Humans have long been trying to make the dream of nanoscopic robots come true. The dream is, in fact, taking on some aspects of reality. Nanoscience has produced components for molecular-scale machines. One such device is a rotor, a movable component that rotates around an axis. Trying to observe such rotational motion on the molecular scale is an extremely difficult undertaking. Japanese researchers at the Universities of Osaka and Kyoto have now met this challenge. As Akira Harada and his team report in the journal Angewandte Chemie, they were able to get "snapshots" of individual molecular rotors caught in motion.
As the subject of their study the researchers chose a rotaxane. This is a two-part molecular system: A rod-shaped molecule is threaded by a second, ring-shaped molecule like a cuff while a stopper at the end of the rod prevents the ring from coming off. The researchers attached one end of the rod to a glass support. To observe the rotational motions of the cuff around the sleeve, the scientists attached a fluorescing side chain to the cuff as a probe.
To observe the rotation of the ring around the rod, the researchers used a microscopic technique called defocused wide-field total internal reflection fluorescence microscopy. This gave snapshots of individual rotaxane molecules in the form of emission patterns. In simplified terms, if the cuff is motionless, the patterns make it possible to calculate the direction in which the probe emits its fluorescent light. This makes it possible to calculate the orientation of the cuff, which remains constant for every snapshot. However, if the cuff is rotating, the emission pattern does not reveal the spatial orientation of the probe.
The researchers showed that the cuff of the rotaxane does not rotate if the sample is dry. However, when it is wet they can see very rapid rotational and vibrational motion. The cuff rotates faster than the time required to snap a picture: the rotational speed is thus over 360° in 300 milliseconds.
This press release is available in German.
Author: Akira Harada, Osaka University (Japan),
chem.sci.osaka-u.ac.jp/lab/harada/Eng/mem/Lab-m11e.htm
Title: Single-Molecule Imaging of Rotaxanes Immobilized on Glass Substrates: Observation of Rotary Movement
Angewandte Chemie International Edition 2008, 47, No. 32, 6077?, doi: 10.1002/anie.200801431
Source: Akira Harada
Wiley-Blackwell
вторник, 17 мая 2011 г.
понедельник, 16 мая 2011 г.
News From The Journal Of Neuroscience
1. Two RIM1 Isoforms Are Present in Active Zones
Pascal S. Kaeser, Hyung-Bae Kwon, Chiayu Q. Chiu, Lunbin Deng, Pablo E. Castillo, and Thomas C. SГјdhof
Presynaptic active zones comprise many proteins that help to ensure rapid neurotransmitter release near postsynaptic receptors, and modification of some of these proteins produces long-term potentiation or depression. Although most active-zone proteins have been assigned to a specific step in the release process (e.g., vesicle docking, priming, or fusion), the molecular mechanisms involved remain unknown, and additional proteins continue to be discovered. This week, Kaeser et al. report that the gene encoding an active-zone scaffolding protein, RIM1О±, encodes a previously undiscovered second isoform, RIM1ОІ. RIM1О± has several protein-interaction domains that enable it to bind several other active-zone proteins. RIM1ОІ lacks the N-terminal protein interaction domain of RIM1О±, but is otherwise identical. RIM1О± and RIM1ОІ have largely overlapping expression patterns and functions. For example, both molecules appear to influence vesicle release probability at both excitatory and inhibitory synapses. But only RIM1О± appears to be involved in protein-kinase-A-dependent presynaptic long-term plasticity.
2. Crk and CrkL Mediate Reelin Signaling
Tae-Ju Park and Tom Curran
Crk and CrkL are widely expressed adaptor proteins whose function is to bring together tyrosine-phosphorylated proteins and their downstream effectors. Crk and CrkL interact with many proteins and are involved in diverse biological process throughout the body. Park and Curran now suggest that Crk and CrkL are important components of the Reelin signaling cascade in neurons. Deletion of both Crk and CrkL specifically in developing neurons produced a phenotype nearly identical to that of reelin mutations. For example, layer formation, neuronal migration, and dendrite development were severely disrupted in the cerebellum, hippocampus, and cerebral cortex. Reelin, an extracellular secreted protein, binds to lipoprotein receptors, resulting in activation of tyrosine kinases that phosphorylate the protein Disabled-1. Disabled-1 then promotes phosphorylation of the kinase Akt. In Crk/CrkL double-knock-out mice, levels of phosphorylated Disabled-1 were comparable to wild-type, but Akt phosphorylation was reduced, placing Crk/CrkL between Disabled-1 and Akt in the Reelin signaling pathway.
3. Estradiol Decreases Cortical Functional Lateralization
Susanne Weis, Markus Hausmann, Barbara Stoffers, RenГ© Vohn, Thilo Kellermann, and Walter Sturm
The cerebral hemispheres are functionally specialized: the left hemisphere is generally dominant in verbal tasks, whereas the right hemisphere dominates in spatial tasks. This asymmetry is thought to depend on inhibition of the nondominant hemisphere by the dominant hemisphere. The degree of functional lateralization varies across individuals, and females tend to exhibit less asymmetry than males. Furthermore, functional cerebral asymmetries vary in women throughout menstrual cycles, and asymmetries in postmenopausal women are comparable to those in men, suggesting that sex hormones alter interhemispheric inhibition. To test this hypothesis, Weis et al. measured brain activity during a verbal task using functional magnetic resonance imaging in men and in women at two points of the menstrual cycle when estradiol levels differed. As predicted, active regions of the left hemisphere inhibited homotypic areas in the right hemisphere in men and in women when their estradiol levels were low, but the inhibition disappeared when estradiol levels were high.
4. Near-Infrared Light Protects Retinas from Mitochondrial Damage
Julio C. Rojas, Jung Lee, Joseph M. John, and F. Gonzalez-Lima
Near-infrared light therapy (NILT) increases survival of cultured neurons exposed to various stressors, improves behavioral recovery from stroke in rabbits, and speeds wound healing in humans. These effects are thought to be mediated by upregulation of mitochondrial proteins, endogenous antioxidants, and antiapoptotic proteins such as heat-shock proteins and Bcl-2. This week, Rojas et al. report that NILT greatly reduced retinal damage and associated behavioral deficits produced in rats by the mitochondrial toxin rotenone. NILT prevented rotenone-induced decreases in light sensitivity and greatly reduced thinning of the retinal layers. Interestingly, NILT increased activity of the mitochondrial respiratory protein cytochrome oxidase and of the antioxidant superoxide dismutase throughout the brain, suggesting that the infrared light can penetrate the skull (at least in rats) and induce neuroprotective effects in the brain. Because many neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, involve mitochondrial dysfunction similar to that produced by rotenone, NILT may prove effective in treating these diseases as well.
Please click here for the current table of contents.
Source: Sara Harris
Society for Neuroscience
View drug information on Estradiol Transdermal System.
Pascal S. Kaeser, Hyung-Bae Kwon, Chiayu Q. Chiu, Lunbin Deng, Pablo E. Castillo, and Thomas C. SГјdhof
Presynaptic active zones comprise many proteins that help to ensure rapid neurotransmitter release near postsynaptic receptors, and modification of some of these proteins produces long-term potentiation or depression. Although most active-zone proteins have been assigned to a specific step in the release process (e.g., vesicle docking, priming, or fusion), the molecular mechanisms involved remain unknown, and additional proteins continue to be discovered. This week, Kaeser et al. report that the gene encoding an active-zone scaffolding protein, RIM1О±, encodes a previously undiscovered second isoform, RIM1ОІ. RIM1О± has several protein-interaction domains that enable it to bind several other active-zone proteins. RIM1ОІ lacks the N-terminal protein interaction domain of RIM1О±, but is otherwise identical. RIM1О± and RIM1ОІ have largely overlapping expression patterns and functions. For example, both molecules appear to influence vesicle release probability at both excitatory and inhibitory synapses. But only RIM1О± appears to be involved in protein-kinase-A-dependent presynaptic long-term plasticity.
2. Crk and CrkL Mediate Reelin Signaling
Tae-Ju Park and Tom Curran
Crk and CrkL are widely expressed adaptor proteins whose function is to bring together tyrosine-phosphorylated proteins and their downstream effectors. Crk and CrkL interact with many proteins and are involved in diverse biological process throughout the body. Park and Curran now suggest that Crk and CrkL are important components of the Reelin signaling cascade in neurons. Deletion of both Crk and CrkL specifically in developing neurons produced a phenotype nearly identical to that of reelin mutations. For example, layer formation, neuronal migration, and dendrite development were severely disrupted in the cerebellum, hippocampus, and cerebral cortex. Reelin, an extracellular secreted protein, binds to lipoprotein receptors, resulting in activation of tyrosine kinases that phosphorylate the protein Disabled-1. Disabled-1 then promotes phosphorylation of the kinase Akt. In Crk/CrkL double-knock-out mice, levels of phosphorylated Disabled-1 were comparable to wild-type, but Akt phosphorylation was reduced, placing Crk/CrkL between Disabled-1 and Akt in the Reelin signaling pathway.
3. Estradiol Decreases Cortical Functional Lateralization
Susanne Weis, Markus Hausmann, Barbara Stoffers, RenГ© Vohn, Thilo Kellermann, and Walter Sturm
The cerebral hemispheres are functionally specialized: the left hemisphere is generally dominant in verbal tasks, whereas the right hemisphere dominates in spatial tasks. This asymmetry is thought to depend on inhibition of the nondominant hemisphere by the dominant hemisphere. The degree of functional lateralization varies across individuals, and females tend to exhibit less asymmetry than males. Furthermore, functional cerebral asymmetries vary in women throughout menstrual cycles, and asymmetries in postmenopausal women are comparable to those in men, suggesting that sex hormones alter interhemispheric inhibition. To test this hypothesis, Weis et al. measured brain activity during a verbal task using functional magnetic resonance imaging in men and in women at two points of the menstrual cycle when estradiol levels differed. As predicted, active regions of the left hemisphere inhibited homotypic areas in the right hemisphere in men and in women when their estradiol levels were low, but the inhibition disappeared when estradiol levels were high.
4. Near-Infrared Light Protects Retinas from Mitochondrial Damage
Julio C. Rojas, Jung Lee, Joseph M. John, and F. Gonzalez-Lima
Near-infrared light therapy (NILT) increases survival of cultured neurons exposed to various stressors, improves behavioral recovery from stroke in rabbits, and speeds wound healing in humans. These effects are thought to be mediated by upregulation of mitochondrial proteins, endogenous antioxidants, and antiapoptotic proteins such as heat-shock proteins and Bcl-2. This week, Rojas et al. report that NILT greatly reduced retinal damage and associated behavioral deficits produced in rats by the mitochondrial toxin rotenone. NILT prevented rotenone-induced decreases in light sensitivity and greatly reduced thinning of the retinal layers. Interestingly, NILT increased activity of the mitochondrial respiratory protein cytochrome oxidase and of the antioxidant superoxide dismutase throughout the brain, suggesting that the infrared light can penetrate the skull (at least in rats) and induce neuroprotective effects in the brain. Because many neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, involve mitochondrial dysfunction similar to that produced by rotenone, NILT may prove effective in treating these diseases as well.
Please click here for the current table of contents.
Source: Sara Harris
Society for Neuroscience
View drug information on Estradiol Transdermal System.
воскресенье, 15 мая 2011 г.
Scientists Discover Crucial Molecule In Cancer Rejection
Researchers at the Centenary Institute in Sydney have discovered a molecule on the surface of immune cells which plays a critical role in cancer rejection.
Using advanced multi-photon microscopy, the scientists have tracked the migration of immune cells called T cells within tumours in experimental models, and found that the surface molecule (CD44) directly impacts whether a tumour progresses or is rejected by T cells.
Professor Wolfgang Weninger, Head of the Immune Imaging program at Centenary, says this discovery advances our knowledge of the immune processes at play in cancer.
"The immune system and cancer were first linked in the 1900s but it wasn't until the 1980s that interactions between the immune system and cancer cells became a focus for medical researchers," says Professor Weninger.
"We know that migration of T cells within tumours is very important for rejection but we didn't know about how it worked. We found that this particular molecule regulates the navigation of T cells in tumours. In its absence, T cells are inhibited in migration and show a defect in their ability to reject a tumour."
Understanding how tumours avoid the natural processes of the immune system is one of the biggest questions in cancer. Finding the answer could significantly improve cancer treatment.
Professor Weninger explains: "By understanding how the immune system fights tumours, we may be able to optimise cancer therapies in the future. It may provide the opportunity to design treatments that mimic certain aspects of immune responses and cellular processes, making cancer treatments less hit and miss and reducing the toll on patients."
Centenary Institute Executive Director, Professor Mathew Vadas, points out this discovery has been made possible by recent advances in research technology - in particular multi-photon microscopy.
"Previously, cancer researchers could only build assumptions by linking series' of still images of the immune system at work," Professor Vadas says. "Multi-photon microscopy allows us to make real time movies showing exactly how the immune cells interact and is opening up new frontiers for medical research."
Professor Weninger, a world leader in this form of imaging, is driving this research revolution using one of Australia's first multi-photon microscopes at the Centenary Institute in Sydney.
This discovery firmly places Professor Weninger and his team's focus on the next piece of the puzzle - how does the actual process of tumour rejection work?
"This next stage of our research is very exciting. What are the physical interactions of T cells and tumours and how do the T cells actually defeat a tumour?" says Professor Weninger. "If we can get to the bottom of these immune system interplays, the benefits for cancer patients around the world could be truly enormous."
About the Centenary Institute
The Centenary Institute is an independent medical research institute, affiliated with Royal Prince Alfred Hospital and the University of Sydney. Our unique blend of highly skilled staff and state-of-the art equipment and facilities has allowed us to become world leaders in three critical areas of medical research - cancer, cardiovascular disease and infectious diseases. For further information about the Centenary Institute, visit centenary.au/.
Publication reference
Mrass P, Kinjyo I, Ng LG, Reiner SL, PurГ© E, Weninger W. CD44 mediates successful interstitial navigation by killer T cells and enables efficient antitumor immunity. Immunity. 2008 Dec;29(6):971-85.
Source: Erin Sharp
Research Australia
Using advanced multi-photon microscopy, the scientists have tracked the migration of immune cells called T cells within tumours in experimental models, and found that the surface molecule (CD44) directly impacts whether a tumour progresses or is rejected by T cells.
Professor Wolfgang Weninger, Head of the Immune Imaging program at Centenary, says this discovery advances our knowledge of the immune processes at play in cancer.
"The immune system and cancer were first linked in the 1900s but it wasn't until the 1980s that interactions between the immune system and cancer cells became a focus for medical researchers," says Professor Weninger.
"We know that migration of T cells within tumours is very important for rejection but we didn't know about how it worked. We found that this particular molecule regulates the navigation of T cells in tumours. In its absence, T cells are inhibited in migration and show a defect in their ability to reject a tumour."
Understanding how tumours avoid the natural processes of the immune system is one of the biggest questions in cancer. Finding the answer could significantly improve cancer treatment.
Professor Weninger explains: "By understanding how the immune system fights tumours, we may be able to optimise cancer therapies in the future. It may provide the opportunity to design treatments that mimic certain aspects of immune responses and cellular processes, making cancer treatments less hit and miss and reducing the toll on patients."
Centenary Institute Executive Director, Professor Mathew Vadas, points out this discovery has been made possible by recent advances in research technology - in particular multi-photon microscopy.
"Previously, cancer researchers could only build assumptions by linking series' of still images of the immune system at work," Professor Vadas says. "Multi-photon microscopy allows us to make real time movies showing exactly how the immune cells interact and is opening up new frontiers for medical research."
Professor Weninger, a world leader in this form of imaging, is driving this research revolution using one of Australia's first multi-photon microscopes at the Centenary Institute in Sydney.
This discovery firmly places Professor Weninger and his team's focus on the next piece of the puzzle - how does the actual process of tumour rejection work?
"This next stage of our research is very exciting. What are the physical interactions of T cells and tumours and how do the T cells actually defeat a tumour?" says Professor Weninger. "If we can get to the bottom of these immune system interplays, the benefits for cancer patients around the world could be truly enormous."
About the Centenary Institute
The Centenary Institute is an independent medical research institute, affiliated with Royal Prince Alfred Hospital and the University of Sydney. Our unique blend of highly skilled staff and state-of-the art equipment and facilities has allowed us to become world leaders in three critical areas of medical research - cancer, cardiovascular disease and infectious diseases. For further information about the Centenary Institute, visit centenary.au/.
Publication reference
Mrass P, Kinjyo I, Ng LG, Reiner SL, PurГ© E, Weninger W. CD44 mediates successful interstitial navigation by killer T cells and enables efficient antitumor immunity. Immunity. 2008 Dec;29(6):971-85.
Source: Erin Sharp
Research Australia
суббота, 14 мая 2011 г.
Metallic Nanostructures Enable The Manufacture Of New Security And Medical Sensor Devices
Scientists have designed tiny new sensor structures that could be used in novel security devices to detect poisons and explosives, or in highly sensitive medical sensors, according to research published tomorrow in Nano Letters.
The new 'nanosensors', which are based on a fundamental science discovery in UK, Belgian and US research groups, could be tailor-made to instantly detect the presence of particular molecules, for example poisons or explosives in transport screening situations, or proteins in patients' blood samples, with high sensitivity.
The researchers were led by Imperial College London physicists funded by the Engineering and Physical Sciences Research Council. The team showed that by putting together two specific 'nanostructures' made of gold or silver, they can make an early prototype device which, once optimised, should exhibit a highly sensitive ability to detect particular chemicals in the immediate surroundings.
The nanostructures are each about 500 times smaller than the width of a human hair. One is shaped like a flat circular disk while the other looks like a doughnut with a hole in the middle. When brought together they interact with light very differently to the way they behave on their own. The scientists have observed that when they are paired up they scatter some specific colours within white light much less, leading to an increased amount of light passing through the structure undisturbed. This is distinctly different to how both structures scatter light separately. This decrease in the interaction with light is in turn affected by the composition of molecules in close proximity to the structures. The researchers hope that this effect can be harnessed to produce sensor devices.
Lead researcher on the project Professor Stefan Maier from Imperial's Department of Physics, and an Associate of Imperial's Institute for Security Science and Technology, said:
"Pairing up these structures has a unique effect on the way they scatter light - an effect which could be very useful if, as our computer simulations suggest, it is extremely sensitive to changes in surrounding environment. With further testing we hope to show that it is possible to harness this property to make a highly sensitive nanosensor."
Metal nanostructures have been used as sensors before, as they interact very strongly with light due to so-called localised plasmon resonances. But this is the first time a pair with such a carefully tailored interaction with light has been created.
The device could be tailored to detect different chemicals by decorating the nanostructure surface with specific 'molecular traps' that bind the chosen target molecules. Once bound, the target molecules would change the colours that the device absorbs and scatters, alerting the sensor to their presence. The team's next step is to test whether the pair of nanostructures can detect chosen substances in lab experiments.
Professor Maier concludes: "This study is a beautiful example of how concepts from different areas of physics fertilise each other - in essence our nanosensor system is a classical analogue of electromagnetically induced transparency, a famous phenomenon from quantum mechanics."
Notes:
The research was conducted by the team at Imperial College London in collaboration with IMEC and the Catholic University in Leuven, Belgium, and Rice University in Houston, Texas.
Source:
Danielle Reeves
Imperial College London
The new 'nanosensors', which are based on a fundamental science discovery in UK, Belgian and US research groups, could be tailor-made to instantly detect the presence of particular molecules, for example poisons or explosives in transport screening situations, or proteins in patients' blood samples, with high sensitivity.
The researchers were led by Imperial College London physicists funded by the Engineering and Physical Sciences Research Council. The team showed that by putting together two specific 'nanostructures' made of gold or silver, they can make an early prototype device which, once optimised, should exhibit a highly sensitive ability to detect particular chemicals in the immediate surroundings.
The nanostructures are each about 500 times smaller than the width of a human hair. One is shaped like a flat circular disk while the other looks like a doughnut with a hole in the middle. When brought together they interact with light very differently to the way they behave on their own. The scientists have observed that when they are paired up they scatter some specific colours within white light much less, leading to an increased amount of light passing through the structure undisturbed. This is distinctly different to how both structures scatter light separately. This decrease in the interaction with light is in turn affected by the composition of molecules in close proximity to the structures. The researchers hope that this effect can be harnessed to produce sensor devices.
Lead researcher on the project Professor Stefan Maier from Imperial's Department of Physics, and an Associate of Imperial's Institute for Security Science and Technology, said:
"Pairing up these structures has a unique effect on the way they scatter light - an effect which could be very useful if, as our computer simulations suggest, it is extremely sensitive to changes in surrounding environment. With further testing we hope to show that it is possible to harness this property to make a highly sensitive nanosensor."
Metal nanostructures have been used as sensors before, as they interact very strongly with light due to so-called localised plasmon resonances. But this is the first time a pair with such a carefully tailored interaction with light has been created.
The device could be tailored to detect different chemicals by decorating the nanostructure surface with specific 'molecular traps' that bind the chosen target molecules. Once bound, the target molecules would change the colours that the device absorbs and scatters, alerting the sensor to their presence. The team's next step is to test whether the pair of nanostructures can detect chosen substances in lab experiments.
Professor Maier concludes: "This study is a beautiful example of how concepts from different areas of physics fertilise each other - in essence our nanosensor system is a classical analogue of electromagnetically induced transparency, a famous phenomenon from quantum mechanics."
Notes:
The research was conducted by the team at Imperial College London in collaboration with IMEC and the Catholic University in Leuven, Belgium, and Rice University in Houston, Texas.
Source:
Danielle Reeves
Imperial College London
пятница, 13 мая 2011 г.
Cells' Grouping Tactic Points To New Cancer Treatments
The study, which used embryonic cells, points to a new way of treating cancer where therapy is targeted at the process of cancer cells grouping together. The aim is to stop cancer cells from spreading and causing secondary tumours.
In order for cells to migrate they form protrusions - much like oars of a boat - in the direction that they want to travel. However, if a single cell is isolated it produces these oars in all directions and ends up rowing in circles. To move around effectively cells must stick together before attempting to travel.
The study, published today in the journal Developmental Cell, explains how this process works. Scientists have discovered that when cells group together the contact with other cells inhibits the formation of protrusions or 'oars'. This means that protrusions only form on the cells that are on the outside edges of the group, causing the group to move in specific direction as the group is pushed by the outermost 'leader' cells.
Dr Roberto Mayor, UCL Department of Cell and Developmental Biology and lead author of the research, said, "Being able to form a group with neighbour cells is advantageous for migration of embryonic cells as well as cancer cells during tumour metastasis - they have strength in unity.
"The findings suggest an alternative way in which cancer treatments might work in the future if therapies can be targeted at the process of group formation to stop cancer cells from spreading and causing secondary tumours."
The experiments were carried out using neural crest cells, which are found next to the developing central nervous system in embryos. These cells can develop into a huge variety of different kind of cells including heart, face, skin and muscle cells. Scientists blocked surface molecules, proteins called N-cadherin, on the neural crest cells that are involved in forming contacts between cells. When they did this the power of the cells to group together was lost, along with any ability to migrate.
It is expected that inhibition of N-cadherin would have the same the effect in cancer cells, which also move in groups during metastasis.
The work was funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the Wellcome Trust.
Source:
Clare Ryan
University College London
In order for cells to migrate they form protrusions - much like oars of a boat - in the direction that they want to travel. However, if a single cell is isolated it produces these oars in all directions and ends up rowing in circles. To move around effectively cells must stick together before attempting to travel.
The study, published today in the journal Developmental Cell, explains how this process works. Scientists have discovered that when cells group together the contact with other cells inhibits the formation of protrusions or 'oars'. This means that protrusions only form on the cells that are on the outside edges of the group, causing the group to move in specific direction as the group is pushed by the outermost 'leader' cells.
Dr Roberto Mayor, UCL Department of Cell and Developmental Biology and lead author of the research, said, "Being able to form a group with neighbour cells is advantageous for migration of embryonic cells as well as cancer cells during tumour metastasis - they have strength in unity.
"The findings suggest an alternative way in which cancer treatments might work in the future if therapies can be targeted at the process of group formation to stop cancer cells from spreading and causing secondary tumours."
The experiments were carried out using neural crest cells, which are found next to the developing central nervous system in embryos. These cells can develop into a huge variety of different kind of cells including heart, face, skin and muscle cells. Scientists blocked surface molecules, proteins called N-cadherin, on the neural crest cells that are involved in forming contacts between cells. When they did this the power of the cells to group together was lost, along with any ability to migrate.
It is expected that inhibition of N-cadherin would have the same the effect in cancer cells, which also move in groups during metastasis.
The work was funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the Wellcome Trust.
Source:
Clare Ryan
University College London
среда, 11 мая 2011 г.
Genes That Confirm A Connection Between Caloric Restriction And Longevity
For nearly 70 years scientists have known that caloric restriction prolongs life. In everything from yeast to primates, a significant decrease in calories can extend lifespan by as much as one-third. But getting under the hood of the molecular machinery that drives this longevity has remained elusive.
Now, reporting in the journal Cell, researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health, have discovered two genes in mammalian cells that act as gatekeepers for cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up and help protect cells from diseases of aging.
"We've reason to believe now that these two genes may be potential drug targets for diseases associated with aging," says David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.
The new genes that Sinclair's group have discovered, in collaboration with Anthony Sauve of Cornell Medical School and Rafael de Cabo of NIH, are called SIRT3 and SIRT4. They are members of a larger class of genes called sirtuins. (Another gene belonging to this family, SIRT1, was shown last year to also have a powerful impact on longevity when stimulated by the red-wine molecule resveratrol.)
In this paper, the newly discovered role of SIRT3 and SIRT4 drives home something scientists have suspected for a long time: mitochondria are vital for sustaining the health and longevity of a cell.
Mitochondria, a kind of cellular organ that lives in the cytoplasm, are often considered to be the cell's battery packs. When mitochondria stability starts to wane, energy is drained out of the cell, and its days are numbered. In this paper, Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a longevity network that maintains the vitality of mitochondria and keeps cells healthy when they would otherwise die.
When cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT. As levels of NAMPT ramp up, a small molecule called NAD begins to amass in the mitochondria. This, in turn, causes the activity of enzymes created by the SIRT3 and SIRT4 genes--enzymes that live in the mitochondria--to increase as well. As a result, the mitochondria grow stronger, energy-output increases, and the cell's aging process slows down significantly. (Interestingly, this same process is also activated by exercise.)
"We're not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result SIRT3 and SIRT4," says Sinclair, "but we do see that normal cell-suicide programs are noticeably attenuated. This is the first time ever that SIRT3 and SIRT4 have been linked to cell survival."
In fact, the mitochondria appear to be so essential to the cell's life that when all other energy sources inside the cell--including the nucleus--are wiped out, yet the mitochondria are kept intact and functional, the cell remains alive.
"Mitochondria are the guardians of cell survival," says Sinclair. "If we can keep boosting levels of NAD in the mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4, then for a period of time the cell really needs nothing else."
Sinclair and his colleagues have coined a phrase for this observation: the Mitochondrial Oasis Hypothesis.
SIRT3 and SIRT4 may now also be potential drug targets for diseases associated with aging. For example, in recent years scientists have become increasingly aware of the importance of mitochondrial function in treating diseases such as cancer, diabetes, and neurodegeneration.
"Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria," says Sinclair. "Such a molecule could be used for many age-related diseases."
According to Suave of Cornell, "This study also highlights how advanced technological methods can help resolve fundamental biological questions in ways that were hard to achieve as recently as a few years ago."
This study is supported by the National Institutes of Health and the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. Sinclair and Suave are consultants to Sirtris Pharmaceuticals, a company aiming to treat diseases by modulating sirtuins. Sinclair is also a cofounder of Sirtris Pharmaceuticals and sits on their advisory board and board of directors.
Full Citation:
Cell, Volume 130, Issue 5, September 21, 2007
"Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival"
Hongying Yang(1,6), Tianle Yang(2), Joseph A. Baur(1), Evelyn Perez(3), Takashi Matsui(5), Juan J. Carmona(1), Dudley W. Lamming(1), Nadja C. Souza-Pinto(4), Vilhelm A. Bohr(4), Anthony Rosenzweig(5), Rafael de Cabo(3), Anthony A. Sauve(2), and David A. Sinclair(1)
1-Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical School, Boston, MA
2-Department of Pharmacology, Weill Medical College of Cornell University, New York, NY
3-Laboratory of Experimental Gerontology
4-Laboratory of Molecular Gerontology, National Institute on Aging, Institutes of Health, Baltimore, MD
5-Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA
6-Present address: Sirtris Pharmaceuticals, Cambridge, MA
Harvard Medical School (hms.harvard) has more than 7,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
Source: Davic Cameron
Harvard Medical School
Now, reporting in the journal Cell, researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health, have discovered two genes in mammalian cells that act as gatekeepers for cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up and help protect cells from diseases of aging.
"We've reason to believe now that these two genes may be potential drug targets for diseases associated with aging," says David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.
The new genes that Sinclair's group have discovered, in collaboration with Anthony Sauve of Cornell Medical School and Rafael de Cabo of NIH, are called SIRT3 and SIRT4. They are members of a larger class of genes called sirtuins. (Another gene belonging to this family, SIRT1, was shown last year to also have a powerful impact on longevity when stimulated by the red-wine molecule resveratrol.)
In this paper, the newly discovered role of SIRT3 and SIRT4 drives home something scientists have suspected for a long time: mitochondria are vital for sustaining the health and longevity of a cell.
Mitochondria, a kind of cellular organ that lives in the cytoplasm, are often considered to be the cell's battery packs. When mitochondria stability starts to wane, energy is drained out of the cell, and its days are numbered. In this paper, Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a longevity network that maintains the vitality of mitochondria and keeps cells healthy when they would otherwise die.
When cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT. As levels of NAMPT ramp up, a small molecule called NAD begins to amass in the mitochondria. This, in turn, causes the activity of enzymes created by the SIRT3 and SIRT4 genes--enzymes that live in the mitochondria--to increase as well. As a result, the mitochondria grow stronger, energy-output increases, and the cell's aging process slows down significantly. (Interestingly, this same process is also activated by exercise.)
"We're not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result SIRT3 and SIRT4," says Sinclair, "but we do see that normal cell-suicide programs are noticeably attenuated. This is the first time ever that SIRT3 and SIRT4 have been linked to cell survival."
In fact, the mitochondria appear to be so essential to the cell's life that when all other energy sources inside the cell--including the nucleus--are wiped out, yet the mitochondria are kept intact and functional, the cell remains alive.
"Mitochondria are the guardians of cell survival," says Sinclair. "If we can keep boosting levels of NAD in the mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4, then for a period of time the cell really needs nothing else."
Sinclair and his colleagues have coined a phrase for this observation: the Mitochondrial Oasis Hypothesis.
SIRT3 and SIRT4 may now also be potential drug targets for diseases associated with aging. For example, in recent years scientists have become increasingly aware of the importance of mitochondrial function in treating diseases such as cancer, diabetes, and neurodegeneration.
"Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria," says Sinclair. "Such a molecule could be used for many age-related diseases."
According to Suave of Cornell, "This study also highlights how advanced technological methods can help resolve fundamental biological questions in ways that were hard to achieve as recently as a few years ago."
This study is supported by the National Institutes of Health and the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. Sinclair and Suave are consultants to Sirtris Pharmaceuticals, a company aiming to treat diseases by modulating sirtuins. Sinclair is also a cofounder of Sirtris Pharmaceuticals and sits on their advisory board and board of directors.
Full Citation:
Cell, Volume 130, Issue 5, September 21, 2007
"Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival"
Hongying Yang(1,6), Tianle Yang(2), Joseph A. Baur(1), Evelyn Perez(3), Takashi Matsui(5), Juan J. Carmona(1), Dudley W. Lamming(1), Nadja C. Souza-Pinto(4), Vilhelm A. Bohr(4), Anthony Rosenzweig(5), Rafael de Cabo(3), Anthony A. Sauve(2), and David A. Sinclair(1)
1-Department of Pathology, Paul F. Glenn Laboratories, Harvard Medical School, Boston, MA
2-Department of Pharmacology, Weill Medical College of Cornell University, New York, NY
3-Laboratory of Experimental Gerontology
4-Laboratory of Molecular Gerontology, National Institute on Aging, Institutes of Health, Baltimore, MD
5-Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, MA
6-Present address: Sirtris Pharmaceuticals, Cambridge, MA
Harvard Medical School (hms.harvard) has more than 7,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.
Source: Davic Cameron
Harvard Medical School
вторник, 10 мая 2011 г.
Study Suggests Antioxidants Are Unlikely To Prevent Aging
Diets and beauty products which claim to have anti-oxidant properties are unlikely to prevent ageing, according to research funded by the Wellcome Trust. Researchers at the Institute of Healthy Ageing at UCL (University College London) say this is because a key fifty year old theory about the causes of ageing is wrong.
"Superoxide" free radicals - oxygen molecules that have an imbalance of electrons to protons - are generated in the body through natural processes such as metabolism. These free radicals can cause oxidation in the body, analogous to rust when iron is exposed to oxygen. Biological systems, such as the human body, are usually able to restrict or repair this damage.
In 1956, Denham Harman proposed the theory that ageing is caused by an accumulation of molecular damage caused by "oxidative stress", the action of reactive forms of oxygen, such as superoxide, on cells. This theory has dominated the field of ageing research for over fifty years. But now, a study published online today in the journal Genes & Development suggests that this theory is probably incorrect and that superoxide is not a major cause of ageing.
"The fact is that we don't understand much about the fundamental mechanisms of ageing," says Dr David Gems from UCL. "The free radical theory of ageing has filled a knowledge vacuum for over fifty years now, but it just doesn't stand up to the evidence."
Dr Gems and colleagues at the Institute of Healthy Ageing studied the action of key genes involved in removing superoxide from the bodies of the nematode worm C. elegans, a commonly-used model for research into ageing. By manipulating these genes, they were able to control the worm's ability to "mop up" surplus superoxide and limit potential damage caused by oxidation.
Contrary to the result predicted by the free radical theory of ageing, the researchers found that the lifespan of the worm was relatively unaffected by its ability to tackle the surplus superoxide. The findings, combined with similar recent findings from the University of Texas using mice, imply that this theory is incorrect.
"One of the hallmarks of ageing is the accumulation of molecular damage, but what causes this damage?" says Dr Gems. "It's clear that if superoxide is involved, it only plays a small part in the story. Oxidative damage is clearly not a universal, major driver of the ageing process. Other factors, such as chemical reactions involving sugars in our body, clearly play a role."
Dr Gems believes the study suggests that anti-ageing products which claim to have anti-oxidant properties are unlikely to have any effect.
"A healthy, balanced diet is very important for reducing the risk of developing many diseases associated with old age, such as cancer, diabetes and osteoporosis," he says. "But there is no clear evidence that dietary antioxidants can slow or prevent ageing. There is even less evidence to support the claims of most anti-ageing products."
The research was welcomed by Dr Alan Schafer, Head of Molecular and Physiological Sciences at the Wellcome Trust.
"With increasing lifespan comes greater exposure and vulnerability to the ageing process," comments Dr Schafer. "Research such as this points to how much we have to learn about ageing, and the importance of understanding the mechanisms behind this process. This new study will encourage researchers to explore new avenues in ageing research."
Source: Craig Brierley
Wellcome Trust
"Superoxide" free radicals - oxygen molecules that have an imbalance of electrons to protons - are generated in the body through natural processes such as metabolism. These free radicals can cause oxidation in the body, analogous to rust when iron is exposed to oxygen. Biological systems, such as the human body, are usually able to restrict or repair this damage.
In 1956, Denham Harman proposed the theory that ageing is caused by an accumulation of molecular damage caused by "oxidative stress", the action of reactive forms of oxygen, such as superoxide, on cells. This theory has dominated the field of ageing research for over fifty years. But now, a study published online today in the journal Genes & Development suggests that this theory is probably incorrect and that superoxide is not a major cause of ageing.
"The fact is that we don't understand much about the fundamental mechanisms of ageing," says Dr David Gems from UCL. "The free radical theory of ageing has filled a knowledge vacuum for over fifty years now, but it just doesn't stand up to the evidence."
Dr Gems and colleagues at the Institute of Healthy Ageing studied the action of key genes involved in removing superoxide from the bodies of the nematode worm C. elegans, a commonly-used model for research into ageing. By manipulating these genes, they were able to control the worm's ability to "mop up" surplus superoxide and limit potential damage caused by oxidation.
Contrary to the result predicted by the free radical theory of ageing, the researchers found that the lifespan of the worm was relatively unaffected by its ability to tackle the surplus superoxide. The findings, combined with similar recent findings from the University of Texas using mice, imply that this theory is incorrect.
"One of the hallmarks of ageing is the accumulation of molecular damage, but what causes this damage?" says Dr Gems. "It's clear that if superoxide is involved, it only plays a small part in the story. Oxidative damage is clearly not a universal, major driver of the ageing process. Other factors, such as chemical reactions involving sugars in our body, clearly play a role."
Dr Gems believes the study suggests that anti-ageing products which claim to have anti-oxidant properties are unlikely to have any effect.
"A healthy, balanced diet is very important for reducing the risk of developing many diseases associated with old age, such as cancer, diabetes and osteoporosis," he says. "But there is no clear evidence that dietary antioxidants can slow or prevent ageing. There is even less evidence to support the claims of most anti-ageing products."
The research was welcomed by Dr Alan Schafer, Head of Molecular and Physiological Sciences at the Wellcome Trust.
"With increasing lifespan comes greater exposure and vulnerability to the ageing process," comments Dr Schafer. "Research such as this points to how much we have to learn about ageing, and the importance of understanding the mechanisms behind this process. This new study will encourage researchers to explore new avenues in ageing research."
Source: Craig Brierley
Wellcome Trust
Подписаться на:
Сообщения (Atom)