Exploring Strategies for Melanoma Detection Utilizing Discrimination Training

Melanoma is the deadliest form of skin cancer. Although melanoma is amenable to visual identification by those who might suffer from the disease, no consensus exists on a single strategy for promoting early detection. To date, the application of behavioral principles has been all but absent from the literature attempting to address this issue. The conceptually systematic knowledgebase on learning and behavior offered by behavior analysis has the potential to contribute substantially toward developing strategies for early detection of melanoma. In particular, generalization is a ubiquitous behavioral process with an extensive literature from which to draw. As such, the purpose of the current series of studies is to employ a use-inspired translational approach to explore strategies for promoting early detection by capitalizing on behavior analytic research regarding the processes of generalization and discrimination (i.e., peak shift). The purpose of the experiments was to (1) use discrimination training to establish generalization and postdiscrimination gradients with moles as stimuli, (2) determine the effects of parametric manipulations of training on postdiscrimination gradients, and (3) evaluate training with multiple discriminative stimuli. Results from Study 1 indicated that discrimination training produced gradient shifts as compared to a control group trained only with the S+. Results from Study 2 indicated that training with an S- more distinct from the S+ produced gradient shifts, but that S- stimuli more similar to the S+ did not. Results from Study 3 indicated that training with two S- stimuli from one extreme of the stimulus array produced relatively weak shifts in postdiscrimination gradients, but that training with an S- at both extremes of the array was effective in producing highly consistent response patterns. Theoretical implications and future directions toward more clinically relevant studies are discussed

Thermodynamics and the Global Optimization of Lennard-Jones clusters

Theoretical design of global optimization algorithms can profitably utilize recent statistical mechanical treatments of potential energy surfaces (PES's). Here we analyze the basin-hopping algorithm to explain its success in locating the global minima of Lennard-Jones (LJ) clusters, even those such as \LJ{38} for which the PES has a multiple-funnel topography, where trapping in local minima with different morphologies is expected. We find that a key factor in overcoming trapping is the transformation applied to the PES which broadens the thermodynamic transitions. The global minimum then has a significant probability of occupation at temperatures where the free energy barriers between funnels are surmountable.Comment: 13 pages, 13 figures, revte

The double-funnel energy landscape of the 38-atom Lennard-Jones cluster

The 38-atom Lennard-Jones cluster has a paradigmatic double-funnel energy landscape. One funnel ends in the global minimum, a face-centred-cubic (fcc) truncated octahedron. At the bottom of the other funnel is the second lowest energy minimum which is an incomplete Mackay icosahedron. We characterize the energy landscape in two ways. Firstly, from a large sample of minima and transition states we construct a disconnectivity tree showing which minima are connected below certain energy thresholds. Secondly we compute the free energy as a function of a bond-order parameter. The free energy profile has two minima, one which corresponds to the fcc funnel and the other which at low temperature corresponds to the icosahedral funnel and at higher temperatures to the liquid-like state. These two approaches show that the greater width of the icosahedral funnel, and the greater structural similarity between the icosahedral structures and those associated with the liquid-like state, are the cause of the smaller free energy barrier for entering the icosahedral funnel from the liquid-like state and therefore of the cluster's preferential entry into this funnel on relaxation down the energy landscape. Furthermore, the large free energy barrier between the fcc and icosahedral funnels, which is energetic in origin, causes the cluster to be trapped in one of the funnels at low temperature. These results explain in detail the link between the double-funnel energy landscape and the difficulty of global optimization for this cluster.Comment: 12 pages, 11 figures, revte

De-novo design of complementary (antisense) peptide mini-receptor inhibitor of interleukin 18 (IL-18).

Complementary (antisense) peptide mini-receptor inhibitors are complementary peptides designed to be receptor-surrogates that act by binding to selected surface features of biologically important proteins thereby inhibiting protein-cognate receptor interactions and subsequent biological effects. Previously, we described a complementary peptide mini-receptor inhibitor of interleukin-1beta (IL-1beta) that was designed to bind to an external surface loop (beta-bulge) of IL-1beta (Boraschi loop) clearly identified in the X-ray crystal structure of this cytokine. Here, we report the de-novo design and rational development of a complementary peptide mini-receptor inhibitor of cytokine interleukin-18 (IL-18), a protein for which there is no known X-ray crystal structure. Using sequence homology comparisons with IL-1beta, putative IL-18 surface loops are identified and used as a starting point for design, including a loop region 1 thought to be equivalent with the Boraschi loop of IL-1beta. Only loop region 1 complementary peptides are found to be promising leads as mini-receptor inhibitors of IL-18 but these are prevented from being properly successful owing to solubility problems. The application of "M-I pair mutagenesis" and inclusion of a C-terminal arginine residue are then sufficient to solve this problem and convert one lead peptide into a functional complementary peptide mini-receptor inhibitor of IL-18. This suggests that the biophysical and biological properties of complementary peptides can be improved in a rational and logical manner where appropriate, further strengthening the potential importance of complementary peptides as inhibitors of protein-protein interactions, even when X-ray crystal structural information is not readily available

The Community Reinvestment Act: An Economic Analysis

The Community Reinvestment Act ( CRA ) provides, innocuously enough, that federal bank supervisors must assess how a depository institution (a bank or savings association) serves the credit needs of its entire community, including low- and moderate-income neighborhoods, consistent with safe and sound operation. The supervisors must take such record into account in evaluating applications to acquire deposit facilities. For many years after its adoption in 1977, the CRA was little more than a vague statement of principle without much real-world effect. In 1989, however, Congress greatly enhanced the CRA\u27s impact as part of the comprehensive banking legislation of that year. This Article offers a preliminary economic analysis of the CRA in its new, post-1989 manifestation