Information Sharing and Cooperative Search in Fisheries

We present a dynamic game of search and learning about the productivity of com-peting fishing locations. Perfect Bayesian Nash equilibrium search patterns for non-cooperating fishermen and members of an information sharing cooperative are com-pared with first-best outcomes. Independent fishermen do not internalize the full valueof information, and do not replicate first-best search. A fishing cooperative faces afree-riding problem, as each coop member prefers that other members undertake costlysearch for information. Pooling contracts among coop members may mitigate, butare not likely to eliminate free riding. Our results explain the paucity of informationsharing in fisheries and suggest regulators use caution in advocating cooperatives as asolution to common pool ineffciencies in fisheries.�search; Information sharing; Dynamic Bayesian game; Fishing cooperative

Prostate-associated gene 4 (PAGE4), an intrinsically disordered cancer/testis antigen, is a novel therapeutic target for prostate cancer

Prostate-associated gene 4 (PAGE4) is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein (IDP) that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun. c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer (PCa). Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease

Prostate-Associated Gene 4 (PAGE4): Leveraging the Conformational Dynamics of a Dancing Protein Cloud as a Therapeutic Target.

Prostate cancer (PCa) is a leading cause of mortality and morbidity globally. While genomic alterations have been identified in PCa, in contrast to some other cancers, use of such information to personalize treatment is still in its infancy. Here, we discuss how PAGE4, a protein which appears to act both as an oncogenic factor as well as a metastasis suppressor, is a novel therapeutic target for PCa. Inhibiting PAGE4 may be a viable strategy for low-risk PCa where it is highly upregulated. Conversely, PAGE4 expression is downregulated in metastatic PCa and, therefore, reinstituting its sustained expression may be a promising option to subvert or attenuate androgen-resistant PCa. Thus, fine-tuning the levels of PAGE4 may represent a novel approach for personalized medicine in PCa

Four-color single-molecule fluorescence with noncovalent dye labeling to monitor dynamic multimolecular complexes

To allow studies of conformational changes within multi-molecular complexes, we present a simultaneous, 4-color single molecule fluorescence methodology implemented with total internal reflection illumination and camera based, wide-field detection. We further demonstrate labeling histidine-tagged proteins non-covalently with tris-Nitrilotriacetic acid (tris-NTA) conjugated dyes to achieve single molecule detection. We combine these methods to co-localize the mismatch repair protein MutSα on DNA while monitoring MutSα-induced DNA bending using Förster resonance energy transfer (FRET) and to monitor assembly of membrane-tethered SNARE protein complexes

Single molecule studies of DNA mismatch repair

DNA mismatch repair involves is a widely conserved set of proteins that is essential to limit genetic drift in all organisms. The same system of proteins plays key roles in many cancer related cellular transactions in humans. Although the basic process has been reconstituted in vitro using purified components, many fundamental aspects of DNA mismatch repair remain hidden due in part to the complexity and transient nature of the interactions between the mismatch repair proteins and DNA substrates. Single molecule methods offer the capability to uncover these transient but complex interactions and allow novel insights into mechanisms that underlie DNA mismatch repair. In this review, we discuss applications of single molecule methodology including electron microscopy, atomic force microscopy, particle tracking, FRET, and optical trapping to studies of DNA mismatch repair. These studies have led to formulation of mechanistic models of how proteins identify single base mismatches in the vast background of matched DNA and signal for their repair

Single-Molecule FRET TACKLE Reveals Highly Dynamic Mismatched DNA−MutS Complexes

The first step in DNA mismatch repair (MMR) is the recognition of DNA mismatches or nucleotide insertions/deletions (IDLs) by MutS and MutS homologs. To investigate the conformational properties of MutS-mismatch complexes, we used single-molecule fluorescence resonance energy transfer (smFRET) to examine the dynamics of MutS-induced DNA bending at a GT-mismatch. The FRET measurements reveal that the MutS-GT-mismatch recognition complex is highly dynamic, undergoing conformational transitions between many states with different degrees of DNA bending. Due to the complexity of the data, we developed an analysis approach, called FRET TACKLE, in which we combine direct analysis of FRET transitions with examination of kinetic lifetimes to identify all of the conformational states and characterize the kinetics of the binding and conformational equilibria. The data reveal that MutS-GT complexes can reside in six different conformations, which have lifetimes that differ by as much as 20-fold and exhibit rates of interconversion that vary by two orders of magnitude. To gain further insight into the dynamic properties of GT-MutS complexes and to bolster the validity of our analysis, we complemented our experimental data with Monte Carlo simulations. Taken together, our results suggest that the dynamics of the MutS-mismatch complex could govern the efficiency of repair of different DNA mismatches. Finally, in addition to revealing these important biological implications of MutS-DNA interactions, this FRET TACKLE method will enable the analysis of the complex dynamics of other biological systems