1. Macroevolutionary test: the test across species
2. positional cloning methods.
Saturday, October 27, 2007
Friday, October 26, 2007
Molecular technologies
1. To prove something is transcription factor: fuse it with a promoter, and look at the downstream luciferase activity
2. interaction between different proteins: Protein precipitation
2. interaction between different proteins: Protein precipitation
Monday, October 15, 2007
Roderick MacKinnon
The Nobel Prize in Chemistry 2003
http://nobelprize.org/nobel_prizes/chemistry/laureates/2003/mackinnon-autobio.html
http://nobelprize.org/nobel_prizes/chemistry/laureates/2003/mackinnon-autobio.html
Potassium channel -Kv2.1
http://www.sciencedirect.com.ezproxy.hsclib.sunysb.edu/science?_ob=ArticleURL&_udi=B6W81-4GC1R5J-3&_user=334567&_coverDate=10%2F31%2F2005&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000017318&_version=1&_urlVersion=0&_userid=334567&md5=5c696ee8356d440545693b7d60914a00
The function of Kv channels can be described in simple terms using the biophysical properties that determine
1. at which membrane potentials the channels will open,
2. how quickly they open in response to the membrane potential achieving these potentials,
3. if open how long they remain so, and
4. when open at what rate do they allow flux of K+ across the membrane (MacKinnon, 2003). While these inherent biophysical properties are clearly encoded within the primary structure of the particular channel subtype, they can also be modified through post-translational events including covalent modifications (usually phosphorylation) and non-covalent protein–protein interactions (Jonas and Kaczmarek, 1996 and Yi et al., 2001). The biophysical characteristics can also be dramatically modified pharmacologically, a fact that serves as the basis for a diverse array of promising therapeutics (Wickenden, 2002).
http://www.sciencedirect.com.ezproxy.hsclib.sunysb.edu/science?_ob=ArticleURL&_udi=B6T36-49PR9Y1-5&_user=334567&_coverDate=11%2F27%2F2003&_fmt=full&_orig=search&_cdi=4938&view=c&_acct=C000017318&_version=1&_urlVersion=0&_userid=334567&md5=2fd40848628da5e0ffe33c8700ec2db1&ref=full
Therefore, the different kinds of K+ channels open in response to different stimuli: a change in the intracellular Ca2+ concentration, the level of certain G-protein subunits in the cell, or the value of the membrane voltage. Underneath this diversity in gating function, K+ channels have diverse structural domains attached in a modular fashion to the conserved pore unit. Ligand-gated K+ channels typically have cytoplasmic or extracellular domains for binding ligands. Voltage-gated K+ channels have integral membrane domains for sensing voltage differences.
The function of Kv channels can be described in simple terms using the biophysical properties that determine
1. at which membrane potentials the channels will open,
2. how quickly they open in response to the membrane potential achieving these potentials,
3. if open how long they remain so, and
4. when open at what rate do they allow flux of K+ across the membrane (MacKinnon, 2003). While these inherent biophysical properties are clearly encoded within the primary structure of the particular channel subtype, they can also be modified through post-translational events including covalent modifications (usually phosphorylation) and non-covalent protein–protein interactions (Jonas and Kaczmarek, 1996 and Yi et al., 2001). The biophysical characteristics can also be dramatically modified pharmacologically, a fact that serves as the basis for a diverse array of promising therapeutics (Wickenden, 2002).
http://www.sciencedirect.com.ezproxy.hsclib.sunysb.edu/science?_ob=ArticleURL&_udi=B6T36-49PR9Y1-5&_user=334567&_coverDate=11%2F27%2F2003&_fmt=full&_orig=search&_cdi=4938&view=c&_acct=C000017318&_version=1&_urlVersion=0&_userid=334567&md5=2fd40848628da5e0ffe33c8700ec2db1&ref=full
Therefore, the different kinds of K+ channels open in response to different stimuli: a change in the intracellular Ca2+ concentration, the level of certain G-protein subunits in the cell, or the value of the membrane voltage. Underneath this diversity in gating function, K+ channels have diverse structural domains attached in a modular fashion to the conserved pore unit. Ligand-gated K+ channels typically have cytoplasmic or extracellular domains for binding ligands. Voltage-gated K+ channels have integral membrane domains for sensing voltage differences.
Friday, October 12, 2007
an article from nature news
News
Nature Medicine 9, 1099 (2003) doi:10.1038/nm0903-1099
Profile: Kári Stefánsson
Helen Pearson
Reykjavik
Outspoken doctor Kári Stefánsson founded Iceland's deCODE Genetics to use its citizens' genealogy in the hunt for human disease genes. Here he speaks of his passion for medicine and for his homeland—and about courting controversy in both.
In the bowels of the world's most notorious biotech company, a robot, balanced on an earthquake-proof concrete slab, is shuffling the chilled blood of 100,000 Icelanders. It is a stark reminder of the propensity of this desolate island, with its jagged lava fields and steaming fissures, to shudder or explode.
The keeper of the samples is Kári Stefánsson, equally famous for his ability to blow up. One of the most controversial characters in human genetics, the Icelander cofounded deCODE Genetics in 1996 to use the island nation's meticulous genealogy records in his hunt for disease genes. Seven years on, the company has a handful of published results and its stock price is hovering around the bottom of the market.
Stefánsson's background mirrors the history of his volcano-strewn country. He can trace his family back to warrior and poet Egill Skallagrimsson, a first-generation Icelander born in AD 910. Perhaps this heritage imbued Stefánsson with a passion for literature: be it novels, poetry or biography, he always has a book on the go. "You cannot be a good scientist without reading 50−60 novels a year," he says.
Books aside, Stefánsson says his driving force is the desire to help diagnose and cure diseases. After studying medicine in Iceland's capital, Reykjavik, he joined the University of Chicago's neurology and neuropathology faculty, subsequently taking a position at Harvard University in Cambridge, Massachusetts.
It was in a coffee shop in nearby Boston that he and longtime colleague Jeffery Gulcher realized their destiny lay back in Iceland. The pair was already using Icelanders' genealogy to link distantly related people and find the genes they shared for multiple sclerosis risk. If they were to extend their hunt to other common conditions, Stefánsson realized, they needed to live in Iceland. Gulcher was less keen but eventually followed him. "The first thing you tell yourself is that it's an interesting idea but completely impractical," Gulcher now says. "But by and large [Stefánsson] ends up being right."
Stefánsson returned to Iceland to face fierce condemnation of his plans. Much of it centered on the Icelandic parliament's decision to allow deCODE to exclusively build and market a centralized health-care database containing patients' medical records, for which participants are presumed to have given consent. A second criticism has surrounded the commercial use of Icelanders' health information and genetics.
Stefánsson recalls this period as his most difficult. "I felt somewhat persecuted," he says. Outside of the health-care database, he says, blood samples—and hence genetic information—have always been donated with informed consent. In response to the second criticism, he says he could not otherwise have raised the capital, and that Iceland has benefited from the new jobs.
Despite his wounded feelings, Stefánsson shoulders some of the blame for eliciting criticism. One reason is his tendency to lash out or speak provocatively where others would hold their tongue. "He's used his personality to his advantage in creating attention," says friend, collaborator and fellow neurologist Allan Levey of Emory School of Medicine in Atlanta, Georgia. "We know he's earned himself a few enemies."
Some of Stefánsson's fiercest opponents have been those in the Icelandic lobby group Mannvernd. Although the health-care database is still passing security checks and has not yet been built, Mannvernd chairman and psychiatrist Peter Hauksson remains opposed to its construction. He also believes that doctors nowadays are not disclosing their financial interests, such as shares, in deCODE. "They have sold their soul," Hauksson says.
But at least on the surface, many Icelanders seem largely supportive of Stefánsson's plans. Around 100,000 of the nation's 285,000 citizens have given blood and consented to its use in deCODE's genetic studies, and polls show that the majority are in favor of the health-care database. "[Stefánsson] is a very good salesman," concedes Tomas Zoega of National University Hospital in Reykjavik and ex-chair of the Icelandic Medical Association's ethics committee. "He's a colorful personality in Iceland.
"While the controversy rumbles on, Stefánsson and his team have been getting on with some science. In the absence of the notorious health-care database, the company has built up the country's genealogy, other medical records and genetic profiles into three linked databases. When studying a particular disease, collaborating doctors hand their patients' medical information to deCODE, where it is then encrypted and fed into the databases. From this, the researchers can identify those individuals who are even remotely related and ask doctors to approach them for blood samples for genetic analysis. Participants get a deCODE T-shirt.
A personal highlight of his work, Stefánsson says, was the discovery of a gene, dubbed neuregulin-1, implicated in schizophrenia—a condition that afflicts his own brother. "It was a bit of a poetic moment," he says. But though the deCODE team claims to have identified genes linked to conditions from hypertension to aging, the scientific community is yet to be convinced. One key test will be whether the associations between gene and disease hold up in other populations, explains geneticist Pui-Yan Kwok of the University of California, San Francisco. "We're waiting to see whether it actually works," he says.
Stefánsson clearly has no such doubts: he says he hopes to convert the disease genes discoveries into "at least ten" real drugs. By founding deCODE, Stefánsson may have chosen a rocky road on a rocky island in the North Atlantic but, he says, "I wouldn't want to be anywhere else in the world."
Nature Medicine 9, 1099 (2003) doi:10.1038/nm0903-1099
Profile: Kári Stefánsson
Helen Pearson
Reykjavik
Outspoken doctor Kári Stefánsson founded Iceland's deCODE Genetics to use its citizens' genealogy in the hunt for human disease genes. Here he speaks of his passion for medicine and for his homeland—and about courting controversy in both.
In the bowels of the world's most notorious biotech company, a robot, balanced on an earthquake-proof concrete slab, is shuffling the chilled blood of 100,000 Icelanders. It is a stark reminder of the propensity of this desolate island, with its jagged lava fields and steaming fissures, to shudder or explode.
The keeper of the samples is Kári Stefánsson, equally famous for his ability to blow up. One of the most controversial characters in human genetics, the Icelander cofounded deCODE Genetics in 1996 to use the island nation's meticulous genealogy records in his hunt for disease genes. Seven years on, the company has a handful of published results and its stock price is hovering around the bottom of the market.
Stefánsson's background mirrors the history of his volcano-strewn country. He can trace his family back to warrior and poet Egill Skallagrimsson, a first-generation Icelander born in AD 910. Perhaps this heritage imbued Stefánsson with a passion for literature: be it novels, poetry or biography, he always has a book on the go. "You cannot be a good scientist without reading 50−60 novels a year," he says.
Books aside, Stefánsson says his driving force is the desire to help diagnose and cure diseases. After studying medicine in Iceland's capital, Reykjavik, he joined the University of Chicago's neurology and neuropathology faculty, subsequently taking a position at Harvard University in Cambridge, Massachusetts.
It was in a coffee shop in nearby Boston that he and longtime colleague Jeffery Gulcher realized their destiny lay back in Iceland. The pair was already using Icelanders' genealogy to link distantly related people and find the genes they shared for multiple sclerosis risk. If they were to extend their hunt to other common conditions, Stefánsson realized, they needed to live in Iceland. Gulcher was less keen but eventually followed him. "The first thing you tell yourself is that it's an interesting idea but completely impractical," Gulcher now says. "But by and large [Stefánsson] ends up being right."
Stefánsson returned to Iceland to face fierce condemnation of his plans. Much of it centered on the Icelandic parliament's decision to allow deCODE to exclusively build and market a centralized health-care database containing patients' medical records, for which participants are presumed to have given consent. A second criticism has surrounded the commercial use of Icelanders' health information and genetics.
Stefánsson recalls this period as his most difficult. "I felt somewhat persecuted," he says. Outside of the health-care database, he says, blood samples—and hence genetic information—have always been donated with informed consent. In response to the second criticism, he says he could not otherwise have raised the capital, and that Iceland has benefited from the new jobs.
Despite his wounded feelings, Stefánsson shoulders some of the blame for eliciting criticism. One reason is his tendency to lash out or speak provocatively where others would hold their tongue. "He's used his personality to his advantage in creating attention," says friend, collaborator and fellow neurologist Allan Levey of Emory School of Medicine in Atlanta, Georgia. "We know he's earned himself a few enemies."
Some of Stefánsson's fiercest opponents have been those in the Icelandic lobby group Mannvernd. Although the health-care database is still passing security checks and has not yet been built, Mannvernd chairman and psychiatrist Peter Hauksson remains opposed to its construction. He also believes that doctors nowadays are not disclosing their financial interests, such as shares, in deCODE. "They have sold their soul," Hauksson says.
But at least on the surface, many Icelanders seem largely supportive of Stefánsson's plans. Around 100,000 of the nation's 285,000 citizens have given blood and consented to its use in deCODE's genetic studies, and polls show that the majority are in favor of the health-care database. "[Stefánsson] is a very good salesman," concedes Tomas Zoega of National University Hospital in Reykjavik and ex-chair of the Icelandic Medical Association's ethics committee. "He's a colorful personality in Iceland.
"While the controversy rumbles on, Stefánsson and his team have been getting on with some science. In the absence of the notorious health-care database, the company has built up the country's genealogy, other medical records and genetic profiles into three linked databases. When studying a particular disease, collaborating doctors hand their patients' medical information to deCODE, where it is then encrypted and fed into the databases. From this, the researchers can identify those individuals who are even remotely related and ask doctors to approach them for blood samples for genetic analysis. Participants get a deCODE T-shirt.
A personal highlight of his work, Stefánsson says, was the discovery of a gene, dubbed neuregulin-1, implicated in schizophrenia—a condition that afflicts his own brother. "It was a bit of a poetic moment," he says. But though the deCODE team claims to have identified genes linked to conditions from hypertension to aging, the scientific community is yet to be convinced. One key test will be whether the associations between gene and disease hold up in other populations, explains geneticist Pui-Yan Kwok of the University of California, San Francisco. "We're waiting to see whether it actually works," he says.
Stefánsson clearly has no such doubts: he says he hopes to convert the disease genes discoveries into "at least ten" real drugs. By founding deCODE, Stefánsson may have chosen a rocky road on a rocky island in the North Atlantic but, he says, "I wouldn't want to be anywhere else in the world."
Tonight's first speaker: Kári Stefánsson
Dr. Kári Stefánsson, M.D., Dr.Med. from the University of Iceland, is the Chairman, CEO and co-founder of deCODE Genetics and a former professor of neurology, neuropathology and neuroscience at Harvard University (1993-1997). From 1993-1996 he was director of neuropathology at Boston's Beth Israel Hospital. Dr. Kári also held faculty positions at the University of Chicago.
Kári opened the NASDAQ Stock Market on July 20, 2005, after deCode's five year anniversary on the NASDAQ Market.
He was on the Time 100 list in 2007.
(Wikipedia.)
http://stephenslab.uchicago.edu/software.html
3rd speaker
Brendan J. Keating
http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx
Kári opened the NASDAQ Stock Market on July 20, 2005, after deCode's five year anniversary on the NASDAQ Market.
He was on the Time 100 list in 2007.
(Wikipedia.)
http://stephenslab.uchicago.edu/software.html
3rd speaker
Brendan J. Keating
http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx
What's this?
What's this website about?
http://www.hedweb.com/confile.htm
What's this person doing?
http://david-pearce.com/
http://www.hedweb.com/confile.htm
What's this person doing?
http://david-pearce.com/
Monday, October 1, 2007
Cannabinoids
Cannabinoids are a group of terpenophenolic compounds present in Cannabis (Cannabis sativa L). The broader definition of cannabinoids refer to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors. The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and arylsulphonamides and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors.[1] The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects.
Currently, there are three general types of cannabinoids: herbal cannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory.
CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain stem that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
THC is the primary psychoactive component of the plant. Medically, it appears to ease moderate pain and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine, GABA or dopamine, endocannabinoids differ in numerous ways from them. Neurotransmitters are commonly small, water-soluble molecules that are contained within, and released from, tiny membrane-bound vesicles inside cells. Vesicles are often found in the tips, ‘terminals’, of long cellular branches called axons, and complex morphological and biochemical specializations mark the location from which vesicular release occurs. Endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
Endocannabinoids are described as ‘retrograde’ transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow. They are in effect released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid releasing cell depends on the nature of the conventional transmitter that is being controlled. When the release of the inhibitory transmitter, GABA, is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. Conversely, when release of the excitatory neurotransmitter, glutamate, is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.
Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence
Currently, there are three general types of cannabinoids: herbal cannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory.
CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain stem that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
THC is the primary psychoactive component of the plant. Medically, it appears to ease moderate pain and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine, GABA or dopamine, endocannabinoids differ in numerous ways from them. Neurotransmitters are commonly small, water-soluble molecules that are contained within, and released from, tiny membrane-bound vesicles inside cells. Vesicles are often found in the tips, ‘terminals’, of long cellular branches called axons, and complex morphological and biochemical specializations mark the location from which vesicular release occurs. Endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
Endocannabinoids are described as ‘retrograde’ transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow. They are in effect released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid releasing cell depends on the nature of the conventional transmitter that is being controlled. When the release of the inhibitory transmitter, GABA, is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. Conversely, when release of the excitatory neurotransmitter, glutamate, is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.
Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence
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