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1.
Perry Molinoff recognizes the distinctions between basic and applied science, between academic and industrial research, and between the preclinical and clinical realities of drug development. But he generally discusses these categories in fluid, practical terms, having throughout his career crossed the lines of distinction that have sometimes been rather heavily drawn among pharmacologists. As a third-year medical student at Harvard, he decided "to take a year off" to conduct laboratory research. After receiving his MD and pursuing further clinical and postdoctoral work, he enjoyed an academic career that included fourteen years as the A.N. Richards Professor and Chair of Pharmacology at the University of Pennsylvania School of Medicine. He has just completed six years as Vice President of Neuroscience and Genitourinary Drug Discovery for Bristol-Myers Squibb and will soon return to teaching, in the Departments of Psychiatry and Pharmacology at Yale University. Referring to himself as either pharmacologist or neuroscientist, depending on context, he has made fundamental discoveries in receptor biology, has overseen the discovery and development of drugs and their subsequent clinical trials, and has mentored a host of pharmacologists and neuroscientists who themselves have established careers in industry and academia. The pursuit of discovery as its own reward emerges as a theme that has marked his professional life (and is perhaps reflected also in the images displayed in his office of the Himalayan mountains, photographed by Molinoff himself from the Everest base camp last year).  相似文献   

2.
Alfred Gilman     
At the age of 10, Alfred Gilman wanted to go to the moon; on a visit to New York's Hayden Planetarium with his parents, he signed up to be an astronaut. Fifty years later, Gilman is preparing to take on a different, yet equally astronomical task. Instead of traveling to outer space, he is heading up a research program to detail the workings of cellular space.  相似文献   

3.
Cellular responses to inputs that vary both temporally and spatially are determined by complex relationships between the components of cell signaling networks. Analysis of these relationships requires access to a wide range of experimental reagents and techniques, including the ability to express the protein components of the model cells in a variety of contexts. As part of the Alliance for Cellular Signaling, we developed a robust method for cloning large numbers of signaling ORFs into Gateway entry vectors, and we created a wide range of compatible expression platforms for proteomics applications. To date, we have generated over 3000 plasmids that are available to the scientific community via the American Type Culture Collection. We have established a website at www.signaling-gateway.org/data/plasmid/ that allows users to browse, search, and blast Alliance for Cellular Signaling plasmids. The collection primarily contains murine signaling ORFs with an emphasis on kinases and G protein signaling genes. Here we describe the cloning, databasing, and application of this proteomics resource for large scale subcellular localization screens in mammalian cell lines.  相似文献   

4.
Richard Weinshilboum has a no-nonsense attitude about pharmacogenetics. He is enthusiastic about the practicalities and ramifications of the field's solid accomplishments, but he carefully measures statements that might feed the hype that is en courant about the brave new postgenomic world of drug therapy. Although the terms "pharmacogenomics" and "pharmacogenetics" are often used interchangeably (a linguistic quirk to which Weinshilboum does not object), he consistently avoids the latter, perhaps more glitzy, word. Weinshilboum has spent over thirty years as a clinical pharmacologist, exploring in particular the variability of drug metabolism that occurs among patients as a function of their genetic constitution. The research efforts from his line of work have materialized into clinical application and have helped to set the stage for the individualization of drug treatment according to each patient's genetic constitution-not yet on the genomewide scale that Weinshilboum enthusiastically foresees, but certainly as pertains to multiple genes and drugs for any given patient. The interview with Weinshilboum occurred at this year's annual meeting of ASPET, at which he was conferred the Harry Gold Award in Clinical Pharmacology.  相似文献   

5.
Wild chimpanzees are known to have a different repertoire of tool use unique to each community. For example, "ant-dipping" is a tool use behavior known in several chimpanzee communities across Africa targeted at driver ants (Dorylus spp.) on the ground, whereas "ant-fishing," which is aimed at carpenter ants (Camponotus spp.) in trees, has primarily been observed among the chimpanzees of Mahale in Tanzania. Although the evidence for differences between field sites is accumulating, we have little knowledge on how these tool use behaviors appear at each site and on how these are modified over time. This study reports two"ant-fishing" sessions which occurred 2 years apart by a young male chimpanzee at Bossou, Guinea. Ant-fishing had never been observed before in this community over the past 27 years. During the first session, at the age of 5, he employed wands of similar length when ant-fishing in trees to those used for ant-dipping on the ground, which is a customary tool use behavior of this community. Two years later, at the age of 7, his tools for ant-fishing were shorter and more suitable for capturing carpenter ants. This observation is a rare example of innovation in the wild and does provide insights into problem-solving and learning processes in chimpanzees.  相似文献   

6.
Macrophage migration inhibitory factor (MIF) is a glycosylated multi-functional protein that acts as an enzyme as well as a cytokine. MIF mediates its actions through a cell surface class II major histocompatibility chaperone, CD74 and co-receptors such as CD44, CXCR2, CXCR4 or CXCR7. MIF has been implicated in the pathogenesis of several acute and chronic inflammatory diseases. Although MIF is a molecule of biomedical importance, a public resource of MIF signaling pathway is currently lacking. In view of this, we carried out detailed data mining and documentation of the signaling events pertaining to MIF from published literature and developed an integrated reaction map of MIF signaling. This resulted in the cataloguing of 68 molecules belonging to MIF signaling pathway, which includes 24 protein-protein interactions, 44 post-translational modifications, 11 protein translocation events and 8 activation/inhibition events. In addition, 65 gene regulation events at the mRNA levels induced by MIF signaling have also been catalogued. This signaling pathway has been integrated into NetPath (http://www.netpath.org), a freely available human signaling pathway resource developed previously by our group. The MIF pathway data is freely available online in various community standard data exchange formats. We expect that data on signaling events and a detailed signaling map of MIF will provide the scientific community with an improved platform to facilitate further molecular as well as biomedical investigations on MIF.  相似文献   

7.
Dr. George Lister delivered the following presentation as the Lee E. Farr Lecturer on May 8, 2011, which served as the culmination of the annual Student Research Day at Yale School of Medicine. He is the Chair of Pediatrics at the University of Texas Southwestern Medical School and Pediatrician-in-Chief at Children's Medical Center of Dallas. In his lecture to the medical students, who had just completed their research theses, Dr. Lister discusses his own work on sudden infant death syndrome (SIDS), demonstrating the complexity of clinical research and proving insight into the traits required of physician scientists. Committed to medical education and recognized by several awards for his mentorship, he ends the talk by imparting valuable advice on future physicians.  相似文献   

8.
On 19 January 2014 Rolf (‘Roffe’) Bernander passed away unexpectedly. Rolf was a dedicated scientist; his research aimed at unravelling the cell biology of the archaeal domain of life, especially cell cycle‐related questions, but he also made important contributions in other areas of microbiology. Rolf had a professor position in the Molecular Evolution programme at Uppsala University, Sweden for about 8 years, and in January 2013 he became chair professor at the Department of Molecular Biosciences, The Wenner‐Gren Institute at Stockholm University in Sweden. Rolf was an exceptional colleague and will be deeply missed by his family and friends, and the colleagues and co‐workers that he leaves behind in the scientific community. He will be remembered for his endless enthusiasm for science, his analytical mind, and his quirky sense of humour.  相似文献   

9.
Although tricyclic antidepressants have been in existence since the 1940s when they were discovered upon screening iminodibenzyl derivatives for other potential therapeutic uses, their mechanism of action has remained unclear [A. Goodman Gilman, T.W. Rall, A.S. Nies, P. Taylor, Goodman and Gilman's The Pharmacological Basis of Therapeutics, eighth ed., Pergamon Press, New York, 1990]. In addition to their ability to hinder the reuptake of biogenic amines, there is mounting evidence that the tricyclic antidepressants inhibit glutamate transmission. Here, intrinsic tryptophan fluorescence spectroscopy is used to document the binding of desipramine, a member of the tricyclic antidepressant family, to a well-defined extracellular glutamate binding domain (S1S2) of the GluR2 subunit of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. The binding is distinct from those of other known effectors of the receptor, including the endogenous sulfated neurosteroids pregnenolone sulfate and 3alpha-hydroxy-5beta-pregnan-20-one sulfate, and is consistent with a conformational change upon binding that is allosterically transmitted to the channel region of the receptor.  相似文献   

10.
Roy Walford died on April 27, 2004, at the age of 79. His contributions to gerontological research in such diverse areas as caloric restriction, genetics of lifespan, immunosenescence, DNA repair and replicative senescence were truly remarkable in their depth and innovation. Significantly, most of the areas that he pioneered during his illustrious research career remain the "hot" areas of current gerontological research. In this sense, he has achieved the most important type of immortality. His death was a major personal and professional loss to numerous scientists within the gerontological community. In launching this new journal on Immunity and Ageing, it is highly fitting, therefore, to remember him on the anniversary of his death by briefly reviewing the contributions of Roy Walford to this important facet of gerontology. Indeed, it was Roy who actually first coined the commonly used term "immunosenescence".  相似文献   

11.
Sir John Sulston was a co-winner of the Nobel Prize for Medicine in 2002. He won the prize for his discoveries concerning "genetic regulation of organ development and programmed cell death," along with his colleagues sydney Brenner and H. Robert Horvitz. Dr. Sulston was founding director of the Sanger Centre, Cambridge, England, which he headed from 1992 to 2000. From 1993 to 2000, he led the British arm of the international team selected to work on the Human Genome Project. He is co-author of the book The Common Thread: A Story of Science, Politics, Ethics, and the Human Genome, published by Joseph Henry Press in 2002.This interview was conducted on December 20, 2002, shortly after Dr. Sulston was awarded his Nobel Prize and was originally broadcast on that date on radio station WPKN-FM in Bridgeport, Connecticut. The interview was conducted by Valerie Richardson, the Managing Editor of The Yale Journal of Biology and Medicine.Dr. Sulston has been an outspoken advocate against letting the data from the Human Genome Project become property of commercial interests that would charge the world's scientific community for its use. Since leaving the Sanger Institute, he has worked with OxFam, the Oxford Campaign for Famine Relief.  相似文献   

12.
Peter Agre, born in 1949 in Northfield Minnesota, shared the 2003 Nobel Prize in Chemistry with Roderick MacKinnon for his discovery of aquaporins, the channel proteins that allow water to cross the cell membrane.Agre''s interest medicine was inspired by the humanitarian efforts of the Medical Missionary program run by the Norwegians of his home community in Minnesota. Hoping to provide new treatments for diseases affecting the poor, he joined a cholera laboratory during medical school at Johns Hopkins. He found that he enjoyed biomedical research, and continued his laboratory studies for an additional year after medical school.Agre completed his clinical training at Case Western Hospitals of Cleveland and the University of North Carolina, and returned to Johns Hopkins in 1981. There, his serendipitous discovery of aquaporins was made while pursuing the identity of the Rhesus (Rh) antigen.For a century, physiologists and biophysicists had been trying to understand the mechanism by which fluid passed across the cell''s plasma membrane. Biophysical evidence indicated a limit to passive diffusion of water, suggesting the existence of another mechanism for water transport across the membrane. The putative "water channel," however, could not be identified.In 1988, while attempting to purify the 30kDa Rh protein, Agre and colleagues began investigating a 28 kDa contaminant that they believed to be a proteolytic fragment of the Rh protein. Subsequent studies over the next 3-4 years revealed that the contaminant was a membrane-spanning oligomeric protein, unrelated to the Rh antigen, and that it was highly abundant in renal tubules and red blood cells. Still, they could not assign a function to it.The breakthrough came following a visit with his friend and former mentor John Parker. After Agre described the properties of the mysterious 28 kDa protein, Parker suggested that it might be the long-sought-after water channel. Agre and colleagues tested this idea by expressing the protein in Xenopus oocytes, which typically have low water permeability. When the test oocytes were placed in a hypotonic solution, they swelled and exploded, thus revealing the function of the unknown protein as a water channel, which they named aquaporin.The Nobel Prize enabled Agre to take his research and scientific interests in new directions. He felt that over the years his work had continually taken him further from his original interests in third-world diseases, so he shifted his focus back in that direction. He now serves as the director of the Malaria institute at Johns Hopkins where he has applied his knowledge to the study of the malarial parasite and the Anopheles mosquito, which both express aquaporins. In addition, since winning the Nobel Prize, he has enjoyed increased opportunities for bringing science to the public and for "encouraging young people to go into science."Download video file.(110M, mp4)  相似文献   

13.
Rao M 《Nature medicine》2011,17(10):1163
In October 2005, Mahendra Rao shocked the scientific community when he quit his job as head of the US National Institute on Aging's stem cell section and announced plans to go into industry. Rao felt that a ban at the time on federal funding for most human embryonic stem cell research hampered researchers in his division and prohibited him from doing the job he was hired to do. So he joined the research-tool giant Invitrogen (which later became Life Technologies) as vice president of regenerative medicine at the company's Maryland facility. Six years on, times have changed in the field of stem cell biology: rules governing taxpayer-backed research involving embryonic stem (ES) cells have been relaxed in the US, and induced pluripotent stem (iPS) cells have come into the fray. Prompted by those changes, Rao opted to return to the US National Institutes of Health (NIH) in August to head the new Intramural Center for Regenerative Medicine. The $52 million center was launched in early 2010 by the agency to develop new therapies using stem cell approaches. With a heightened focus at the NIH on translational medicine, Elie Dolgin spoke to Rao to find out how he plans to turn stem cell discoveries into cell-based therapies.  相似文献   

14.
Conclusions By the time George Wilton Field concluded his work at the marine laboratory his initial scientific concerns had forced him directly into local politics. He pleaded with little success with the community of South Kingstown, and with no success with the town of Narragansett, to create and maintain a permanent breach:Is it not possible for the acute business sense and the broad philanthropy of the community to sweep aside petty, local, and personal jealousies which are now blocking practical progress for the establishment of a permanent breach at Point Judith Pond? It is truly criminal neglect which permits fifteen hundred acres of valuable water-farming area to lie practically idle and rapidly deteriorate with each passing year.... In the opinion of the writer the Point Judith Pond and those of similar type could be made the seat of oyster, clam, crab, herring, white perch, and striped bass fisheries.30 In the summer of 1899 Field was invited to teach a summer course on echinoderms at the MBL in Woods Hole, and to conduct summer research in a laboratory of the U.S. Fish Commission, also located at Woods Hole. When the summer was over, he remained there. Whether he had intentions of returning to resume his position in Rhode Island is unclear. At this point all correspondence with the Agricultural Experiment Station ceases, and Field's last report is a brief statement in the annual report of the experiment station for 1900 wherein he laments the variety of experiments he has not been able to carry to conclusion, such as a study of the artificial fertilization of water analogous to the method of chemically fertilizing the land for crops.The correspondence reveals that the enthusiasm Field brought to Point Judith Pond in 1896 was gradually sapped by his own fragile health, by three years' exposure to the local politics surrounding the southern Rhode Island fishing industry, and by a college administration determined to remove the stench of his invertebrates. He sought a refuge in the sheltered world of pure research at the U.S. Fish Commission Laboratory, where he set out to investigate the Origin of Sex using, as his animal models, squid and toadfish.On November 14, 1899, the Board of Managers of the college ordered the director of the experiment station to dispose of the marine laboratory at Point Judith Pond.31 How long the laboratory at Buttonwood Point survived in the institutional memory of the University of Rhode Island is open to question. The current Graduate School of Oceanography, in the event, traces its history back to 1937, not 1896.Nevertheless, Field and his one-room marine station established a precedent of land-grant marine research that other state colleges would follow, including Rhode Island itself, which reestablished its marine station, this time permanently, at South Ferry in 1937. In his brief research career in Rhode Island, George Wilton Field had discovered the same coastal attributes that would lead later to the creation of one of the world's major marine research centers at the University of Rhode Island's Graduate School of Oceanography.And, in a measure of triumph for his work, little more than a year after Field left for Woods Hole and his laboratory was dismantled, the town of South Kingstown voted the funds necessary to begin the construction of a permanent breachway.32 Whether Field's scientific reasoning and the conclusions of his marine research played any part in finally deciding the thirty-year-old debate in the affirmative will probably never be known. What is evident is that Field had no patience for those who could not see the results of his research as clearly as he could himself.  相似文献   

15.
In addition to the well-known metabolic functions of NAD and NADP, it is rapidly emerging that these 2 pyridine nucleotides and their derivatives also play important roles in cell signaling. Surprisingly, a number of NAD(P) metabolizing enzymes and NAD(P) targets have been found on the outer surface of the plasma membrane and the presence of NAD has been confirmed in extracellular fluids. These findings have opened the door to a new field of research aimed at elucidating the contribution of extracellular pyridine nucleotides in physiological signaling pathways and pathological conditions.  相似文献   

16.
Abstract

Two series of novel fluorinated nucleosides dimers with an unnatural 1,2,3-triazole linkage were synthesized. The obtained molecules were prepared using “click” chemistry approach based on copper(I) catalyzed Huisgen azide–alkyne cycloaddition. It was performed between 3′- and 5′-azido-nucleosides as the azide components, and the 3′-O- and 5′-O-propargyl-nucleosides as the alkyne components. Based on analysis of the 3 Brunton, L. L.; Lazo, J. S.; Parker, K. L. (Eds.), Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, Medical Publishing Division: New York, NY, 2006. [Google Scholar]JHH, 3 Brunton, L. L.; Lazo, J. S.; Parker, K. L. (Eds.), Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, Medical Publishing Division: New York, NY, 2006. [Google Scholar]JH1′C2 and 3 Brunton, L. L.; Lazo, J. S.; Parker, K. L. (Eds.), Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th ed.; McGraw-Hill, Medical Publishing Division: New York, NY, 2006. [Google Scholar]JH1′C6 we estimated conformational preferences of sugar part and orientation around glycosidic bond. All described nucleosides dimers analogs were characterized by spectroscopic methods and evaluated for their in vitro cytotoxicity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7).  相似文献   

17.
English Chemist Harold Kroto shared the 1996 Nobel Prize in Chemistry with Robert Curl and Richard Smalley for their discovery of Fullerenes (C60), molecules composed completely of carbon (C60) that form hollow spheres (also known as Buckyballs), tubes, or ellipsoids. These structures hold the potential for use in future technologies ranging from drug development and antimicrobial agents, to armor and superconductors.Harold Kroto was born in Wisbech, Cambridgeshire in 1939 and grew up in Bolton. Educated at Bolton School, he entered Sheffield University in 1958 to study Chemistry. During his time there he played tennis for the university team, illustrated the university''s magazine covers, and played folk music with other students. Enjoying his time at Sheffield very much, he chose to stay on and complete a Ph.D. in Chemistry under Richard Dixon.Following graduation in 1964, Kroto went on to post doc at the National Research Council (NRC) in Ottowa, Canada where microwave spectroscopy became his specialty. After two years of study at the NRC he spent a year at Bell Laboratories. He then accepted a position as a tutorial fellow at the University of Sussex, where he was soon offered a permanent position. There, he applied his expertise in microwave spectroscopy to the field of astronomy and spent several fruitful years detecting long carbon chains in the interstellar medium.Upon hearing of the work of Richard Smalley at Rice, who developed a laser that could vaporize graphite, Kroto thought they could use Smalley''s instrument to see carbon chains similar to those they had observed in interstellar matter. He suggested his idea for an experiment to Bob Curl, also at Rice. In 1985 he traveled to Rice to perform the experiment (and also to visit a half-price bookstore he''d heard about in Houston).Although he felt certain that the apparatus would create the carbon chains, the experiment revealed a totally unexpected result: the spontaneous formation of spherical shapes, which they called Buckminster Fullerenes in honor of the architect who popularized the geodesic dome.Though he is pleased to have received the Nobel Prize, Kroto does not believe in prizes or competition as a motivator for scientific (or athletic) progress. Rather, he believes that the pursuit of science or athletics should be simply for the enjoyment or interest in the subject matter, and he prefers to investigate subjects that other people aren''t working on.Kroto has mixed feelings about the effect the prize has had on his life. On the one hand, he would like to be able to spend more time pursuing graphic design, something he has always deeply enjoyed. On the other hand, he now enjoys a sense of responsibility for supporting the scientific community.As an atheist, Kroto feels that science is, in itself, atheistic. He doesn''t accept anything without evidence. Kroto expresses concern about people holding positions of power who do not use evidence as a basis for decision-making. "When they are prepared to accept one of 20-30 stories from thousands of years ago, I wonder what else they are prepared to accept when it comes to decisions which affect me?"Kroto is particularly worried about the effect of policies that require the teaching of non-scientific ideas, to the detriment of evidence-based scientific education. He points to the forced teaching of creationism in public schools and the existence of a "creation museum" in the United States as sources of misinformation that have given rise to "a whole generation of school children who''ve been abused."Download video file.(80M, mp4)  相似文献   

18.
During the early 1960s, Morris Goodman used a variety of immunological tests to demonstrate the very close genetic relationships among humans, chimpanzees, and gorillas. Molecular anthropologists often point to this early research as a critical step in establishing their new specialty. Based on his molecular results, Goodman challenged the widely accepted taxonomic classification that separated humans from chimpanzees and gorillas in two separate families. His claim that chimpanzees and gorillas should join humans in family Hominidae sparked a well-known conflict with George Gaylord Simpson, Ernst Mayr, and other prominent evolutionary biologists. Less well known, but equally significant, were a series of disagreements between Goodman and other prominent molecular evolutionists concerning both methodological and theoretical issues. These included qualitative versus quantitative data, the role of natural selection, rates of evolution, and the reality of molecular clocks. These controversies continued throughout Goodman’s career, even as he moved from immunological techniques to protein and DNA sequence analysis. This episode highlights the diversity of methods used by molecular evolutionists and the conflicting conclusions drawn from the data that these methods generated.  相似文献   

19.
Michael Akam has been awarded the 2007 Kowalevsky medal for his many research accomplishments in the area of evolutionary developmental biology. We highlight three tributaries of Michael’s contribution to evolutionary developmental biology. First, he has made major contributions to our understanding of development of the fruit fly, Drosophila melanogaster. Second, he has maintained a consistent focus on several key problems in evolutionary developmental biology, including the evolving role of Hox genes in arthropods and, more recently, the evolution of segmentation mechanisms. Third, Michael has written a series of influential reviews that have integrated progress in developmental biology into an evolutionary perspective. Michael has also made a large impact on the field through his effective mentorship style, his selfless promotion of younger colleagues, and his leadership of the University Museum of Zoology at Cambridge and the European community of evolutionary developmental biologist.  相似文献   

20.
Floyd Bloom says that he grew up, surrounded by doctors and pills, in a drug store in Dallas, where his father and uncles were pharmacists. He is a natural storyteller, readily recalling the people and events that have shaped his career. His narrative skills were apparent as early as high school, where he was encouraged, partially on the basis of aptitude tests, to pursue a career in journalism or public relations, and to stay away from hard subjects like math and science. In college, he majored in German literature, although he pursued premedical studies in accordance with his father's wishes. During his medical school and residency experiences in St. Louis, he recounts, he always attempted to carry in his mind an organized way of explaining his academic and clinical activities to the professors and attending physicians that might quiz him. His subsequent research into the central nervous system similarly benefited from his ability not only to anticipate and formulate questions, the answers to which often required the development of new methods, technologies, and alliances, but also to place his findings in novel contexts where they could be conceptually appreciated and utilized. The prospect of telling good scientific stories was one of the factors that later drew Bloom to the position of Editor-in-Chief of Science magazine (1995-2000). While there, he was instrumental in widening the contexts in which the magazine presents science, and in shaping the ways that scientific information is electronically disseminated across the globe. Currently on sabbatical from Scripps, Floyd Bloom continues to explore, as CEO of a startup company in La Jolla, the entrepreneurial contexts in which his own research can be applied.  相似文献   

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