Histidine phosphorylation of P-selectin upon stimulation of human platelets: A novel pathway for activation-dependent signal transduction

AbstractTransient phosphorylation of histidine characterizes the two-component systems in prokaryotes that control important physiological functions, but analogous events have not been implicated in signal transduction in mammalian cells. To explore histidine phosphorylation during activation of human cells, stimulated platelets were analyzed for the formation of protein phosphohistidine in a model system employing P-selectin. P-selectin, a leukocyte adhesion molecule, undergoes rapid phosphorylation and selective dephosphorylation of tyrosine, serine, and threonine. We now establish that phosphorylation following platelet activation with thrombin or collagen generates phosphohistidine at histidines on the cytoplasmic tail of P-selectin. With thrombin stimulation, the kinetics of phosphohistidine appearance and disappearance on P-selectin are very rapid. Platelets exhibit a novel ligand-induced signaling pathway to generate phosphohistidine. These results provide direct biochemical evidence for the induction of rapid and reversible histidine phosphorylation in mammalian cells upon cell activation and represent a novel paradigm for mammalian cell signaling

Engineered Bivalent Ligands to Bias ErbB Receptor-mediated Signaling and Phenotypes

The ErbB receptor family is dysregulated in many cancers, and its therapeutic manipulation by targeted antibodies and kinase inhibitors has resulted in effective chemotherapies. However, many malignancies remain refractory to current interventions. We describe a new approach that directs ErbB receptor interactions, resulting in biased signaling and phenotypes. Due to known receptor-ligand affinities and the necessity of ErbB receptors to dimerize to signal, bivalent ligands, formed by the synthetic linkage of two neuregulin-1β (NRG) moieties, two epidermal growth factor (EGF) moieties, or an EGF and a NRG moiety, can potentially drive homotypic receptor interactions and diminish formation of HER2-containing heterodimers, which are implicated in many malignancies and are a prevalent outcome of stimulation by native, monovalent EGF, or NRG. We demonstrate the therapeutic potential of this approach by showing that bivalent NRG (NN) can bias signaling in HER3-expressing cancer cells, resulting in some cases in decreased migration, inhibited proliferation, and increased apoptosis, whereas native NRG stimulation increased the malignant potential of the same cells. Hence, this new approach may have therapeutic relevance in ovarian, breast, lung, and other cancers in which HER3 has been implicated

MartiTracks: A Geometrical Approach for Identifying Geographical Patterns of Distribution

Panbiogeography represents an evolutionary approach to biogeography, using rational cost-efficient methods to reduce initial complexity to locality data, and depict general distribution patterns. However, few quantitative, and automated panbiogeographic methods exist. In this study, we propose a new algorithm, within a quantitative, geometrical framework, to perform panbiogeographical analyses as an alternative to more traditional methods. The algorithm first calculates a minimum spanning tree, an individual track for each species in a panbiogeographic context. Then the spatial congruence among segments of the minimum spanning trees is calculated using five congruence parameters, producing a general distribution pattern. In addition, the algorithm removes the ambiguity, and subjectivity often present in a manual panbiogeographic analysis. Results from two empirical examples using 61 species of the genus Bomarea (2340 records), and 1031 genera of both plants and animals (100118 records) distributed across the Northern Andes, demonstrated that a geometrical approach to panbiogeography is a feasible quantitative method to determine general distribution patterns for taxa, reducing complexity, and the time needed for managing large data sets

Tyrosine kinase signalling in breast cancer: ErbB family receptor tyrosine kinases

ERBB family receptor tyrosine kinases are overexpressed in a significant subset of breast cancers. One of these receptors, HER2/neu, or ErbB-2, is the target for a new rational therapeutic antibody, Herceptin. Other inhibitors that target this receptor, and another family member, the epidermal growth factor (EGF) receptor, are moving into clinical trials. Both of these receptors are sometimes overexpressed in breast cancer, and still subject to regulation by hormones and other physiological regulators. Optimal use of therapeutics targeting these receptors will require consideration of the several modes of regulation of these receptors and their interactions with steroid receptors

sitchensis

Salix sitchensis Sanson ex BongardSitka willow;velvet willowsaule de Sitka0.6 mile east of US 101 at Sixes.Shrub growing over sharp bank of SixesMaterial used in preparation of: Crovello, Theodore J. 1968. A numerical taxonomic study of the genus Salix, sect. Sitchenses. Univ. Calif. Publ. Bot. 44: 1-61

sitchensis

Salix sitchensis Sanson ex BongardSitka willow;velvet willowsaule de Sitka0.6 mile east of US 101 at Sixes. Growing 100 feet west of #655.Shrub, growing over sharp bank of Sixes River.Material used in preparation of: Crovello, Theodore J. 1968. A numerical taxonomic study of the genus Salix, sect. Sitchenses. Univ. Calif. Publ. Bot. 44: 1-61

The Impact of Online Training on the Reliability of Direct Behavior Ratings

Direct Behavior Rating (DBR) has emerged as a useful assessment method to identify behavioral risk and monitor behavioral progress. The development of an online training module has provided an option for low cost training accessible to a wide variety of users at their convenience. Although evaluation of the DBR online training module has demonstrated improved rater accuracy following completion, reliability of obtained scores has not been fully explored. An improvement in reliability of scores is desired to allow for flexible use across raters and increased efficiency in decision-making. In this study, four teachers simultaneously rated the activity engagement and disruptive behavior of six children during their ice skating activity at a summer day camp. Ratings were analyzed within a generalizability theory (GT) framework. Results suggest that completion of the online training module may result in some improvement in the reliability of data generated from DBR-SIS

Quantitative Approaches To Phytogeography

vii,280 hal,;ill,;30 c

sp

0.5 miles south of Holy City.Along road to Summit roadbelow maple and redwood treesShrub 15 feet tall. Across road from #679. Same plant as No. 593. Material used in preparation of: Crovello, Theodore J. 1968. A numerical taxonomic study of the genus Salix, sect. Sitchenses. Univ. Calif. Publ. Bot. 44: 1-61