Fungal Mediator Tail Subunits Contain Classical Transcriptional Activation Domains

Classical activation domains within DNA-bound eukaryotic transcription factors make weak interactions with coactivator complexes, such as Mediator, to stimulate transcription. How these interactions stimulate transcription, however, is unknown. The activation of reporter genes by artificial fusion of Mediator subunits to DNA binding domains that bind to their promoters has been cited as evidence that the primary role of activators is simply to recruit Mediator. We have identified potent classical transcriptional activation domains in the C termini of several tail module subunits of Saccharomyces cerevisiae, Candida albicans, and Candida dubliniensis Mediator, while their N-terminal domains are necessary and sufficient for their incorporation into Mediator but do not possess the ability to activate transcription when fused to a DNA binding domain. This suggests that Mediator fusion proteins actually are functioning in a manner similar to that of a classical DNA-bound activator rather than just recruiting Mediator. Our finding that deletion of the activation domains of S. cerevisiae Med2 and Med3, as well as C. dubliniensis Tlo1 (a Med2 ortholog), impairs the induction of certain genes shows these domains function at native promoters. Activation domains within coactivators are likely an important feature of these complexes and one that may have been uniquely leveraged by a common fungal pathogen

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida Albicans Mediator

The multisubunit eukaryotic Mediator complex integrates diverse positive and negative gene regulatory signals and transmits them to the core transcription machinery. Mutations in individual subunits within the complex can lead to decreased or increased transcription of certain subsets of genes, which are highly specific to the mutated subunit. Recent studies suggest a role for Mediator in epigenetic silencing. Using white-opaque morphological switching in Candida albicans as a model, we have shown that Mediator is required for the stability of both the epigenetic silenced (white) and active (opaque) states of the bistable transcription circuit driven by the master regulator Wor1. Individual deletions of eight C. albicans Mediator subunits have shown that different Mediator subunits have dramatically diverse effects on the directionality, frequency, and environmental induction of epigenetic switching. Among the Mediator deletion mutants analyzed, only Med12 has a steady-state transcriptional effect on the components of the Wor1 circuit that clearly corresponds to its effect on switching. The MED16 and MED9 genes have been found to be among a small subset of genes that are required for the stability of both the white and opaque states. Deletion of the Med3 subunit completely destabilizes the opaque state, even though the Wor1 transcription circuit is intact and can be driven by ectopic expression of Wor1. The highly impaired ability of the med3 deletion mutant to mate, even when Wor1 expression is ectopically induced, reveals that the activation of the Wor1 circuit can be decoupled from the opaque state and one of its primary biological consequences

Cis-regulatory basis of sister cell type divergence in the vertebrate retina

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the ke

A new species of \u3cem\u3eKochius\u3c/em\u3e from Avra Valley, southern Arizona (Scorpiones: Vaejovidae)

A new scorpion species, Kochius colluvius sp. n. is described (Scorpiones: Vaejovidae). This small brown species is found in the Avra Valley near Tucson, Arizona, USA. It appears to be most similar to Kochius sonorae (Williams, 1971) and K. hirsuticauda (Banks, 1910). On all fingers examined, the fixed finger has 6 ID denticles and the movable finger has 7. There is no scalloping of the chela fingers. This species differs from all other vaejovids in Arizona by having a coarsely granulated exoskeleton

Amplification of TLO Mediator Subunit Genes Facilitate Filamentous Growth in Candida Spp

Funding: This work was funded by the National Institutes of Allergy and Infectious Disease (AI113390, LCM) and the National Institutes of General Medical Sciences (GM62483, LCM). The funders had no role in study design, data collection and analysis, decision topublish, or preparation of the manuscript.Non peer reviewedPublisher PD

The Tlo Proteins Are Stoichiometric Components of Candida albicans Mediator Anchored via the Med3 Subunit

The amplification of the TLO (for telomere-associated) genes in Candida albicans, compared to its less pathogenic, close relative Candida dubliniensis, suggests a role in virulence. Little, however, is known about the function of the Tlo proteins. We have purified the Mediator coactivator complex from C. albicans (caMediator) and found that Tlo proteins are a stoichiometric component of caMediator. Many members of the Tlo family are expressed, and each is a unique member of caMediator. Protein expression analysis of individual Tlo proteins, as well as the purification of tagged Tlo proteins, demonstrate that there is a large free population of Tlo proteins in addition to the Mediator-associated population. Coexpression and copurification of Tloα12 and caMed3 in Escherichia coli established a direct physical interaction between the two proteins. We have also made a C. albicans med3Δ/Δ strain and purified an intact Mediator from this strain. The analysis of the composition of the med3Δ Mediator shows that it lacks a Tlo subunit. Regarding Mediator function, the med3Δ/Δ strain serves as a substitute for the difficult-to-make tloΔ/Δ C. albicans strain. A potential role of the TLO and MED3 genes in virulence is supported by the inability of the med3Δ/Δ strain to form normal germ tubes. This study of caMediator structure provides initial clues to the mechanism of action of the Tlo genes and a platform for further mechanistic studies of caMediator\u27s involvement in gene regulatory patterns that underlie pathogenesis

Strong lensing constraints on the velocity dispersion and density profile of elliptical galaxies

We use the statistics of strong gravitational lensing from the CLASS survey to impose constraints on the velocity dispersion and density profile of elliptical galaxies. This approach differs from much recent work, where the luminosity function, velocity dispersion and density profile were typically {\it assumed} in order to constrain cosmological parameters. It is indeed remarkable that observational cosmology has reached the point where we can consider using cosmology to constrain astrophysics, rather than vice versa. We use two different observables to obtain our constraints (total optical depth and angular distributions of lensing events). In spite of the relatively poor statistics and the uncertain identification of lenses in the survey, we obtain interesting constraints on the velocity dispersion and density profiles of elliptical galaxies. For example, assuming the SIS density profile and marginalizing over other relevant parameters, we find 168 km/s < sigma_* < 200 km/s (68% CL), and 158 km/s < sigma_* < 220 km/s (95% CL). Furthermore, if we instead assume a generalized NFW density profile and marginalize over other parameters, the slope of the profile is constrained to be 1.50 < beta < 2.00 (95% CL). We also constrain the concentration parameter as a function of the density profile slope in these models. These results are essentially independent of the exact knowledge of cosmology. We briefly discuss the possible impact on these constraints of allowing the galaxy luminosity function to evolve with redshift, and also possible useful future directions for exploration.Comment: Uses the final JVAS/CLASS sample, more careful choice of ellipticals, added discussion of possible biases. Final results essentially unchanged. Matches the MNRAS versio

Estimation of the Co-prevalence of Age-related macular degeneration and Glaucoma

poster abstractPurpose: Age-related macular degeneration (AMD) and glaucoma are the two most common blinding eye diseases in the U.S. and may be further disabling when concomitant. The purpose of this study is to estimate the past, present and future co-prevalence of AMD and glaucoma by national surveys and population projection data. Methods: We combined the age, race and ethnicity data from the latest 2005 to 2008 National Health and Nutrition Examination Survey (NHANES) and the 2002 and 2008 National Health Interview Survey (NHIS). Participants’ positive answers were defined as a “yes” when asked if they had ever been told by a doctor/health care professional that they had macular degeneration or glaucoma (or high pressure of the eye). The co-prevalence of AMD and glaucoma was determined by dividing the number of individuals who answered “yes” to both questions by the total number of respondents. Mean and age-stratified estimates were obtained for non-Hispanic Whites, Hispanics and non-Hispanic Blacks separately. The 2008 National Population Projection data was used to determine the number of affected individuals presently as well as in 2030 and 2050. Results: Using previous NHANES and NHIS data, the mean co-prevalence of AMD and glaucoma varied among racial/ethnic groups: 0.5% in Whites; 0.3% in Hispanics; and 0.2% in Blacks. Co-prevalence increased with increasing age: for Whites, estimates ranged from 0% in those aged 40-49 years to 2.7% for 80 years and older; this trend was observed among the other groups but was more dramatic in Hispanics (0.1% to 2.9%) than Blacks (0% to 0.3%). Using National Population Projection data for 2015, the estimated current population is 535,270 (83% Whites; 10% Hispanics; 7% Blacks). The number of affected individuals will continue to grow but demonstrate changing demographics: in 2030 to 800,111 (80% Whites; 14% Hispanics; 7% Blacks); and in 2050 to 1,082,731 (71% Whites; 22% Hispanics; 6% Blacks). Conclusions: The mean co-prevalence of AMD and glaucoma is greatest among non-Hispanic Whites and individuals 70 years and older. More than half-a-million Americans, predominantly non-Hispanic Whites, suffer from concomitant eye diseases presently. Growing populations in the coming years will affect an increasing number of Hispanics. This new information suggests that future health care policy decisions would need to adapt to this growing, changing population

Supersymmetric Boost on Intersecting D-branes

We study the effect of the Born-Infeld electric field on the supersymmetric configuration of various composite D-branes. We show that the generic values of the electric field do not affect the supersymmetry but, as it approaches $1/2\pi\alpha'$ keeping the magnetic field finite, various combinations of the magnetic fields allow up to 8 supersymmetries. We also explore the unbroken supersymmetries for two intersecting D-strings which are in uniform or relative motion. For a finite uniform Lorentz boost, 16 supersymmetries are guaranteed only when they are parallel. For an infinite one, 8 supersymmetries are preserved only when both the D-strings are oriented to the forward or backward direction of the boost. Under a finite relative boost, 8 supersymmetries are preserved only when the intersecting angle is less than $\pi/2$ and the intersecting point moves at the speed of light. As for an infinite relative boost, 8 supersymmetries are preserved regardless of the values of the intersecting angle.Comment: 27 pages using REVTeX4, 7 figure