding sites are in nucleosome free regions in yeast cells, whereas Brg1 binding sites are occupied by nucleosomes. Nucleosome disassembly during hyphal initiation exposes the binding sites for both regulators. During hyphal elongation, Brg1-mediated Hda1 recruitment causes nucleosome repositioning and occlusion of Nrg1 binding sites. We suggest that nucleosome repositioning is the underlying mechanism for the yeast-hyphal transition. The hypha-specific regulator Ume6 is a key downstream target of Brg1 and functions after Brg1 as a built-in positive feedback regulator of the hyphal transcriptional program to sustain hyphal development. With the levels of Nrg1 and Brg1 dynamically and sensitively controlled by the two major cellular growth pathways, temporal changes in nucleosome positioning during the yeast-to-hypha transition provide a mechanism for signal integration and cell fate specification. This mechanism is likely used broadly in development.
Author Summary
Candida is part of the gut microflora in healthy individuals, but can disseminate and cause systemic disease when the host's immune system is suppressed. Its ability to grow as yeast and hyphae in response to environmental cues is a major virulence attribute. Hyphal development requires temporary clearing of the transcription inhibitor Nrg1 upon activation of cAMP/PKA for initiation and promoter recruitment of the histone deacetylase Hda1 under reduced Tor1 signaling for maintenance. Here, we show that, during hyphal initiation when Nrg1 is gone, expression of the GATA family transcription factor Brg1 is activated under reduced Tor1 signaling. Accumulated Brg1 recruits Hda1 to hyphal promoters to reposition nucleosomes, leading to obstruction of Nrg1 binding sites and sustained hyphal development. The nucleosome repositioning during the yeast-hyphal transition provides a mechanism for temporal integration of extracellular signals and cell-fate specification. The hypha-specific transcription factor Ume6 functions after Brg1 in this succession of feed-forward regulation of hyphal development. Since misregulation of either Nrg1 or Ume6 causes altered virulence, and Brg1 regulates both Nrg1 accessibility and Ume6 transcription, our findings should provide a better understanding of how Candida controls its morphological program in different host niches to exist as a commensal and a pathogen.
Related Articles
A G1 Cyclin Is Necessary for Maintenance of Filamentous Growth in Candida albicans
Loeb, Jonathan D. J.
Sepulveda-Becerra, Marisa
Hazan, Idit
Liu, Haoping
Molecular and Cellular Biology
Candida albicans undergoes a dramatic morphological transition in response to various growth conditions. This ability to switch from a yeast form to a hyphal form is required for its pathogenicity. The intractability of Candida to traditional genetic approaches has hampered the study of the molecular mechanism governing this developmental switch. Our approach is to use the more genetically tractable yeast Saccharomyces cerevisiae to yield clues about the molecular control of filamentation for further studies in Candida. G1 cyclins Cln1 and Cln2 have been implicated in the control of morphogenesis in S. cerevisiae. We show that C. albicans CLN1 (CaCLN1) has the same cell cycle-specific expression pattern as CLN1 and CLN2 of S. cerevisiae. To investigate whether G1 cyclins are similarly involved in the regulation of cell morphogenesis during the yeast-to-hypha transition of C. albicans, we mutated CaCLN1. Cacln1/Cacln1 cells were found to be slower than wild-type cells in cell cycle progression. The Cacln1/Cacln1 mutants were also defective in hyphal colony formation on several solid media. Furthermore, while mutant strains developed germ tubes under several hypha-inducing conditions, they were unable to maintain the hyphal growth mode in a synthetic hypha-inducing liquid medium and were deficient in the expression of hypha-specific genes in this medium. Our results suggest that CaCln1 may coordinately regulate hyphal development with signal transduction pathways in response to various environmental cues.
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Hyphal Development in Candida albicans Requires Two Temporally Linked Changes in Promoter Chromatin for Initiation and Maintenance
Lu, Yang
Su, Chang
Wang, Allen
Liu, Haoping
PLoS Biology
Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. albicans is able to switch reversibly between yeast and hyphal growth forms in response to environmental cues. Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear. Here we show that hyphal development involves two sequential regulations of the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis via activation of the cAMP-PKA pathway. Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling. Hda1 deacetylates a subunit of the NuA4 histone acetyltransferase module, leading to eviction of the NuA4 acetyltransferase module and blockage of Nrg1 access to promoters of hypha-specific genes. Promoter recruitment of Hda1 for hyphal maintenance happens only during the period when Nrg1 is gone. The sequential regulation of hyphal development by the activation of the cAMP-PKA pathway and reduced Tor1 signaling provides a molecular mechanism for plasticity of dimorphism and how C. albicans adapts to the varied host environments in pathogenesis. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals during development and cell fate specification.
Author Summary
Many organisms are able to change their phenotype in response to changes in the environment, a phenomenon referred to as plasticity. Candida albicans, a major opportunistic fungal pathogen of humans, can undergo reversible morphological changes between yeast (spherical) and hyphal (filamentous) forms of growth in response to environmental cues. This morphological plasticity is essential for its pathogenesis and survival in its hosts. In this study, we show that hyphal development is initiated and maintained by two major nutrient-sensing cellular growth pathways that act by removing the inhibition provided by the transcriptional repressor Nrg1. While initiation requires a rapid but temporary disappearance of Nrg1 via activation of the cAMP-dependent protein kinase A pathway, maintenance requires the recruitment to promoters of the Hda1 histone deacetylase under conditions of reduced signaling by the target of rapamycin (TOR) kinase, leading to chromatin remodeling that blocks Nrg1 access to the promoters of hypha-specific genes. We observed that recruitment of Hda1 to promoters happens only during the time window when Nrg1 is absent. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals in the regulation of gene expression and phenotypic plasticity during development and cell fate specification.
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Conjugated Linoleic Acid Inhibits Hyphal Growth in Candida albicans by Modulating Ras1p Cellular Levels and Downregulating TEC1 Expression▿†
Shareck, Julie
Nantel, André
Belhumeur, Pierre
Eukaryotic Cell
The polymorphic yeast Candida albicans exists in yeast and filamentous forms. Given that the morphogenetic switch coincides with the expression of many virulence factors, the yeast-to-hypha transition constitutes an attractive target for the development of new antifungal agents. Since an untapped therapeutic potential resides in small molecules that hinder C. albicans filamentation, we characterized the inhibitory effect of conjugated linoleic acid (CLA) on hyphal growth and addressed its mechanism of action. CLA inhibited hyphal growth in a dose-dependent fashion in both liquid and solid hypha-inducing media. The fatty acid blocked germ tube formation without affecting cellular growth rates. Global transcriptional profiling revealed that CLA downregulated the expression of hypha-specific genes and abrogated the induction of several regulators of hyphal growth, including TEC1, UME6, RFG1, and RAS1. However, neither UME6 nor RFG1 was necessary for CLA-mediated hyphal growth inhibition. Expression analysis showed that the downregulation of TEC1 expression levels by CLA depended on RAS1. In addition, while RAS1 transcript levels remained constant in CLA-treated cells, its protein levels declined with time. With the use of a strain expressing GFP-Ras1p, CLA treatment was also shown to affect Ras1p localization to the plasma membrane. These findings suggest that CLA inhibits hyphal growth by affecting the cellular localization of Ras1p and blocking the increase in RAS1 mRNA and protein levels. Combined, these effects should prevent the induction of the Ras1p signaling pathway. This study provides the biological and molecular explanations that underlie CLA's ability to inhibit hyphal growth in C. albicans.
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Role of Hyphal Formation in Interactions of Candida albicans with Endothelial Cells
Phan, Quynh T.
Belanger, Paul H.
Filler, Scott G.
Infection and Immunity
The ability to change from yeast to hyphal morphology is a major virulence determinant of Candida albicans. Mutants with defined defects in filamentation regulatory pathways have reduced virulence in mice. However, is it poorly understood why hyphal formation is critical for C. albicans to cause hematogenously disseminated infections. We used recently constructed mutants to examine the role of hyphal formation in the interactions of C. albicans with endothelial cells in vitro. These interactions included the ability of the mutants to invade and injure endothelial cells. Because the formation of hyphae may influence the host inflammatory response to C. albicans, we also investigated the capacity of these mutants to stimulate endothelial cells to express E-selectin and intercellular adhesion molecule 1. We infected endothelial cells with C. albicans strains containing homozygous null mutations in the following filamentation regulatory genes: CLA4, CPH1, EFG1, and TUP1. Whereas the wild-type strain formed true hyphae on endothelial cells, we found that neither the Δefg1 nor the Δcph1 Δefg1 double mutant germinated. The Δtup1 mutant formed only pseudohyphae. We also found that the Δefg1, Δcph1 Δefg1, and Δtup1 mutants had significantly reduced capacities to invade and injure endothelial cells. Therefore, Efg1p and Tup1p contribute to virulence by regulating hyphal formation and the factors that enable C. albicans to invade and injure endothelial cells. With the exception of the Δcph1 Δefg1 mutant, all other mutants stimulated endothelial cells to express at least one of the leukocyte adhesion molecules. Therefore, the combined activities of Cph1p and Efg1p are required for C. albicans to stimulate a proinflammatory response in endothelial cells.
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A genome-wide transcriptional analysis of morphology determination in Candida albicans
Carlisle, Patricia L.
Kadosh, David
Molecular Biology of the Cell
Morphology determination is critical for virulence of the human fungal pathogen Candida albicans. A genome-wide transcriptional analysis shows that genes associated with specifying the C. albicans pseudohyphal morphology represent a subset of hyphal genes and reveals fundamental differences between forward and reverse morphological transitions.
Candida albicans, the most common cause of human fungal infections, undergoes a reversible morphological transition from yeast to pseudohyphal and hyphal filaments, which is required for virulence. For many years, the relationship among global gene expression patterns associated with determination of specific C. albicans morphologies has remained obscure. Using a strain that can be genetically manipulated to sequentially transition from yeast to pseudohyphae to hyphae in the absence of complex environmental cues and upstream signaling pathways, we demonstrate by whole-genome transcriptional profiling that genes associated with pseudohyphae represent a subset of those associated with hyphae and are generally expressed at lower levels. Our results also strongly suggest that in addition to dosage, extended duration of filament-specific gene expression is sufficient to drive the C. albicans yeast-pseudohyphal-hyphal transition. Finally, we describe the first transcriptional profile of the C. albicans reverse hyphal-pseudohyphal-yeast transition and demonstrate that this transition involves not only down-regulation of known hyphal-specific, genes but also differential expression of additional genes that have not previously been associated with the forward transition, including many involved in protein synthesis. These findings provide new insight into genome-wide expression patterns important for determining fungal morphology and suggest that in addition to similarities, there are also fundamental differences in global gene expression as pathogenic filamentous fungi undergo forward and reverse morphological transitions.
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Regulation of the Cdc42/Cdc24 GTPase Module during Candida albicans Hyphal Growth
Bassilana, Martine
Hopkins, Julie
Arkowitz, Robert A.
Eukaryotic Cell
The Rho G protein Cdc42 and its exchange factor Cdc24 are required for hyphal growth of the human fungal pathogen Candida albicans. Previously, we reported that strains ectopically expressing Cdc24 or Cdc42 are unable to form hyphae in response to serum. Here we investigated the role of these two proteins in hyphal growth, using quantitative real-time PCR to measure induction of hypha-specific genes together with time lapse microscopy. Expression of the hypha-specific genes examined depends on the cyclic AMP-dependent protein kinase A pathway culminating in the Efg1 and Tec1 transcription factors. We show that strains with reduced levels of CDC24 or CDC42 transcripts induce hypha-specific genes yet cannot maintain their expression in response to serum. Furthermore, in serum these mutants form elongated buds compared to the wild type and mutant budding cells, as observed by time lapse microscopy. Using Cdc24 fused to green fluorescent protein, we also show that Cdc24 is recruited to and persists at the germ tube tip during hyphal growth. Altogether these data demonstrate that the Cdc24/Cdc42 GTPase module is required for maintenance of hyphal growth. In addition, overexpression studies indicate that specific levels of Cdc24 and Cdc42 are important for invasive hyphal growth. In response to serum, CDC24 transcript levels increase transiently in a Tec1-dependent fashion, as do the G-protein RHO3 and the Rho1 GTPase activating protein BEM2 transcript levels. These results suggest that a positive feedback loop between Cdc24 and Tec1 contributes to an increase in active Cdc42 at the tip of the germ tube which is important for hypha formation.
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Telomeric ORFs (TLOs) in Candida spp. Encode Mediator Subunits That Regulate Distinct Virulence Traits
Haran, John
Boyle, Hannah
Hokamp, Karsten
Yeomans, Tim
Liu, Zhongle
Church, Michael
Fleming, Alastair B.
Anderson, Matthew Z.
Berman, Judith
Myers, Lawrence C.
Sullivan, Derek J.
Moran, Gary P.
PLoS Genetics
The TLO genes are a family of telomere-associated ORFs in the fungal pathogens Candida albicans and C. dubliniensis that encode a subunit of the Mediator complex with homology to Med2. The more virulent pathogen C. albicans has 15 copies of the gene whereas the less pathogenic species C. dubliniensis has only two (CdTLO1 and CdTLO2). In this study we used C. dubliniensis as a model to investigate the role of TLO genes in regulating virulence and also to determine whether TLO paralogs have evolved to regulate distinct functions. A C. dubliniensis tlo1Δ/tlo2Δ mutant is unable to form true hyphae, has longer doubling times in galactose broth, is more susceptible to oxidative stress and forms increased levels of biofilm. Transcript profiling of the tlo1Δ/tlo2Δ mutant revealed increased expression of starvation responses in rich medium and retarded expression of hypha-induced transcripts in serum. ChIP studies indicated that Tlo1 binds to many ORFs including genes that exhibit high and low expression levels under the conditions analyzed. The altered expression of these genes in the tlo1Δ/tlo2Δ null mutant indicates roles for Tlo proteins in transcriptional activation and repression. Complementation of the tlo1Δ/tlo2Δ mutant with TLO1, but not TLO2, restored wild-type filamentous growth, whereas only TLO2 fully suppressed biofilm growth. Complementation with TLO1 also had a greater effect on doubling times in galactose broth. The different abilities of TLO1 and TLO2 to restore wild-type functions was supported by transcript profiling studies that showed that only TLO1 restored expression of hypha-specific genes (UME6, SOD5) and galactose utilisation genes (GAL1 and GAL10), whereas TLO2 restored repression of starvation-induced gene transcription. Thus, Tlo/Med2 paralogs encoding Mediator subunits regulate different virulence properties in Candida spp. and their expansion may account for the increased adaptability of C. albicans relative to other Candida species.
Author Summary
Candida albicans and C. dubliniensis are fungal pathogens of humans. Both species possess TLO genes encoding proteins with homology to the Med2 subunit of Mediator. The more virulent pathogen C. albicans has 15 copies of the TLO gene whereas the less pathogenic species C. dubliniensis has only two (TLO1 and TLO2). In this study we show that a C. dubliniensis mutant missing both TLO1 and TLO2 is defective in virulence functions, including hyphal growth and stress responses but forms increased levels of biofilm. Analysis of gene expression in the tlo1Δ/tlo2Δ mutant revealed extensive differences relative to wild-type cells, including aberrant expression of starvation responses in nutrient-rich medium and retarded expression of hypha-induced transcripts in serum. Tlo1 protein was found to interact with genes and this was associated with both gene activation and repression. TLO1 was found to be better at restoring hyphal growth compared to TLO2 and but was less effective than TLO2 in supressing biofilm formation in the tlo1Δ/tlo2Δ strain. Thus, Tlo proteins regulate many virulence properties in Candida spp. and the expansion of the TLO family in C. albicans may account for the increased adaptability of this species relative to other Candida species.
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Candida albicans Int1p Interacts with the Septin Ring in Yeast and Hyphal Cells
Gale, Cheryl
Gerami-Nejad, Maryam
McClellan, Mark
Vandoninck, Sandy
Longtine, Mark S.
Berman, Judith
Molecular Biology of the Cell
The ability to switch between yeast and hyphal morphologies is an important virulence factor for the opportunistic pathogen Candida albicans. Although the kinetics of appearance of the filamentous ring that forms at the incipient septum differ in yeast and cells forming hyphae (germ tubes) (Soll and Mitchell, 1983), the molecular mechanisms that regulate this difference are not known. Int1p, a C. albicans gene product with similarity in its C terminus to Saccharomyces cerevisiae Bud4p, has a role in hyphal morphogenesis. Here we report that in S. cerevisiae, Int1p expression results in the growth of highly polarized cells with delocalized chitin and defects in cytokinesis and bud-site selection patterns, phenotypes that are also seen in S. cerevisiae septin mutant strains. Expression of high levels of Int1p in S. cerevisiae generated elaborate spiral-like structures at the periphery of the polarized cells that contained septins and Int1p. In addition, Int1p coimmunoprecipitated with the Cdc11p and Cdc12p septins, and Cdc12p is required for the establishment and maintenance of these Int1p/septin spirals. Although Swe1p kinase contributes to INT1-induced filamentous growth in S. cerevisiae, it is not required for the formation of ectopic Int1p/septin structures. In C. albicans, Int1p was important for the axial budding pattern and colocalized with Cdc3p septin in a ring at the mother-bud neck of yeast and pseudohyphal cells. Under conditions that induce hyphae, both Cdc3p and Int1p localized to a ring distal to the junction of the mother cell and germ tube. Thus, placement of the Int1p/septin ring with respect to the mother–daughter cell junction distinguishes yeast/pseudohyphal growth from hyphal growth in C. albicans.
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Modulation of Phagosomal pH by Candida albicans Promotes Hyphal Morphogenesis and Requires Stp2p, a Regulator of Amino Acid Transport
Vylkova, Slavena
Lorenz, Michael C.
PLoS Pathogens
Candida albicans, the most important fungal pathogen of humans, has a unique interaction with macrophages in which phagocytosis induces a switch from the yeast to hyphal form, allowing it to escape by rupturing the immune cell. While a variety of factors induce this switch in vitro, including neutral pH, it is not clear what triggers morphogenesis within the macrophage where the acidic environment should inhibit this transition. In vitro, C. albicans grown in similar conditions in which amino acids are the primary carbon source generate large quantities of ammonia to raise the extracellular pH and induce the hyphal switch. We show here that C. albicans cells neutralize the macrophage phagosome and that neutral pH is a key inducer of germination in phagocytosed cells by using a mutant lacking STP2, a transcription factor that regulates the expression of multiple amino acid permeases, that is completely deficient in alkalinization in vitro. Phagocytosed stp2Δ mutant cells showed significant reduction in hypha formation and escaped from macrophages less readily compared to wild type cells; as a result stp2Δ mutant cells were killed at a higher rate and caused less damage to RAW264.7 macrophages. Stp2p-regulated import leads to alkalinization of the phagosome, since the majority of the wild type cells fail to co-localize with acidophilic dyes, whereas the stp2Δ mutant cells were located in acidic phagosomes. Furthermore, stp2Δ mutant cells were able to form hyphae and escape from neutral phagosomes, indicating that the survival defect in these cells was pH dependent. Finally, these defects are reflected in an attenuation of virulence in a mouse model of disseminated candidiasis. Altogether our results suggest that C. albicans utilizes amino acids to promote neutralization of the phagosomal pH, hyphal morphogenesis, and escape from macrophages.
Author Summary
The innate immune system represents a key barrier that fungal pathogens such as Candida albicans must overcome in order to disseminate through the host. C. albicans cells phagocytosed by macrophages initiate a complex program that involves a large-scale reprogramming of metabolism and transcription and results in the switch to a hyphal form that can penetrate and kill the macrophage. Though a number of signals are known to induce this morphological transition in vitro, what does so following phagocytosis has been unclear. We previously showed that C. albicans rapidly neutralizes acidic, nutrient-poor media that resembles the phagolysosome and that this is deficient in mutants impaired in amino acid import due to a mutation in STP2. In this paper, we investigate whether this happens within the macrophage as well. We show here that, in contrast to wild-type cells, stp2Δ mutants occupy an acidic phagosome and are unable to initiate hyphal differentiation. Because of this, they are more sensitive to killing and do less damage to the macrophages than cells that can neutralize the phagolysosome. We conclude that alteration of phagosomal pH is an important virulence adaptation in this species.
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The Candida albicans HYR1 gene, which is activated in response to hyphal development, belongs to a gene family encoding yeast cell wall proteins.
Bailey, D A
Feldmann, P J
Bovey, M
Gow, N A
Brown, A J
Journal of Bacteriology
A hyphally regulated gene (HYR1) from the dimorphic human pathogenic fungus Candida albicans was isolated and characterized. Northern (RNA) analyses showed that the HYR1 mRNA was induced specifically in response to hyphal development when morphogenesis was stimulated by serum addition and temperature elevation, increases in both culture pH and temperature, or N-acetylglucosamine addition. The HYR1 gene sequence revealed a 937-codon open reading frame capable of encoding a protein with an N-terminal signal sequence, a C-terminal glycosylphosphatidylinositol-anchoring domain, 17 potential N glycosylation sites, and a large domain rich in serine and threonine (51% of 230 residues). These features are observed in many yeast cell wall proteins, but no homologs are present in the databases. In addition, Hyr1p contained a second domain rich in glycine, serine, and asparagine (79% of 239 residues). The HYR1 locus in C. albicans CAI4 was disrupted by "Ura-blasting," but the resulting homozygous delta hyr1/delta hyr1 null mutant displayed no obvious morphological phenotype. The growth rates for yeast cells and hyphae and the kinetics of germ tube formation in the null mutant were unaffected. Aberrant expression of HYR1 in yeast cells, when an ADH1-HYR1 fusion was used, did not stimulate hyphal formation in C. albicans or pseudohyphal growth in Saccharomyces cerevisiae. HYR1 appears to encode a nonessential component of the hyphal cell wall.
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The Pathogen Candida albicans Hijacks Pyroptosis for Escape from Macrophages
Uwamahoro, Nathalie
Verma-Gaur, Jiyoti
Shen, Hsin-Hui
Qu, Yue
Lewis, Rowena
Lu, Jingxiong
Bambery, Keith
Masters, Seth L.
Vince, James E.
Naderer, Thomas
Traven, Ana
The fungal pathogen Candida albicans causes macrophage death and escapes, but the molecular mechanisms remained unknown. Here we used live-cell imaging to monitor the interaction of C. albicans with macrophages and show that C. albicans kills macrophages in two temporally and mechanistically distinct phases. Early upon phagocytosis, C. albicans triggers pyroptosis, a proinflammatory macrophage death. Pyroptosis is controlled by the developmental yeast-to-hypha transition of Candida. When pyroptosis is inactivated, wild-type C. albicans hyphae cause significantly less macrophage killing for up to 8 h postphagocytosis. After the first 8 h, a second macrophage-killing phase is initiated. This second phase depends on robust hyphal formation but is mechanistically distinct from pyroptosis. The transcriptional regulator Mediator is necessary for morphogenesis of C. albicans in macrophages and the establishment of the wild-type surface architecture of hyphae that together mediate activation of macrophage cell death. Our data suggest that the defects of the Mediator mutants in causing macrophage death are caused, at least in part, by reduced activation of pyroptosis. A Mediator mutant that forms hyphae of apparently wild-type morphology but is defective in triggering early macrophage death shows a breakdown of cell surface architecture and reduced exposed 1,3 β-glucan in hyphae. Our report shows how Candida uses host and pathogen pathways for macrophage killing. The current model of mechanical piercing of macrophages by C. albicans hyphae should be revised to include activation of pyroptosis by hyphae as an important mechanism mediating macrophage cell death upon C. albicans infection.
Upon phagocytosis by macrophages, Candida albicans can transition to the hyphal form, which causes macrophage death and enables fungal escape. The current model is that the highly polarized growth of hyphae results in macrophage piercing. This model is challenged by recent reports of C. albicans mutants that form hyphae of wild-type morphology but are defective in killing macrophages. We show that C. albicans causes macrophage cell death by at least two mechanisms. Phase 1 killing (first 6 to 8 h) depends on the activation of the pyroptotic programmed host cell death by fungal hyphae. Phase 2 (up to 24 h) is rapid and depends on robust hyphal formation but is independent of pyroptosis. Our data provide a new model for how the interplay between fungal morphogenesis and activation of a host cell death pathway mediates macrophage killing by C. albicans hyphae.
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A Functional Portrait of Med7 and the Mediator Complex in Candida albicans
Tebbji, Faiza
Chen, Yaolin
Richard Albert, Julien
Gunsalus, Kearney T. W.
Kumamoto, Carol A.
Nantel, André
Sellam, Adnane
Whiteway, Malcolm
PLoS Genetics
Mediator is a multi-subunit protein complex that regulates gene expression in eukaryotes by integrating physiological and developmental signals and transmitting them to the general RNA polymerase II machinery. We examined, in the fungal pathogen Candida albicans, a set of conditional alleles of genes encoding Mediator subunits of the head, middle, and tail modules that were found to be essential in the related ascomycete Saccharomyces cerevisiae. Intriguingly, while the Med4, 8, 10, 11, 14, 17, 21 and 22 subunits were essential in both fungi, the structurally highly conserved Med7 subunit was apparently non-essential in C. albicans. While loss of CaMed7 did not lead to loss of viability under normal growth conditions, it dramatically influenced the pathogen's ability to grow in different carbon sources, to form hyphae and biofilms, and to colonize the gastrointestinal tracts of mice. We used epitope tagging and location profiling of the Med7 subunit to examine the distribution of the DNA sites bound by Mediator during growth in either the yeast or the hyphal form, two distinct morphologies characterized by different transcription profiles. We observed a core set of 200 genes bound by Med7 under both conditions; this core set is expanded moderately during yeast growth, but is expanded considerably during hyphal growth, supporting the idea that Mediator binding correlates with changes in transcriptional activity and that this binding is condition specific. Med7 bound not only in the promoter regions of active genes but also within coding regions and at the 3′ ends of genes. By combining genome-wide location profiling, expression analyses and phenotyping, we have identified different Med7p-influenced regulons including genes related to glycolysis and the Filamentous Growth Regulator family. In the absence of Med7, the ribosomal regulon is de-repressed, suggesting Med7 is involved in central aspects of growth control.
Author Summary
In this study, we have investigated Mediator function in the human fungal pathogen C. albicans. An initial screening of conditionally regulated Mediator subunits showed that the Med7 of C. albicans was not essential, in contrast to the situation noted for S. cerevisiae. While loss of CaMed7 did not lead to loss of viability under normal growth conditions, it dramatically influenced the pathogen's ability to grow in different carbon sources, to form hyphae and biofilms, and to colonize the gastrointestinal tracts of mice. We used location profiling to determine Mediator binding under yeast and hyphal morphologies characterized by different transcription profiles. We observed a core set of specific and common genes bound by Med7 under both conditions; this specific core set is expanded considerably during hyphal growth, supporting the idea that Mediator binding correlates with changes in transcriptional activity and that this binding is condition specific. Med7 bound not only in the promoter regions of active genes but also of inactive genes and within coding regions and at the 3′ ends of genes. By combining genome-wide location profiling, expression analyses and phenotyping, we have identified different Med7 regulons including genes related to glycolysis and the Filamentous Growth Regulator family.
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A Forkhead Transcription Factor Is Important for True Hyphal as well as Yeast Morphogenesis in Candida albicans
Bensen, Eric S.
Filler, Scott G.
Berman, Judith
Eukaryotic Cell
Candida albicans is an important pathogen of immunocompromised patients which grows with true hyphal, pseudohyphal, and yeast morphologies. The dynamics of cell cycle progression are markedly different in true hyphal relative to pseudohyphal and yeast cells, including nuclear movement and septin ring positioning. In Saccharomyces cerevisiae, two forkhead transcription factors (ScFKH1 and ScFKH2) regulate the expression of B-cyclin genes. In both S. cerevisiae and Schizosaccharomyces pombe, forkhead transcription factors also influence morphogenesis. To explore the molecular mechanisms that connect C. albicans morphogenesis with cell cycle progression, we analyzed CaFKH2, the single homolog of S. cerevisiae FKH1/FKH2. C. albicans cells lacking CaFkh2p formed constitutive pseudohyphae under all yeast and hyphal growth conditions tested. Under hyphal growth conditions levels of hyphae-specific mRNAs were reduced, and under yeast growth conditions levels of several genes encoding proteins likely to be important for cell wall separation were reduced. Together these results imply that Fkh2p is required for the morphogenesis of true hyphal as well as yeast cells. Efg1p and Cph1p, two transcription factors that contribute to C. albicans hyphal growth, were not required for the pseudohyphal morphology of fkh2 mutants, implying that Fkh2p acts in pathways downstream of and/or parallel to Efg1p and Cph1p. In addition, cells lacking Fkh2p were unable to damage human epithelial or endothelial cells in vitro, suggesting that Fkh2p contributes to C. albicans virulence.
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Depletion of a Polo-like Kinase in Candida albicans Activates Cyclase-dependent Hyphal-like Growth
Bachewich, Catherine
Thomas, David Y.
Whiteway, Malcolm
Molecular Biology of the Cell
Morphogenesis in the fungal pathogen Candida albicans is an important virulence-determining factor, as a dimorphic switch between yeast and hyphal growth forms can increase pathogenesis. We identified CaCDC5, a cell cycle regulatory polo-like kinase (PLK) in C. albicans and demonstrate that shutting off its expression induced cell cycle defects and dramatic changes in morphology. Cells lacking CaCdc5p were blocked early in nuclear division with very short spindles and unseparated chromatin. GFP-tagged CaCdc5p localized to unseparated spindle pole bodies, the spindle, and chromatin, consistent with a role in spindle elongation at an earlier point in the cell cycle than that described for the homologue Cdc5p in yeast. Strikingly, the cell cycle defects were accompanied by the formation of hyphal-like filaments under yeast growth conditions. Filament growth was determinate, as the filaments started to die after 24 h. The filaments resembled serum-induced hyphae with respect to morphology, organization of cytoplasmic microtubules, localization of nuclei, and expression of hyphal-specific components. Filament formation required CaCDC35, but not EFG1 or CPH1. Similar defects in spindle elongation and a corresponding induction of filaments occurred when yeast cells were exposed to hydroxyurea. Because CaCdc5p does not appear to act as a direct repressor of hyphal growth, the data suggest that a target of CaCdc5p function is associated with hyphal-like development. Thus, an internal, cell cycle–related cue can activate hyphal regulatory networks in Candida.
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Candida albicans VAC8 Is Required for Vacuolar Inheritance and Normal Hyphal Branching
Barelle, Caroline J.
Richard, Mathias L.
Gaillardin, Claude
Gow, Neil A. R.
Brown, Alistair J. P.
Eukaryotic Cell
Hyphal growth is prevalent during most Candida albicans infections. Current cell division models, which are based on cytological analyses of C. albicans, predict that hyphal branching is intimately linked with vacuolar inheritance in this fungus. Here we report the molecular validation of this model, showing that a specific mutation that disrupts vacuolar inheritance also affects hyphal division. The armadillo repeat-containing protein Vac8p plays an important role in vacuolar inheritance in Saccharomyces cerevisiae. The VAC8 gene was identified in the C. albicans genome sequence and was resequenced. Homozygous C. albicans vac8Δ deletion mutants were generated, and their phenotypes were examined. Mutant vac8Δ cells contained fragmented vacuoles, and minimal vacuolar material was inherited by daughter cells in hyphal or budding forms. Normal rates of growth and hyphal extension were observed for the mutant hyphae on solid serum-containing medium. However, branching frequencies were significantly increased in the mutant hyphae. These observations are consistent with a causal relationship between vacuolar inheritance and the cell division cycle in the subapical compartments of C. albicans hyphae. The data support the hypothesis that cytoplasmic volume, rather than cell size, is critical for progression through G1.
Related Articles
Candida albicans Morphogenesis Is Not Required for Macrophage Interleukin 1β Production
Wellington, Melanie
Koselny, Kristy
Krysan, Damian J.
The interaction of Candida albicans with macrophages induces the production of interleukin 1β (IL-1β) through inflammasome activation in a process that is required for host survival. C. albicans hypha formation has been linked to IL-1β production, but the question of whether hyphae are sufficient to trigger IL-1β production has not been examined directly. To address this question, a C. albicans library of 165 transcription factor deletion mutants was screened for strains with altered IL-1β production by lipopolysaccharide (LPS)-primed J774 cells, a murine macrophage-like cell line. Eight mutants with decreased and two mutants with increased IL-1β secretion were identified. In addition, 12 mutants with previously identified morphology deficits were found to induce IL-1β secretion to levels similar to those of the wild type. Examination of the morphology of both low and normal IL-1β-inducing mutants in macrophages revealed that two mutants (upc2Δ/upc2Δ and ahr1Δ/Δ mutants) were indistinguishable from the wild type with respect to morphology yet induced low levels of IL-1β; conversely, the ndt80Δ/Δ mutant was deficient for hypha formation but induced levels of IL-1β similar to those of the wild type. Transcription factor mutants deficient for IL-1β secretion also caused markedly lower levels of macrophage lysis. Similarly, the ability of a mutant to cause macrophage lysis was independent of its ability to form hyphae. Taken together, our observations indicate that the physical formation of hyphae is not sufficient to trigger IL-1β secretion or macrophage lysis and suggest that other mechanisms, such as pyroptosis, a caspase-1-dependent response to intracellular pathogens, may play a role in the interaction of macrophages with C. albicans.
The ability of Candida albicans to transition from yeast to filamentous cells plays an important and complex role in pathogenesis. Recent results from a number of investigators indicate that the host responds to yeast and hyphal C. albicans differently. For example, a C. albicans mutant unable to form hyphae also fails to induce interleukin 1β (IL-1β) secretion from macrophages. We have identified C. albicans transcription factor mutants that have decreased IL-1β secretion but retain the ability to form hyphae in response to macrophages. In addition, these mutants cause significantly less macrophage lysis. These observations indicate that the physical presence of the hyphal structure in the macrophage is not sufficient to trigger IL-1β secretion nor does it cause physical lysis of the cell. Our data indicate that characteristics of hyphae separate from its physical morphology are responsible for triggering the release of IL-1β release and causing macrophage lysis. Since these observations are inconsistent with some current models, alternative mechanisms for the interaction of C. albicans with macrophages must be considered.
Related Articles
Candida albicans Hyphal Formation and Virulence Assessed Using a Caenorhabditis elegans Infection Model ▿
Pukkila-Worley, Read
Peleg, Anton Y.
Tampakakis, Emmanouil
Mylonakis, Eleftherios
Eukaryotic Cell
Candida albicans colonizes the human gastrointestinal tract and can cause life-threatening systemic infection in susceptible hosts. We study here C. albicans virulence determinants using the nematode Caenorhabditis elegans in a pathogenesis system that models candidiasis. The yeast form of C. albicans is ingested into the C. elegans digestive tract. In liquid media, the yeast cells then undergo morphological change to form hyphae, which results in aggressive tissue destruction and death of the nematode. Several lines of evidence demonstrate that hyphal formation is critical for C. albicans pathogenesis in C. elegans. First, two yeast species unable to form hyphae (Debaryomyces hansenii and Candida lusitaniae) were less virulent than C. albicans in the C. elegans assay. Second, three C. albicans mutant strains compromised in their ability to form hyphae (efg1Δ/efg1Δ, flo8Δ/flo8Δ, and cph1Δ/cph1Δ efg1Δ/efg1Δ) were dramatically attenuated for virulence. Third, the conditional tet-NRG1 strain, which enables the external manipulation of morphogenesis in vivo, was more virulent toward C. elegans when the assay was conducted under conditions that permit hyphal growth. Finally, we demonstrate the utility of the C. elegans assay in a screen for C. albicans virulence determinants, which identified several genes important for both hyphal formation in vivo and the killing of C. elegans, including the recently described CAS5 and ADA2 genes. These studies in a C. elegans-C. albicans infection model provide insights into the virulence mechanisms of an important human pathogen.
Related Articles
Candida albicans Hyphal Formation and the Expression of the Efg1-Regulated Proteinases Sap4 to Sap6 Are Required for the Invasion of Parenchymal Organs
Felk, Angelika
Kretschmar, Marianne
Albrecht, Antje
Schaller, Martin
Beinhauer, Sabine
Nichterlein, Thomas
Sanglard, Dominique
Korting, Hans C.
Schäfer, Wilhelm
Hube, Bernhard
Infection and Immunity
The ability to change between yeast and hyphal cells (dimorphism) is known to be a virulence property of the human pathogen Candida albicans. The pathogenesis of disseminated candidosis involves adhesion and penetration of hyphal cells from a colonized mucosal site to internal organs. Parenchymal organs, such as the liver and pancreas, are invaded by C. albicans wild-type hyphal cells between 4 and 24 h after intraperitoneal (i.p.) infection of mice. In contrast, a hypha-deficient mutant lacking the transcription factor Efg1 was not able to invade or damage these organs. To investigate whether this was due to the inability to undergo the dimorphic transition or due to the lack of hypha-associated factors, we investigated the role of secreted aspartic proteinases during tissue invasion and their association with the different morphologies of C. albicans. Wild-type cells expressed a distinct pattern of SAP genes during i.p. infections. Within the first 72 h after infection, SAP1, SAP2, SAP4, SAP5, SAP6, and SAP9 were the most commonly expressed proteinase genes. Sap1 to Sap3 antigens were found on yeast and hyphal cells, while Sap4 to Sap6 antigens were predominantly found on hyphal cells in close contact with host cells, in particular, eosinophilic leukocytes. Mutants lacking EFG1 had either noticeably reduced or higher expressed levels of SAP4 to SAP6 transcripts in vitro depending on the culture conditions. During infection, efg1 mutants had a strongly reduced ability to produce hyphae, which was associated with reduced levels of SAP4 to SAP6 transcripts. Mutants lacking SAP1 to SAP3 had invasive properties indistinguishable from those of wild-type cells. In contrast, a triple mutant lacking SAP4 to SAP6 showed strongly reduced invasiveness but still produced hyphal cells. When the tissue damage of liver and pancreas caused by single sap4, sap5, and sap6 and double sap4 and -6, sap5 and -6, and sap4 and -5 double mutants was compared to the damage caused by wild-type cells, all mutants which lacked functional SAP6 showed significantly reduced tissue damage. These data demonstrate that strains which produce hyphal cells but lack hypha-associated proteinases, particularly that encoded by SAP6, are less invasive. In addition, it can be concluded that the reduced virulence of hypha-deficient mutants is not only due to the inability to form hyphae but also due to modified expression of the SAP genes normally associated with the hyphal morphology.
Related Articles
The G1 Cyclin Cln3 Regulates Morphogenesis in Candida albicans
Lazo, Bernardo Chapa y
Bates, Steven
Sudbery, Peter
Eukaryotic Cell
In Saccharomyces cerevisiae, the G1 cyclin Cln3 initiates the Start of a mitotic cell cycle in response to size and nutrient inputs. Loss of Cln3 delays but does not prevent Start, due to the eventual Cln3-independent transcription of CLN1 and CLN2. When unbudded cells of the human pathogen Candida albicans were depleted of the G1 cyclin Cln3 they increased in size but did not bud. Thus, unlike S. cerevisiae, Cln3 is essential for budding in C. albicans. However, eventually the large unbudded cells spontaneously produced filamentous forms. The morphology was growth medium dependent; on nutritionally poor medium the polarized outgrowths fulfilled the formal criteria for true hyphae. This state is stable, and continued growth leads to a hyphal mycelium, which invades the agar substratum. Interestingly, it is also required for normal hyphal development, as Cln3-depleted cells develop morphological abnormalities if challenged with hyphal inducing signals such as serum or neutral pH. Taken together, these results show that, in C. albicans, Cln3 has assumed a critical role in coordinating mitotic cell division with differentiation.
Related Articles
Release from Quorum-Sensing Molecules Triggers Hyphal Formation during Candida albicans Resumption of Growth†
Enjalbert, Brice
Whiteway, Malcolm
Eukaryotic Cell
Candida albicans is a pathogenic fungus able to change morphology in response to variations in its growth environment. Simple inoculation of stationary cells into fresh medium at 37°C, without any other manipulations, appears to be a powerful but transient inducer of hyphal formation; this process also plays a significant role in classical serum induction of hyphal formation. The mechanism appears to involve the release of hyphal repression caused by quorum-sensing molecules in the growth medium of stationary-phase cells, and farnesol has a strong but incomplete role in this process. We used DNA microarray technology to study both the resumption of growth of Candida albicans cells and molecular regulation involving farnesol. Maintaining farnesol in the culture medium during the resumption of growth both delays and reduces the induction of hypha-related genes yet triggers expression of genes encoding drug efflux components. The persistence of farnesol also prevents the repression of histone genes during hyphal growth and affects the expression of putative or demonstrated morphogenesis-regulating cyclin genes, such as HGC1, CLN3, and PCL2. The results suggest a model explaining the triggering of hyphae in the host based on quorum-sensing molecules.
Related Articles
CAP1, an Adenylate Cyclase-Associated Protein Gene, Regulates Bud-Hypha Transitions, Filamentous Growth, and Cyclic AMP Levels and Is Required for Virulence of Candida albicans
Bahn, Yong-Sun
Sundstrom, Paula
Journal of Bacteriology
In response to a wide variety of environmental stimuli, the opportunistic fungal pathogen Candida albicans exits the budding cycle, producing germ tubes and hyphae concomitant with expression of virulence genes, such as that encoding hyphal wall protein 1 (HWP1). Biochemical studies implicate cyclic AMP (cAMP) increases in promoting bud-hypha transitions, but genetic evidence relating genes that control cAMP levels to bud-hypha transitions has not been reported. Adenylate cyclase-associated proteins (CAPs) of nonpathogenic fungi interact with Ras and adenylate cyclase to increase cAMP levels under specific environmental conditions. To initiate studies on the relationship between cAMP signaling and bud-hypha transitions in C. albicans, we identified, cloned, characterized, and disrupted the C. albicans CAP1 gene. C. albicans strains with inactivated CAP1 budded in conditions that led to germ tube formation in isogenic strains with CAP1. The addition of 10 mM cAMP and dibutyryl cAMP promoted bud-hypha transitions and filamentous growth in the cap1/cap1 mutant in liquid and solid media, respectively, showing clearly that cAMP promotes hypha formation in C. albicans. Increases in cytoplasmic cAMP preceding germ tube emergence in strains having CAP1 were markedly diminished in the budding cap1/cap1 mutant. C. albicans strains with deletions of both alleles of CAP1 were avirulent in a mouse model of systemic candidiasis. The avirulence of a germ tube-deficient cap1/cap1 mutant coupled with the role of Cap1 in regulating cAMP levels shows that the Cap1-mediated cAMP signaling pathway is required for bud-hypha transitions, filamentous growth, and the pathogenesis of candidiasis.
Related Articles
Small-Molecule Inhibitors of the Budded-to-Hyphal-Form Transition in the Pathogenic Yeast Candida albicans
Toenjes, Kurt A.
Munsee, Suzanne M.
Ibrahim, Ashraf S.
Jeffrey, Rachel
Edwards, John E.
Johnson, Douglas I.
Antimicrobial Agents and Chemotherapy
The pathogenic yeast Candida albicans can exist in multiple morphological states, including budded, pseudohyphal, and true hyphal forms. The ability to convert between the budded and hyphal forms, termed the budded-to-hyphal-form transition, is important for virulence and is regulated by multiple environmental and cellular signals. To identify inhibitors of this morphological transition, a microplate-based morphological assay was developed. With this assay, the known actin-inhibiting drugs latrunculin-A and jasplakinolide were shown to inhibit the transition in a dose-dependent and reversible manner. Five novel small molecules that reversibly inhibited the transition and hyphal elongation without affecting budded growth were identified. These molecules inhibited hyphal growth induced by Spider, Lee's, M199 pH 8, and 10% serum-containing media, with two molecules having a synergistic effect. The molecules also differentially affected the hyphal form-specific gene expression of HWP1 and endocytosis without disrupting the actin cytoskeleton or septin organization. Structural derivatives of one of the molecules were more effective inhibiters than the original molecule, while other derivatives had decreased efficacies. Several of the small molecules were able to reduce C. albicans-dependent damage to endothelial cells by inhibiting the budded-to-hyphal-form transition. These studies substantiated the effectiveness of the morphological assay and identified several novel molecules that, by virtue of their ability to inhibit the budded-to-hyphal-form transition, may be exploited as starting points for effective antifungal therapeutics in the future.
Related Articles
Transcription Profiling of Candida albicans Cells Undergoing the Yeast-to-Hyphal TransitionD⃞
Nantel, André
Dignard, Daniel
Bachewich, Catherine
Harcus, Doreen
Marcil, Anne
Bouin, Anne-Pascale
Sensen, Christoph W.
Hogues, Hervé
van het Hoog, Marco
Gordon, Paul
Rigby, Tracey
Benoit, François
Tessier, Daniel C.
Thomas, David Y.
Whiteway, Malcolm
Molecular Biology of the Cell
The ability of the pathogenic fungus Candida albicans to switch from a yeast to a hyphal morphology in response to external signals is implicated in its pathogenicity. We used glass DNA microarrays to investigate the transcription profiles of 6333 predicted ORFs in cells undergoing this transition and their responses to changes in temperature and culture medium. We have identified several genes whose transcriptional profiles are similar to those of known virulence factors that are modulated by the switch to hyphal growth caused by addition of serum and a 37°C growth temperature. Time course analysis of this transition identified transcripts that are induced before germ tube initiation and shut off later in the developmental process. A strain deleted for the Efg1p and Cph1p transcription factors is defective in hyphae formation, and its response to serum and increased temperature is almost identical to the response of a wild-type strain grown at 37°C in the absence of serum. Thus Efg1p and Cph1p are needed for the activation of the transcriptional program that is induced by the presence of serum.
Related Articles
Microevolution of Candida albicans in Macrophages Restores Filamentation in a Nonfilamentous Mutant
Wartenberg, Anja
Linde, Jörg
Martin, Ronny
Schreiner, Maria
Horn, Fabian
Jacobsen, Ilse D.
Jenull, Sabrina
Wolf, Thomas
Kuchler, Karl
Guthke, Reinhard
Kurzai, Oliver
Forche, Anja
d'Enfert, Christophe
Brunke, Sascha
Hube, Bernhard
PLoS Genetics
Following antifungal treatment, Candida albicans, and other human pathogenic fungi can undergo microevolution, which leads to the emergence of drug resistance. However, the capacity for microevolutionary adaptation of fungi goes beyond the development of resistance against antifungals. Here we used an experimental microevolution approach to show that one of the central pathogenicity mechanisms of C. albicans, the yeast-to-hyphae transition, can be subject to experimental evolution. The C. albicans cph1Δ/efg1Δ mutant is nonfilamentous, as central signaling pathways linking environmental cues to hyphal formation are disrupted. We subjected this mutant to constant selection pressure in the hostile environment of the macrophage phagosome. In a comparatively short time-frame, the mutant evolved the ability to escape macrophages by filamentation. In addition, the evolved mutant exhibited hyper-virulence in a murine infection model and an altered cell wall composition compared to the cph1Δ/efg1Δ strain. Moreover, the transcriptional regulation of hyphae-associated, and other pathogenicity-related genes became re-responsive to environmental cues in the evolved strain. We went on to identify the causative missense mutation via whole genome- and transcriptome-sequencing: a single nucleotide exchange took place within SSN3 that encodes a component of the Cdk8 module of the Mediator complex, which links transcription factors with the general transcription machinery. This mutation was responsible for the reconnection of the hyphal growth program with environmental signals in the evolved strain and was sufficient to bypass Efg1/Cph1-dependent filamentation. These data demonstrate that even central transcriptional networks can be remodeled very quickly under appropriate selection pressure.
Author Summary
Pathogenic microbes often evolve complex traits to adapt to their respective hosts, and this evolution is ongoing: for example, microorganisms are developing resistance to antimicrobial compounds in the clinical setting. The ability of the common human pathogenic fungus, Candida albicans, to switch from yeast to hyphal (filamentous) growth is considered a central virulence attribute. For example, hyphal formation allows C. albicans to escape from macrophages following phagocytosis. A well-investigated signaling network integrates different environmental cues to induce and maintain hyphal growth. In fact, deletion of two central transcription factors in this network results in a mutant that is both nonfilamentous and avirulent. We used experimental evolution to study the adaptation capability of this mutant by continuous co-incubation within macrophages. We found that this selection regime led to a relatively rapid re-connection of signaling between environmental cues and the hyphal growth program. Indeed, the evolved mutant regained the ability to filament and its virulence in vivo. This bypass of central transcription factors was based on a single nucleotide exchange in a gene encoding a component of the general transcription regulation machinery. Our results show that even a complex regulatory network, such as the transcriptional network which governs hyphal growth, can be remodeled via microevolution.
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"How Much is Bob Barker Income"
Profession:Game Show Host, Presenter
Date of Birth: Dec 12, 1923
Nicknames: Robert William Barker
Height: 1.85 m
Ethnicity: Caucasian American, Sioux
Country: United States of America
Date of Birth: Dec 12, 1923
Nicknames: Robert William Barker
Height: 1.85 m
Ethnicity: Caucasian American, Sioux
Country: United States of America
Bob Barker
Bob Barker Net Worth is $70 Million. Robert William "Bob" Barker is an American former TV game show host and a full-fledged TV legend and icon. Born on December 12, 1923 he has an estimated net worth of $70 million and the distinction of having been. Robert William "Bob" Barker (...
Bob Barker Net Worth is $70 Million.Bob Barker Net Worth is $70 Million. Robert William "Bob" Barker is an American former TV game show host and a full-fledged TV legend and icon. Born on December 12, 1923 he has an estimated net worth of $70 million and the distinction of having been Robert William "Bob" Barker is a former American television game show host. He is best known for hosting CBS's The Price Is Right from 1972 to 2007, making it the longest-running daytime game show in North American television history, and for hosting Truth or Consequences from 1956 to 1975.
Born in Washington to modest circumstances, Barker enlisted in the United States Navy on the outbreak of World War II. After working at radio stations, Barker began his game show career in 1956, hosting Truth or Consequences. From there, he hosted various game shows as well as the Miss Universe pageants. Eventually, he hosted The Price Is Right, beginning in 1972. When his wife Dorothy Jo died, Barker became an advocate for animal rights. Since then, Barker has been a long-time supporter of animal rights, and of animal-rights activism, including groups such as the United Activists for Animal Rights and the Sea Shepherd Conservation Society. In 2007, Barker retired from ho...
Bob Barker Latest News
Neutral Bay's big yellow dog to get some essential grooming from creators Gillie and Marc after vandals attack
Sculptors Gillie and Marc Chattner with a sample of their work. Picture: Bob Barker. Big Dog has been standing guard on the doorstep of the Traffic Jam Galleries at Neutral Bay since November last year. Gallery owner Rebecca Pierce refuses to give in to ...
Posted: May 26, 2016, 7:02 pm
Watch Stephen Colbert Riff on Kanye West's Epic 'Ellen' Rant
"No apologies necessary. That was the realest daytime TV has gotten since Bob Barker neutered a cat on live TV. Did it right on the dinette set," Colbert joked. "Now, a lot of people after seeing that are saying Kanye engaged in a rambling, incoherent word ...
Posted: May 24, 2016, 7:11 am
Meet Bob Barker, This Week's Adoptable Power-Walking Dog
This week, instead of an adoptable running dog, we've got an adoptable walking dog for you all to "awwww" at — and maybe go scoop up from PAWS 2nd Street adoption center in Old City! (Because despite what us Be Wellers might think, not everyone in ...
Posted: May 20, 2016, 10:59 am
Come on down! Bob Barker returns to The Price Is Right once more... but it's just an April Fools prank
Bob last returned to the show for the December 12, 2013 episode that honoured his 90th birthday. He also made an appearance in 2009 for a special Showcase round. Barker also hosted the game show Truth Or Consequences from 1956 to 1974 and with his time on ...
Posted: March 31, 2015, 5:47 pm
Nederland student wins car at just the right time
gets to channel his inner Bob Barker. For the 14 th straight year, he presented a Nederland High School student with a car —this time it was a brand new 2016 Toyota Scion from a drawing on Wednesday morning at The Performing Arts Center on campus.
Posted: May 25, 2016, 6:07 pm
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12 Year-Old With Two Moms Gives Touching Testimony At Marriage Equality Hearing
Sixth-grader Matthew Lannon testified at the marriage equality hearing in Rhode Island on Thursday, asking the panel, " Do you believe that my parents are equal to every other straight couple in Rhode Island?"
Matthew, with his two moms, watching and lending him support, was one of the many advocates and opponents of gay marriage to testify before the House Judiciary Committee Thursday evening at the RI State House.
"My parents and all the other gay and lesbian people here want to be happy, just like you. All they want is to be treated fairly. But unlike most of you, they have to come again here year after year and explain over and over why their love is equal to yours. This year, you have the opportunity to change that. I say, choose love"
He knocked it out of the park:
6. Hear Matthew's Testimony:
We can only hope his words touched these icy hearts:
- A Cincinnati zoo is defending its decision to kill a gorilla after a boy fell into an exhibit.
- Former U.S. Attorney General Eric Holder said Edward Snowden performed a "public service" leaking surveillance secrets.
- The GOP spent years building a Latino outreach project. Now Republicans worry it died with Donald Trump's nomination.


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Friday, 27 May 2016
Last updated 16 hours ago
Nov 8 2010 | 11:23am ET
Hedge funds posted their second-straight winning month in October, according to the Hennessee Group.
The Hennessee Hedge Fund Index rose 1.95% last month as all but one of the firm's strategy indices gained ground for the second month in a row. The index is up 6.75% on the year.
Private investments in public equities and private financing funds led the way in October, rising 3.71% on the month (7.61% year-to-date). Financial equities and international funds also enjoyed strong returns, adding 3.48% (5.51% YTD) and 3.37% (9.24% YTD), respectively.
"The financial markets continued to rally as the companies reported solid earnings and the Fed announced an additional round of quantitative easing. Hedge funds posted strong positive performance, but lagged traditional benchmarks due to conservative exposure levels and losses from hedges," Hennessee co-founder Charles Gradante said. "Arbitrage, event-driven and credit strategies continue to drive gains, outperforming long/short equity strategies for the month and year-to-date."
All three of Hennessee's major hedge fund strategy meta-indices posted big gains on the month, led by global macro funds at 2.4% (6.87% YTD). Arbitrage and event-driven funds were up 1.97% (9.33% YTD) and long/short equity funds 1.72% (5.36% YTD).
Despite the strong gains, only PIPE funds bested the Standard & Poor's 500 Index—and just barely—with the broader market index adding 3.69% on the month. The hedge fund index is still beating U.S. stocks, with the S&P500 up 6.11% on the year.
May 25 2016 | 5:07pm ET
The popularity of liquid alternatives strategies has blossomed in recent years,...
May 18 2016 | 7:43pm ET
What do the rise of the Internet, the sinking of the Titanic, 9/11, and Stephen...
May 19 2016 | 8:42pm ET
Peer-to-peer lending platform LendingClub Corp. has been in the news since the firm...


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So far only a cheese lover.
Hi, my name is Cathy DeJoria and I would love to learn about cheesemaking. I enjoy cooking and make bread at least once a week. I also enjoy wine and beer which seems to be a theme on this list as both go so well with cheese.
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|By Business Wire
Article Rating:
|April 16, 2012 08:30 AM EDT
Apple® today announced the new iPad®, the third generation of its category defining mobile device, will arrive in South Korea and 11 additional countries on Friday, April 20. The new iPad features a stunning new Retina™ display, Apple's new A5X chip with quad-core graphics and a 5 megapixel iSight® camera with advanced optics for capturing amazing photos and 1080p HD video. The new iPad still delivers the same all-day 10 hour battery life* while remaining amazingly thin and light.
In addition to South Korea, the new iPad also will be available beginning on Friday, April 20 in Brunei, Croatia, Cyprus, Dominican Republic, El Salvador, Guatemala, Malaysia, Panama, St Maarten, Uruguay and Venezuela. Beginning on Friday, April 27, the new iPad will be available in Colombia, Estonia, India, Israel, Latvia, Lithuania, Montenegro, South Africa and Thailand.
The new iPad Wi-Fi models will be available in black or white for a suggested retail price of $499 (US) for the 16GB model, $599 (US) for the 32GB model and $699 (US) for the 64GB model. The iPad Wi-Fi + 4G models will be available for a suggested retail price of $629 (US) for the 16GB model, $729 (US) for the 32GB model and $829 (US) for the 64GB model.** The new iPad will be sold through the Apple Online Store (www.apple.com) and select Apple Authorized Resellers. Additionally, iPad 2 is available at a more affordable price starting at just $399.
*Battery life depends on device settings, usage and other factors. Actual results vary.
**4G LTE is supported only on AT&T and Verizon networks in the U.S. and on Bell, Rogers and Telus networks in Canada. Data plans sold separately.
Apple designs Macs, the best personal computers in the world, along with OS X, iLife, iWork and professional software. Apple leads the digital music revolution with its iPods and iTunes online store. Apple has reinvented the mobile phone with its revolutionary iPhone and App Store, and is defining the future of mobile media and computing devices with iPad.
NOTE TO EDITORS: For additional information visit Apple's PR website (www.apple.com/pr), or call Apple's Media Helpline at (408) 974-2042.
© 2012 Apple Inc. All rights reserved. Apple, the Apple logo, Mac, Mac OS, Macintosh, iPad, Retina and iSight are trademarks of Apple. Other company and product names may be trademarks of their respective owners.
SYS-CON Events announced today that MangoApps will exhibit at SYS-CON's 18th International Cloud Expo®, which will take place on June 7-9, 2016, at the Javits Center in New York City, NY. MangoApps provides modern company intranets and team collaboration software, allowing workers to stay connected and productive from anywhere in the world and from any device. For more information, please visit https://www.mangoapps.com/.
May. 29, 2016 03:30 AM EDT Reads: 939
The essence of data analysis involves setting up data pipelines that consist of several operations that are chained together – starting from data collection, data quality checks, data integration, data analysis and data visualization (including the setting up of interaction paths in that visualization). In our opinion, the challenges stem from the technology diversity at each stage of the data pipeline as well as the lack of process around the analysis.
May. 29, 2016 02:45 AM EDT Reads: 1,476
Designing IoT applications is complex, but deploying them in a scalable fashion is even more complex. A scalable, API first IaaS cloud is a good start, but in order to understand the various components specific to deploying IoT applications, one needs to understand the architecture of these applications and figure out how to scale these components independently. In his session at @ThingsExpo, Nara Rajagopalan is CEO of Accelerite, will discuss the fundamental architecture of IoT applications, ...
May. 29, 2016 02:00 AM EDT Reads: 1,306
SYS-CON Events announced today that Tintri Inc., a leading producer of VM-aware storage (VAS) for virtualization and cloud environments, will exhibit at the 18th International CloudExpo®, which will take place on June 7-9, 2016, at the Javits Center in New York City, New York, and the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA.
May. 29, 2016 01:30 AM EDT Reads: 2,470
In his session at 18th Cloud Expo, Bruce Swann, Senior Product Marketing Manager at Adobe, will discuss how the Adobe Marketing Cloud can help marketers embrace opportunities for personalized, relevant and real-time customer engagement across offline (direct mail, point of sale, call center) and digital (email, website, SMS, mobile apps, social networks, connected objects). Bruce Swann has more than 15 years of experience working with digital marketing disciplines like web analytics, social med...
May. 29, 2016 01:00 AM EDT Reads: 1,402
A strange thing is happening along the way to the Internet of Things, namely far too many devices to work with and manage. It has become clear that we'll need much higher efficiency user experiences that can allow us to more easily and scalably work with the thousands of devices that will soon be in each of our lives. Enter the conversational interface revolution, combining bots we can literally talk with, gesture to, and even direct with our thoughts, with embedded artificial intelligence, wh...
May. 29, 2016 12:45 AM EDT Reads: 2,050
SYS-CON Events announced today that EastBanc Technologies will exhibit at SYS-CON's 18th International Cloud Expo®, which will take place on June 7-9, 2016, at the Javits Center in New York City, NY. EastBanc Technologies has been working at the frontier of technology since 1999. Today, the firm provides full-lifecycle software development delivering flexible technology solutions that seamlessly integrate with existing systems – whether on premise or cloud. EastBanc Technologies partners with p...
May. 28, 2016 11:00 PM EDT Reads: 2,374
The IoTs will challenge the status quo of how IT and development organizations operate. Or will it? Certainly the fog layer of IoT requires special insights about data ontology, security and transactional integrity. But the developmental challenges are the same: People, Process and Platform. In his session at @ThingsExpo, Craig Sproule, CEO of Metavine, will demonstrate how to move beyond today's coding paradigm and share the must-have mindsets for removing complexity from the development proc...
May. 28, 2016 07:00 PM EDT Reads: 1,962
SYS-CON Events announced today BZ Media LLC has been named "Media Sponsor" of SYS-CON's 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. BZ Media LLC is a high-tech media company that produces technical conferences and expositions, and publishes a magazine, newsletters and websites in the software development, SharePoint, mobile development and Commercial Drone markets.
May. 28, 2016 07:00 PM EDT Reads: 3,633
SYS-CON Events announced today that ContentMX, the marketing technology and services company with a singular mission to increase engagement and drive more conversations for enterprise, channel and SMB technology marketers, has been named "Sponsor & Exhibitor Lounge Sponsor" of SYS-CON's 18th Cloud Expo, which will take place on June 7-9, 2016, at the Javits Center in New York City, New York. "CloudExpo is a great opportunity to start a conversation with new prospects, but what happens after the...
May. 28, 2016 07:00 PM EDT Reads: 1,260
SYS-CON Events announced today that Alert Logic, Inc., the leading provider of Security-as-a-Service solutions for the cloud, will exhibit at SYS-CON's 18th International Cloud Expo®, which will take place on June 7-9, 2016, at the Javits Center in New York City, NY. Alert Logic, Inc., provides Security-as-a-Service for on-premises, cloud, and hybrid infrastructures, delivering deep security insight and continuous protection for customers at a lower cost than traditional security solutions. Ful...
May. 28, 2016 06:45 PM EDT Reads: 2,908
WebRTC is bringing significant change to the communications landscape that will bridge the worlds of web and telephony, making the Internet the new standard for communications. Cloud9 took the road less traveled and used WebRTC to create a downloadable enterprise-grade communications platform that is changing the communication dynamic in the financial sector. In his session at @ThingsExpo, Leo Papadopoulos, CTO of Cloud9, will discuss the importance of WebRTC and how it enables companies to fo...
May. 28, 2016 03:45 PM EDT Reads: 2,545
The IoT is changing the way enterprises conduct business. In his session at @ThingsExpo, Eric Hoffman, Vice President at EastBanc Technologies, discuss how businesses can gain an edge over competitors by empowering consumers to take control through IoT. We'll cite examples such as a Washington, D.C.-based sports club that leveraged IoT and the cloud to develop a comprehensive booking system. He'll also highlight how IoT can revitalize and restore outdated business models, making them profitable...
May. 28, 2016 02:00 PM EDT Reads: 2,932
IoT generates lots of temporal data. But how do you unlock its value? How do you coordinate the diverse moving parts that must come together when developing your IoT product? What are the key challenges addressed by Data as a Service? How does cloud computing underlie and connect the notions of Digital and DevOps What is the impact of the API economy? What is the business imperative for Cognitive Computing? Get all these questions and hundreds more like them answered at the 18th Cloud Expo...
May. 28, 2016 01:00 PM EDT Reads: 2,361
SYS-CON Events announced today the How to Create Angular 2 Clients for the Cloud Workshop, being held June 7, 2016, in conjunction with 18th Cloud Expo | @ThingsExpo, at the Javits Center in New York, NY. Angular 2 is a complete re-write of the popular framework AngularJS. Programming in Angular 2 is greatly simplified. Now it's a component-based well-performing framework. The immersive one-day workshop led by Yakov Fain, a Java Champion and a co-founder of the IT consultancy Farata Systems and...
May. 28, 2016 11:00 AM EDT Reads: 4,065
Customer experience has become a competitive differentiator for companies, and it's imperative that brands seamlessly connect the customer journey across all platforms. With the continued explosion of IoT, join us for a look at how to build a winning digital foundation in the connected era – today and in the future. In his session at @ThingsExpo, Chris Nguyen, Group Product Marketing Manager at Adobe, will discuss how to successfully leverage mobile, rapidly deploy content, capture real-time d...
May. 28, 2016 10:45 AM EDT Reads: 1,635
SYS-CON Events announced today that BMC Software has been named "Siver Sponsor" of SYS-CON's 18th Cloud Expo, which will take place on June 7-9, 2015 at the Javits Center in New York, New York. BMC is a global leader in innovative software solutions that help businesses transform into digital enterprises for the ultimate competitive advantage. BMC Digital Enterprise Management is a set of innovative IT solutions designed to make digital business fast, seamless, and optimized from mainframe to mo...
May. 28, 2016 09:45 AM EDT Reads: 2,278
What a difference a year makes. Organizations aren't just talking about IoT possibilities, it is now baked into their core business strategy. With IoT, billions of devices generating data from different companies on different networks around the globe need to interact. From efficiency to better customer insights to completely new business models, IoT will turn traditional business models upside down. In the new customer-centric age, the key to success is delivering critical services and apps wit...
May. 28, 2016 09:15 AM EDT Reads: 1,208
Join us at Cloud Expo | @ThingsExpo 2016 – June 7-9 at the Javits Center in New York City and November 1-3 at the Santa Clara Convention Center in Santa Clara, CA – and deliver your unique message in a way that is striking and unforgettable by taking advantage of SYS-CON's unmatched high-impact, result-driven event / media packages.
May. 28, 2016 09:00 AM EDT Reads: 2,446
In his keynote at 18th Cloud Expo, Andrew Keys, Co-Founder of ConsenSys Enterprise, will provide an overview of the evolution of the Internet and the Database and the future of their combination – the Blockchain. Andrew Keys is Co-Founder of ConsenSys Enterprise. He comes to ConsenSys Enterprise with capital markets, technology and entrepreneurial experience. Previously, he worked for UBS investment bank in equities analysis. Later, he was responsible for the creation and distribution of life ...
May. 28, 2016 08:45 AM EDT Reads: 2,002


text:
|By Business Wire
Article Rating:
|November 12, 2012 11:01 AM EST
Samsung Electronics Co., Ltd., a global leader in advanced semiconductor solutions, announced that its Exynos 5 Dual application processor powers the new Nexus 10 tablet from Google, with the highest WQXGA (2560x1600) resolution in the market. The Exynos 5 Dual is the world's first application processor based on the ARM® Cortex™-A15 CPU, which has been designed with both performance and power efficiency in mind to bring superb user experience in mobile devices.
"We are very pleased to reveal that Samsung's most advanced mobile application processor, the Exynos 5 Dual, is the engine that powers Google's Nexus 10 tablet," said TH Kim, vice president of System LSI marketing, Device Solutions, Samsung Electronics. "Exynos 5 Dual is our first application processor designed specifically for high-end tablets and mobile computing applications. With ARM's newest Cortex™ A15 core and Samsung's low-power 32nm High-K Metal Gate (HKMG) process, customers can expect incredible performance with astounding energy efficiency."
The Exynos 5 Dual, with two ARM® Cortex™-A15 CPUs running at a blazing 1.7GHz, accompanied by four powerful Mali™-T604 GPU cores, full high definition multimedia capabilities, built-in ISP for camera/image processing, and the widest memory bandwidth available in mobile SoCs at 12.8 GB/s, is the only solution currently in the market to support the richest media and computing experience in stunning WQXGA resolution within the mobile environment.
For more information about Samsung's Eyxnos 5 Dual and other Exynos application processors, visit www.samsung.com/exynos and follow us at www.twitter.com/SamsungExynos.
About Samsung Electronics Co., Ltd.
Samsung Electronics Co., Ltd. is a global leader in semiconductor, telecommunication, digital media and digital convergence technologies with 2011 consolidated sales of US$143.1 billion. Employing approximately 206,000 people in 197 offices across 72 countries, the company operates two separate organizations to coordinate its nine independent business units: Digital Media & Communications, comprising Visual Display, Mobile Communications, Telecommunication Systems, Digital Appliances, IT Solutions, and Digital Imaging; and Device Solutions, consisting of Memory, System LSI and LED. Recognized for its industry-leading performance across a range of economic, environmental and social criteria, Samsung Electronics was named the world's most sustainable technology company in the 2011 Dow Jones Sustainability Index. For more information, please visit www.samsung.com.
Samsung and the stylized Samsung design are trademarks and service marks of Samsung Electronics Co., Ltd. Other trademarks are the property of their respective owners.
SYS-CON Events announced today that ContentMX, the marketing technology and services company with a singular mission to increase engagement and drive more conversations for enterprise, channel and SMB technology marketers, has been named "Sponsor & Exhibitor Lounge Sponsor" of SYS-CON's 18th Cloud Expo, which will take place on June 7-9, 2016, at the Javits Center in New York City, New York. "CloudExpo is a great opportunity to start a conversation with new prospects, but what happens after the...
May. 28, 2016 11:15 AM EDT Reads: 1,196
SYS-CON Events announced today the How to Create Angular 2 Clients for the Cloud Workshop, being held June 7, 2016, in conjunction with 18th Cloud Expo | @ThingsExpo, at the Javits Center in New York, NY. Angular 2 is a complete re-write of the popular framework AngularJS. Programming in Angular 2 is greatly simplified. Now it's a component-based well-performing framework. The immersive one-day workshop led by Yakov Fain, a Java Champion and a co-founder of the IT consultancy Farata Systems and...
May. 28, 2016 11:00 AM EDT Reads: 4,041
Customer experience has become a competitive differentiator for companies, and it's imperative that brands seamlessly connect the customer journey across all platforms. With the continued explosion of IoT, join us for a look at how to build a winning digital foundation in the connected era – today and in the future. In his session at @ThingsExpo, Chris Nguyen, Group Product Marketing Manager at Adobe, will discuss how to successfully leverage mobile, rapidly deploy content, capture real-time d...
May. 28, 2016 10:45 AM EDT Reads: 1,612
SYS-CON Events announced today that BMC Software has been named "Siver Sponsor" of SYS-CON's 18th Cloud Expo, which will take place on June 7-9, 2015 at the Javits Center in New York, New York. BMC is a global leader in innovative software solutions that help businesses transform into digital enterprises for the ultimate competitive advantage. BMC Digital Enterprise Management is a set of innovative IT solutions designed to make digital business fast, seamless, and optimized from mainframe to mo...
May. 28, 2016 09:45 AM EDT Reads: 2,252
What a difference a year makes. Organizations aren't just talking about IoT possibilities, it is now baked into their core business strategy. With IoT, billions of devices generating data from different companies on different networks around the globe need to interact. From efficiency to better customer insights to completely new business models, IoT will turn traditional business models upside down. In the new customer-centric age, the key to success is delivering critical services and apps wit...
May. 28, 2016 09:15 AM EDT Reads: 1,178
Join us at Cloud Expo | @ThingsExpo 2016 – June 7-9 at the Javits Center in New York City and November 1-3 at the Santa Clara Convention Center in Santa Clara, CA – and deliver your unique message in a way that is striking and unforgettable by taking advantage of SYS-CON's unmatched high-impact, result-driven event / media packages.
May. 28, 2016 09:00 AM EDT Reads: 2,420
In his keynote at 18th Cloud Expo, Andrew Keys, Co-Founder of ConsenSys Enterprise, will provide an overview of the evolution of the Internet and the Database and the future of their combination – the Blockchain. Andrew Keys is Co-Founder of ConsenSys Enterprise. He comes to ConsenSys Enterprise with capital markets, technology and entrepreneurial experience. Previously, he worked for UBS investment bank in equities analysis. Later, he was responsible for the creation and distribution of life ...
May. 28, 2016 08:45 AM EDT Reads: 1,970
SYS-CON Events announced today that MobiDev will exhibit at SYS-CON's 18th International Cloud Expo®, which will take place on June 7-9, 2016, at the Javits Center in New York City, NY. MobiDev is a software company that develops and delivers turn-key mobile apps, websites, web services, and complex software systems for startups and enterprises. Since 2009 it has grown from a small group of passionate engineers and business managers to a full-scale mobile software company with over 200 develope...
May. 28, 2016 07:15 AM EDT Reads: 2,654
SoftLayer operates a global cloud infrastructure platform built for Internet scale. With a global footprint of data centers and network points of presence, SoftLayer provides infrastructure as a service to leading-edge customers ranging from Web startups to global enterprises. SoftLayer's modular architecture, full-featured API, and sophisticated automation provide unparalleled performance and control. Its flexible unified platform seamlessly spans physical and virtual devices linked via a world...
May. 28, 2016 06:00 AM EDT Reads: 2,243
Companies can harness IoT and predictive analytics to sustain business continuity; predict and manage site performance during emergencies; minimize expensive reactive maintenance; and forecast equipment and maintenance budgets and expenditures. Providing cost-effective, uninterrupted service is challenging, particularly for organizations with geographically dispersed operations.
May. 28, 2016 05:00 AM EDT Reads: 2,103
SYS-CON Events announced today TechTarget has been named "Media Sponsor" of SYS-CON's 18th International Cloud Expo, which will take place on June 7–9, 2016, at the Javits Center in New York City, NY, and the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. TechTarget is the Web's leading destination for serious technology buyers researching and making enterprise technology decisions. Its extensive global networ...
May. 28, 2016 05:00 AM EDT Reads: 3,223
SYS-CON Events announced today that Commvault, a global leader in enterprise data protection and information management, has been named "Bronze Sponsor" of SYS-CON's 18th International Cloud Expo, which will take place on June 7–9, 2016, at the Javits Center in New York City, NY, and the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. Commvault is a leading provider of data protection and information management...
May. 28, 2016 04:15 AM EDT Reads: 3,186
SYS-CON Events announced today Object Management Group® has been named "Media Sponsor" of SYS-CON's 18th International Cloud Expo, which will take place on June 7–9, 2016, at the Javits Center in New York City, NY, and the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA.
May. 28, 2016 03:00 AM EDT Reads: 2,541
As cloud and storage projections continue to rise, the number of organizations moving to the cloud is escalating and it is clear cloud storage is here to stay. However, is it secure? Data is the lifeblood for government entities, countries, cloud service providers and enterprises alike and losing or exposing that data can have disastrous results. There are new concepts for data storage on the horizon that will deliver secure solutions for storing and moving sensitive data around the world. ...
May. 28, 2016 03:00 AM EDT Reads: 1,312
SYS-CON Events announced today that MangoApps will exhibit at SYS-CON's 18th International Cloud Expo®, which will take place on June 7-9, 2016, at the Javits Center in New York City, NY. MangoApps provides modern company intranets and team collaboration software, allowing workers to stay connected and productive from anywhere in the world and from any device. For more information, please visit https://www.mangoapps.com/.
May. 28, 2016 02:30 AM EDT Reads: 823
The essence of data analysis involves setting up data pipelines that consist of several operations that are chained together – starting from data collection, data quality checks, data integration, data analysis and data visualization (including the setting up of interaction paths in that visualization). In our opinion, the challenges stem from the technology diversity at each stage of the data pipeline as well as the lack of process around the analysis.
May. 28, 2016 01:30 AM EDT Reads: 1,457
The IoTs will challenge the status quo of how IT and development organizations operate. Or will it? Certainly the fog layer of IoT requires special insights about data ontology, security and transactional integrity. But the developmental challenges are the same: People, Process and Platform. In his session at @ThingsExpo, Craig Sproule, CEO of Metavine, will demonstrate how to move beyond today's coding paradigm and share the must-have mindsets for removing complexity from the development proc...
May. 28, 2016 01:00 AM EDT Reads: 1,937
Designing IoT applications is complex, but deploying them in a scalable fashion is even more complex. A scalable, API first IaaS cloud is a good start, but in order to understand the various components specific to deploying IoT applications, one needs to understand the architecture of these applications and figure out how to scale these components independently. In his session at @ThingsExpo, Nara Rajagopalan is CEO of Accelerite, will discuss the fundamental architecture of IoT applications, ...
May. 28, 2016 01:00 AM EDT Reads: 1,264
A strange thing is happening along the way to the Internet of Things, namely far too many devices to work with and manage. It has become clear that we'll need much higher efficiency user experiences that can allow us to more easily and scalably work with the thousands of devices that will soon be in each of our lives. Enter the conversational interface revolution, combining bots we can literally talk with, gesture to, and even direct with our thoughts, with embedded artificial intelligence, wh...
May. 28, 2016 12:30 AM EDT Reads: 2,025
SYS-CON Events announced today that Tintri Inc., a leading producer of VM-aware storage (VAS) for virtualization and cloud environments, will exhibit at the 18th International CloudExpo®, which will take place on June 7-9, 2016, at the Javits Center in New York City, New York, and the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA.
May. 28, 2016 12:15 AM EDT Reads: 2,443


text:
Choose the period
Today, I figured I needed to clean my room. I ended up finding my $135 calculator that I'd accused my ex-boyfriend of selling for gas money. That's also the reason I dumped him. FML
by supertango500 / 03/11/2013 at 2:56pm / United States / Money
Today, I saw a woman breastfeeding at the natural foods market. It's the first time I've seen a woman's nipple in over two years. I've been married for ten. FML
by themouseman1212 / 03/10/2013 at 12:13pm / United States / Intimacy
Today, I held hands with the boy I like. Without thinking, I commented that his right hand is softer, as if he only used lotion on that one hand. And then we stood there in terribly awkward silence. FML
by Anonymous / 03/13/2013 at 12:57am / United States (Missouri) / Love
Today, I found out that my wife makes mashed potatoes by using her dirty feet to crush the potatoes because apparently this is a "healthy, natural" way to make them, and it also cleans her feet. I've been eating her mashed potatoes at least once every week. FML
by Anonymous / 03/05/2013 at 12:25am / Miscellaneous
Today, I was at the airport, when a lady came up and loudly asked if she could sit next to me. I have serious social issues, so to avoid having to talk to her, I pretended I was deaf and couldn't hear her. She immediately broke out her sign language skills. FML
by human lava lamp / 03/10/2013 at 3:54pm / United States (Connecticut) / Miscellaneous
Today, I invited my long-lost best friend over, because I haven't seen her much since she got a new boyfriend. 20 minutes into hanging out, he showed up at my door. He still hasn't left, and they're having sex on my couch right now. FML
by kenleybunch / 03/12/2013 at 9:22am / United States (North Carolina) / Intimacy
Today, my teacher read my story about a haunted house for a class assignment. She liked it very much and turned it in to the office to be sent into a state writing competition. An hour later, I was called to the office where the guidance counselor called my work "disturbing" and said I "need help". FML
by Anonymous / 03/08/2013 at 6:29am / United States (Virginia) / Miscellaneous
Today, thinking my girlfriend had left her little black thong in the dryer to tease me, I sent her a picture of me seductively posing with it. She didn't text back, but a few hours later my 16 year old daughter asked if she'd left anything in the dryer. FML
by Anonymous / 03/11/2013 at 5:52pm / United States (Texas) / Intimacy
Today, my grandma gave me a sex talk. Not the usual one, either. This one was about blowjobs. I had to sit politely as she explained it's something all women have to learn if they want a well-behaved husband, but that it's an "acquired taste". Gag me. FML
by butnotlikethat / 03/15/2013 at 8:05pm / China (Jiangxi) / Intimacy
Today, I was outside at a café and looked at my phone. When I did, a woman halfway across the patio started screaming at me, demanding I tell her who I was texting and why. She then sprinted over, furious at me for apparently badmouthing her to somebody. All I did was check the time. FML
by Anonymous / 03/17/2013 at 7:00am / United States (Illinois) / Miscellaneous
Today, our dog jumped on the bed while my fiancé and I were having sex, and let out the most horrific fart. My fiancé, like a gentleman, held my nose closed while he continued banging me. FML
by cremyfrozentreat / 03/10/2013 at 9:40am / United States (Florida) / Intimacy
Today, I invited my girlfriend to go eat out, hoping to put her in a really romantic mood. She decided to tell her friend, who then invited herself and another couple along. I ended up being made fifth wheel, and had to sit alone at an adjacent table. FML
by Anonymous / 03/13/2013 at 7:22pm / United States / Love
Today, being too poor to buy makeup, I walked into Macy's and "tested" some products out, just so I could look nice for my job interview. FML
by Anonymous / 03/13/2013 at 9:47am / United States (California) / Work
- 1Today, I found out my parents have been slipping birth control pills into my morning orange juice… 2Today, I found out my husband has been catfishing my sixteen year-old brother for over a year. FML 3Today, I babysat a kid who was such a bratty little prick that I actually considered walking out on…