Epigenetic and Conventional Regulation Is Distributed among Activators of FLO11 Allowing Tuning of Population-Level Heterogeneity in Its Expression

Epigenetic switches encode their state information either locally, often via covalent modification of DNA or histones, or globally, usually in the level of a trans-regulatory factor. Here we examine how the regulation of cis-encoded epigenetic switches controls the extent of heterogeneity in gene expression, which is ultimately tied to phenotypic diversity in a population. We show that two copies of the FLO11 locus in Saccharomyces cerevisiae switch between a silenced and competent promoter state in a random and independent fashion, implying that the molecular event leading to the transition occurs locally at the promoter, in cis. We further quantify the effect of trans regulators both on the slow epigenetic transitions between a silenced and competent promoter state and on the fast promoter transitions associated with conventional regulation of FLO11. We find different classes of regulators affect epigenetic, conventional, or both forms of regulation. Distributing kinetic control of epigenetic silencing and conventional gene activation offers cells flexibility in shaping the distribution of gene expression and phenotype within a population.     

Size Matters: Metastatic Cluster Size and Stromal Recruitment in the Establishment of Successful Prostate Cancer to Bone Metastases

Prostate cancer (PCa) impacts over 180,000 men every year in the USA alone, with 26,000 patients expected to succumb to the disease (cancer.gov). The primary cause of death is metastasis, with secondary lesions most commonly occurring in the skeleton. Prostate cancer to bone metastasis is an important, yet poorly understood, process that is difficult to explore with experimental techniques alone. To this end we have utilized a hybrid (discrete–continuum) cellular automaton model of normal bone matrix homeostasis that allowed us to investigate how metastatic PCa can disrupt the bone microenvironment. Our previously published results showed that PCa cells can recruit mesenchymal stem cells (MSCs) that give rise to bone-building osteoblasts. MSCs are also thought to be complicit in the establishment of successful bone metastases (Lu, in Mol Cancer Res 4(4):221–233, 2006). Here we have explored the aspects of early metastatic colonization and shown that the size of PCa clusters needs to be within a specific range to become successfully established: sufficiently large to maximize success, but not too large to risk failure through competition among cancer and stromal cells for scarce resources. Furthermore, we show that MSC recruitment can promote the establishment of a metastasis and compensate for relatively low numbers of PCa cells seeding the bone microenvironment. Combined, our results highlight the utility of biologically driven computational models that capture the complex and dynamic dialogue between cells during the initiation of active metastases.     

Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK

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Exploiting polarity and chirality to probe the Hsp90 C-terminus

Inhibition of the Hsp90 C-terminus is an attractive therapeutic approach for the treatment of cancer. Novobiocin, the first Hsp90 C-terminal inhibitor identified, contains a synthetically complex noviose sugar that has limited the generation of structure-activity relationships for this region of the molecule. The work described herein utilizes various ring systems as noviose surrogates to explore the size and nature of the surrounding binding pocket.     

APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway

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Collection of airborne bacteria and yeast through water-based condensational growth

One limitation in air sampling of airborne microorganisms is their inactivation by forceful impaction and/or dehydration during the collection process. Proper inhalation risk assessments require proof of viability, as non-viable microorganisms cannot cause infectious diseases. In this study, laboratory-generated aerosols of a vegetative bacterium (E. coli) or yeast (S. kudriavzevii) were collected by a laminar-flow water-based condensational “growth tube collector (GTC),” and the GTC’s collection efficiencies were compared with those using an industry standard BioSampler. Collection efficiencies resulting from two types of collection media, phosphate-buffered saline (PBS) and nutrient media (Nutrient Broth, NB, for E. coli, and Yeast Tryptone Glucose Broth, YTGB, for S. kudriavzevii) were also assessed. Both the GTC and the BioSampler performed equally when PBS was used as the collection medium for E. coli, whereas more viable E. coli cells were collected in the GTC than the BioSampler with NB. For S. kudriavzevii, the GTC outperformed the BioSampler using either PBS or YTGB. This is likely because aerosolized E. coli cells can better survive impaction than S. kudriavzevii under the conditions used, and the BioSampler has a much higher collection efficiency for particles in the size range of single-celled E. coli than S. kudriavzevii. Moreover, the GTC had a detection limit one order of magnitude lower for yeast aerosols compared with that of the BioSampler. These results indicate that the GTC is a promising device for sampling viable aerosolized gram-negative bacteria and yeast, as it is less damaging to these types of microorganisms during the collection process.     

Bioenergetic theory predicts infection dynamics of human schistosomes in intermediate host snails across ecological gradients

Epidemiological dynamics depend on the traits of hosts and parasites, but hosts and parasites are heterogeneous entities that exist in dynamic environments. Resource availability is a particularly dynamic and potent environmental driver of within‐host infection dynamics (temporal patterns of growth, reproduction, parasite production and survival). We developed, parameterised and validated a model for resource‐explicit infection dynamics by incorporating a parasitism module into dynamic energy budget theory. The model mechanistically explained the dynamic multivariate responses of the human parasite Schistosoma mansoni and its intermediate host snail to variation in resources and host density. At the population level, feedbacks mediated by resource competition could create a unimodal relationship between snail density and human risk of exposure to schistosomes. Consequently, weak snail control could backfire if reductions in snail density release remaining hosts from resource competition. If resource competition is strong and relevant to schistosome production in nature, it could inform control strategies.