Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation.

Mutation and translocation of fibroblast growth factor receptors often lead to aberrant signaling and cancer. This work focuses on the t(8;22)(p11;q11) chromosomal translocation which creates the breakpoint cluster region (BCR) fibroblast growth factor receptor1 (FGFR1) (BCR-FGFR1) fusion protein. This fusion occurs in stem cell leukemia/lymphoma, which can progress to atypical chronic myeloid leukemia, acute myeloid leukemia, or B-cell lymphoma. This work focuses on the biochemical characterization of BCR-FGFR1 and identification of novel therapeutic targets. The tyrosine kinase activity of FGFR1 is required for biological activity as shown using transformation assays, interleukin-3 independent cell proliferation, and liquid chromatography/mass spectroscopy analyses. Furthermore, BCR contributes a coiled-coil oligomerization domain, also essential for oncogenic transformation by BCR-FGFR1. The importance of salt bridge formation within the coiled-coil domain is demonstrated, as disruption of three salt bridges abrogates cellular transforming ability. Lastly, BCR-FGFR1 acts as a client of the chaperonin heat shock protein 90 (Hsp90), suggesting that BCR-FGFR1 relies on Hsp90 complex to evade proteasomal degradation. Transformed cells expressing BCR-FGFR1 are sensitive to the Hsp90 inhibitor Ganetespib, and also respond to combined treatment with Ganetespib plus the FGFR inhibitor BGJ398. Collectively, these data suggest novel therapeutic approaches for future stem cell leukemia/lymphoma treatment: inhibition of BCR oligomerization by disruption of required salt bridges; and inhibition of the chaperonin Hsp90 complex

Human Cytomegalovirus US28: A Functionally Selective Chemokine Binding Receptor

The Human Cytomegalovirus (HCMV)-encoded chemokine receptor US28 is the most well-characterized of the four chemokine receptor-like molecules found in the HCMV genome. US28 been studied as an important virulence factor for HCMV-mediated vascular disease and, more recently, in models of HCMV-associated malignancy. US28 is a rare multi-chemokine family binding receptor with the ability to bind ligands from two distinct chemokine classes. Ligand binding to US28 activates cell-type and ligand-specific signaling pathways leading to cellular migration, an example receptor functional selectivity. Additionally, US28 has been demonstrated to constitutively activate PLC and NFkB. Understanding the structure/function relationships between US28, its ligands and intracellular signaling molecules will provide essential clues for effective pharmacological targeting this multifunctional chemokine receptor

GERMANY AND THE BALANCE BETWEEN THREATS AND CAPACITIES IN EUROPE

Njemačka je u sigurnosnom smislu stavljena pred težak izbor. S jedne strane, od nje se očekuje da nakon ponovnog ujedinjenja odigra značajniju ulogu u Europi i globalnoj sigurnosti, a da istodobno ponovno ne izazove osjeć aj ugroženosti kod drugih zemalja, osobito kod svojih istočnih susjeda. Ispitivanja javnog mnijenja Nijemaca i stanovnika srednje i istočne Europe otkrivaju velike teškoće, postane li Njemačka nametljivija. Promjene u njezinu ponašanju i tumačenju ustava upućuju na sazrijevanje ili “normalizaciju” njemačke vanjske politike. Dosad su te promjene naglašavale tradicionalne oblike diplomacije i savezničkog ponašanja usmjerenog na korištenje povećanih kapaciteta ujedinjene Njemačke, kojima se neposrednije ostvaruju njemački interesi. Raspravlja se o alternativnim načinima na koje se može ispunjavati značajnija sigurnosna uloga, pogotovo s obzirom na podatke o tome kako Njemačku vide susjedni narodi i njihovo vodstvo.Germany\u27s security dilemma is to fulfill the larger role in Europe and global security that is expected after reunification, while not rekindling a sense of threat particularly among neighbors to the east. Opinion surveys of Germans and Central/East Europeans reveal substantial difficulties were Germany to become more assertive. Changes in German behavior and constitutional interpretation suggest a maturation or “normalization” of German foreign policy. Thus far, these changes have emphasized traditional forms of diplomacy and alliance behavior focused on using the enlarged capacities of a reunited Germany that more directly pursue German interests. An alternative ways by which to perform a larger security role are discussed, particularly in light of data regarding the mutual perceptions of Germans among neighboring peoples and leaders

Functions of Fibroblast Growth Factor Receptors in cancer defined by novel translocations and mutations

AbstractThe four receptor tyrosine kinases (RTKs) within the family of Fibroblast Growth Factor Receptors (FGFRs) are critical for normal development but also play an enormous role in oncogenesis. Mutations and/or abnormal expression often lead to constitutive dimerization and kinase activation of FGFRs, and represent the primary mechanism for aberrant signaling. Sequencing of human tumors has revealed a plethora of somatic mutations in FGFRs that are frequently identical to germline mutations in developmental syndromes, and has also identified novel FGFR fusion proteins arising from chromosomal rearrangements that contribute to malignancy. This review details approximately 200 specific point mutations in FGFRs and 40 different fusion proteins created by translocations involving FGFRs that have been identified in human cancer. This review discusses the effects of these genetic alterations on downstream signaling cascades, and the challenge of drug resistance in cancer treatment with antagonists of FGFRs

Spatial methods for event reconstruction in CLEAN

In CLEAN (Cryogenic Low Energy Astrophysics with Noble gases), a proposed neutrino and dark matter detector, background discrimination is possible if one can determine the location of an ionizing radiation event with high accuracy. We simulate ionizing radiation events that produce multiple scintillation photons within a spherical detection volume filled with liquid neon. We estimate the radial location of a particular ionizing radiation event based on the observed count data corresponding to that event. The count data are collected by detectors mounted at the spherical boundary of the detection volume. We neglect absorption, but account for Rayleigh scattering. To account for wavelength-shifting of the scintillation light, we assume that photons are absorbed and re-emitted at the detectors. Here, we develop spatial Maximum Likelihood methods for event reconstruction, and study their performance in computer simulation experiments. We also study a method based on the centroid of the observed count data. We calibrate our estimates based on training data

Differences in Ethnic and Sport Culture Salience Among College Students Participating in NCAA and Recreational Sports

This study aims to (1) examine differences between Ethnic Majority (European American) and Ethnic Minority (African American, Latina/o, Asian/Asian American, Pacific Islander, and Other) student athletes’ ratings of importance of their Ethnic Culture, (2) examine differences in the importance of Sport Culture among NCAA and Recreational (i.e., Club and Intramural) student athletes, and (3) determine if Ethnic Identification and Athlete Type interact to predict the importance of Ethnic Culture and Sport Culture. Student athletes were asked to fill out a demographic questionnaire, and then rate the importance of several cultural domains (i.e. Ethnic Culture and Sport Culture) using a novel measure, the Cultural Domain Menu (CDM). After a descriptive analysis was performed, Analysis of Variances (ANOVA) and several t-tests were conducted to test differences among Ethnic Majority and Ethnic Minority student athletes in the importance of their Ethnic and Sport Cultures. Findings demonstrated a significant difference between Ethnic Majority and Ethnic Minority student athletes’ ratings of the importance of their Ethnic Culture: Ethnic Majority ratings were found to be lower compared to Ethnic Minority student athletes. Results also showed a significant difference between NCAA and Recreational student athletes in their ratings of their Sport Culture: NCAA student athletes were found to rank their Sport Culture as more salient. Implications, limitations, and future directions for this study are discussed in regard to the results. These results serve as a great indicator of the mental health issues of importance when aiming to serve student athletes from different backgrounds

Green, Adam. Selling the Race: Culture, Community and Black Chicago, 1940–1955. Chicago: University of Chicago Press, 2007. 280 pp.

Agreement is developing among agricultural scientists on the emerging inability of agriculture to meet growing global food demands. Changes in trends of weather conditions projected by global climate models will challenge physiological limits of crops and exacerbate the global food challenge by 2050. These climate- and constraint-driven crop production challenges are interconnected within a complex global economy, where diverse factors add to price volatility and food scarcity. Our scenarios of the impact of climate change on food security through 2050 for internationally traded crops show that climate change does not threaten near-term US food security due to the availability of adaptation strategies. However, as climate continues to change beyond 2050 current adaptation measures will not be sufficient to meet growing food demand. Climate scenarios for higher-level carbon emissions exacerbate the food shortfall, although uncertainty in projections of future precipitation is a limitation to impact studies