CIT ID: 6176
Program date: Monday, January 28, 2008, 12:00:00 PM
Presented by: William N. Zagotta, Ph.D., University of Washington

Abstract:

Cyclic nucleotide-regulated channels, such as CNG channels and HCN channels, underlie the primary electrical signals in phototransduction and olfactory transduction and control the repetitive firing activity of cardiac and neuronal cells. Activation of these channels involves the direct binding of cyclic nucleotide to an intracellular domain of the channel. Dr. Zagotta's lab has been interested in understanding the molecular mechanism for this allostery. To do this, they have employed a number of fluorescence approaches combined with patch-clamp fluorometry, a technique for simultaneously recording electrical current and fluorescence from excised inside-out patches. They explored the structure and conformational rearrangements of the C-terminal gating ring of the cyclic nucleotide-gated channel CNGA1 during activation by cyclic nucleotides. By monitoring fluorescent resonance energy transfer (FRET) between membrane-resident quenchers and fluorophores attached to the channel, Dr. Zagotta's lab detected no movement orthogonal to the membrane during channel activation. By monitoring FRET between fluorophores within the C-terminal region, they determined that the C-terminal end of the C-linker and the end of the C-helix move apart when channels open. They conclude that during channel activation, a portion of the gating ring moves parallel to the plasma membrane, hinging toward the central axis of the channel.

NIH Neuroscience Seminar Series

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	Description	Runtime			Description	Runtime
	Enhanced Audio Podcast	1:01:42			Enhanced Video Podcast	1:01:42

CIT ID: 6207
Program date: Wednesday, January 23, 2008, 3:00:00 PM
Presented by: Carol Prives, Columbia University Biological Sciences

Abstract:

The focus of much of the work in Dr. Prives' laboratory is the functions of p53 and its negative regulator and transcriptional target, Mdm2. Two general areas are being investigated, how p53 functions as a transcription factor and the roles and regulation of Mdm2. P53 is a sequence-specific transcriptional activator of genes involved in cellular outcomes such as cell cycle arrest and apoptosis. We have identified a new co-regulator of select p53 targets, Cas/Cse1L, a protein previously shown to be involved in nuclear transport. Cas/Cse1L binds to the promoters of a subset of p53 targets and levels of Cas/Cse1L are correlated with the extent to which these genes are induced by p53. Atne p53 target promoter, PIG3, Cas/Cse1L has a long range inhibitory effect on tri-methylation of histone H3 lysine 27, a repressive modification, which could explain how Cas/Cse1L and p53 cooperate to regulate some p53 targets and apoptosis. Another project stems from our earlier finding that in some cells p53 is impaired in its ability to induce transcription from some of its target genes when cells are blocked in S phase. We have extended these findings by showing that while p53 can bind to its sites within these promoters and recruit histone acetylases, TFIID and RNA polymerase, transcription elongation by RNA polymerase is significantly reduced when the DNA replication checkpoint is activated. Our data implicate the checkpoint kinases in this block to elongation of p53 targets. Regarding our studies on Mdm2, an extensive yeast two-hybrid screen led to the identification of RPS7, a ribosomal protein that can interact with and regulate Mdm2. Ribosomal stress leads to the appearance of RPS7 in the nucleoplasm and RPS7 inhibits Mdm2 E3 ligase activity in vivo and in vitro. Our data also suggest that the Mdm2 homologue, MdmX, is involved in RPS7 repression of Mdm2. Further, ablation of RPS7 causes both increased turnover of Mdm2 and decreased p53 after treatment of cells with several genotoxic agents. Our data thus implicate ribosomal and nucleolar stress as being very important for DNA damage signaling to p53. Interestingly as well, RPS7 itself is a substrate of the Mdm2 E3 ligase activity suggesting a new circuit whereby a negative regulator of Mdm2 is itself an Mdm2 target.

Dr. Prives was born in Montreal, Canada and received her BSc degree in 1962 and Ph.D. in 1966 at McGill University. After spending a year at the University of British Columbia, she did post-doctoral research at Albert Einstein College of Medicine, Bronx, N.Y. in the laboratory of Dr. J.T. August from 1968 through 1971 where she held a Damon Runyon Fellowship. In 1971 she worked in the laboratory of Dr. E. Ehrenfeld. She then went to the Weizmann Institute on a senior visiting fellowship where she worked on a project jointly sponsored by Professors Ernest Winocour and Michel Revel. In 1974 she was appointed as intermediate scientist, in 1975 she was promoted to the rank of senior scientist (equivalent to Assistant Professor in American universities) and in 1977 she was promoted to Associate Professor with tenure at the Weizmann Institute. She left Israel for a sabbatical in 1978 to work in the laboratory of Dr. George Khoury at the NIH. In 1979 she took a position as Associate Professor at the Department of Biological Sciences at Columbia University. She was awarded tenure at Columbia in 1982 and was promoted to Full Professor in 1987. In 1995 she was appointed the Da Costa Professor of Biology at Columbia. In 1996 she was the recipient of a MERIT award from the NIH and in 1998 she was awarded a Research Professorship from the American Cancer Society. In 2000 she became a member of the American Academy of Arts and Sciences and in 2005 she was elected to the Institute of Medicine.

For more information, visit
http://www.columbia.edu/cu/biology/faculty/prives

WALS

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	Description	Runtime			Description	Runtime
	Enhanced Audio Podcast	1:02:45			Enhanced Video Podcast	1:02:45

CIT ID: 6206
Program date: Wednesday, January 16, 2008, 3:00:00 PM
Presented by: Lawrence W. Green, University of California at San Francisco School of Medicine

Abstract:

This examination of the evidence-based medicine movement first reviews some recent events that have accelerated the search for ways to improve the quality of practice, which tends to be defined as the degree to which practice is following evidence-based guidelines. It proposes five ways to make research more relevant to practice: The first is the conventional and most widely and aggressively pursued path of pushing evidence through a pipeline to practitioners by means of continuing education, systematic reviews of the research literature converted into evidence-based practice guidelines, and the simplification of those guidelines with chart reminders, video and computer-based information systems, and similar devices to make the dissemination and application of the evidence more efficient and manageable in practice settings. Some major limitations and consequences of this “pipeline” strategy will be reviewed. The second approach is to shift the priorities of research-funding agencies and processes of peer review. Such priorities would reorient the production of research to make it more relevant to practice. This strategy will be illustrated with the experience of the U.S. Centers for Disease Control (CDC) and the Canadian Institute for Health Research. This strategy will depend also on a reorientation of the journal editing, peer review and publishing priorities to give greater emphasis to external validity. The third approach is to put greater emphasis on participatory research that engages practitioners more actively at least in formulating the research questions and interpreting the results, if not also in collecting and analyzing the data. Some defining features of participatory research will be reviewed. The fourth approach is translating research from distant and often artificial circumstances under which the evidence was produced to the local culture and “real-world” circumstances in which the application of the evidence would be required. This would call on greater use of theory to fill gaps in the evidence. Finally, a combination of these first four into a strategy of producing a more practice-based research agenda would have the dual benefits of making the research more relevant to practice and making the practitioners more receptive to the evidence because it would be produced under circumstances more like their own.

Lawrence W. Green is Adjunct Professor of Epidemiology and Biostatistics in the School of Medicine and is Co-Leader of the Society, Diversity and Disparities Program in the Comprehensive Cancer Center at the University of California at San Francisco. He joined CDC in 1999 as Distinguished Fellow-Visiting Scientist to study what accounted for the success of tobacco control in the last third of the 20th century, and how we might take those lessons to other areas of public health. He served as Director of CDC’s World Health Organization Collaborating Center on Global Tobacco Control and as Acting Director of the Office on Smoking and Health. He then served as the Director of CDC’s Office of Science and Extramural Research. He was then Visiting Professor at the University of California at Berkeley School of Public Health and the first Health and Society Visiting Professor at the University of Maryland. For most of the 1990s, Dr. Green was the Director of the Institute of Health Promotion Research and Professor and Head of the Division of Preventive Medicine and Health Promotion, Department of Health Care and Epidemiology, at the University of British Columbia in Canada.

For more information, visit
http://rwjcsp.unc.edu/NAC/NAC_green.html

WALS

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	Description	Runtime			Description	Runtime
	Enhanced Audio Podcast	59:47			Enhanced Audio Podcast	59:47

CIT ID: 6175
Program date: Monday, January 14, 2008, 12:00:00 PM
Presented by: Robert Edwards, Ph.D., University of California, San Francisco

Abstract:

Synaptic vesicles appear very homogeneous, and within a particular nerve terminal, they are generally presumed to contain the same set of integral membrane proteins. However, considerable work has demonstrated that synaptic vesicles differ dramatically in their functional properties. Only a fraction of all the vesicles, the recycling pool accounts for essentially all the evoked release. In contrast, the reserve pool is much more difficult to mobilize. Although the difference between these pools is often considered to reflect differences in their history, or association with cytoskeletal proteins, work on the recycling of a specific synaptic vesicle protein now suggests that the pools may differ in their molecular components. In particular, we find that vesicular glutamate transporter 1 (VGLUT1) recycles by two distinct endocytic pathways, which may in turn target to the different synaptic vesicle pools. The mechanism of endocytosis may therefore dictate the properties of exocytosis. We will also present data about the physiological role of VGLUT3, an atypical isoform expressed largely by neurons considered to use a transmitter other than glutamate.

NIH Neuroscience Seminar Series

Audio Podcasts				Video Podcasts
	Description	Runtime			Description	Runtime
	Enhanced Audio Podcast	1:08:05			Enhanced Video Podcast	1:08:05

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