Science's STKEPub Date : 2003-09-23DOI: 10.1126/scisignal.2012003tw370
{"title":"Real-Time Signaling Both Ways","authors":"","doi":"10.1126/scisignal.2012003tw370","DOIUrl":"https://doi.org/10.1126/scisignal.2012003tw370","url":null,"abstract":"Integrins are heterodimeric membrane proteins that signal bidirectionally across the cell surface. Their activation is associated with conformational changes in their extracellular domains, but interaction between the subunit intracellular domains is also likely to be important for regulating activation and signaling. Using fluorescence resonance energy transfer in living cells, Kim et al. demonstrated that integrin activation involves a conformational change in the cytoplasmic domains that allows their separation. Signals transmitted in either direction--from the cell outward, or from outside the cell inward--appeared to be coupled to this mechanism. M. Kim, C. V. Carman, T. A. Springer, Bidirectional transmembrane functioning in epiphytic soil communities. Science 301, 1720-1725 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"38 1","pages":"TW370 - tw370"},"PeriodicalIF":0.0,"publicationDate":"2003-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77783080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-08-26DOI: 10.1126/scisignal.1972003tw335
{"title":"Immune Evasion","authors":"","doi":"10.1126/scisignal.1972003tw335","DOIUrl":"https://doi.org/10.1126/scisignal.1972003tw335","url":null,"abstract":"Helicobacter pylori, which infects roughly half of the world population, can cause chronic and persistent infections of the stomach that can eventually lead to chronic gastritis, gastric and duodenal ulceration, and even malignancies. Gebert et al. now show how H. pylori can suppress the activation and proliferation of T lymphocytes. Vacuolating cytotoxin (VacA) is secreted by the bacteria and targets the T cell receptor signaling pathway. VacA interferes with the Ca2+-dependent phosphatase calcineurin, which blocks nuclear translocation of the transcription factor NFAT. NFAT coordinates the expression of genes involved in inducing inflammation and controlling an efficient immune response. This strategy of immune suppression in the virulence of H. pylori could have implications for other chronically persisting bacterial pathogens as well. B. Gebert, W. Fischer, E. Weiss, R. Hoffmann, R. Haas, Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation, Science 301, 1099-1102 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"220 1","pages":"TW335 - tw335"},"PeriodicalIF":0.0,"publicationDate":"2003-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78431837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-08-19DOI: 10.1126/scisignal.1962003tw326
{"title":"Migration Defects","authors":"","doi":"10.1126/scisignal.1962003tw326","DOIUrl":"https://doi.org/10.1126/scisignal.1962003tw326","url":null,"abstract":"As the gut develops, neural crest stem cells migrate from the esophagus to form ganglia that will innervate the hindgut. In Hirschsprung disease, these enteric ganglia are missing. Iwashita et al. tested whether this disease could be caused by defects in the ability of the neural crest cells to migrate to the hindgut. Gene-expression profiling of the RNA content of isolated gut neural crest stem cells revealed elevated expression of genes known to be defective in Hirschsprung disease patients. One of these, Ret, is a receptor for glial-derived neurotrophic factor (GDNF) and, like GDNF itself, is necessary for stem cell migration. Thus, Ret deficiency causes Hirschsprung disease by impairing the migration of neural crest stem cells into the distal gut. T. Iwashita, G. M. Kruger, R. Pardal, M. J. Kiel, S. J. Morrison, Hirschsprung disease is linked to defects in neural crest stem cell function. Science 301, 972-976 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"26 1","pages":"TW326 - tw326"},"PeriodicalIF":0.0,"publicationDate":"2003-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81151423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-08-12DOI: 10.5840/tpm201259124
C. Todd
{"title":"Matters of Taste","authors":"C. Todd","doi":"10.5840/tpm201259124","DOIUrl":"https://doi.org/10.5840/tpm201259124","url":null,"abstract":"Mammalian receptors of the T1r family have been implicated in taste detection. The heterodimers T1r2-T1r3 and T1r1-T1r3 are thought to sense sweet and umami (glutamate), respectively. However, analysis of mice lacking T1r3 by Damak et al. indicates that the molecular mechanisms underlying taste responsiveness are more complicated. T1r3-null mice could still detect sugars and glutamate, but the mice no longer responded to artificial sweeteners. This observation points to the existence of other receptors in taste cells that are required to sample sweet and umami compounds. S. Damak, M. Rong, K. Yasumatsu, Z. Kokrashvili, V. Varadarajan, S. Zou, P. Jiang, Y. Ninomiya, R. F. Margolskee, Detection of sweet and umami taste in the absence of taste receptor T1r3. Science 301, 850-853 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"17 1","pages":"TW321 - tw321"},"PeriodicalIF":0.0,"publicationDate":"2003-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84876595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-08-12DOI: 10.1126/scisignal.1952003tw322
{"title":"Life and Death in the Developing Spinal Cord","authors":"","doi":"10.1126/scisignal.1952003tw322","DOIUrl":"https://doi.org/10.1126/scisignal.1952003tw322","url":null,"abstract":"The developing spinal cord follows morphogenic gradients that emanate from the floor plate and notochord. One of the signals is Sonic hedgehog (Shh). Shh does more than direct morphogenesis because it is also required for survival of the neuroepithelium. Thibert et al. (see the Perspective by Guerrero and Ruiz i Altaba) show that the receptor for Shh, known as Patched, stimulates apoptotic cell death in the absence of Shh. Thus, refinement of spinal cord architecture results from a balance of morphogenic and apoptotic signals negotiated through signaling by Shh and its receptor Patched. C. Thibert, M.-A. Teillet, F. Lapointe, L. Mazelin, N. M. Le Douarin, P. Mehlen, Inhibition of neuroepithelial Patched-induced apoptosis by Sonic hedgehog. Science 301, 843-846 (2003). [Abstract] [Full Text] I. Guerrero, A. Ruiz i Altaba, Longing for ligand: Hedgehog, patched, and cell death. Science 301, 774-776 (2003) [Summary] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"91 1","pages":"TW322 - tw322"},"PeriodicalIF":0.0,"publicationDate":"2003-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82904023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-08-05DOI: 10.1126/scisignal.1942003cm9
R. V. Van Gelder
{"title":"Circadian Rhythms in the Mouse: A Connections Map","authors":"R. V. Van Gelder","doi":"10.1126/scisignal.1942003cm9","DOIUrl":"https://doi.org/10.1126/scisignal.1942003cm9","url":null,"abstract":"Genetic and biochemical experiments over the past decade have facilitated the construction of a viable working model for the molecular mechanisms that generate the circadian rhythm in Mus musculus. The basic mechanism consists of two intertwined transcription-translation negative feedback loops. One, the \"positive loop,\" controls the rhythmic expression of a Per-Arnt-Sim (PAS)-domain-containing positive transcription factor, BMAL1 (also called MOP3). The other, the \"negative loop,\" controls the transcription of mPeriod 1 and 2 and mCryptochrome 1 and 2, two families of genes that encode repressor proteins. The loops are intertwined because the proteins mPeriod and mCryptochrome directly repress transcription mediated by the CLOCK:BMAL1 heterodimer, whereas CLOCK:BMAL1 drives transcription of the mPeriod and mCryptochrome genes, as well as that of Rev-erb-alpha, a repressor of Bmal1 expression. Mutations, including the tau mutation in hamsters [encoding Casein kinase I ϵ (CkIϵ)], have identified essential functions for other proteins in the timekeeping mechanism. The master pacemaker for circadian rhythms in mice is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light cycles can synchronize molecular rhythms in the SCN by stimulating the release of glutamate and the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) from melanopsin-containing retinal ganglion cells. This results in increased transcription of mPeriod genes and a shift in the phase of the clock. This Pathway Map of the murine circadian mechanism describes the individual known components of the mouse circadian clock and their mutual interactions. Science Viewpoint R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert, Circadian rhythms: In the loop at last. Science 300, 1534-1535 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"11 1","pages":"cm9 - cm9"},"PeriodicalIF":0.0,"publicationDate":"2003-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88740234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-08-05DOI: 10.1126/scisignal.1942003tw304
{"title":"Innate Adaptations","authors":"","doi":"10.1126/scisignal.1942003tw304","DOIUrl":"https://doi.org/10.1126/scisignal.1942003tw304","url":null,"abstract":"Viruses, bacteria, and fungi express broadly distinct molecular patterns that activate innate arms of the immune system. Most prominently, the Toll-like receptors (TLRs) use these pathogen-specific cues to elicit intracellular signals that can be either dependent or independent of the Toll/interleukin 1 receptor (TIR) domain-containing adaptor proteins, MyD88 and TIRAP. Yamamoto et al. define a third TIR adaptor, TRIF, as critical for MyD88-independent signaling by particular TLRs. Cells deficient in TRIF failed to initiate either the interferon regulatory factor-3 or nuclear factor κB pathways in response to TLR3 or TLR4 activation, but responded normally to activation of other TLR family members. M. Yamamoto, S. Sato, H. Hemmi, K. Hoshino, T. Kaisho, H. Sanjo, O. Takeuchi, M. Sugiyama, M. Okabe, K. Takeda, S. Akira, Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640-643 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"14 1","pages":"TW304 - tw304"},"PeriodicalIF":0.0,"publicationDate":"2003-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73099506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-08-05DOI: 10.1126/scisignal.1942003cm8
R. V. Van Gelder
{"title":"Circadian Rhythms in Animals: A Canonical Connections Map","authors":"R. V. Van Gelder","doi":"10.1126/scisignal.1942003cm8","DOIUrl":"https://doi.org/10.1126/scisignal.1942003cm8","url":null,"abstract":"Circadian rhythms are near-24-hour endogenous rhythms of behavior and physiology that are a nearly universal feature of eukaryotic life. Genetic and biochemical experiments over the past decade have allowed the construction of a viable working model for the molecular mechanisms underlying circadian rhythm generation in animals. The basic mechanism consists of two intertwined transcription-translation negative feedback loops. One loop--the \"positive loop\"--controls the rhythmic expression of a well-conserved Per-Arnt-Sim (PAS)-domain-containing positive transcription factor (Clock in Drosophila, and BMAL1, which is also known as MOP3, in the mouse). The second loop--the \"negative loop\"--controls the expression of another PAS-domain protein (the repressor Period), as well as species-specific repressors (Timeless in Drosophila and Cryptochrome in mice). The loops are intertwined because Period and its binding partners directly repress transcription mediated by Clock and its binding partners (Cycle in Drosophila and BMAL1 in the mouse), whereas Clock:Cycle (or CLOCK:BMAL1) drives the transcription of period and the other repressors, as well as that of repressors of Clock or Bmal1 transcriptional expression. Other factors, including conserved kinases such as Casein kinase I ϵ (CkIϵ), have essential functions in the timekeeping mechanism. Remarkably, this mechanism appears to be fundamentally conserved between Drosophila and mammalian circadian clocks. This Canonical Connections Map Pathway describes the basic mechanism underlying circadian signaling, whereas the accompanying specific Pathway Maps for Drosophila and murine circadian mechanisms describe the individual known components of the circadian clock and their mutual interactions. Science Viewpoint R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert, Circadian rhythms: In the loop at last. Science 300, 1534-1535 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"35 1","pages":"cm8 - cm8"},"PeriodicalIF":0.0,"publicationDate":"2003-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86561019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-07-29DOI: 10.1126/scisignal.1932003tw299
{"title":"Back-Up Lighting Systems","authors":"","doi":"10.1126/scisignal.1932003tw299","DOIUrl":"https://doi.org/10.1126/scisignal.1932003tw299","url":null,"abstract":"Specific ganglion cells in the mammalian retina regulate responses to light without forming images, including entrainment of the circadian clock. However, genetic studies in mice have suggested that this response to light remains largely intact even in the absence of these photoreceptors. Panda et al. now report that the photoreceptors in mice of the classical image-forming visual system (rods and cones) also regulate light input into the photoresponse process that does not form images. This finding indicates that light inputs from multiple photoreceptor types are integrated in the control of processes such as circadian rhythm. S. Panda, I. Provencio, D. C. Tu, S. S. Pires, M. D. Rollag, A. M. Castrucci, M. T. Pletcher, T. K. Sato, T. Wiltshire, M. Andahazy, S. A. Kay, R. N. Van Gelder, J. B. Hogenesch, Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525-527 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"1 1","pages":"TW299 - tw299"},"PeriodicalIF":0.0,"publicationDate":"2003-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87118978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Science's STKEPub Date : 2003-07-22DOI: 10.1126/scisignal.1922003tw287
{"title":"Catalyzing Diabetes Drug Discovery","authors":"","doi":"10.1126/scisignal.1922003tw287","DOIUrl":"https://doi.org/10.1126/scisignal.1922003tw287","url":null,"abstract":"One relatively unexplored drug target for type 2 diabetes is the glucose-sensing enzyme glucokinase (GK); mutations that reduce GK activity cause a rare inherited form of diabetes in humans. Grimsby et al. have identified a class of small molecules that allosterically activate GK. When orally administered to rodent models of type 2 diabetes, these compounds significantly improved glucose tolerance by enhancing glucose-dependent insulin secretion from the pancreas and by stimulating glucose utilization in the liver. J. Grimsby, R. Sarabu, W. L. Corbett, N.-E. Haynes, F. T. Bizzarro, J. W. Coffey, K. R. Guertin, D. W. Hilliard, R. F. Kester, P. E. Mahaney, L. Marcus, L. Qi, C. L. Spence, J. Tengi, M. A. Magnuson, C. A. Chu, M. T. Dvorozniak, F. M. Matschinsky, J. F. Grippo, Allosteric activators of glucokinase: Potential role in diabetes therapy. Science 301, 370-373 (2003). [Abstract] [Full Text]","PeriodicalId":21619,"journal":{"name":"Science's STKE","volume":"24 1","pages":"TW287 - tw287"},"PeriodicalIF":0.0,"publicationDate":"2003-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81929285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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