R ESEARCH A RTICLES yond saturation) and found all to be in good Accelerator Conference, L. Gennari, Ed. (IEEE, Piscat- Fawley for his help with the simulation code GINGER, agreement with theory. The detailed exper- away, NJ, 1995), pp. 183Ð185. P. Emma for many insights into the design of the 28. K.-J. Kim, M. Xie, Nucl. Instrum. Methods Phys. Rev. bunch compressor system, and the people of the imental confirmation of the SASE process Sect. A 331, 359 (1993). Argonne Wakefield Accelerator for the occasional and the beam manipulation methodologies 29. W. Fawley, “An Informal Manual for GINGER and Its testing of laser and rf equipment. This work is sup- required to achieve saturation will continue Post-processor XPLOTGIN,” BP Tech Note-104 (Law- ported by the U.S. Department of Energy, Office of rence Berkeley National Laboratory, Berkeley, CA, Basic Energy Sciences, under contract W-31-109- to improve and move the process to shorter 1995). ENG-38. wavelengths, creating the possibility of 30. This work would not have been possible without the building a very high brightness, tunable outstanding help and dedication of the Advanced 16 February 2001; accepted 20 April 2001 Photon Source (APS) technicians, the supporting en- Published online 17 May 2001; coherent x-ray source. gineers and scientists, and the management and ad- 10.1126/science.1059955 ministrative staff of the APS. In addition, we thank W. Include this information when citing this paper. References and Notes 1. J. L. Laclare, in Proceedings of the IEEE 1993 Particle Accelerator Conference, S. T. Coneliassen, Ed. (IEEE, Piscataway, NJ, 1993), pp. 1427Ð1431. 2. J. N. Galayda, in Proceedings of the IEEE 1995 Particle G-Protein Signaling Through Accelerator Conference, L. Gennari, Ed. (IEEE, Piscat- away, NJ, 1995), pp. 4Ð8. 3. H. Kamitsubo, in Proceedings of the IEEE 1997 Particle Tubby Proteins Accelerator Conference, M. Comyn, M. K. Craddock, 1 2 4 M. 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(IEEE, Piscataway, NJ, 1999), pp. 2489Ð expectancy and is a primary risk factor for The tubby protein is a member of a homol- 2491. 19. I. B. Vasserman, N. A. Vinokurov, R. J. Dejus, AIP Conf. type II diabetes, heart disease, and hyperten- ogous family with four members (tubby and Proc. 521, 368 (2000). sion (3, 4). TULPs 1 to 3) encoded in the human genome 20. E. Gluskin et al., Nucl. Instrum. Methods Phys. Rev. The tubby strain of obese mice (5) provides (9–11) and with others present in various mul- Sect. A 429, 358 (1999). 21. N. D. Arnold et al.,inProceedings of the Twenty one of the few defined models for adult-onset ticellular organisms (12). These proteins feature Second Free-Electron Laser Conference, V. Litvinenko, obesity. The tubby gene, which is highly ex- a characteristic “tubby domain” of about 260 Y. Wu, Eds. [Nucl. Instrum. Methods Phys. Rev. Sect. pressed in the paraventricular nucleus of the amino acids at the COOH-terminus that forms a A (2000)]. 22. G. 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Yu, S. Krinsky, R. L. Gluckstern, Phys. Rev. Lett. 4 USA. Center for Biomolecular Interaction Analysis, outlines a long, positively charged groove im- 64, 3011 (1990). University of Utah, Salt Lake City, UT 84132, USA. 25. Y. Chin, K.-J. Kim, M. Xie, Phys. Rev. A 46, 6662 plicated in DNA binding (15). Tubby proteins (1992). *To whom correspondence should be addressed at also include NH -terminal regions that, in their 26. M. Xie, Nucl. Instrum. Methods Phys. Rev. Sect. A the Structural Biology Program, Mount Sinai School of 2 445, 59 (2000). Medicine, Room 16-20, 1425 Madison Avenue, New primary sequence, resemble activation domains 27. ࿜࿜࿜࿜ ,inProceedings of the IEEE 1995 Particle York, NY 10029, USA. E-mail: [email protected] from known transcription factors (15). Al- www.sciencemag.org SCIENCE VOL 292 15 JUNE 2001 2041 R ESEARCH A RTICLES though the NH2-terminal domain of tubby can Here we show that tubby, a molecule for brane, but also contains a functional nu- activate transcription of reporter constructs which loss of function leads to obesity, serves clear localization signal. Confocal laser when fused to GAL4, potential targets of tran- as a downstream effector of GPCRs that sig- scanning microscopy of Neuro-2A cells ␣ scriptional regulation by tubby have not yet nal through the Gq subclass of G proteins. transfected with green fluorescent protein been identified. Furthermore, little is known Tubby is anchored to the plasma membrane (GFP)–tubby fusion proteins revealed that about signaling pathways regulating the func- through binding phosphatidylinositol 4,5- tubby initially localizes to the plasma mem- ␣ tion of tubby. bisphosphate [PtdIns(4,5)P2]. G q, but nei- brane. However, beginning at about 36 hours Genetic and physiological studies have re- ther other G␣ proteins nor G␤␥ subunits, after transfection, fluorescence starts to accu- vealed a host of signaling molecules that play releases tubby from the plasma membrane mulate within the cell nucleus without dimin- critical roles in the neuroendocrine regulation of through phospholipase C–␤ (PLC-␤)–medi- ishing at the plasma membrane (Fig.