In cells, as in cities, disposing of garbage and recycling anything that can be reused is an essential service. In both city and cell, health problems can arise when the process breaks down.
New research by University of Michigan cell biologist Haoxing Xu and colleagues reveals key details about how the cell's garbage dump and recycling center, the lysosome, functions. These insights, which may lead to better understanding of conditions such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and Charcot-Marie-Tooth (CMT) disease, suggest new avenues of treatment for these and other diseases that cause nerves and muscles to malfunction.
The research, published this week in the online, multidisciplinary journal Nature Communications, focused on gateways called calcium channels in the lysosome membrane. Calcium channels, which also are found in the membranes surrounding muscle and nerve cells, are made of proteins that respond to signals in the form of electrical impulses. When the proper signal comes along, the proteins open the channel, allowing calcium to pass through. The calcium, in turn, triggers some vital process such as muscle contraction or the release of a hormone or neurotransmitter (a chemical messenger involved in nerve transmission).
Scientists know a lot about the workings of calcium channels in the surfaces of muscle and nerve cells, but understanding what goes in the lysosome - a tiny pouch hidden inside the cell - has been a challenge, said Xu. Consequently, the exact identity of the protein involved and how it becomes activated have remained a mystery.
To explore the channel and its workings, Xu's group modified a technique known as the patch clamp, in which a scaled-down pipette and electrodes are attached to a cell membrane to record the activity of one or more proteins making up the channel. With their modification, which they call the lysosome patch clamp, the researchers determined that a protein called TRPML1 serves as the calcium channel in lysosomes and that a lipid known as PI(3,5)P2 carries the signal that activates the protein.
This particular protein and lipid aren't obscure characters previously unknown to science. A mutation in the gene that produces TRPML1 is known to cause Type IV mucolipidosis (ML4), a genetic disorder that affects mainly Jews of Eastern European background and results in mental retardation, poor vision and diminished motor abilities. And mutations in the enzymes needed to make PI(3,5) P2 cause a variety of neurodegenerative diseases including ALS and CMT.
The protein TRPML1 also is of interest because of the unusual way it does its work.
"While other channel proteins are in the 'passenger' seats of the membrane traffic, TRPML1 is in the 'driver' seat," said Xu, an assistant professor of molecular, cellular and developmental biology. This suggests that manipulating TRPML1 channel activity using channel activators or inhibitors could affect membrane traffic.
"If you can activate the channel, it might be possible to overcome the membrane traffic defects caused by the disease-causing mutations. Luckily, small-molecule chemicals that can stimulate TRPML1 channel activity are already available, " Xu said.
He and collaborator Miriam Meisler, a human genetics professor at the U-M Medical School, have experiments underway to see if they can prevent or reverse the course of disease in a mouse model of ALS by increasing activity of the TRPML1 channel.
If the strategy is successful, Xu hopes to explore its use in treating other neurological diseases.
"If the system we're studying turns out to be compromised in more common diseases, the method of increasing channel activity could have important implications for their treatment," he said.
Xu's coauthors on the Nature Communications paper are postdoctoral fellows Xian-ping Dong, Xiping Cheng and Yanling Zhang; graduate students Dongbiao Shen, Xiang Wang, and Qi Zhang; and undergraduate students Taylor Dawson and Xinran Li, all at U-M; Lois Weisman, who is the Sarah Winans Newman Collegiate Professor in the Life Sciences at U-M; and Markus Delling of Children's Hospital Boston.
The research was funded by the U-M Department of Molecular, Cellular & Developmental Biology; the U-M Biological Sciences Scholars Program; the U-M Initiative on Rare Disease Research, the Michigan Alzheimer's Disease Research Center, the National Multiple Sclerosis Society and the National Institutes of Health.
Source:
Nancy Ross-Flanigan
University of Michigan
четверг, 29 сентября 2011 г.
понедельник, 26 сентября 2011 г.
Heart Attack Damage May Be Lessened By Novel Compound
A novel drug designed to lessen muscle damage from a heart attack has passed initial safety tests at the Duke Clinical Research Institute. Results of the study, available online and to be published in the February 19 issue of the journal Circulation, reflect the first time the drug has been tested in humans.
The drug, known as KAI-9803, blocks the activity of an enzyme called delta protein kinase C that triggers cell and tissue death in the aftermath of percutaneous coronary intervention, or PCI. PCI is a set of procedures including balloon angioplasty and stent placement that clear and prop open clogged coronary blood vessels that lead to a heart attack - a process known as reperfusion.
Although the trial (known as DELTA-MI) was not designed to demonstrate the efficacy of KAI-9803, researchers say early data suggest it appears to be a promising compound.
"We've needed something like this for a long time," says Dr. Matthew Roe, a cardiologist at Duke and the lead investigator of the trial.
Roe says many people may not realize that the heart suffers damage at two major points in a heart attack: first, when a blockage in a coronary artery prevents blood and oxygen from getting to the heart, and then again when the patient undergoes PCI and normal blood flow is restored through reperfusion.
"We may not be able to intervene in the first stage of a heart attack, but we think there may be ways to limit damage caused by reperfusion injury," he says.
Researchers randomized 154 patients who had suffered heart attacks and were eligible for PCI into either one of four dosing levels of KAI-9803 or a placebo. Patients underwent PCI - with physicians injecting the drug directly into their coronary blood vessels during the procedure.
"The goal of the treatment is to flood the heart damaged by the heart attack with the drug immediately before blood flow is restored and then again, immediately afterwards," says Roe. "We believe that bathing the area with this novel compound may block the damaging cascade of events that are triggered specifically by delta protein kinase C when blood is restored to the heart muscle," he says.
Earlier studies in animals showed that KAI-9803 lessened damage to the heart muscle and quickly restored its pumping function.
"We designed the DELTA MI trial to find out if KAI-9803 is safe for humans, and we accomplished that goal; we did not see any serious side effects," says Roe. "We also found, however, many promising signs of beneficial drug activity such as lessened damage to the heart muscle and improvement in electrical conductivity in the heart that corresponded to restoration of blood flow to the heart muscle. As a result, we feel this drug has the potential to be helpful in reducing the impact of a heart attack in humans."
The study, funded by KAI Pharmaceuticals, included contributions from researchers in 48 institutions throughout the U.S., Canada, Brazil and Europe.
Source: Michelle Gailiun
Duke University Medical Center
The drug, known as KAI-9803, blocks the activity of an enzyme called delta protein kinase C that triggers cell and tissue death in the aftermath of percutaneous coronary intervention, or PCI. PCI is a set of procedures including balloon angioplasty and stent placement that clear and prop open clogged coronary blood vessels that lead to a heart attack - a process known as reperfusion.
Although the trial (known as DELTA-MI) was not designed to demonstrate the efficacy of KAI-9803, researchers say early data suggest it appears to be a promising compound.
"We've needed something like this for a long time," says Dr. Matthew Roe, a cardiologist at Duke and the lead investigator of the trial.
Roe says many people may not realize that the heart suffers damage at two major points in a heart attack: first, when a blockage in a coronary artery prevents blood and oxygen from getting to the heart, and then again when the patient undergoes PCI and normal blood flow is restored through reperfusion.
"We may not be able to intervene in the first stage of a heart attack, but we think there may be ways to limit damage caused by reperfusion injury," he says.
Researchers randomized 154 patients who had suffered heart attacks and were eligible for PCI into either one of four dosing levels of KAI-9803 or a placebo. Patients underwent PCI - with physicians injecting the drug directly into their coronary blood vessels during the procedure.
"The goal of the treatment is to flood the heart damaged by the heart attack with the drug immediately before blood flow is restored and then again, immediately afterwards," says Roe. "We believe that bathing the area with this novel compound may block the damaging cascade of events that are triggered specifically by delta protein kinase C when blood is restored to the heart muscle," he says.
Earlier studies in animals showed that KAI-9803 lessened damage to the heart muscle and quickly restored its pumping function.
"We designed the DELTA MI trial to find out if KAI-9803 is safe for humans, and we accomplished that goal; we did not see any serious side effects," says Roe. "We also found, however, many promising signs of beneficial drug activity such as lessened damage to the heart muscle and improvement in electrical conductivity in the heart that corresponded to restoration of blood flow to the heart muscle. As a result, we feel this drug has the potential to be helpful in reducing the impact of a heart attack in humans."
The study, funded by KAI Pharmaceuticals, included contributions from researchers in 48 institutions throughout the U.S., Canada, Brazil and Europe.
Source: Michelle Gailiun
Duke University Medical Center
пятница, 23 сентября 2011 г.
Embryonic Pathway Delivers Stem Cell Traits
Studies of how cancer cells spread have led to a surprising discovery about the creation of cells with adult stem cell characteristics, offering potentially major implications for regenerative medicine and for cancer treatment.
Some cancer cells acquire the ability to migrate through the body by re-activating biological programs that have lain dormant since the embryo stage, as the lab of Whitehead Member Robert Weinberg has helped to demonstrate in recent years. Now scientists in the Weinberg lab have shown that both normal and cancer cells that are induced to follow one of these pathways may gain properties of adult stem cells, including the ability to self-renew.
In a paper published online by Cell former postdoctoral researcher Sendurai Mani and his colleagues demonstrated in mice and in human cells that cells that have undergone an "epithelial-to-mesenchymal" (EMT) transition acquire several important characteristics of stem cells. Conversely, the researchers also showed that naturally existing normal stem cells as well as tumor-seeding cancer stem cells show characteristics of the post-EMT cells, including the acquisition of mesenchymal cell traits, which are usually associated with connective tissue cells.
Epithelial cells, which make up most of the human body, bind together in sheet-like structures. In embryonic development, the EMT process breaks up cell-cell adhesion in the epithelial layer, and converts epithelial cells into more loosely associated mesenchymal cells. In the context of cancer development, some cancer cells within a primary cancer may undergo an EMT, migrate through the body to their end destination, and there resume their epithelial form through a reverse process (the mesenchymal-to-epithelial transition).
Mani and his colleagues have identified FOXC2, one of the key genes involved in invasion and metastasis. In addition, FOXC2 appears to program the metastatic ability of some breast cancers.
Mani knew that during embryonic development, FOXC2 expression is restricted to mesoderm and mesoderm-derived cells when they are in an undifferentiated state, and its expression disappears once these cells differentiate. Similarly, his experiments showed that epithelial cells that undergo EMT express FOXC2, but that expression is lost when they revert back to an epithelial state.
In collaboration with Andrea Richardson and Jeffery Kutok, pathologists at Boston's Brigham and Women's Hospital, Mani went on to study FOXC2 expression in normal human breast tissue. It turned out that such cells were located precisely where researchers expect to find mammary epithelial stem cells.
As he pondered these findings and the earlier results about FOXC2's role in metastasis, Mani wondered: Just what were these cells generated by EMT that expressed FOXC2"
Were they simply fibroblasts, the most common cells in normal connective tissue" Or were they actually stem cells"
"I asked Mai-Jing Liao, another postdoc in the Weinberg lab, to check whether the cells generated by EMT would have any stem cell properties," recalls Mani, now an assistant professor in the department of molecular pathology at the University of Texas's M. D. Anderson Cancer Center in Houston. "He said, 'You must be out of your mind, but it won't take more than half an hour to check.'"
Much to Liao's surprise, when he examined cells that had undergo an EMT, his tests did highlight surface proteins that are key markers for stem cells.
The researchers found that the cells that underwent the EMT process were mesenchymal-like in appearance and demonstrated stem-cell surface markers. The cells also displayed an increased ability to grow in suspension, forming structures called mammospheres - another trait of mammary stem cells. Some cells in the resulting mammospheres showed, in turn, stem cell markers, indicating they could differentiate into two kinds of mammary cells. And cells in the mammospheres retained their stem cell properties even after the EMT induction process was stopped.
Furthermore, when the Weinberg lab scientists isolated stem-cell-like cells from cultured human mammary epithelial cells or from mouse breast tissue, their properties were very similar to the EMT-induced cells. Working with Kornelia Polyak of Dana-Farber Cancer Institute and Harvard Medical School, Mani found that this was also true with normal and tumor cells obtained from human patients.
"This for us is a very exciting discovery, not only because of its unexpectedness but because it offers a route by which one could in principle generate unlimited numbers of stem cells committed to create a specific cell type," says Weinberg, who is also a professor of biology at Massachusetts Institute of Technology. "One could imagine, for example, that if one takes skin cells and induces them to undergo an EMT, they could become skin stem cells."
Importantly, the researchers also demonstrated that inducing the EMT process can produce cells with many characteristics of cancer stem cells. (Beginning in 2003, scientists in various labs have identified these self-renewing, tumor-seeding cells in a number of solid tumors.)
This finding could help to answer a key question about metastasis: When tumor cells spread into different sites, how do they multiply enough to form a dangerous new tumor"
"If you take a population of human cancer cells that normally form a tumor very inefficiently and induce an EMT, their tumor-initiating abilities increase by about a hundred-fold, so that it takes about 10,000 cells rather than a million cells to form a tumor," says Wenjun Guo, co-lead author on the paper and postdoctoral researcher in the Weinberg lab. "This suggests cancer stem cells are using pre-existing normal stem cell machinery to propagate their own self-renewal and therefore their tumor-initiating ability."
Mani is continuing his research on the EMT/cancer stem cell connection and its role in cancer metastasis at the M. D. Anderson Cancer Center. Researchers in the Weinberg lab will investigate the EMT process with other cell lines. They also will attempt to give final proof in mice that the process creates completely defined stem cells, by taking cells from mouse mammary fat pads, inducing an EMT for some of the cells, returning the resulting cells to the fat pad, and seeing if they can regenerate the mammary gland.
This research was supported by the Breast Cancer Research Foundation, the MIT Ludwig Center for Molecular Oncology and the National Cancer Institute. Mani was supported by a Department of Defense postdoctoral fellowship.
Full citation:
Cell/, online publication May 15, Print Edition, Volume 133 (4)
"The epithelial-mesenchymal transition generates cells with properties of stem cells"
Sendurai A. Mani (1,3,9,10), Wenjun Guo (1,9), Mai-Jing Liao (1,9), Elinor Ng Eaton (1), Ayyakkannu Ayyanan (4), Alicia Zhou (1), Mary Brooks (1), Ferenc Reinhard (1), Cheng Cheng Zhang (1), Michail Shipitsin (5,6), Lauren L. Campbell (5,7), Kornelia Polyak (5,6,7), Cathrin Brisken(4), Jing Yang (1,8), Robert A. Weinberg (1,2,).
1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142
2. Department of Biology and MIT Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge MA 02139
3. Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, 7435 Fannin St, Houston, TX 77054
4. Ecole polytechnique fГ©dГ©rale de Lausanne (EPFL) ISREC - Swiss Institute for Experimental Cancer Research, CH-1066, Epalinges, Switzerland
5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
6. Department of Medicine, Harvard Medical School, Boston, MA 02115
7. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115
8. Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0636
9. These authors contributed equally to this work
Source: Cristin Carr
Whitehead Institute for Biomedical Research
Some cancer cells acquire the ability to migrate through the body by re-activating biological programs that have lain dormant since the embryo stage, as the lab of Whitehead Member Robert Weinberg has helped to demonstrate in recent years. Now scientists in the Weinberg lab have shown that both normal and cancer cells that are induced to follow one of these pathways may gain properties of adult stem cells, including the ability to self-renew.
In a paper published online by Cell former postdoctoral researcher Sendurai Mani and his colleagues demonstrated in mice and in human cells that cells that have undergone an "epithelial-to-mesenchymal" (EMT) transition acquire several important characteristics of stem cells. Conversely, the researchers also showed that naturally existing normal stem cells as well as tumor-seeding cancer stem cells show characteristics of the post-EMT cells, including the acquisition of mesenchymal cell traits, which are usually associated with connective tissue cells.
Epithelial cells, which make up most of the human body, bind together in sheet-like structures. In embryonic development, the EMT process breaks up cell-cell adhesion in the epithelial layer, and converts epithelial cells into more loosely associated mesenchymal cells. In the context of cancer development, some cancer cells within a primary cancer may undergo an EMT, migrate through the body to their end destination, and there resume their epithelial form through a reverse process (the mesenchymal-to-epithelial transition).
Mani and his colleagues have identified FOXC2, one of the key genes involved in invasion and metastasis. In addition, FOXC2 appears to program the metastatic ability of some breast cancers.
Mani knew that during embryonic development, FOXC2 expression is restricted to mesoderm and mesoderm-derived cells when they are in an undifferentiated state, and its expression disappears once these cells differentiate. Similarly, his experiments showed that epithelial cells that undergo EMT express FOXC2, but that expression is lost when they revert back to an epithelial state.
In collaboration with Andrea Richardson and Jeffery Kutok, pathologists at Boston's Brigham and Women's Hospital, Mani went on to study FOXC2 expression in normal human breast tissue. It turned out that such cells were located precisely where researchers expect to find mammary epithelial stem cells.
As he pondered these findings and the earlier results about FOXC2's role in metastasis, Mani wondered: Just what were these cells generated by EMT that expressed FOXC2"
Were they simply fibroblasts, the most common cells in normal connective tissue" Or were they actually stem cells"
"I asked Mai-Jing Liao, another postdoc in the Weinberg lab, to check whether the cells generated by EMT would have any stem cell properties," recalls Mani, now an assistant professor in the department of molecular pathology at the University of Texas's M. D. Anderson Cancer Center in Houston. "He said, 'You must be out of your mind, but it won't take more than half an hour to check.'"
Much to Liao's surprise, when he examined cells that had undergo an EMT, his tests did highlight surface proteins that are key markers for stem cells.
The researchers found that the cells that underwent the EMT process were mesenchymal-like in appearance and demonstrated stem-cell surface markers. The cells also displayed an increased ability to grow in suspension, forming structures called mammospheres - another trait of mammary stem cells. Some cells in the resulting mammospheres showed, in turn, stem cell markers, indicating they could differentiate into two kinds of mammary cells. And cells in the mammospheres retained their stem cell properties even after the EMT induction process was stopped.
Furthermore, when the Weinberg lab scientists isolated stem-cell-like cells from cultured human mammary epithelial cells or from mouse breast tissue, their properties were very similar to the EMT-induced cells. Working with Kornelia Polyak of Dana-Farber Cancer Institute and Harvard Medical School, Mani found that this was also true with normal and tumor cells obtained from human patients.
"This for us is a very exciting discovery, not only because of its unexpectedness but because it offers a route by which one could in principle generate unlimited numbers of stem cells committed to create a specific cell type," says Weinberg, who is also a professor of biology at Massachusetts Institute of Technology. "One could imagine, for example, that if one takes skin cells and induces them to undergo an EMT, they could become skin stem cells."
Importantly, the researchers also demonstrated that inducing the EMT process can produce cells with many characteristics of cancer stem cells. (Beginning in 2003, scientists in various labs have identified these self-renewing, tumor-seeding cells in a number of solid tumors.)
This finding could help to answer a key question about metastasis: When tumor cells spread into different sites, how do they multiply enough to form a dangerous new tumor"
"If you take a population of human cancer cells that normally form a tumor very inefficiently and induce an EMT, their tumor-initiating abilities increase by about a hundred-fold, so that it takes about 10,000 cells rather than a million cells to form a tumor," says Wenjun Guo, co-lead author on the paper and postdoctoral researcher in the Weinberg lab. "This suggests cancer stem cells are using pre-existing normal stem cell machinery to propagate their own self-renewal and therefore their tumor-initiating ability."
Mani is continuing his research on the EMT/cancer stem cell connection and its role in cancer metastasis at the M. D. Anderson Cancer Center. Researchers in the Weinberg lab will investigate the EMT process with other cell lines. They also will attempt to give final proof in mice that the process creates completely defined stem cells, by taking cells from mouse mammary fat pads, inducing an EMT for some of the cells, returning the resulting cells to the fat pad, and seeing if they can regenerate the mammary gland.
This research was supported by the Breast Cancer Research Foundation, the MIT Ludwig Center for Molecular Oncology and the National Cancer Institute. Mani was supported by a Department of Defense postdoctoral fellowship.
Full citation:
Cell/, online publication May 15, Print Edition, Volume 133 (4)
"The epithelial-mesenchymal transition generates cells with properties of stem cells"
Sendurai A. Mani (1,3,9,10), Wenjun Guo (1,9), Mai-Jing Liao (1,9), Elinor Ng Eaton (1), Ayyakkannu Ayyanan (4), Alicia Zhou (1), Mary Brooks (1), Ferenc Reinhard (1), Cheng Cheng Zhang (1), Michail Shipitsin (5,6), Lauren L. Campbell (5,7), Kornelia Polyak (5,6,7), Cathrin Brisken(4), Jing Yang (1,8), Robert A. Weinberg (1,2,).
1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142
2. Department of Biology and MIT Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge MA 02139
3. Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, 7435 Fannin St, Houston, TX 77054
4. Ecole polytechnique fГ©dГ©rale de Lausanne (EPFL) ISREC - Swiss Institute for Experimental Cancer Research, CH-1066, Epalinges, Switzerland
5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
6. Department of Medicine, Harvard Medical School, Boston, MA 02115
7. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115
8. Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0636
9. These authors contributed equally to this work
Source: Cristin Carr
Whitehead Institute for Biomedical Research
вторник, 20 сентября 2011 г.
New 'test tubes' far smaller than the width of a hair
Using a water droplet 1 trillion times smaller than a liter of club soda as a sort of nanoscale test tube, a University of Washington scientist is conducting chemical analysis and experimentation at unprecedented tiny scales.
The method captures a single cell, or even a small subcellular structure called an organelle, within a droplet. It then employs a powerful laser microscope to study the contents and examine chemical processes, and a laser beam is used to manipulate the cell or even just a few molecules, combining them with other molecules to form new substances.
This nanoscale "laboratory" is so minuscule that it covers just 1 percent of the width of a human hair, said Daniel Chiu, a UW associate chemistry professor who is developing the unique method.
"Anything you can do in the test tube we hope to be able to do in the droplet. We just don't need a lot of cells. We don't even need one cell, just a few molecules," Chiu said.
The new approach makes it easier to get a wide range of information about a cell. Researchers typically use microscopy to see how proteins move within a cell and collect spatial information, but that provides very little biochemical information, Chiu said. Likewise, they can use large amounts of material in a test tube to understand biochemical processes, but that doesn't provide the fine detail of microscopy.
"The cell is very small but it is very complex," Chiu said. "It has many hundreds of thousands of proteins. It is probably the ultimate nanomachine."
The new method, employing a process called microfluidics, allows researchers to perform chemical analysis and to study structure and form at the same time.
The tiny droplet is contained in a microfluidic device, which is far too small to be seen with the naked eye and is mounted on a platform about the size of a dime so researchers can carry it from one place to another. The device has water in one channel and oil in an adjoining channel. The target - a cell, an organelle or just a few molecules - is placed at the interface between the oil and water using a laser beam, so the target is encapsulated as the water droplet is formed.
Once the droplet captures its target, it is held fast while researchers use lasers to manipulate it and conduct analysis and experimentation.
"If you have 10 molecules that you're interested in, you can combine those with other molecules to make new molecules," Chiu said. "You can control their reactivity, move them and combine them if they are confined in a droplet. As soon as you put them in a test tube, they're diffused and you lose the ability to see them."
Chiu presents his work Monday during a session of the American Chemical Society's fall meeting in Washington, D.C.
The new method allows researchers to address specific biological questions that cannot be answered by testing in large quantities in the test tube, such as how organelles within a cell differ from each other, or how different proteins are expressed within the same cell, Chiu said.
"At this point it is still limited to fundamental biological studies," he said. "It provides finer, higher resolution than working with standard test tubes. There are things you cannot find out in bulk, and every cell and organelle is different."
Currently Chiu is focused on continuing development of the process, essentially creating a nanoscale test tube. But he believes the process holds great promise for future chemical and biological research.
"We're still trying to develop the process and to understand the chemistry at this small scale, which could be very different from chemistry at the macro scale," he said.
For more information, contact Chiu at (206) 543-1655 or chiuchem.washington
Vince Stricherz
vincesu.washington
206-543-2580
University of Washington
uwnews
The method captures a single cell, or even a small subcellular structure called an organelle, within a droplet. It then employs a powerful laser microscope to study the contents and examine chemical processes, and a laser beam is used to manipulate the cell or even just a few molecules, combining them with other molecules to form new substances.
This nanoscale "laboratory" is so minuscule that it covers just 1 percent of the width of a human hair, said Daniel Chiu, a UW associate chemistry professor who is developing the unique method.
"Anything you can do in the test tube we hope to be able to do in the droplet. We just don't need a lot of cells. We don't even need one cell, just a few molecules," Chiu said.
The new approach makes it easier to get a wide range of information about a cell. Researchers typically use microscopy to see how proteins move within a cell and collect spatial information, but that provides very little biochemical information, Chiu said. Likewise, they can use large amounts of material in a test tube to understand biochemical processes, but that doesn't provide the fine detail of microscopy.
"The cell is very small but it is very complex," Chiu said. "It has many hundreds of thousands of proteins. It is probably the ultimate nanomachine."
The new method, employing a process called microfluidics, allows researchers to perform chemical analysis and to study structure and form at the same time.
The tiny droplet is contained in a microfluidic device, which is far too small to be seen with the naked eye and is mounted on a platform about the size of a dime so researchers can carry it from one place to another. The device has water in one channel and oil in an adjoining channel. The target - a cell, an organelle or just a few molecules - is placed at the interface between the oil and water using a laser beam, so the target is encapsulated as the water droplet is formed.
Once the droplet captures its target, it is held fast while researchers use lasers to manipulate it and conduct analysis and experimentation.
"If you have 10 molecules that you're interested in, you can combine those with other molecules to make new molecules," Chiu said. "You can control their reactivity, move them and combine them if they are confined in a droplet. As soon as you put them in a test tube, they're diffused and you lose the ability to see them."
Chiu presents his work Monday during a session of the American Chemical Society's fall meeting in Washington, D.C.
The new method allows researchers to address specific biological questions that cannot be answered by testing in large quantities in the test tube, such as how organelles within a cell differ from each other, or how different proteins are expressed within the same cell, Chiu said.
"At this point it is still limited to fundamental biological studies," he said. "It provides finer, higher resolution than working with standard test tubes. There are things you cannot find out in bulk, and every cell and organelle is different."
Currently Chiu is focused on continuing development of the process, essentially creating a nanoscale test tube. But he believes the process holds great promise for future chemical and biological research.
"We're still trying to develop the process and to understand the chemistry at this small scale, which could be very different from chemistry at the macro scale," he said.
For more information, contact Chiu at (206) 543-1655 or chiuchem.washington
Vince Stricherz
vincesu.washington
206-543-2580
University of Washington
uwnews
суббота, 17 сентября 2011 г.
How Cancer Cells Survive A Chemotherapy Drug
What separates the few cancer cells that survive chemotherapy - leaving the door open to recurrence - from those that don't? Weizmann Institute scientists developed an original method for imaging and analyzing many thousands of living cells to reveal exactly how a chemotherapy drug affects each one.
For research student Ariel Cohen, together with Naama Geva-Zatorsky and Eran Eden in the lab of Prof. Uri Alon of the Institute's Molecular Cell Biology Department, the question posed an interesting challenge. To approach it, they needed a method that would allow them to cast a wide net on the one hand - to sift through the numerous cellular proteins that could conceivably affect survival - but that would let them zoom in on the activities of individual cells in detail, on the other. Letting the computer take over the painstaking work of searching for anomalies enabled the team to look at the behavior of over 1000 different proteins. Even so, it took several years to complete the project, which entailed tagging the specific proteins in each group of cancer cells with a fluorescent gene and capturing a series of time-lapse images over 72 hours. A second, fainter fluorescent marker was added to outline the cells, so the computer could identify them. A chemotherapy drug was introduced 24 hours into this period, after which the cells began the process of either dying or defending themselves against the drug.
The team's efforts have produced a comprehensive library of tagged cells, images and data on cancer cell proteins - a virtual goldmine of ready material for further cancer research. And they succeeded in pinpointing two proteins that seem to play a role in cancer cell survival.
Although most of the proteins behaved similarly in all the cells, the researchers found that a small subset of them - around five percent - could act unpredictably, even when the cells and drug exposure were identical. The scientists called these proteins bimodal, as they acted in one of two ways.
The team then asked whether any of the bimodal proteins they had identified were those that occasionally promote cell survival. They found two molecules that seem to fit the bill. One of them, known by the letters DDX5, is a multitasking protein that, among other things, plays a role in initiating the production of other proteins. The other, RFC1, also plays varied roles, including directing the repair of damaged DNA. When the researchers blocked the production of these proteins in the cancer cells, the drug became much more efficient at wiping out the growth.
Cohen: 'This method gave us tremendous insight into how a cell responds to a drug. By conducting an unbiased study - we started with no preconceived notions of which proteins were involved - we were able to pinpoint possible new drug targets and to see how certain activities might boost the effectiveness of current drugs.'
Prof. Uri Alon's research is supported by the Kahn Family Foundation for Humanitarian Support and Keren Isra - Pa'amei Tikva.
For the scientific paper, please see: sciencemag/cgi/reprint/322/5907/1511.pdf
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Source: Yivsam Azgad
Weizmann Institute of Science
For research student Ariel Cohen, together with Naama Geva-Zatorsky and Eran Eden in the lab of Prof. Uri Alon of the Institute's Molecular Cell Biology Department, the question posed an interesting challenge. To approach it, they needed a method that would allow them to cast a wide net on the one hand - to sift through the numerous cellular proteins that could conceivably affect survival - but that would let them zoom in on the activities of individual cells in detail, on the other. Letting the computer take over the painstaking work of searching for anomalies enabled the team to look at the behavior of over 1000 different proteins. Even so, it took several years to complete the project, which entailed tagging the specific proteins in each group of cancer cells with a fluorescent gene and capturing a series of time-lapse images over 72 hours. A second, fainter fluorescent marker was added to outline the cells, so the computer could identify them. A chemotherapy drug was introduced 24 hours into this period, after which the cells began the process of either dying or defending themselves against the drug.
The team's efforts have produced a comprehensive library of tagged cells, images and data on cancer cell proteins - a virtual goldmine of ready material for further cancer research. And they succeeded in pinpointing two proteins that seem to play a role in cancer cell survival.
Although most of the proteins behaved similarly in all the cells, the researchers found that a small subset of them - around five percent - could act unpredictably, even when the cells and drug exposure were identical. The scientists called these proteins bimodal, as they acted in one of two ways.
The team then asked whether any of the bimodal proteins they had identified were those that occasionally promote cell survival. They found two molecules that seem to fit the bill. One of them, known by the letters DDX5, is a multitasking protein that, among other things, plays a role in initiating the production of other proteins. The other, RFC1, also plays varied roles, including directing the repair of damaged DNA. When the researchers blocked the production of these proteins in the cancer cells, the drug became much more efficient at wiping out the growth.
Cohen: 'This method gave us tremendous insight into how a cell responds to a drug. By conducting an unbiased study - we started with no preconceived notions of which proteins were involved - we were able to pinpoint possible new drug targets and to see how certain activities might boost the effectiveness of current drugs.'
Prof. Uri Alon's research is supported by the Kahn Family Foundation for Humanitarian Support and Keren Isra - Pa'amei Tikva.
For the scientific paper, please see: sciencemag/cgi/reprint/322/5907/1511.pdf
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Source: Yivsam Azgad
Weizmann Institute of Science
среда, 14 сентября 2011 г.
Humanized Mouse Infected With HIV Vaginally And Rectally Allows Testing
The "humanized mouse" developed by Dr. J. Victor Garcia-Martinez has allowed the University of Texas Southwestern physician-scientist to conduct HIV/AIDS studies that would have been impossible without such a small animal model of HIV infection. The virus only infects humans and chimpanzees, which are protected as endangered species.
But because the new mouse model is a chimera, with a human immune system, it can be infected. Last year, using these humanized mice, a team of scientists led by Dr. Garcia-Martinez demonstrated that antiretroviral drugs given before and after exposure to HIV could prevent vaginal transmission of the virus. That suggests the possibility that women at high risk of HIV infection might one day be able to take a pill on a regular basis. And, since the drugs tested are already available, having gone through the long and complex approval process, that day might be sooner rather than later.
On Sunday, April 19, Dr. Garcia-Martinez tells fellow scientists attending Experimental Biology 2009 in New Orleans that the team is now using the mouse model to obtain evidence that these same approaches apply to protecting men.
Dr. Garcia-Martinez's presentation, updating improvements in the humanized mouse and in the progress of this and other work using the mouse model of human HIV/AIDS infection, is part of the scientific program of the American Society for Biochemistry and Molecular Biology.
First created in 2006, by Dr. Garcia and colleagues at UT Southwestern and the University of Minnesota, the humanized mouse used in these studies represented a new frontier in the preclinical testing of experimental drugs. Early mice models of disease were created by breeding mice that were immunodeficient in order that they would not reject grafts of human tissue. The big advance in the mouse created by Dr. Garcia-Martinez's group is that the mouse develops a human immune system, thanks to transfer of fetal human liver and thymic tissue cells that repopulate the bone marrow, which produces more cells.
The problem with using animals other than humans and chimpanzees for HIV/AIDS studies had been that the other animals, including ordinary mice, never become infected even when exposed to massive amounts of the virus. But the Garcia-Martinez mouse model (called BLT for bone marrow-liver-thymus) can easily be infected with HIV by both rectal and vaginal transmission, since both areas of the mouse body contain human cells.
With a long term-goal to investigate novel approaches to prevent HIV transmission, the team began with male to female infection. Women are at higher risk of infection during heterosexual sex with an infected partner, and women worldwide account for more than half of the estimated 11,000 newly acquired infections every day, with a majority of those transmissions occurring via the vaginal route. However, says Dr. Garcia-Martinez, male to male sexual contact accounts for a high proportion of the HIV/AIDS cases in the United States and rates of such transmission continue to rise, despite extensive educational campaigns.
Dr. Garcia-Martinez believes these statistics clearly reflect an urgent need to devise and implement potential interventions that could prevent both vaginal and rectal HIV-1 transmission especially among high-risk populations. The humanized mouse model provides an increasingly effective tool to move in that direction.
Work in his laboratory is funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Source:
Sylvia Wrobel
Federation of American Societies for Experimental Biology
But because the new mouse model is a chimera, with a human immune system, it can be infected. Last year, using these humanized mice, a team of scientists led by Dr. Garcia-Martinez demonstrated that antiretroviral drugs given before and after exposure to HIV could prevent vaginal transmission of the virus. That suggests the possibility that women at high risk of HIV infection might one day be able to take a pill on a regular basis. And, since the drugs tested are already available, having gone through the long and complex approval process, that day might be sooner rather than later.
On Sunday, April 19, Dr. Garcia-Martinez tells fellow scientists attending Experimental Biology 2009 in New Orleans that the team is now using the mouse model to obtain evidence that these same approaches apply to protecting men.
Dr. Garcia-Martinez's presentation, updating improvements in the humanized mouse and in the progress of this and other work using the mouse model of human HIV/AIDS infection, is part of the scientific program of the American Society for Biochemistry and Molecular Biology.
First created in 2006, by Dr. Garcia and colleagues at UT Southwestern and the University of Minnesota, the humanized mouse used in these studies represented a new frontier in the preclinical testing of experimental drugs. Early mice models of disease were created by breeding mice that were immunodeficient in order that they would not reject grafts of human tissue. The big advance in the mouse created by Dr. Garcia-Martinez's group is that the mouse develops a human immune system, thanks to transfer of fetal human liver and thymic tissue cells that repopulate the bone marrow, which produces more cells.
The problem with using animals other than humans and chimpanzees for HIV/AIDS studies had been that the other animals, including ordinary mice, never become infected even when exposed to massive amounts of the virus. But the Garcia-Martinez mouse model (called BLT for bone marrow-liver-thymus) can easily be infected with HIV by both rectal and vaginal transmission, since both areas of the mouse body contain human cells.
With a long term-goal to investigate novel approaches to prevent HIV transmission, the team began with male to female infection. Women are at higher risk of infection during heterosexual sex with an infected partner, and women worldwide account for more than half of the estimated 11,000 newly acquired infections every day, with a majority of those transmissions occurring via the vaginal route. However, says Dr. Garcia-Martinez, male to male sexual contact accounts for a high proportion of the HIV/AIDS cases in the United States and rates of such transmission continue to rise, despite extensive educational campaigns.
Dr. Garcia-Martinez believes these statistics clearly reflect an urgent need to devise and implement potential interventions that could prevent both vaginal and rectal HIV-1 transmission especially among high-risk populations. The humanized mouse model provides an increasingly effective tool to move in that direction.
Work in his laboratory is funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Source:
Sylvia Wrobel
Federation of American Societies for Experimental Biology
воскресенье, 11 сентября 2011 г.
ECCO Urges MEPs To Think Of Patients' Interests When They Vote On A Review Of A Directive On The Protection Of Animals Used For Scientific Purposes
The European CanCer Organisation - has urged members of the European Parliament not to forget the interests of patients when they take a crucial vote on amendments to the EU Directive on the protection of animals used for scientific purposes (Review of Directive 86/609/EEC).
President of ECCO, Professor Alexander M.M. Eggermont, has written to the members of the European Parliament Agriculture Committee, who will be voting on the issue tomorrow, highlighting ECCO's concerns about several of the amendments that are being proposed.
"ECCO's primary mission is to improve human health, and to win the fight against cancer. We hope that MEPs will not forget this in their understandable desire to protect laboratory animals," writes Prof Eggermont. "We would like to point out that some of the contents of the revised Directive, as well as some amendments proposed by Committee members, could affect the lives of millions of European cancer patients in the years to come.
"We are particularly concerned about two areas:
- the proposed restrictions of the use of non-human primates in medical research
- amendments which would severely limit, if not stop entirely, essential medical research, making the administrative procedures hugely cumbersome
"Because non-human primates are our nearest animal 'relation', their use in medical research is a difficult issue which raises considerable moral concerns. However, there are areas where their use is essential. The Directive proposal to limit the use of primates to research that 'is undertaken with a view to the avoidance, prevention, diagnosis or treatment of life-threatening or debilitating clinical conditions in human beings' may prevent these animals being used in some areas of fundamental research where the primary aim is to gain new knowledge. It is not always possible to demonstrate the relevance of such knowledge to particular diseases or conditions at the time the work is proposed.
"Perhaps most worrying of all are several amendments which, if passed, would raise the regulatory hurdles so high that it seems likely that essential research could be held up for years. Introducing such lengthy administrative procedures will not improve animal welfare, but will greatly affect European medical research. We are particularly concerned about amendment 311, proposed by Mr [Neil] Parish, which calls for all applications for research projects involving animals to be subject to public consultation, in order that regulatory authorities may have 'access to the widest range of views on which to base decisions'. While this may seem as though it will bring about a welcome increase in transparency, medical researchers know from experience that the vast majority of views transmitted will come through organised write-in campaigns from animal rights groups, and collecting and collating them all will add months to the already lengthy process of authorisation.
"On behalf of European patients, doctors, and researchers, we ask you most sincerely to allow us to continue to work to reduce the burden of cancer and not to put unnecessary barriers in our way," concludes Prof Eggermont.
Notes
ECCO - the European CanCer Organisation - exists to uphold the right of all European cancer patients to the best possible treatment and care and to promote interaction between all organisations involved in cancer research, education, treatment and care at the European level
Source
European CanCer Organisation
President of ECCO, Professor Alexander M.M. Eggermont, has written to the members of the European Parliament Agriculture Committee, who will be voting on the issue tomorrow, highlighting ECCO's concerns about several of the amendments that are being proposed.
"ECCO's primary mission is to improve human health, and to win the fight against cancer. We hope that MEPs will not forget this in their understandable desire to protect laboratory animals," writes Prof Eggermont. "We would like to point out that some of the contents of the revised Directive, as well as some amendments proposed by Committee members, could affect the lives of millions of European cancer patients in the years to come.
"We are particularly concerned about two areas:
- the proposed restrictions of the use of non-human primates in medical research
- amendments which would severely limit, if not stop entirely, essential medical research, making the administrative procedures hugely cumbersome
"Because non-human primates are our nearest animal 'relation', their use in medical research is a difficult issue which raises considerable moral concerns. However, there are areas where their use is essential. The Directive proposal to limit the use of primates to research that 'is undertaken with a view to the avoidance, prevention, diagnosis or treatment of life-threatening or debilitating clinical conditions in human beings' may prevent these animals being used in some areas of fundamental research where the primary aim is to gain new knowledge. It is not always possible to demonstrate the relevance of such knowledge to particular diseases or conditions at the time the work is proposed.
"Perhaps most worrying of all are several amendments which, if passed, would raise the regulatory hurdles so high that it seems likely that essential research could be held up for years. Introducing such lengthy administrative procedures will not improve animal welfare, but will greatly affect European medical research. We are particularly concerned about amendment 311, proposed by Mr [Neil] Parish, which calls for all applications for research projects involving animals to be subject to public consultation, in order that regulatory authorities may have 'access to the widest range of views on which to base decisions'. While this may seem as though it will bring about a welcome increase in transparency, medical researchers know from experience that the vast majority of views transmitted will come through organised write-in campaigns from animal rights groups, and collecting and collating them all will add months to the already lengthy process of authorisation.
"On behalf of European patients, doctors, and researchers, we ask you most sincerely to allow us to continue to work to reduce the burden of cancer and not to put unnecessary barriers in our way," concludes Prof Eggermont.
Notes
ECCO - the European CanCer Organisation - exists to uphold the right of all European cancer patients to the best possible treatment and care and to promote interaction between all organisations involved in cancer research, education, treatment and care at the European level
Source
European CanCer Organisation
четверг, 8 сентября 2011 г.
Gene In Breast Cancer Pathway Identified
Scientists at Albert Einstein College of Medicine of Yeshiva University have discovered how a gene crucial in triggering the spread of breast cancer is turned on and off. The findings could help predict whether breast tumors will metastasize and also reveal potential drug targets for preventing metastasis. The study will appear in the May 20th online edition of the Journal of Cell Science.
A few years ago, Einstein scientists discovered a gene called ZBP1 (zipcode binding protein 1), which helps cells to move, grow and organize spatially. "ZBP1 is very active in the developing embryo but largely silent in adult tissues," says Robert H. Singer, Ph.D., professor and co-chair of anatomy and structural biology and co-director of the Gruss-Lipper Biophotonics Center at Einstein. He is one of ZBP1's discoverers and leader of the current study.
Researchers have subsequently found that ZBP1 is reactivated in several types of cancer, including breast, colorectal, and non-small cell lung cancers; but the gene is silenced in metastasizing cancer cells, as was shown by Dr. Singer and another Einstein scientist, John Condeelis, Ph.D., who also is co-chair of anatomy and structural biology and co-director of the Gruss-Lipper Biophotonics Center at Einstein. The purpose of the current study was to find how the ZBP1 gene is activated and silenced and how it influences the spread of breast cancer.
After examining mouse, rat, and human breast cancer cells, Dr. Singer and his team found that ZBP1 silencing occurs when a methyl group (CH3) attaches to ZBP1's promoter region (the segment of a gene where gene expression is initiated). The attachment of CH3 prevents the promoter from binding to a protein called beta-catenin. And without beta-catenin, the ZBP1 gene is effectively silenced.
The study also showed that the silencing of ZBP1 increases cancer cells' ability to migrate and promotes the proliferation of metastatic cells.
The findings have important implications for forecasting breast cancer outcomes. According to the researchers, signs of ZBP1 silencing in breast cancer cells would indicate that a breast tumor is likely to spread - information that would help in choosing a treatment strategy.
The study also points to potential targets for drug treatment. "If you could turn on this protein in cancer cells, or prevent it from being turned off, you could seriously reduce the ability of the cells to metastasize," says Dr. Singer.
The research team is investigating whether the ZBP1 gene in cancer cells could be reactivated - and the cells prevented from metastasizing - by selectively removing CH3 from the ZBP1 promoter.
The paper, "Increased proliferation and migration of breast metastatic cells results from ZBP1 repression by blocking beta-catenin promoter binding," is published in the May 20, 2009, online edition of the Journal of Cell Science. Wei Gu, M.D., Ph.D., instructor in anatomy and structural biology at Einstein, is the lead author. Feng Pan, Ph.D., now at NYU School of Medicine, is a co-author.
Source:
Deirdre Branley
Albert Einstein College of Medicine
A few years ago, Einstein scientists discovered a gene called ZBP1 (zipcode binding protein 1), which helps cells to move, grow and organize spatially. "ZBP1 is very active in the developing embryo but largely silent in adult tissues," says Robert H. Singer, Ph.D., professor and co-chair of anatomy and structural biology and co-director of the Gruss-Lipper Biophotonics Center at Einstein. He is one of ZBP1's discoverers and leader of the current study.
Researchers have subsequently found that ZBP1 is reactivated in several types of cancer, including breast, colorectal, and non-small cell lung cancers; but the gene is silenced in metastasizing cancer cells, as was shown by Dr. Singer and another Einstein scientist, John Condeelis, Ph.D., who also is co-chair of anatomy and structural biology and co-director of the Gruss-Lipper Biophotonics Center at Einstein. The purpose of the current study was to find how the ZBP1 gene is activated and silenced and how it influences the spread of breast cancer.
After examining mouse, rat, and human breast cancer cells, Dr. Singer and his team found that ZBP1 silencing occurs when a methyl group (CH3) attaches to ZBP1's promoter region (the segment of a gene where gene expression is initiated). The attachment of CH3 prevents the promoter from binding to a protein called beta-catenin. And without beta-catenin, the ZBP1 gene is effectively silenced.
The study also showed that the silencing of ZBP1 increases cancer cells' ability to migrate and promotes the proliferation of metastatic cells.
The findings have important implications for forecasting breast cancer outcomes. According to the researchers, signs of ZBP1 silencing in breast cancer cells would indicate that a breast tumor is likely to spread - information that would help in choosing a treatment strategy.
The study also points to potential targets for drug treatment. "If you could turn on this protein in cancer cells, or prevent it from being turned off, you could seriously reduce the ability of the cells to metastasize," says Dr. Singer.
The research team is investigating whether the ZBP1 gene in cancer cells could be reactivated - and the cells prevented from metastasizing - by selectively removing CH3 from the ZBP1 promoter.
The paper, "Increased proliferation and migration of breast metastatic cells results from ZBP1 repression by blocking beta-catenin promoter binding," is published in the May 20, 2009, online edition of the Journal of Cell Science. Wei Gu, M.D., Ph.D., instructor in anatomy and structural biology at Einstein, is the lead author. Feng Pan, Ph.D., now at NYU School of Medicine, is a co-author.
Source:
Deirdre Branley
Albert Einstein College of Medicine
понедельник, 5 сентября 2011 г.
An Advance On New Generations Of Chemotherapy And Antiviral Drugs
Researchers are describing progress toward developing a new generation of chemotherapy agents that target and block uncontrolled DNA replication - a hallmark of cancer, viral infections, and other diseases - more effectively than current drugs in ways that may produce fewer side effects. Their article is scheduled for the Aug. 27 issue of ACS' Biochemistry, a weekly journal.
In the article, Anthony J. Berdis updates and reviews worldwide research efforts to develop drugs that target DNA polymerases, the enzymes responsible for assembling DNA from its component parts. Several promising strategies are already in use that inhibit uncontrolled DNA replication, particularly in anticancer therapy, but most produce severe side effects and are hampered by drug resistance, the researcher notes.
Berdis says that one of the more promising strategies to date involves the use of so-called nucleoside analogues, artificial pieces of DNA that inhibit replication by substituting for natural segments. Most nucleoside analogues directly target the active site of the polymerase enzyme, a non-specific approach that can also harm healthy cells which contain the enzyme. Berdis describes an alternative approach in which the drugs directly target damaged DNA while avoiding healthy DNA, side-stepping the polymerase enzymes of normal cells. The development, which shows promise in preliminary lab studies, could lead to improved nucleoside analogues with fewer side effects, he says. - MTS
"DNA Polymerases as Therapeutic Targets"
Biochemistry, 47 (32), 8253 - 8260, 2008. 10.1021/bi801179f
Download Full Text Article
American Chemical Society
In the article, Anthony J. Berdis updates and reviews worldwide research efforts to develop drugs that target DNA polymerases, the enzymes responsible for assembling DNA from its component parts. Several promising strategies are already in use that inhibit uncontrolled DNA replication, particularly in anticancer therapy, but most produce severe side effects and are hampered by drug resistance, the researcher notes.
Berdis says that one of the more promising strategies to date involves the use of so-called nucleoside analogues, artificial pieces of DNA that inhibit replication by substituting for natural segments. Most nucleoside analogues directly target the active site of the polymerase enzyme, a non-specific approach that can also harm healthy cells which contain the enzyme. Berdis describes an alternative approach in which the drugs directly target damaged DNA while avoiding healthy DNA, side-stepping the polymerase enzymes of normal cells. The development, which shows promise in preliminary lab studies, could lead to improved nucleoside analogues with fewer side effects, he says. - MTS
"DNA Polymerases as Therapeutic Targets"
Biochemistry, 47 (32), 8253 - 8260, 2008. 10.1021/bi801179f
Download Full Text Article
American Chemical Society
пятница, 2 сентября 2011 г.
Do Angry Men Get Noticed?
By comparing how quickly human facial expressions of different types are detected in a crowd of neutral faces, researchers have demonstrated that male angry faces are a priority for visual processing - particularly for male observers. The findings are reported by Mark Williams of the Massachusetts Institute of Technology and Jason Mattingley of the University of Melbourne, Australia, and appear in the June 6th issue of Current Biology.
In evolutionary terms, it makes sense that our attention is attracted by threat in the environment. It has long been hypothesized that facial expressions that signal potential threat, such as anger, may capture attention and therefore "stand out" in a crowd. In fact, there are specific brain regions that are dedicated to processing threatening facial expressions. Given the many differences between males and females, with males being larger and more physically aggressive than females, one might also suspect differences in the way in which threat is detected from individuals of different genders.
In the new work, Williams and Mattingley show that angry male faces are found more rapidly than angry female faces by both men and women. In addition, men find angry faces of both genders faster than women, whereas women find socially relevant expressions (for example, happy or sad) more rapidly. The work suggests that although males are biased toward detecting threatening faces, and females are more attuned to socially relevant expressions, both sexes prioritize the detection of angry male faces; in short, angry men get noticed. The advantage for detecting angry male faces is consistent with the notion that human perceptual processes have been shaped by evolutionary pressures arising from the social environment.
Heidi Hardman
hhardmancell
Cell Press
cellpress/
In evolutionary terms, it makes sense that our attention is attracted by threat in the environment. It has long been hypothesized that facial expressions that signal potential threat, such as anger, may capture attention and therefore "stand out" in a crowd. In fact, there are specific brain regions that are dedicated to processing threatening facial expressions. Given the many differences between males and females, with males being larger and more physically aggressive than females, one might also suspect differences in the way in which threat is detected from individuals of different genders.
In the new work, Williams and Mattingley show that angry male faces are found more rapidly than angry female faces by both men and women. In addition, men find angry faces of both genders faster than women, whereas women find socially relevant expressions (for example, happy or sad) more rapidly. The work suggests that although males are biased toward detecting threatening faces, and females are more attuned to socially relevant expressions, both sexes prioritize the detection of angry male faces; in short, angry men get noticed. The advantage for detecting angry male faces is consistent with the notion that human perceptual processes have been shaped by evolutionary pressures arising from the social environment.
Heidi Hardman
hhardmancell
Cell Press
cellpress/
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