The Evolutionary Origin of the Runx/CBFbeta Transcription Factors – Studies of the Most Basal Metazoans

BACKGROUND. Members of the Runx family of transcriptional regulators, which bind DNA as heterodimers with CBFβ, are known to play critical roles in embryonic development in many triploblastic animals such as mammals and insects. They are known to regulate basic developmental processes such as cell fate determination and cellular potency in multiple stem-cell types, including the sensory nerve cell progenitors of ganglia in mammals. RESULTS. In this study, we detect and characterize the hitherto unexplored Runx/CBFβ genes of cnidarians and sponges, two basal animal lineages that are well known for their extensive regenerative capacity. Comparative structural modeling indicates that the Runx-CBFβ-DNA complex from most cnidarians and sponges is highly similar to that found in humans, with changes in the residues involved in Runx-CBFβ dimerization in either of the proteins mirrored by compensatory changes in the binding partner. In situ hybridization studies reveal that Nematostella Runx and CBFβ are expressed predominantly in small isolated foci at the base of the ectoderm of the tentacles in adult animals, possibly representing neurons or their progenitors. CONCLUSION. These results reveal that Runx and CBFβ likely functioned together to regulate transcription in the common ancestor of all metazoans, and the structure of the Runx-CBFβ-DNA complex has remained extremely conserved since the human-sponge divergence. The expression data suggest a hypothesis that these genes may have played a role in nerve cell differentiation or maintenance in the common ancestor of cnidarians and bilaterians.National Science Foundation (IBN-0212773, FP-91656101-0); Boston University SPRInG (20-202-8103-9); Israel Science Foundation (825/07

IDS Project: Community and Innovation

This chapter discusses the distributed, volunteer nature of an information delivery cooperative which became formally designated as the IDS Project and how a “coalition of the willing” has been able to move the resource sharing community forward on a national scale through innovations in training, support, and technology. The authors use a case study approach to highlight some of the major accomplishments of the IDS Project, such as the Article Licensing Information Availability Service (ALIAS), IDS Search, the Mentor Program, and the Regional Users Groups. The team-based structure of the IDS Project allows for groups to work independently and from multiple locations while still creating a synergistic result through the combination of community and innovation. Distributed teams often provide enriched user skills for the group but often cause difficulties due to the distance, communication, and differing requirements of the different local institutions. The IDS Project’s use of technology and periodic face-to-face meetings has reduced the issues with distributed teams and created highly effective working groups. These groups, such as the mentors and the Technology Development Team, have provided excellent service and training to the member libraries. Through the use of the Best Practices Toolkit, the Getting It System Toolkit, ILLiad Addons produced by IDS, and other national services, the IDS Project has made it possible for libraries that use ILLiad to benefit from its developments

Mass wasting triggered by seasonal CO₂ sublimation under Martian atmospheric conditions: Laboratory experiments

Sublimation is a recognized process by which planetary landscapes can be modified. However, interpretation of whether sublimation is involved in downslope movements on Mars and other bodies is restricted by a lack of empirical data to constrain this mechanism of sediment transport and its influence on landform morphology. Here we present the first set of laboratory experiments under Martian atmospheric conditions which demonstrate that the sublimation of CO2 ice from within the sediment body can trigger failure of unconsolidated, regolith slopes and can measurably alter the landscape. Previous theoretical studies required CO2 slab ice for movements, but we find that only frost is required. Hence, sediment transport by CO2 sublimation could be more widely applicable (in space and time) on Mars than previously thought. This supports recent work suggesting CO2 sublimation could be responsible for recent modification in Martian gullies

Characterizing the contaminating distance distribution for Bayesian supernova cosmology

Measurements of the equation of state of dark energy from surveys of thousands of Type Ia Supernovae (SNe Ia) will be limited by spectroscopic follow-up and must therefore rely on photometric identification, increasing the chance that the sample is contaminated by Core Collapse Supernovae (CC SNe). Bayesian methods for supernova cosmology can remove contamination bias while maintaining high statistical precision but are sensitive to the choice of parameterization of the contaminating distance distribution. We use simulations to investigate the form of the contaminating distribution and its dependence on the absolute magnitudes, light curve shapes, colors, extinction, and redshifts of core collapse supernovae. We find that the CC luminosity function dominates the distance distribution function, but its shape is increasingly distorted as the redshift increases and more CC SNe fall below the survey magnitude limit. The shapes and colors of the CC light curves generally shift the distance distribution, and their effect on the CC distances is correlated. We compare the simulated distances to the first year results of the SDSS-II SN survey and find that the SDSS distance distributions can be reproduced with simulated CC SNe that are ~1 mag fainter than the standard Richardson et al. (2002) luminosity functions, which do not produce a good fit. To exploit the full power of the Bayesian parameter estimation method, parameterization of the contaminating distribution should be guided by the current knowledge of the CC luminosity functions, coupled with the effects of the survey selection and magnitude-limit, and allow for systematic shifts caused by the parameters of the distance fit.Comment: 17 pages, 5 figures; accepted for publication in the Astrophysical Journa

GUCY2C lysosomotropic endocytosis delivers immunotoxin therapy to metastatic colorectal cancer.

The emergence of targeted cancer therapy has been limited by the paucity of determinants which are tumor-specific and generally associated with disease, and have cell dynamics which effectively deploy cytotoxic payloads. Guanylyl cyclase C (GUCY2C) may be ideal for targeting because it is normally expressed only in insulated barrier compartments, including intestine and brain, but over-expressed by systemic metastatic colorectal tumors. Here, we reveal that GUCY2C rapidly internalizes from the cell surface to lysosomes in intestinal and colorectal cancer cells. Endocytosis is independent of ligand binding and receptor activation, and is mediated by clathrin. This mechanism suggests a design for immunotoxins comprising a GUCY2C-directed monoclonal antibody conjugated through a reducible disulfide linkage to ricin A chain, which is activated to a potent cytotoxin in lysosomes. Indeed, this immunotoxin specifically killed GUCY2C-expressing colorectal cancer cells in a lysosomal- and clathrin-dependent fashion. Moreover, this immunotoxin reduced pulmonary tumors \u3e80% (

Tumor radiation therapy creates therapeutic vaccine responses to the colorectal cancer antigen GUCY2C.

PURPOSE: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. METHODS AND MATERIALS: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. RESULTS: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P CONCLUSIONS: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance of modality sequence optimization before the initiation of clinical trials of RT and IT to maximize immune and antitumor responses