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Simple Chemical Cocktail Shows First Promise for Limb Re-Growth in MammalsScienceDaily (Apr. 6, 2011) — Move over, newts and salamanders. The mouse may join you as the only animal that can re-grow their own severed limbs. Researchers are reporting that a simple chemical cocktail can coax mouse muscle fibers to become the kinds of cells found in the first stages of a regenerating limb.Their study, the first demonstration that mammal muscle can be turned into the biological raw material for a new limb, appears in the journal ACS Chemical Biology.Darren R. Williams and Da-Woon Jung say their "relatively simple, gentle, and reversible" methods for creating the early stages of limb regeneration in mouse cells "have implications for both regenerative medicine and stem cell biology." In the future, they suggest, the chemicals they use could speed wound healing by providing new cells at the injured site before the wound closes or becomes infected. Their methods might also shed light on new ways to switch adult cells into the all-purpose, so-called "pluripotent," stem cells with the potential for growing into any type of tissue in the body.The scientists describe the chemical cocktail that they developed and used to turn mouse muscle fibers into muscle cells. Williams and Jung then converted the muscle cells turned into fat and bone cells. Those transformations were remarkably similar to the initial processes that occur in the tissue of newts and salamanders that is starting to regrow severed limbs.
Scientists Turn Back the Clock On Adult Stem Cells AgingScienceDaily (Sep. 20, 2011) — Researchers have shown they can reverse the aging process for human adult stem cells, which are responsible for helping old or damaged tissues regenerate. The findings could lead to medical treatments that may repair a host of ailments that occur because of tissue damage as people age.A research group led by the Buck Institute for Research on Aging and the Georgia Institute of Technology conducted the study in cell culture, which appears in the September 1, 2011 edition of the journal Cell Cycle.The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. A research group led by the Buck Institute for Research on Aging in collaboration with the Georgia Institute of Technology, conducted the study that pinpoints what is going wrong with the biological clock underlying the limited division of human adult stem cells as they age."We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional 'genomic junk'," said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.Adult stem cells are important because they help keep human tissues healthy by replacing cells that have gotten old or damaged. They're also multipotent, which means that an adult stem cell can grow and replace any number of body cells in the tissue or organ they belong to. However, just as the cells in the liver, or any other organ, can get damaged over time, adult stem cells undergo age-related damage. And when this happens, the body can't replace damaged tissue as well as it once could, leading to a host of diseases and conditions. But if scientists can find a way to keep these adult stem cells young, they could possibly use these cells to repair damaged heart tissue after a heart attack; heal wounds; correct metabolic syndromes; produce insulin for patients with type 1 diabetes; cure arthritis and osteoporosis and regenerate bone.The team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. They thought so because body cells are known to experience a shortening of the caps found at the ends of chromosomes, known as telomeres. But adult stem cells are known to maintain their telomeres. Much of the damage in aging is widely thought to be a result of losing telomeres. So there must be different mechanisms at play that are key to explaining how aging occurs in these adult stem cells, they thought.Researchers used adult stem cells from humans and combined experimental techniques with computational approaches to study the changes in the genome associated with aging. They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups."We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons," said King Jordan, associate professor in the School of Biology at Georgia Tech."Retroransposons were previously thought to be non-functional and were even labeled as 'junk DNA', but accumulating evidence indicates these elements play an important role in genome regulation," he added.While the young adult stem cells were able to suppress transcriptional activity of these genomic elements and deal with the damage to the DNA, older adult stem cells were not able to scavenge this transcription. New discovery suggests that this event is deleterious for the regenerative ability of stem cells and triggers a process known as cellular senescence."By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture," said Lunyak."Furthermore, by rewinding the cellular clock in this way, we were not only able to rejuvenate 'aged' human stem cells, but to our surprise we were able to reset them to an earlier developmental stage, by up-regulating the "pluripotency factors" -- the proteins that are critically involved in the self-renewal of undifferentiated embryonic stem cells." she said.Next the team plans to use further analysis to validate the extent to which the rejuvenated stem cells may be suitable for clinical tissue regenerative applications.The study was conducted by a team with members from the Buck Institute for Research on Aging, the Georgia Institute of Technology, the University of California, San Diego, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, International Computer Science Institute, Applied Biosystems and Tel-Aviv University.
Removing Old Cells Could Extend Human LifeJennifer Welsh, LiveScience Staff WriterDate: 02 November 2011 Time: 02:00 PM Removal of specific cells that accumulate with age can delay or prevent the onset of age-related disorders, new research suggests. If adapted for humans, this intervention may represent an avenue for treating or delaying age-related diseases and improving healthy lifespan in humans.The old adage "Out with the old and in with the new" could help prevent age-related diseases if applied to certain cells, new research on mice suggests.By removing the body's worn-out cells, called senescent cells, several times during the lifetime of aging-accelerated mice, researchers were able to spare the mice of cataracts, aging skin and muscle loss."We started treating animals when they were really young, before they started to establish these senescent cells," study researcher Darren Baker, of the Mayo Clinic College of Medicine in Minnesota, told LiveScience. "As a cell became senescent we would remove it; we saw a really profound effect."Senescent cells These cells were once important contributors to their cellular community. Eventually cells get old and start showing signs of wear and tear that could lead to cancer, so the body essentially "turns them off." When cells get turned off in mammals (including humans and mice), they can take one of two paths, either dying off or sticking around in a senescent state.For some reason, the ones that stick around start pumping out odd proteins. These chemical signals have a strange impact on the cells around them, and researchers have speculated that these chemicals can lead to age-related diseases.The number of senescent cells increases as tissues age; at most they will make up 15 percent of cells in mammalian tissues, the researchers said.Still, "that small percent is enough to cause major consequences," Baker said. "They start to turn on a variety of genes that are not good and are thought to be detrimental to the overall function of the tissue."Out with the oldIn the new study, the team bred mice to age quickly, getting cataracts, weakened muscles and loss of fat deposits by the time they are 10 months old, when they die of heart disease.At the mice's 3-week birthdays, the researchers treated them with a drug that would cause their senescent cells to commit suicide, and they repeated this treatment every three days. Compared with the untreated mice that kept all their senescent cells, these drug-treated mice had stronger muscles, fewer cataracts and less wrinkled skin (because their fat deposits in their skin were in better shape).The researchers also let some of these mice grow up, and didn't start treating them until they were 5 months old. At this point the mice had already developed aging diseases, including cataracts, and were suffering from muscle and fat loss. The scientists weren't able to "undo" the aging that had already occurred, but after repeated treatment to remove the senescent cells, deterioration of the mouse muscles and fat cells stopped. [7 Ways the Mind and Body Change With Age]Healthy aging The mice still had other age-related signs and didn't have an extended lifetime; basically, the drug extended the proportion of "healthy time" in their lives. The researchers said they believe death (and these other aging diseases) is caused through different pathways that aren't affected by these senescent cells.They are repeating their study on normal mice, without the accelerated aging mutation, but these studies will take years to complete, because normal mice live so much longer (to about 3 years).Since the study was performed using mice, the researchers still have a long way to go before they reach a human therapy. The senescent cell-clearing technique couldn't be used on humans, since it would require inserting a special gene into human embryos, as was done with mice embryos.However, Baker said the researchers could use the information they gather from these mouse studies to develop therapies for humans. Gene therapies could be used to target senescent cells, or scientists could use a vaccine to train the human immune system to attack these cells. Such therapies are far in the future, though, and still require lots of basic science to back them up.The study was published today (Nov. 2) in the journal Nature
Body Rebuilding: Researchers Regenerate Muscle Tissue in MiceScienceDaily (Nov. 29, 2011) — A team of scientists from Worcester Polytechnic Institute (WPI) and CellThera, a private company located in WPI's Life Sciences and Bioengineering Center, have regenerated functional muscle tissue in mice, opening the door for a new clinical therapy to treat people who suffer major muscle trauma.The team used a novel protocol to coax mature human muscle cells into a stem cell-like state and grew those reprogrammed cells on biopolymer microthreads. The threads were placed in a wound created by surgically removing a large section of leg muscle from a mouse. Over time, the threads and cells restored near-normal function to the muscle, as reported in the paper "Restoration of Skeletal Muscle Defects with Adult Human Cells Delivered on Fibrin Microthreads," published in the current issue of the journal Tissue Engineering Part A. Surprisingly, the microthreads, which were used simply as a scaffold to support the reprogrammed human cells, actually seemed to accelerate the regeneration process by recruiting progenitor mouse muscle cells, suggesting that they alone could become a therapeutic tool for treating major muscle trauma."We are pleased with the progress of this work, and frankly we were surprised by the level of muscle regeneration that was achieved," said Raymond Page, assistant professor of biomedical engineering at WPI, chief scientific officer at CellThera, and corresponding author on the paper.The current study is part of a multi-year program funded, in part, by grants from the National Institutes of Health and DARPA, the advanced research program of the U.S Department of Defense, to support the development of new technologies and therapies for people who suffer serious wounds and limb loss.Mammalian skeletal muscles are able to repair small injuries caused by excessive exertion or minor trauma by recruiting muscle progenitor cells, which have not fully developed into muscle fibers, to the site of injury to rebuild the muscle. With major injuries, however, the body's first priority is to stop the bleeding, so scar tissue forms quickly at the wound site and overrides any muscle repair.In the current study, the WPI/CellThera team combined two novel technologies to try to prevent scar formation and prompt muscle re-growth. The first was a method they had developed previously for reprogramming mature human skin cells without employing viruses or extra genes (Cloning, Stem Cells. 2009 Jul 21). The reprogrammed cells express stem cell genes and multiply in great numbers, but don't differentiate into specific tissues. The second was the use of biopolymer microthreads as a scaffold to support the cells. Developed by George Pins, associate professor of biomedical engineering at WPI, the threads--about the thickness of a human hair--are made of fibrin, a protein that helps blood clot.Researchers removed a portion of the tibialis anterior leg muscle in several mice (the muscle was chosen because injury to it affects the foot's range of motion but doesn't prevent the mice from walking). In some mice, the injuries were left to heal on their own. In others, the wound was filled with bundles of microthreads seeded with reprogrammed human muscle cells. The untreated mice developed significant scarring at the injury site, with no restoration of muscle function. In sharp contrast, the mice that received the reprogrammed cells grew new muscle fibers and developed very little scarring.Tests done 10 weeks after implantation showed that the regenerated tibialis anterior muscle functioned with nearly as much strength as an uninjured muscle. The scientists expected that most of the regenerated muscle would be composed of human cells, since the implanted cells were from human muscle. Surprisingly, most of the new muscle fibers were made of mouse cells. The team theorized that the fibrin microthreads, which in their composition and shape are similar to muscle fibers, may encourage resident mouse progenitor cells to migrate into the wound and begin restoring the tissue (they may also forestall the natural inflammatory response that leads to scarring after a major injury).This surprise finding suggests that fibrin microthreads alone could be used to treat major muscle trauma while research on enhancing regeneration with reprogrammed human cells continues. "The contribution of the fibrin microthreads alone to wound healing should not be understated," the authors wrote. "While this clearly points to room for improving cell delivery techniques, it suggests that fibrin microthreads alone have tremendous potential for reducing fibrosis and remodeling large muscle injuries. Future studies will address, more completely, the capability of microthreads alone and determine, at what point, a combinational cell therapy is required for full functional tissue restoration."
When we add here this = immortal - super smart - hybrid humanLearning high-performance tasks with no conscious effort may soon be possible New research suggests it may be possible to use brain technology to learn to play a piano, reduce mental stress or hit a curve ball with little or no conscious effort. It's the kind of thing seen in Hollywood's "Matrix" franchise....Source: National Science Foundation
Neuroscientists Boost Memory in Mice Using Genetics and a New Memory-Enhancing DrugScienceDaily (Dec. 8, 2011) — When the activity of a molecule that is normally elevated during viral infections is inhibited in the brain, mice learn and remember better, researchers at Baylor College of Medicine reported in a recent article in the journal Cell."The molecule PKR (the double-stranded RNA-activated protein kinase) was originally described as a sensor of viral infections, but its function in the brain was totally unknown," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and senior author of the paper. Since the activity of PKR is altered in a variety of cognitive disorders, Costa-Mattioli and colleagues decided to take a closer look at its role in the mammalian brain.Super memoryThe authors discovered that mice lacking PKR in the brain have a kind of "super" memory. "We found that when we genetically inhibit PKR, we increased the excitability of brain cells and enhanced learning and memory, in a variety of behavioral tests," he said. For instance, when the authors assessed spatial memory (the memory for people, places and events) through a test in which mice use visual cues for finding a hidden platform in a circular pool, they found that normal mice had to repeat the task multiple times over many days in order to remember the platform's location. By contrast, mice lacking PKR learned the task after only one training session.Costa-Mattioli and colleagues wanted to know how this molecular process actually works. They found that when PKR is inhibited, the increased synaptic activity (that is, the enhanced communication between neurons) is caused by gamma interferon, another molecule involved in immunity."These data are totally unexpected, and show that two molecules classically known to play a role in viral infection and the immune response regulate the kind of brain activity that leads to the formation of long-term memory in the adult brain," said Costa-Mattioli.Drug targets PKRAnother key finding made by Costa-Mattioli and his team of researchers was the fact that this process could be mimicked by a PKR inhibitor -- a small molecule that blocks PKR activity and thus acts as a "memory-enhancing drug.""It is indeed quite amazing that we can also enhance both memory and brain activity with a drug that specifically targets PKR." Definitely then, the next step is to use what we have learned in mice and to try to improve brain function in people suffering from memory loss, said Costa-Mattioli.Although Costa-Mattioli's memory pill may be years away from approval by the U.S. Food and Drug Administration, its impact on society and medicine could be very profound. There are roughly 6 million Americans and 35 million people world-wide with Alzheimer's disease and more than 70 million Americans over the age of 60 who may suffer from aged-associated impairment of memory.Costa-Mattioli said, "More investigation is undoubtedly necessary to translate these findings to effective therapies but we would be delighted if our scientific studies were to contribute in some way to this ultimate goal.""Our identity and uniqueness is made up of our memories," Costa-Mattioli said. "This molecule could hold the key to how we can keep our memories longer, but also how we create new ones."Others who contributed to the research include: first author Ping Jun Zhu, Wei Huang, Jong W. Yoo, Loredana Stoica, Hongyi Zhou, Jeffrey Noebels, all at BCM; Andon N. Placzek, currently with Mercer University School of Medicine; Michael J. Friedlander and Djanenkhodja Kalikulov currently with Virginia Tech; Kresimir Krnjevic, McGill University; and John C. Bell, Ottawa Health Research Institute.The research was supported through funding from the Searle Scholars Program (award to Costa-Mattioli), the Cynthia and George Mitchell Founds (award to Costa-Mattioli), the National Institute of Neurological Diseases and Stroke, the National Institute for Child Health and Development, the BCM Intellectual and Developmental Disabilities Research Center and the National Eye Institute.
Drug Reverses Aging-Associated Changes in Brain Cells, Animal Study ShowsScienceDaily (Dec. 7, 2011) — Drugs that affect the levels of an important brain protein involved in learning and memory reverse cellular changes in the brain seen during aging, according to an animal study in the December 7 issue of The Journal of Neuroscience. The findings could one day aid in the development of new drugs that enhance cognitive function in older adults.Aging-related memory loss is associated with the gradual deterioration of the structure and function of synapses (the connections between brain cells) in brain regions critical to learning and memory, such as the hippocampus. Recent studies suggested that histone acetylation, a chemical process that controls whether genes are turned on, affects this process. Specifically, it affects brain cells' ability to alter the strength and structure of their connections for information storage, a process known as synaptic plasticity, which is a cellular signature of memory.In the current study, Cui-Wei Xie, PhD, of the University of California, Los Angeles, and colleagues found that compared with younger rats, hippocampi from older rats have less brain-derived neurotrophic factor (BDNF) -- a protein that promotes synaptic plasticity -- and less histone acetylation of the Bdnf gene. By treating the hippocampal tissue from older animals with a drug that increased histone acetylation, they were able to restore BDNF production and synaptic plasticity to levels found in younger animals. "These findings shed light on why synapses become less efficient and more vulnerable to impairment during aging," said Xie, who led the study. "Such knowledge could help develop new drugs for cognitive aging and aging-related neurodegenerative diseases, such as Alzheimer's disease," she added.The researchers also found that treating the hippocampal tissue from older animals with a different drug that activates a BDNF receptor also reversed the synaptic plasticity deficit in the older rats. Because histone acetylation is important in many functions throughout the body, these findings offer a potential pathway to treat aging-related synaptic plasticity deficits without interfering with histone acetylation. "It appears that lifelong shifts in gene regulation steadily deprive the brain of a key growth factor and cause a collapse of the 'machinery' supporting memory, cognition, and the viability of neurons," said Gary Lynch, PhD, a synaptic plasticity expert at the University of California, Irvine. "The very good news suggested by this study is that it may be possible to reverse these effects."The research was supported by the National Institute on Aging and UCLA Older Americans Independence Center.
Genetic Code of World's Oldest Person May Reveal Recipe for Long LifeChristopher Wanjek, LiveScience Bad Medicine ColumnistDate: 16 October 2011 Time: 09:23 AM ET Studying the genetics of centenarians could reveal a recipe for a long life, with scientists finding coveted genes are major players.The 115-year-old Hendrikje van Andel-Schipper, who held the title of world's oldest human before she died in 2004, attributed her longevity to eating herring every day. But doctors had a hunch it was a little more than that. After all, everyone and their uncle eats herring in van Andel-Schipper's native country of the Netherlands.Turns out their hunch was right. It was the herring and a group of coveted genes known to help prevent circulatory disease and Alzheimer's and Parkinson's disease. The genes likely led to van Andel-Schipper's remarkable mental clarity at such an advanced age as well as her ability to lick breast cancer . . . at age 100.Dutch researcher Henne Holstege of the VU University Medical Center in Amsterdam presented the initial findings from an analysis of van Andel-Schipper’s genes on Oct. 14 at the annual meeting of the International Congress of Human Genetics in Montreal.Herring + good genes - herring = long life Holstege said she hopes van Andel-Schipper's unique genetic blueprint, called a genome, can serve as a reference for future studies of longevity genes. She compared van Andel-Schipper's genome to a checklist of all that's needed to combat the ravages of aging. No other centenarian has been studied as thoroughly. [7 Ways the Mind and Body Change With Age]Van Andel-Schipper was robust and didn't enter a nursing home until age 105. Researchers grew intrigued by her mental acuity during her later years. Her performance in mental tests at age 113 was above average for a healthy adult between the ages of 60 and 75. Ultimately van Andel-Schipper died of stomach cancer, which is ironic because this type of cancer is rare today but was common in 1890, the year she was born.Fortunately, van Andel-Schipper decided to donate her body to medical science when she was just a sweet, young thing at age 82, allowing researchers to look more deeply for the underlying causes of her remarkable longevity.Upon van Andel-Schipper's death, an autopsy of her brain showed no signs of even minor dementia, previously thought to be inevitable for the elderly. Doctors also found no sign of plaque in her arteries. While it is true that van Andel-Schipper's favorite fish, herring, contains heart-healthy omega-3 fatty acids, doctors had never seen such a pristine vascular system in the elderly. [10 New Ways to Eat Well]Key to living past 100Holstege and her Dutch and American colleagues are only in the initial stages of van Andel-Schipper's genome analysis, and no results have been published. Doctors hope that a better understanding of longevity genes can lead to medicines that can suppress the genes that cause disease and activate the genes that promote long life.The late van Andel-Schipper is unique in that she was among the fewer than 30 people in modern times known to live longer than 115 years; and she is also one of only a few hundred people (so far) to have their complete genome analyzed.Maybe being the world's oldest person isn't the best goal in life. The title usually is short-lived, with some sinister senior in a rocking chair out to take your title away. But at least you know to get there you don't have to eat herring every day. All you need is that magic combination of genes, distributed to roughly 1 in a billion people.
REGENERATIVE MEDICINE Posted By: CuriousDate: Wednesday, 23 April 2008, 5:54 a.m. The Defense Department today launched a five-year, Army-led cooperative effort to leverage cutting-edge medical technology to develop new ways to assist service members who’ve suffered severe, disfiguring wounds during their wartime service. The newly established Armed Forces Institute of Regenerative Medicine, known by the acronym AFIRM, will serve as the military’s operational agency for the effort, Dr. S. Ward Casscells, the assistant secretary of defense for health affairs, told reporters at a Pentagon news conference. A key component of the initiative is to harness stem cell research and technology in finding innovative ways to use a patient’s natural cellular structure to reconstruct new skin, muscles and tendons, and even ears, noses and fingers, Casscells said.
'Pixie Dust' From Pig's Bladder Regrows Man's Finger Created: Thursday, 01 May 2008, 9:45 AM CDT 05/01/2008 -- With the help of an experimental powder, a man’s severed finger has regrown to its original length in just four weeks, reports London’s Daily Mail.Lee Spievack, of Cincinnati, who sliced almost half an inch off the top of one of his fingers, described the powder as “pixie dust,” according to the newspaper.The “pixie dust” is actually extra-cellular matrix, bursting with collagen and is made from a dried pig’s bladder, the newspaper reports.The dust was designed to regenerate damaged ligaments in horses, the Daily Mail said.Collagen is known to give skin strength and elasticity. It is thought that the dust kick-starts the body's natural healing process by sending out signals that mobilize the body's own cells into repairing the damaged tissue, according to the newspaper.Spievack said his finger even has a fingernail and fingerprint.“The second time I put it (the dust) on, I could already see the growth,” Spievack said. “Each day it was up further. Finally, it closed up and was a finger. It took about four weeks before it was sealed.”Spievack injured his finger three years ago when it got caught in the propeller of a model plane. He did not want a skin graft, opting instead to try the “pixie dust.”“There are all sorts of signals in the body,” said Dr. Stephen Badylak of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh. “We have signals that are good for forming scar tissue and others that are good for regenerating tissues."One way to think about these matrices is that we've taken out many of the stimuli for scar tissue formation and left those signals which were always there for constructive remodeling."Essentially, the powder directs tissues to grow fresh instead of forming a scar.Spievak has not lost any bone, nerves or tendon material.
One Gene Lost = One Limb Regained? Scientists Demonstrate Mammalian Regeneration Through a Single Gene DeletionScienceDaily (Mar. 16, 2010) — A quest that began over a decade ago with a chance observation has reached a milestone: the identification of a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice long thought to have been lost through evolution and reserved for creatures like flatworms, sponges, and some species of salamander.In a report published in the Proceedings of the National Academy of Sciences, researchers from The Wistar Institute demonstrate that mice that lack the p21 gene gain the ability to regenerate lost or damaged tissue.Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a blastema, a structure associated with rapid cell growth and de-differentiation as seen in amphibians. According to the Wistar researchers, the loss of p21 causes the cells of these mice to behave more like embryonic stem cells than adult mammalian cells, and their findings provide solid evidence to link tissue regeneration to the control of cell division."Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring," said the project's lead scientist Ellen Heber-Katz, Ph.D., a professor in Wistar's Molecular and Cellular Oncogenesis program. "While we are just beginning to understand the repercussions of these findings, perhaps, one day we'll be able to accelerate healing in humans by temporarily inactivating the p21 gene."Heber-Katz and her colleagues used a p21 knockout mouse to help solve a mystery first encountered in 1996 regarding another mouse strain in her laboratory. MRL mice, which were being tested in an autoimmunity experiment, had holes pierced in their ears to create a commonly used life-long identification marker. A few weeks later, investigators discovered that the earholes had closed without a trace. While the experiment was ruined, it left the researchers with a new question: Was the MRL mouse a window into mammalian regeneration?The discovery set the Heber-Katz laboratory off on two parallel paths. Working with geneticists Elizabeth Blankenhorn, Ph.D., at Drexel University, and James Cheverud, Ph.D., at Washington University, the laboratory focused on mapping the critical genes that turn MRL mice into healers. Meanwhile, cellular studies ongoing at Wistar revealed that MRL cells behaved very differently than cells from "non-healer" mouse strains in culture. Khamilia Bedebaeva, M.D., Ph.D., having studied genetic effects following the Chernobyl reactor radiation accident, noticed immediately that these cells were atypical, showing profound differences in cell cycle characteristics and DNA damage. This led Andrew Snyder, Ph.D., to explore the DNA damage pathway and its effects on cell cycle control.Snyder found that p21, a cell cycle regulator, was consistently inactive in cells from the MRL mouse ear. P21 expression is tightly controlled by the tumor suppressor p53, another regulator of cell division and a known factor in many forms of cancer. The ultimate experiment was to show that a mouse lacking p21 would demonstrate a regenerative response similar to that seen in the MRL mouse. And this indeed was the case. As it turned out, p21 knockout mice had already been created, were readily available, and widely used in many studies. What had not been noted was that these mice could heal their ears."In normal cells, p21 acts like a brake to block cell cycle progression in the event of DNA damage, preventing the cells from dividing and potentially becoming cancerous," Heber-Katz said. "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported."In fact, the researchers saw an increase in apoptosis in MRL mice -- also known as programmed cell death -- the cell's self-destruct mechanism that is often switched on when DNA has been damaged. According to Heber-Katz, this is exactly the sort of behavior seen in naturally regenerative creatures."The combined effects of an increase in highly regenerative cells and apoptosis may allow the cells of these organisms to divide rapidly without going out of control and becoming cancerous," Heber-Katz said. "In fact, it is similar to what is seen in mammalian embryos, where p21 also happens to be inactive after DNA damage. The down regulation of p21 promotes the induced pluripotent state in mammalian cells, highlighting a correlation between stem cells, tissue regeneration, and the cell cycle."The study was supported by grants from the Harold G. and Leila Y. Mathers Foundation, the F.M. Kirby Foundation, the W.W. Smith Foundation, the National Institute for General Medical Sciences and National Cancer Institute.Study investigators also include Wistar researchers Paul M. Lieberman, Ph.D.; Dmitri Gourevitch M.D.; Lise Clark D.V.M., Ph.D.; Xiang-Ming Zhang; and John Leferovich. Snyder, formerly of the Lieberman laboratory at Wistar, and Bedebaeva are co-first authors on this paper. James Cheverud of Washington University is also a co-author on this paper.
Now this is something worthy of the nobel prize. I am sure I dont have to explain how this basic step is so important. Just last night I was watching Stargate Universe where someone finds out they will develop ALS, then this article comes along and basically we now have the first step needed for a cure for that. Heck not only is this a step towards cures, but this is a step towards anti-aging treatments.
Scientists Create Stable, Self-Renewing Neural Stem CellsScienceDaily (Apr. 25, 2011) — In a paper published in the April 25 early online edition of the Proceedings of the National Academy of Sciences, researchers at the University of California, San Diego School of Medicine, the Gladstone Institutes in San Francisco and colleagues report a game-changing advance in stem cell science: the creation of long-term, self-renewing, primitive neural precursor cells from human embryonic stem cells (hESCs) that can be directed to become many types of neuron without increased risk of tumor formation."It's a big step forward," said Kang Zhang, MD, PhD, professor of ophthalmology and human genetics at Shiley Eye Center and director of the Institute for Genomic Medicine, both at UC San Diego. "It means we can generate stable, renewable neural stem cells or downstream products quickly, in great quantities and in a clinical grade -- millions in less than a week -- that can be used for clinical trials and, eventually, for clinical treatments. Until now, that has not been possible."Human embryonic stem cells hold great promise in regenerative medicine due to their ability to become any kind of cell needed to repair and restore damaged tissues. But the potential of hESCs has been constrained by a number of practical problems, not least among them the difficulty of growing sufficient quantities of stable, usable cells and the risk that some of these cells might form tumors.To produce the neural stem cells, Zhang, with co-senior author Sheng Ding, PhD, a former professor of chemistry at The Scripps Research Institute and now at the Gladstone Institutes, and colleagues added small molecules in a chemically defined culture condition that induces hESCs to become primitive neural precursor cells, but then halts the further differentiation process."And because it doesn't use any gene transfer technologies or exogenous cell products, there's minimal risk of introducing mutations or outside contamination," Zhang said. Assays of these neural precursor cells found no evidence of tumor formation when introduced into laboratory mice.By adding other chemicals, the scientists are able to then direct the precursor cells to differentiate into different types of mature neurons, "which means you can explore potential clinical applications for a wide range of neurodegenerative diseases," said Zhang. "You can generate neurons for specific conditions like amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Parkinson's disease or, in the case of my particular research area, eye-specific neurons that are lost in macular degeneration, retinitis pigmentosa or glaucoma."The new process promises to have broad applications in stem cell research. The same method can be used to push induce pluripotent stem cells (stem cells artificially derived from adult, differentiated mature cells) to become neural stem cells, Zhang said. "And in principle, by altering the combination of small molecules, you may be able to create other types of stem cells capable of becoming heart, pancreas, or muscle cells, to name a few."The next step, according to Zhang, is to use these stem cells to treat different types of neurodegenerative diseases, such as macular degeneration or glaucoma in animal models.Funding for this research came, in part, from grants from National Institutes of Health Director's Transformative R01 Program, the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, the National Eye Institute, the National Institute of Mental Health, the California Institute for Regenerative Medicine, a VA Merit Award, the Macula Vision Research Foundation, Research to Prevent Blindness, a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and the Richard and Carol Hertzberg Fund.Co-authors of the study include Wenlin Li, Yu Zhang, Wanguo Wei, Rajesh Ambasudhan, Tongxiang Lin, Janghwan Kim, Department of Chemistry, The Scripps Research Institute; Woong Sun, Xiaolei Wang, UCSD Institute for Genomic Medicine and Shiley Eye Center, Department of Anatomy, Korea University College of Medicine, Seoul, Korea; Peng Xia, Maria Talantova, Stuart A. Lipton, Del E. Webb Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research Institute; Woon Ryoung Kim, Department of Anatomy, Korea University College of Medicine, Seoul, Korea
Do 68 Molecules Hold The Key To Understanding Disease?ScienceDaily (Sep. 4, 2008) — Why is it that the origins of many serious diseases remain a mystery? In considering that question, a scientist at the University of California, San Diego School of Medicine has come up with a unified molecular view of the indivisible unit of life, the cell, which may provide an answer.Reviewing findings from multiple disciplines, Jamey Marth, Ph.D., UC San Diego Professor of Cellular and Molecular Medicine and Investigator with the Howard Hughes Medical Institute, realized that only 68 molecular building blocks are used to construct these four fundamental components of cells: the nucleic acids (DNA and RNA), proteins, glycans and lipids. His work, which illustrates the primary composition of all cells, is published in the September issue of Nature Cell Biology.Like the periodic table of elements, first published in 1869 by Russian chemist Dmitri Mendeleev, is to chemistry, Marth’s visual metaphor offers a new framework for biologists.This new illustration defines the basic molecular building blocks of life and currently includes 32 glycans (sugar linkages found throughout the cell) and eight kinds of lipids (which compose cell membranes) along with the more well-known 20 amino acids that are used to make proteins and the eight nucleosides that compose the nucleic acids, DNA and RNA.“These 68 building blocks provide the structural basis for the molecular choreography that constitutes the entire life of a cell,” said Marth. “And two of the four cellular components are produced by these molecular building blocks in processes that cannot be encoded by the genes. These cellular components – the glycans and lipids – may now hold the keys to uncovering the origins of many grievous diseases that continue to evade understanding.”Currently, the vast majority of medical research looks to the human genome and proteome for answers, but those answers remain elusive, and perhaps for good reason.“We have now found instances where the pathogenesis of widespread and chronic diseases can be attributed to a change in the glycome, for example, in the absence of definable changes in the genome or proteome,” Marth said, adding that, as biomedical researchers, “we need to begin to cultivate the integration of disciplines in a holistic and rigorous way in order to perceive and most effectively manipulate the biological mechanisms of health and disease.”“What is important is that no one has composed it and laid it out so clearly before,” said Ajit Varki, M.D., Distinguished Professor of Medicine and Cellular and Molecular Medicine and founder and co-director of the Glycobiology Research and Training Center at UC San Diego School of Medicine, and chief editor of the major textbook in the field, The Essentials of Glycobiology. “Glycobiology, for example, is a relatively new field of study in which researchers at UC San Diego have much expertise, and Dr. Marth’s work further illustrates the importance of these glycan molecules.”Marth believes that biology should become more integrative both in academic and research settings. “I’m one who believes that we don’t need to sacrifice breadth of knowledge in order to acquire depth of understanding.”
Science with real bite: Full set of teeth grown in the lab (mouse teeth)By Fiona MacraeLast updated at 5:26 PM on 13th July 2011Comments (26) Share Scientists have grown fully formed teeth from stem cells.The artificial teeth looked like the real thing, were sensitive to pain and could chew food.The breakthrough was made on mice but could pave the way for those who lose teeth to decay or injury being able to ‘grow’ replacements. Cutting edge: A bioengineered tooth, bottom right, successfully transplanted into the jaw of a mouseThe researchers harnessed the power of stem cells – ‘master cells’ which have the potential to be used to grow any part of the body – to generate teeth.Two types of stem cell which between them contain all the instructions for making teeth were mixed together and grown in the lab in a mixture of chemicals and vitamins that started their transformation.After five days, they had formed a tiny ‘tooth bud’. The fledgling tooth was then placed in a tailor-made plastic box deep inside a mouse’s body, where over the next 60 days it grew to form a full tooth. While this might seem bizarre, putting it inside the body ensured it had access to the fluids and chemical signals it needed to develop further.When fully grown, it was taken out of the box and transplanted deep into the jawbone of a mouse that had had a tooth removed.Six weeks later, it had fused with the jawbone, the journal PLoS ONE reports. The tooth had all the components of normal teeth, including enamel, crown and root, and connective fibres to fix it to bone. Glowing report: The tooth bud, marked with fluorescent dye, shortly after transplantationThe researchers, from Tokyo University of Science, have previously transplanted tooth buds into mice and watched and waited for them to break through the gum.But given how slowly human teeth grow, they think transplanting fully-formed teeth is much more practical. Human teeth bioengineered in this way could provide a more natural-looking alternative to false teeth and synthetic implants. A tooth that matches the real thing would also have psychological benefits for patients.'The bioengineered teeth were fully functional ... there was no trouble biting and eating food after transplantation,' wrote Masamitsu Oshima, assistant professor at the Research Institute for Science and Technology, Tokyo University of Science.The researchers hope this is a step towards the development of new human organs grown from a patient's own cells.'At present, researchers worldwide do not have the method to culture three-dimensional organs in vitro (outside the body),' Professor Takashi Tsuji, who led the research, said.'It is important to develop technologies for the culture of the bioengineered organ ... for the realization of future organ replacement regenerative therapy.' Wise precaution: Brushing your own teeth is still a good idea until replacements can be grown Likely to cost around £2,000 each – the same as the implants used at the moment – the stem cell teeth may also produce a more natural ‘bite’.However, the research is still at an early stage and researchers say it will be at least a decade before people can ‘grow their own teeth’.Hurdles to be overcome include finding a suitable source of stem cells for use in the human mouth. Damien Walmsley, scientific advisor to the British Dental Association, warned the bioengineering was still a long way from being something that will directly benefit patients. ‘For the foreseeable future, it is important patients brush twice a day with fluoride toothpaste, restrict their intake of sugary food and drinks and visit their dentist regularly,’ he said.
Filling Without Drilling: Pain-Free Way of Tackling Dental Decay Reverses Acid Damage and Re-Builds TeethScienceDaily (Aug. 23, 2011) — Researchers at the University of Leeds have discovered a pain-free way of tackling dental decay that reverses the damage of acid attack and re-builds teeth as new.The pioneering treatment promises to transform the approach to filling teeth forever.Tooth decay begins when acid produced by bacteria in plaque dissolves the mineral in the teeth, causing microscopic holes or 'pores' to form. As the decay process progresses these micro-pores increase in size and number. Eventually the damaged tooth may have to be drilled and filled to prevent toothache, or even removed.The very thought of drilling puts many people off going to see their dentist, whether or not they actually need treatment. This tendency to miss check-ups and ignore niggling aches and pains means that existing problems get worse and early signs of decay in other teeth are overlooked.It's a vicious cycle, but one that can be broken, according to researchers at the University of Leeds who have developed a revolutionary new way to treat the first signs of tooth decay. Their solution is to arm dentists with a peptide-based fluid that is literally painted onto the tooth's surface. The peptide technology is based on knowledge of how the tooth forms in the first place and stimulates regeneration of the tooth defect."This may sound too good to be true, but we are essentially helping acid-damaged teeth to regenerate themselves. It is a totally natural non-surgical repair process and is entirely pain-free too," said Professor Jennifer Kirkham, from the University of Leeds Dental Institute, who has led development of the new technique.The 'magic' fluid was designed by researchers in the University of Leeds' School of Chemistry, led by Dr Amalia Aggeli. It contains a peptide known as P 11-4 that -- under certain conditions -- will assemble together into fibres. In practice, this means that when applied to the tooth, the fluid seeps into the micro-pores caused by acid attack and then spontaneously forms a gel. This gel then provides a 'scaffold' or framework that attracts calcium and regenerates the tooth's mineral from within, providing a natural and pain-free repair.The technique was recently taken out of the laboratory and tested on a small group of adults whose dentist had spotted the initial signs of tooth decay. The results from this small trial have shown that P 11-4 can indeed reverse the damage and regenerate the tooth tissue."The results of our tests so far are extremely promising," said Professor Paul Brunton, who is overseeing the patient testing at the University of Leeds Dental Institute. "If these results can be repeated on a larger patient group, then I have no doubt whatsoever that in two to three years time this technique will be available for dentists to use in their daily practice.""The main reason that people don't go to the dentist regularly is fear. If we can offer a treatment that is completely non-invasive, that doesn't involve a mechanical drill, then we can change that perceived link between dental treatment and pain. This really is more than filling without drilling, this is a novel approach that enables the patients to keep their natural teeth!"The study is being funded by credentis ag who have licensed the technology and are preparing to introduce P11-4 to dentists worldwide.
The outer layer of a human tooth is called the enamel. It is 1-1.5 mm thick and iscomposed of hydroxyapatite (HAP) crystals. Early tooth decay involves microscopicdamage to the enamel (holes <50 ?m deep) by acid-forming bacteria, which cannot berepaired by simple filling materials because perfect adhesion with the enamel does notoccur due to differences of chemical composition and structure. Our paste grows HAPcrystals, which are exactly like those in natural enamel, at the affected site within 15min...
Quote from: ArniK on November 29, 2010, 02:32:54 PMI found a link on Yahoo to a story about this, but the link was a 404. So I did a quick search and found the patent. I'll give you the link I found, but trust me, it is pretty heavy biology and chemistry to read. The summary from the search page and a short clip I took from the patent itself will tell a little bit of the story.Telomeres are like the little plastic ends of shoelaces, except they are on the ends of DNA sequences. Your lil shoe lace plastic thingy disappears and your shoe lace starts to fray, it goes bad quickly. Same with your DNA with no telomere, no replication and you have cell death. So if your cells don't die, neither do you. This one only applies to mice, but after reading the patent, well a lot of it anyway, they are not that far away from human testing. One day the doc will tell you to "Drink this," and you will live to be hundreds or thousands of years old if you stop sky diving and mountain climbing.QuoteProtein and peptide fragments from mouse telomerase reverse transcriptaseAbstract: This invention provides for murine telomerase reverse transcriptase (mTERT) enzyme proteins and nucleic acids, including methods for isolating and expressing these nucleic acids and proteins, which have application to the control of cell proliferation and aging, including the control of age-related diseases, such as cancer. ...(below from the actual patent...)In one embodiment of the invention, recombinant mTERT is expressed in normal, diploid mortal cells to provide for indefinitely proliferating cells, immortalization of cells, or to facilitate long-term culture or replication of the cells. Telomerase enzyme complex components, such as nucleic acid telomeric sequence template molecules (mTERC, for example) or other associated proteins, that are beneficial for expression or act as modulators of activity, can also be co-expressed. This invention provides methods to obtain indefinitely proliferating cells and diploid immortal cells with an otherwise normal phenotype and karyotype. This aspect of the invention is of enormous practical and commercial utility; for example, the FDA and public would value the production of recombinant proteins from normal cells to minimize concern regarding viral or other contamination of the products made from such cells as are commonly used today. The present invention allows one to produce indefinitely proliferating and immortal hybrids of B lymphocytes and myeloma cells to obtain hybridomas for monoclonal antibody production. Using the methods of this invention, transfection of mTERT protein and telomerase enzyme activity into B lymphocytes allows one to generate indefinitely proliferating cells and immortal cells for antibody production.http://www.freshpatents.com/-dt20090430ptan20090111157.php
I found a link on Yahoo to a story about this, but the link was a 404. So I did a quick search and found the patent. I'll give you the link I found, but trust me, it is pretty heavy biology and chemistry to read. The summary from the search page and a short clip I took from the patent itself will tell a little bit of the story.Telomeres are like the little plastic ends of shoelaces, except they are on the ends of DNA sequences. Your lil shoe lace plastic thingy disappears and your shoe lace starts to fray, it goes bad quickly. Same with your DNA with no telomere, no replication and you have cell death. So if your cells don't die, neither do you. This one only applies to mice, but after reading the patent, well a lot of it anyway, they are not that far away from human testing. One day the doc will tell you to "Drink this," and you will live to be hundreds or thousands of years old if you stop sky diving and mountain climbing.QuoteProtein and peptide fragments from mouse telomerase reverse transcriptaseAbstract: This invention provides for murine telomerase reverse transcriptase (mTERT) enzyme proteins and nucleic acids, including methods for isolating and expressing these nucleic acids and proteins, which have application to the control of cell proliferation and aging, including the control of age-related diseases, such as cancer. ...(below from the actual patent...)In one embodiment of the invention, recombinant mTERT is expressed in normal, diploid mortal cells to provide for indefinitely proliferating cells, immortalization of cells, or to facilitate long-term culture or replication of the cells. Telomerase enzyme complex components, such as nucleic acid telomeric sequence template molecules (mTERC, for example) or other associated proteins, that are beneficial for expression or act as modulators of activity, can also be co-expressed. This invention provides methods to obtain indefinitely proliferating cells and diploid immortal cells with an otherwise normal phenotype and karyotype. This aspect of the invention is of enormous practical and commercial utility; for example, the FDA and public would value the production of recombinant proteins from normal cells to minimize concern regarding viral or other contamination of the products made from such cells as are commonly used today. The present invention allows one to produce indefinitely proliferating and immortal hybrids of B lymphocytes and myeloma cells to obtain hybridomas for monoclonal antibody production. Using the methods of this invention, transfection of mTERT protein and telomerase enzyme activity into B lymphocytes allows one to generate indefinitely proliferating cells and immortal cells for antibody production.http://www.freshpatents.com/-dt20090430ptan20090111157.php
Protein and peptide fragments from mouse telomerase reverse transcriptaseAbstract: This invention provides for murine telomerase reverse transcriptase (mTERT) enzyme proteins and nucleic acids, including methods for isolating and expressing these nucleic acids and proteins, which have application to the control of cell proliferation and aging, including the control of age-related diseases, such as cancer. ...(below from the actual patent...)In one embodiment of the invention, recombinant mTERT is expressed in normal, diploid mortal cells to provide for indefinitely proliferating cells, immortalization of cells, or to facilitate long-term culture or replication of the cells. Telomerase enzyme complex components, such as nucleic acid telomeric sequence template molecules (mTERC, for example) or other associated proteins, that are beneficial for expression or act as modulators of activity, can also be co-expressed. This invention provides methods to obtain indefinitely proliferating cells and diploid immortal cells with an otherwise normal phenotype and karyotype. This aspect of the invention is of enormous practical and commercial utility; for example, the FDA and public would value the production of recombinant proteins from normal cells to minimize concern regarding viral or other contamination of the products made from such cells as are commonly used today. The present invention allows one to produce indefinitely proliferating and immortal hybrids of B lymphocytes and myeloma cells to obtain hybridomas for monoclonal antibody production. Using the methods of this invention, transfection of mTERT protein and telomerase enzyme activity into B lymphocytes allows one to generate indefinitely proliferating cells and immortal cells for antibody production.
'Elixir of youth' drug could fight HIV and ageing 17:53 13 November 2008 by Linda Geddes For similar stories, visit the HIV and AIDS Topic Guide A drug extracted from a plant used in Chinese medicine has helped immune cells fight HIV and raises the possibility of slowing the ageing process in other parts of our bodies.The method hinges upon telomeres - caps of repetitive DNA found at the ends of chromosomes. These get shorter as cells age and are thought to affect the cell's lifespan.The caps can be rebuilt with an enzyme called telomerase, and some people have suggested it might be possible to extend human life by boosting telomerase production - though this has never been tested.Now Rita Effros at the University of California in Los Angeles has used a drug that boosts telomerase to enhance the immune response to viruses.Effros and her colleagues had previously inserted part of the telomerase gene into so-called killer T-cells - immune cells that fight infections including HIV - and found that the cells had stronger anti-viral activity than normal. However, such gene therapy is not a practical way of treating the millions of people infected with HIV.In the latest work, Effros took killer T-cells from HIV-infected people and exposed them to TAT2. Developed by Geron Corporation of Menlo Park, California, TAT2 is a drug extracted from the root of a plant called Astragalus that is thought to boost telomerase production and is traditionally used in Chinese medicine as a boost for the immune system.She found that TAT2 reduced telomere shortening, increased cells' ability to divide, and enhanced their antiviral activity.This effect was blocked when a second drug was used to inhibit telomerase, suggesting that TAT2 was indeed working through the enzyme - although the exact mechanism is not understood.Immune boost"It is beginning to look like telomerase is doing more than just keeping telomeres from getting too short," says Effros. "It seems to be mediating some anti-viral mechanisms as well."Interestingly, a previous study suggested that people with HIV who control the infection for many years without developing AIDS, have killer T-cells with high telomerase activity and longer telomeres.Ultimately, Effros hopes that TAT2 could be used to supplement existing anti-retroviral drugs, by boosting the immune systems of people with HIV.Aubrey de Grey of the Methuselah Foundation, which promotes research into lifespan extension, says the study is a big step forward."It is what we would have hoped," he says. "We've thought for some time that, by activating telomerase in these cells, we could extend their proliferative capacity. What was completely unclear was whether that would [have negative side effects]. These cells become fully functional as a result of the restoration of their proliferative capacity."However, some safety concerns remain, as telomerase is known to be produced at higher than normal rates in cancer cells.Low cancer riskThe good news is that when TAT2 was added to tumour cells it didn't affect the amount of telomerase that was produced by the cells. Neither did it change the growth characteristics of immune cells that were incubated with a virus that can trigger cancer."We are fairly confident at this point that TAT2 won't enhance cancer development," says Effros, although she cautions that further trials are needed to confirm this.Her confidence is also boosted by the fact that Astragalus is used in Chinese medicine without any obvious adverse effects. She warns, though, against taking large doses of Astragalus to try and mimic the TAT2 effect. "Uncontrolled use of any herbal drug is not wise and I would not advocate it," she says.Effros and de Grey believe that TAT2 could also find applications in other diseases and general ageing - though these have not yet been tested. Killer T-cells fight many other viruses besides HIV, and often enter into a state of anergy - where they stop dividing but won't die - in elderly people. Since response to flu vaccine in elderly people seems to be correlated with having lots of killer T-cells with short telomeres, "One can envision perhaps improving the vaccine response and other anti-viral responses in the elderly by TAT2," says Effros.And in terms of more general tissue regeneration, "if TAT2 can do what the telomerase gene seems to do by keeping cells growing and functioning longer, maybe it could help in tissue regeneration approaches to ageing."
J Med Virol. 2009 Jan;81(1):16-26.Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).Yamamoto N, Ushijima N, Koga Y.SourceDivision of Molecular Immunology and Immunotherapy, Socrates Institute for Therapeutic Immunology, Philadelphia, Pennsylvania 19126-3305, USA. firstname.lastname@example.orgAbstractSerum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-N-acetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore, macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage activating factor (termed GcMAF), which produces no side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a large amount of Fc-receptors as well as an enormous variation of receptors that recognize IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and constantly release HIV virions, the activated macrophages rapidly intercept the released HIV virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18 weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection, which was also confirmed by no infectious center formation by provirus inducing agent-treated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were maintained for 7 years.
Quote from: Kalter Rauch on July 18, 2008, 11:56:09 AMI found this story on the CtoC site...... http://www.dailymail.co.uk/health/artic ... l?ITO=1490 QuoteDementia patient makes 'amazing' progress after using infra-red helmetBy David DerbyshireLast updated at 2:26 AM on 15th July 2008Two months ago Clem Fennell was fading fast.The victim of an aggressive type of dementia, the 57-year-old businessmen was unable to answer the phone, order a meal or string more than a couple of words together.In desperation, his family agreed to try a revolutionary new treatment - a bizarre-looking, experimental helmet devised by a British GP that bathes the brain in infra-red light twice a day.To their astonishment, Mr Fennel began to make an astonishing recovery in just three weeks.My husband, Clem, was fading away. It is as if he is back" said his wife Vickey Fennell, 55. "His personality has started to show again. We are absolutely thrilled."While the helmet has yet to be proven in clinical trials, the family say the effects of the 10 minute sessions are incredible. Mr Fennell can now hold conversations and go shopping unaccompanied.The treatment is the brainchild of Dr Gordon Dougal, a County Durham GP. He believes the device could eventually help thousands of dementia patients."Potentially, this is hugely significant," said Dr Dougal, who is based in Easington, County Durham and is a director of Virulite, a medical research company.Developed with Sunderland University, the helmet has 700 LED lights that penetrate the skull. They are thought to be the right wavelength to stimulate the growth of brain cells, slowing down the decline in memory and brain function and reversing symptoms of dementia...searching/Dr Gordon Dougal yields a lot of material which I find really interesting because of parallels with some of my own ideas and experiments...eg. modulating the circadian rhythm by means of photo-stimulation of the pineal gland.I want to investigate this because I suspect that the basic OS of the brain is incredibly slow due to its baseline frequency set by the 24 hr. circadian cycle. As shown by induced "altered states", it is clear that the brain has a wide range of response to chemical stimuli. Likewise, the photo response of the pineal gland indicates the possibility that other brain tissues may also be light sensitive...as Dr. Dougal has apparently demonstrated.
I found this story on the CtoC site...... http://www.dailymail.co.uk/health/artic ... l?ITO=1490 QuoteDementia patient makes 'amazing' progress after using infra-red helmetBy David DerbyshireLast updated at 2:26 AM on 15th July 2008Two months ago Clem Fennell was fading fast.The victim of an aggressive type of dementia, the 57-year-old businessmen was unable to answer the phone, order a meal or string more than a couple of words together.In desperation, his family agreed to try a revolutionary new treatment - a bizarre-looking, experimental helmet devised by a British GP that bathes the brain in infra-red light twice a day.To their astonishment, Mr Fennel began to make an astonishing recovery in just three weeks.My husband, Clem, was fading away. It is as if he is back" said his wife Vickey Fennell, 55. "His personality has started to show again. We are absolutely thrilled."While the helmet has yet to be proven in clinical trials, the family say the effects of the 10 minute sessions are incredible. Mr Fennell can now hold conversations and go shopping unaccompanied.The treatment is the brainchild of Dr Gordon Dougal, a County Durham GP. He believes the device could eventually help thousands of dementia patients."Potentially, this is hugely significant," said Dr Dougal, who is based in Easington, County Durham and is a director of Virulite, a medical research company.Developed with Sunderland University, the helmet has 700 LED lights that penetrate the skull. They are thought to be the right wavelength to stimulate the growth of brain cells, slowing down the decline in memory and brain function and reversing symptoms of dementia...searching/Dr Gordon Dougal yields a lot of material which I find really interesting because of parallels with some of my own ideas and experiments...eg. modulating the circadian rhythm by means of photo-stimulation of the pineal gland.I want to investigate this because I suspect that the basic OS of the brain is incredibly slow due to its baseline frequency set by the 24 hr. circadian cycle. As shown by induced "altered states", it is clear that the brain has a wide range of response to chemical stimuli. Likewise, the photo response of the pineal gland indicates the possibility that other brain tissues may also be light sensitive...as Dr. Dougal has apparently demonstrated.
Dementia patient makes 'amazing' progress after using infra-red helmetBy David DerbyshireLast updated at 2:26 AM on 15th July 2008Two months ago Clem Fennell was fading fast.The victim of an aggressive type of dementia, the 57-year-old businessmen was unable to answer the phone, order a meal or string more than a couple of words together.In desperation, his family agreed to try a revolutionary new treatment - a bizarre-looking, experimental helmet devised by a British GP that bathes the brain in infra-red light twice a day.To their astonishment, Mr Fennel began to make an astonishing recovery in just three weeks.My husband, Clem, was fading away. It is as if he is back" said his wife Vickey Fennell, 55. "His personality has started to show again. We are absolutely thrilled."While the helmet has yet to be proven in clinical trials, the family say the effects of the 10 minute sessions are incredible. Mr Fennell can now hold conversations and go shopping unaccompanied.The treatment is the brainchild of Dr Gordon Dougal, a County Durham GP. He believes the device could eventually help thousands of dementia patients."Potentially, this is hugely significant," said Dr Dougal, who is based in Easington, County Durham and is a director of Virulite, a medical research company.Developed with Sunderland University, the helmet has 700 LED lights that penetrate the skull. They are thought to be the right wavelength to stimulate the growth of brain cells, slowing down the decline in memory and brain function and reversing symptoms of dementia...
Rebuilding the Brain's CircuitryScienceDaily (Nov. 24, 2011) — Neuron transplants have repaired brain circuitry and substantially normalized function in mice with a brain disorder, an advance indicating that key areas of the mammalian brain are more reparable than was widely believed.Collaborators from Harvard University, Massachusetts General Hospital, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) transplanted normally functioning embryonic neurons at a carefully selected stage of their development into the hypothalamus of mice unable to respond to leptin, a hormone that regulates metabolism and controls body weight. These mutant mice usually become morbidly obese, but the neuron transplants repaired defective brain circuits, enabling them to respond to leptin and thus experience substantially less weight gain.Repair at the cellular-level of the hypothalamus -- a critical and complex region of the brain that regulates phenomena such as hunger, metabolism, body temperature, and basic behaviors such as sex and aggression -- indicates the possibility of new therapeutic approaches to even higher level conditions such as spinal cord injury, autism, epilepsy, ALS (Lou Gehrig's disease), Parkinson's disease, and Huntington's disease."There are only two areas of the brain that are known to normally undergo ongoing large-scale neuronal replacement during adulthood on a cellular level -- so-called 'neurogenesis,' or the birth of new neurons -- the olfactory bulb and the subregion of the hippocampus called the dentate gyrus, with emerging evidence of lower level ongoing neurogenesis in the hypothalamus," said Jeffrey Macklis, Harvard University professor of stem cell and regenerative biology and HMS professor of neurology at Massachusetts General Hospital, and one of three corresponding authors on the paper. "The neurons that are added during adulthood in both regions are generally smallish and are thought to act a bit like volume controls over specific signaling. Here we've rewired a high-level system of brain circuitry that does not naturally experience neurogenesis, and this restored substantially normal function."The two other senior authors on the paper are Jeffrey Flier, dean of Harvard Medical School, and Matthew Anderson, HMS professor of pathology at BIDMC.The findings are to appear Nov. 25 in Science.In 2005, Jeffrey Flier, then the George C. Reisman professor of medicine at BIDMC, published a landmark study, also in Science, showing that an experimental drug spurred the addition of new neurons in the hypothalamus and offered a potential treatment for obesity. But while the finding was striking, the researchers were unsure whether the new cells functioned like natural neurons.Macklis's laboratory had for several years developed approaches to successfully transplanting developing neurons into circuitry of the cerebral cortex of mice with neurodegeneration or neuronal injury. In a landmark 2000 Nature study, the researchers demonstrated induction of neurogenesis in the cerebral cortex of adult mice, where it does not normally occur. While these and follow-up experiments appeared to rebuild brain circuitry anatomically, the new neurons' level of function remained uncertain.To learn more, Flier, an expert in the biology of obesity, teamed up with Macklis, an expert in central nervous system development and repair, and Anderson, an expert in neuronal circuitries and mouse neurological disease models.The groups used a mouse model in which the brain lacks the ability to respond to leptin. Flier and his lab have long studied this hormone, which is mediated by the hypothalamus. Deaf to leptin's signaling, these mice become dangerously overweight.Prior research had suggested that four main classes of neurons enabled the brain to process leptin signaling. Postdocs Artur Czupryn and Maggie Chen, from Macklis's and Flier's labs, respectively, transplanted and studied the cellular development and integration of progenitor cells and very immature neurons from normal embryos into the hypothalamus of the mutant mice using multiple types of cellular and molecular analysis. To place the transplanted cells in exactly the correct and microscopic region of the recipient hypothalamus, they used a technique called high-resolution ultrasound microscopy, creating what Macklis called a "chimeric hypothalamus" -- like the animals with mixed features from Greek mythology.Postdoc Yu-Dong Zhou, from Anderson's lab, performed in-depth electrophysiological analysis of the transplanted neurons and their function in the recipient circuitry, taking advantage of the neurons' glowing green from a fluorescent jellyfish protein carried as a marker.These nascent neurons survived the transplantation process and developed structurally, molecularly, and electrophysiologically into the four cardinal types of neurons central to leptin signaling. The new neurons integrated functionally into the circuitry, responding to leptin, insulin, and glucose. Treated mice matured and weighed approximately 30 percent less than their untreated siblings or siblings treated in multiple alternate ways.The researchers then investigated the precise extent to which these new neurons had become wired into the brain's circuitry using molecular assays, electron microscopy for visualizing the finest details of circuits, and patch-clamp electrophysiology, a technique in which researchers use small electrodes to investigate the characteristics of individual neurons and pairs of neurons in fine detail. Because the new cells were labeled with fluorescent tags, postdocs Czupryn, Zhou, and Chen could easily locate them.The Zhou and Anderson team found that the newly developed neurons communicated to recipient neurons through normal synaptic contacts, and that the brain, in turn, signaled back. Responding to leptin, insulin and glucose, these neurons had effectively joined the brain's network and rewired the damaged circuitry."It's interesting to note that these embryonic neurons were wired in with less precision than one might think," Flier said. "But that didn't seem to matter. In a sense, these neurons are like antennas that were immediately able to pick up the leptin signal. From an energy-balance perspective, I'm struck that a relatively small number of genetically normal neurons can so efficiently repair the circuitry.""The finding that these embryonic cells are so efficient at integrating with the native neuronal circuitry makes us quite excited about the possibility of applying similar techniques to other neurological and psychiatric diseases of particular interest to our laboratory," said Anderson.The researchers call their findings a proof of concept for the broader idea that new neurons can integrate specifically to modify complex circuits that are defective in a mammalian brain.The researchers are interested in further investigating controlled neurogenesis -- directing growth of new neurons in the brain from within -- the subject of much of Macklis's research as well as Flier's 2005 paper, and a potential route to new therapies."The next step for us is to ask parallel questions of other parts of the brain and spinal cord, those involved in ALS and with spinal cord injuries," Macklis said. "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can."This study was funded by the National Institutes of Health, the Jane and Lee Seidman Fund for Central Nervous System Research, the Emily and Robert Pearlstein Fund for Nervous System Repair, the Picower Foundation, the National Institute of Neurological Disorders and Stroke, Autism Speaks, and the Nancy Lurie Marks Family Foundation.
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