The skin cells of four adults with schizophrenia provide an unprecedented window into how the disease began before they were born.

Scientists call the findings the first proof of concept for the hypothesis that a common genomic pathway lies at the root of schizophreniaand say the work is a step toward the design of treatments that could be administered to pregnant mothers at high risk for bearing a child with schizophrenia, potentially preventing the disease before it begins.

We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here.

In the last 10 years, genetic investigations into schizophrenia have been plagued by an ever-increasing number of mutations found in patients with the disease, says Michal K. Stachowiak, professor of pathology and anatomical sciences at the University at Buffalo. We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here.

The authors gained insight into the early brain pathology of schizophrenia by using skin cells from four adults with schizophrenia and four adults without the disease. The cells were reprogrammed back into induced pluripotent stem cells and then into neuronal progenitor cells.

By studying induced pluripotent stem cells developed from different patients, we recreated the process that takes place during early brain development in utero, thus obtaining an unprecedented view of how this disease develops, said Stachowiak. This work gives us an unprecedented insight into those processes.

Stachowiak says the research, published in Schizophrenia Research, is a proof of concept for a hypothesis he and colleagues published in 2013 that proposed that a single genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways involving more than 100 genes believed to be involved in schizophrenia.

This research shows that there is a common dysregulated gene program that may be impacting more than 1,000 genes and that the great majority of those genes are targeted by the dysregulated nuclear FGFR1, Stachowiak says.

When even one of the many schizophrenia-linked genes undergoes mutation, by affecting the INFS it throws off the development of the brain as a whole, similar to the way that an entire orchestra can be affected by a musician playing just one wrong note, he says.

The next step in the research is to use these induced pluripotent stem cells to further study how the genome becomes dysregulated, allowing the disease to develop.

We will utilize this strategy to grow cerebral organoidsmini-brains in a senseto determine how this genomic dysregulation affects early brain development and to test potential preventive or corrective treatments.

Other researchers from University at Buffalo and the Icahn School of Medicine at Mt. Sinai are coauthors of the work, which was funded by NYSTEM, the Patrick P. Lee Foundation, the National Science Foundation, and the National Institutes of Health.

Source: University at Buffalo

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Medical tourism is alive and well in places all over the world. Thailand, Mexico and Colombia are just some of the destinations where people travel in order to get affordable health care. While finances are the main concern of medical tourists, another reason to make the trip is for services that arent provided in a travelers local city or country. Stem Cells are still a controversial topic in many countries and while research is being conducted, people who might benefit from the treatments may not be able to locate a qualified provider. Why travel so far just for stem cell treatment? Well.

They May Be Able To Cure Cancer

Cancer is one of the most prevalent diseases out there without a cure. With so many people falling ill to this disease, the need for a cure is more important than ever. Stem cell studies are being conducted and researchers have found that stem cell therapy can be used to add healthy cells into the system to suppress the disease while stimulating the growth of new and healthy marrow. Hodgkins Lymphoma, breast cancer and ovarian cancer may benefit the most from these treatments.

They Could Be Capable of Treating Blood Disease

According to NSI Stem Cell, stem cell therapy may be able to provide the body with regenerative and healthy blood cells to combat blood disease. With healthy blood cells in the system, diseases like Sickle Cell Anemia, Fanconi Anemia and Thalassemia could be effectively treated.

They Have The Ability To Treat Injuries and Wounds

By increasing blood vessels and improving blood supply, stem cells could treat both chronic and acute wounds, especially in older patients who dont heal as quickly. Specifically, stem cell therapy could help treat surface wounds, limb gangrene and the replacement of jawbone.

Research Is Being Done On a Huge Variety of Treatment Potential

Stem cells are constantly undergoing research to uncover their potential when it comes to medical treatments. Some of the treatments being explored include:

-Auto-immune Disease: These cells may be able to repair and regenerate damaged tissue for people suffering from Rheumatoid Arthritis, Buergers Disease, and Systemic Lupus.

-Neurodegeneration: They could help with diseases such as MS and Parkinsons.

-Brain & Spinal Cord Injuries: The cells could reduce inflammation and help to form healthy, new tissue.

-Heart Conditions: Stem cells are being utilized to create new blood vessels, reverse tissue loss and regenerate heart muscle tissue.

-Tooth & Hair Replacement: They can help grow thinning hair and replace missing teeth.

-Vision Loss: Retinal cells are being injected into the eyes to improve vision.

-Pancreatic Cells: Healthy Beta Cells in the pancreas are being produced by stem cells. These therapies would help diabetic patients and allow them to decrease their dependence on insulin.

-Orthopedics: Stem cells can be utilized to treat arthritis and ligament/tendon injuries.

-HIV/Aids: Researchers are looking into using stem cells to produce an immune system that is resistant to disease.

The Cost of Treatment Will Vary But Can Be Affordable

While it may seem that the cost of stem cell therapy would be extremely high, the truth is that it varies. It all depends on the treatment necessary but the range could be from $1,000 to $100,000. In the future, insurance companies may even cover costs for some treatments.

Stem Cells Come From Multiple Sources

Stem cells come from a whole variety of places including bone marrow, adipose tissue, blood and umbilical cords. In the case of extraction from adipose tissue, they can be harvested and then put back in a patient after only a couple of days. All of the procedures to acquire the stem cells can be done with willing participants and donors.

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Two years ago, Doreen Flynn of Lewiston, Maine, won her case against the U.S. government, successfully arguing that bone-marrow donors should be able to receive compensation.

Flynn, a mother of three girls who are afflicted with a rare, hereditary blood disease called Fanconis anemia, has a strong interest in bone-marrow transplantation. At the time of the court ruling, her oldest daughter, Jordan, 14, had already received a transplant, and one of the younger twins, Jorja, was expected to need one in a few years.

Locating a marrow donor is often a needle-in-a-haystack affair. The odds that two random individuals will have the same tissue type are less than 1 in 10,000, and the chances are much lower for blacks. Among the precious few potential donors who are matched, nearly half dont follow through with the actual donation. Too often, patients dont survive the time it takes to hunt for another donor.

Allowing compensation for donations could enlarge the pool of potential donors and increase the likelihood that compatible donors will follow through. So the ruling by a three-judge panel of the U.S. Court of Appeals for the Ninth Circuit was promising news for the 12,000 people with cancer and blood diseases currently looking for a marrow donor. (James F. Childress, an ethicist at the University of Virginia, and I submitted an amicus brief in the case.)

Soon after the verdict, Shaka Mitchell, a lawyer in Nashville, Tennessee, and co-founder of the nonprofit MoreMarrowDonors.org, began collecting funds to underwrite $3,000 donor benefits, which were to be given as scholarships, housing allowances or gifts to charity.

Mitchell also invited a team of economists to evaluate the effects of the ruling on peoples willingness to join a registry and to donate when they are found to be a match. The researchers were to specifically assess whether cash payments would be any more or less persuasive than noncash rewards or charitable donations.

Now comes the bad news. On Oct. 2, the U.S. Department of Health and Human Services proposed a new rule that would overturn the Ninth Circuits decision. The government proposes designating a specific form of bone marrow -- circulating bone-marrow stem cells derived from blood -- as a kind of donation that, under the 1984 National Organ Transplant Act, cannot be compensated. If this rule goes into effect (the public comment period ends today), anyone who pays another person for donating these cells would be subject to as much as five years in prison and a $50,000 fine.

The problem with this rule is that donating bone marrow is not like donating an essential organ. Indeed, the Ninth Circuit based its decision on the fact that modern bone-marrow procurement, a process known as apheresis, is more akin to drawing blood. In the early 1980s, when the transplant act was written, the process was more demanding, involving anesthesia and the use of large, hollow needles to extract marrow from a donors hip. But today, more than two-thirds of marrow donations are done via apheresis. Blood is taken from a donors arm, the bone-marrow stem cells are filtered out, and the blood is then returned to the donor through a needle in the other arm.

The Ninth Circuit panel held that these filtered stem cells are merely components of blood -- no different from blood-derived plasma, platelets and clotting factors, for which donor compensation is allowed.

The strongest opposition to compensation comes from the National Marrow Donor Program, the Minneapolis-based nonprofit that maintains the nations largest donor registry. Michael Boo, the programs chief strategy officer, says of reimbursement, Is that what we want people to be motivated by?

The problem with this logic is that altruism has proven insufficient to motivate enough people to give marrow and, as a result, people die.

HHS is presumably under pressure from the National Marrow Donor Program. The department does not otherwise explain its proposed rule except to claim that compensation runs afoul of the transplant acts intent to ban commodification of human stem cells and to curb opportunities for coercion and exploitation, encourage altruistic donation and decrease the likelihood of disease transmission.

But how could such concerns plausibly apply to marrow stem cells and not to blood plasma? The process of collecting plasma is safe: No serious infection has been transmitted in plasma-derived products in nearly two decades, according to the Plasma Protein Therapeutics Association. Strenuous screening and testing in a robust regulatory environment, coupled with voluntary industry standards and sophisticated manufacturing processes, have created what has been called the safest blood product available today.

Outlawing compensation for stem blood cells but not mature blood cells might even violate the constitutional guarantee of equal protection of the law, according to Jeff Rowes, a lawyer at the Institute for Justice, which represented Flynn.

HHS should withdraw its proposal. Ideally, Congress should thwart future regulatory mischief by amending the National Organ Transplant Act to stipulate that marrow stem cells are not organs.

Each year, 2,000 to 3,000 Americans in need of marrow transplants die waiting for a match. Altruism is a virtue, but clearly it is not a dependable motive for marrow donation.

---

Satel, a psychiatrist and a resident scholar at the American Enterprise Institute, is a co-author of Brainwashed: The Seductive Appeal of Mindless Neuroscience. To contact the editor responsible for this story: Mary Duenwald at mduenwald@bloomberg.net.

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Scientific research builds its own momentum as one discovery triggers another, building an ongoing wave of unexpected possibilities. In the world of glaucoma, such a surge began when advances in stem cell research opened doors experts had never imagined.

With this new perspective, they began to consider innovative ways to use specialized cells in the eye, like retinal pigment epithelial cells and ganglion cells. Today researchers continue to follow that path, knowing that each small step they take may lead to future glaucoma treatments.

What Are Retinal Pigment Epithelium (RPE) Cells?

Most people know at least a little about the retina. The retina is a thin tissue that's about an inch in diameter, yet it contains all the photoreceptor cells responsible for beginning vision and their circuits that produce signals that become vision.

If you could look beneath the retina, you'd find a sheet of black cells called the retinal pigment epithelium, (RPE). The easiest way to describe the RPE is to say it supports the retina, but that doesn't begin describe its value. These cells help by renewing the light-absorbing pigments contained in the rod and cone photoreceptors on a daily basis. They also enhance vision by absorbing scattered light. They ensure survival of photoreceptor cells by delivering nutrients, while also serving as a barrier that blocks damaging substances from getting into the retina. The RPE also stops free radicals before they can damage the retina.

The retinal pigment epithelial cells are shaped like a six-sided hexagon, so they fit together as tight as a puzzle. Tiny projections extend from RPE cells, reach out to cover photoreceptor cells and carry nutrients into the cells. When RPE cells are damaged, photoreceptor cells die, ultimately leading to blindness.

What do RPE Cells Have to do Glaucoma?

Glaucoma doesn't typically damage RPE cells, but thanks to advances in stem cell research, it looks like RPE cells may play a crucial role in finding a cure to the degenerative disease. Experts have been studying stem cells for the last seven decades, but their time and effort is beginning to pay off.

Researchers discovered that mature stem cells from various places in the body can be removed and injected with a combination of genes that reprogram the adult cells back into their fresh embryonic state. These cells are called induced pluripotent stem cells. This has been put into practice in the lab, where adult stem cells taken from bone marrow were reprogrammed to grow into various eye cells.

When certain induced pluripotent stem cells are grown together with RPE cells, they can be reprogrammed to turn into photoreceptor cells and other retinal cells. It may even be possible to develop a group of protective nerve cells in the retina -- retinal ganglion cells -- that are damaged by glaucoma. While these amazing discoveries have yet to take shape as a viable treatment option for glaucoma, they certainly make it possible to believe that research using RPE cells may one day lead to a novel stem cell-based treatment that could stop or even reverse the progression of glaucoma.

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Research on retinal pigment epithelial cells promises new future treatment for glaucoma patients - Science Daily

Bone Marrow Stem Cells Comments Off on Research on retinal pigment epithelial cells promises new future treatment for glaucoma patients – Science Daily | February 23rd, 2017

Call me a creature of habit, or just plain boring, but Ive been wearing my hair long, blonde, straight, and side-parted for more than 15 years. The only thing thats really changed is how much of it I have left. Whether the result of bleach, blowouts, stress, hormones, genetics, or all of the above, Ive been shedding like a cheap angora sweater since the age of 30. And, to make matters worse, the hair I do have is fine, fragile, and flyaway.

It wasnt always so. Flipping through old photo albums, I found evidence not only of my natural color (a long-forgotten brown) but also of the graphic, blunt bob I sported in my early 20s. I had oodles of hair back then and would smooth it to my head with pomade and push it behind my earsmuch like Guido Palau did on some of the models in Pradas spring runway show, I noted smugly.

Efforts in the ensuing years to save my ever-sparser strands have been all but futile. You name it, Ive tried it: platelet-rich plasma (PRP), treatments in which your own blood is spun down to platelets and injected into your scalp; mesotherapy (painful vitamin shots, also in the scalp); oral supplements; acupuncture; massage; herbal remedies; and high-tech hair products. Ive even resorted to wearing a silly-looking helmet that bathed my head in low-level laser light and was said to stimulate failing follicles. At this point, I would soak my mane in mares milk under the glow of a waxing supermoon if I thought it would help.

Since hair regeneration is one of the cosmetics-research worlds holiest grails (read: potential multibillion-dollar industry), Ive always hoped that a bona fide breakthrough was around the corner, and prayed it would arrive well ahead of my dotage. As it turns out, it might actually be a five-hour flight from New Yorkand around $10,000away.

It was the celebrity hairstylist Sally Hershberger who whispered the name Roberta F. Shapiro into my ear. You have to call her, she said. She is on to something, and it could be big. Shapiro, a well-respected Manhattan pain-management specialist, treats mostly chronic and acute musculoskeletal and myofascial conditions, like disc disease and degeneration, pinched nerves, meniscal tears, and postLyme disease pain syndromes. Her patient list reads like a whos who of the citys power (and pain-afflicted) elite, and her practice is so busy, she could barely find time to speak with me. According to Shapiro, a possible cure for hair loss was never on her agenda.

But thats exactly what she thinks she may have stumbled upon in the course of her work with stem cell therapy. About eight years ago, she started noticing a commonality among many of her patientsevidence of autoimmune disease with inflammatory components. Frustrated that she was merely palliating their discomfort and not addressing the underlying problems, Shapiro began to look beyond traditional treatments and drug protocols to the potential healing and regenerative benefits of stem cellsspecifically, umbilical cordderived mesenchymal stem cells, which, despite being different from the controversial embryonic stem cells, are used in the U.S. only for research purposes. After extensive vetting, she began bringing patients to the Stem Cell Institute, in Panama City, Panama, which she considers the most sophisticated, safe, and aboveboard facility of its kind. Its not a spa, or a feel-good, instant-fix kind of place, nor is it one of those bogus medical-tourism spots, she says. Lori Kanter Tritsch, a 55-year-old New York architect (and the longtime partner of Este Lauder Executive Chairman William Lauder) is a believer. She accompanied Shapiro to Panama for relief from what had become debilitating neck pain caused by disc bulges and stenosis from arthritis, and agreed to participate in this story only because she believes in the importance of a wider conversation about stem cells. If it works for hair rejuvenation, or other cosmetic purposes, great, but that was not at all my primary goal in having the treatment, Kanter Tritsch said.

While at the Stem Cell Institute, Kanter Tritsch had around 100 million stem cells administered intravenously (a five-minute process) and six intramuscular injections of umbilical cord stem cellderived growth factor (not to be confused with growth hormone, which has been linked to cancer). In the next three months, she experienced increased mobility in her neck, was able to walk better, and could sleep through the night. She also lost a substantial amount of weight (possibly due to the anti-inflammatory effect of the stem cells), and her skin looked great. Not to mention, her previously thinning hair nearly doubled in volume.

As Shapiro explains it, the process of hair loss is twofold. The first factor is decreased blood supply to hair follicles, or ischemia, which causes a slow decrease in their function. This can come from aging, genetics, or autoimmune disease. The second is inflammation. One of the reasons I think mesenchymal stem cells are working to regenerate hair is that stem cell infiltration causes angiogenesis, which is a fancy name for regrowing blood vessels, or in this case, revascularizing the hair follicles, Shapiro notes. Beyond that, she says, the cells have a very strong anti-inflammatory effect.

For clinical studies shes conducting in Panama, Shapiro will employ her proprietary technique of microfracturing, or injecting the stem cells directly into the scalp. She thinks this unique delivery method will set her procedure apart. But, she cautions, this is a growing science, and we are only at the very beginning. PRP is like bathwater compared with amniotic- or placenta-derived growth factor, or better yet, umbilical cordderived stem cells.

Realizing that not everyone has the money or inclination to fly to Panama for a treatment that might not live up to their expectations, Hershberger and Shapiro are in the process of developing Platinum Clinical, a line of hair products containing growth factor harvested from amniotic fluid and placenta. (Shapiro stresses that these are donated remnants of a live birth that would otherwise be discarded.) The products will be available later this year at Hershbergers salons.

With follicular salvation potentially within reach, I wondered if it might be time to revisit the blunt bob of my youth. I call Palau, and inquire about that sleek 1920s do he created for Prada. Fine hair can actually work better for a style like this, he says. In fact, designers often prefer models with fine hair, so the hairstyle doesnt overpower the clothing. Then he confides, Sometimes, if a girl has too much hair, we secretly braid it away. Say what? I know, its the exact opposite of what women want in the real world. But models are starting to realize that fine hair can be an asset. Look, at some point you have to embrace what you have and work with it. Wise words, perhaps, and proof that, like pretty much everything else, thick hair is wasted on the young.

From the Minimalist to the Bold, the 5 Best Hair Trends of New York Fashion Week

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Thanks to Stem Cell Therapy, Thinning Hair May Be a Thing of the Past - W Magazine

Skin Stem Cells Comments Off on Thanks to Stem Cell Therapy, Thinning Hair May Be a Thing of the Past – W Magazine | February 23rd, 2017

February 18, 2017 at 1:00 am | By Lisa Turpin Special to the News-Press

National Donor Day, observed on Feb. 14, is a great time to register as an organ, eye, and tissue donor or to make an appointment to donate blood or platelets.

What could show more love on Valentines Day than the act of giving ones body to help another?

Whether you are a living donor of blood products, stem cells, kidney or liver, register with your state as an organ donor, or make the decision for your loved one to be a donor, you are truly giving the gift of life.

Nationally, more than 119,000 people are waiting for an organ transplant, including 2,091 children.

That doesnt include the number waiting for a bone marrow (stem cell) matched donor which is much more complicated to find.

Significant progress continues in the advancement of transplantation medicine with goals of lengthening life spans, restoring function, appearance, and quality of life.

But it still takes the generosity of donors and their loved ones to make a transplant possible.

Claudia Swigart of Pinehurst believes the true value of organ donation is the gift of time.

In her case, fifteen years with her husband Wendell that she, their five combined children, thirteen grandchildren, and twelve great-grandchildren may not have had.

Wendell and his three siblings all had Polycystic Kidney Disease (PKD), an inherited condition causing cysts to form in the kidney causing damage and kidney failure.

Wendell worked in the mine here in the Valley, shares Claudia.

He found out he had Polycystic Kidney Disease when he was thirty-four and he was careful, he exercised, ate healthy and never smoked. He didnt have any kidney problems until he was sixty-three and had to have open heart surgery.

The surgery was hard on Wendell and his lungs collapsed, he nearly died and it put his kidneys in distress.

He started dialysis after that and was eventually put on the kidney transplant list to receive a transplant at Sacred Heart Medical Center.

The dialysis center in Pinehurst had not opened, so Claudia drove Wendell to Coeur dAlene two times a week for three-hour treatments.

Claudia shared, I am so thankful they opened a dialysis center here. Its exhausting enough to be on dialysis without the traveling.

But there is more to this story.

We always liked telling everyone we could about what happened because we knew God had His hand in the plan, explains Claudia.

They normally traveled to Arizona in their camper for the winter.

Wendell would arrange to have dialysis at the center in Arizona instead of Coeur dAlene.

Well, in 2001 we were planning on leaving so Wendell called to remove himself from the transplant list while we were gone. But, when he called to arrange dialysis at the center in Arizona, they were full! said Claudia.

Since Wendell couldnt have dialysis in Arizona, they were forced to stay home which meant he remained on the transplant list.

Just a few weeks later we got the call! Claudia exclaimed.

Wendell was told he had a matched kidney on the way from a donor in Alaska.

Wendell was sixty-five at the time and he asked if there were any younger people waiting for transplants, anyone still raising young kids who needed it more than he did. His doctor knew he was that kind of man and firmly told him that it was Wendells kidney and he was taking it!

Wendells kidney was such a good match he never experienced any problems or symptoms of rejection.

The transplant coordinators said that the Swigarts could write a letter to the donors family in Alaska if they wanted to have communication with them or thank them.

We wrote a letter to the family two months later and Wendell told them he would take real good care of the kidney, Claudia said.

Wendell did take great care of himself but unfortunately fought esophageal cancer unrelated to his kidneys and passed away in March of 2016 at the age of 80.

The donors family never wrote back, so they do not know the identity of the donor, but Claudia and Wendell were glad they sent the thank-you letter.

We went back to Arizona the year after the transplant and didnt have to worry about dialysis any more. We may never have gotten to do that and he sure wouldnt have had the life he had without the generosity of the donor and their family.

Wendell Swigart had 15 extra quality years with his bride and they celebrated their forty-sixth wedding anniversary before his passing.

Statistics say that only three out of 1,000 people who die are candidates for organ donation, and thats if their families agree to donation.

Even if you register as a donor, it is still up to your family to make the final decision.

Making your family aware that you want to be a donor is the most important thing you can do. For more information visit http://www.donatelife.net or http://www.Organize.org.

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Adult stem cells collected directly from human fat are more stable than other cells -- such as fibroblasts from the skin -- and have the potential for use in anti-aging treatments, according to researchers from the Perelman School of Medicine at the University of Pennsylvania. They made the discovery after developing a new model to study chronological aging of these cells. They published their findings this month in the journal Stem Cells.

Chronological aging shows the natural life cycle of the cells -- as opposed to cells that have been unnaturally replicated multiple times or otherwise manipulated in a lab. In order to preserve the cells in their natural state, Penn researchers developed a system to collect and store them without manipulating them, making them available for this study. They found stem cells collected directly from human fat -- called adipose-derived stem cells (ASCs) -- can make more proteins than originally thought. This gives them the ability to replicate and maintain their stability, a finding that held true in cells collected from patients of all ages.

"Our study shows these cells are very robust, even when they are collected from older patients," said Ivona Percec, MD, director of Basic Science Research in the Center for Human Appearance and the study's lead author. "It also shows these cells can be potentially used safely in the future, because they require minimal manipulation and maintenance."

Stem cells are currently used in a variety of anti-aging treatments and are commonly collected from a variety of tissues. But Percec's team specifically found ASCs to be more stable than other cells, a finding that can potentially open the door to new therapies for the prevention and treatment of aging-related diseases.

"Unlike other adult human stem cells, the rate at which these ASCs multiply stays consistent with age," Percec said. "That means these cells could be far more stable and helpful as we continue to study natural aging."

ASCs are not currently approved for direct use by the Food and Drug Administration, so more research is needed. Percec said the next step for her team is to study how chromatin is regulated in ASCs. Essentially, they want to know how tightly the DNA is wound around proteins inside these cells and how this affects aging. The more open the chromatin is, the more the traits affected by the genes inside will be expressed. Percec said she hopes to find out how ASCs can maintain an open profile with aging.

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Skin Stem Cells Comments Off on Stem cells collected from fat may have use in anti-aging treatments … – Science Daily | February 18th, 2017

As a boy growing up in Nigeria, Abba Zubair dreamed of becoming an astronaut.

But as he prepared to apply to college, an advisor told him to find a different path.

He said it may be a long time before Nigeria sends rockets and astronauts into space, so I should consider something more practical, Zubair saud.

He decided to become a physician, and is currently the medical and scientific director of the Cell Therapy Laboratory at the Mayo Clinic in Jacksonville. And while hell almost certainly never get to make a journey outside the Earths atmosphere himself, if the weather stays good Saturday hell be sending a payload into space.

A SpaceX Falcon 9 rocket is scheduled to launch at 10:01 a.m. Saturday from the Kennedy Space Center on a cargo delivery mission to the International Space Station. Among the cargo it will be carrying are several samples of donated adult stem cells from Zubairs research lab.

Zubair believes adult stem cells, extracted from bone marrow, are the future of regenerative medicine. Currently at the Mayo Clinic in Jacksonville they are being used in clinical trials to treat knee injuries and transplanted lungs.

But a big problem with using stem cells to treat illnesses is that it may require up to 200 million cells to treat a human being and the cells take a long time to reproduce. Based on studies using simulators on Earth, Zubair believes that the stem cells will more quickly mass produce in microgravity.

Thats the hypothesis hell be testing as the stem cells from his lab spend a month aboard the space station. Astronauts will conduct experiments measuring changes in the cells. They will then be returned on an unmanned rocket and Zubair will continue to study them in his lab.

We want to undersrand the process by which stem cells divide so we can grow them at a faster rate and also so we can suppress them when treating cancer, he said.

Zubair became interested in the idea of sending stem cells into space four years ago, when he learned of a request for proposals that involved medicine and outer space. Hes been trying to arrange to send stem cells into space for three years.

In May 2015, he sent stem cells to the edge of space as a hot-air balloon carried a capsule filled with cells from his lab to about 100,000 feet then dropped the capsule. The idea was to test how the cells handled re-entry into the Earths atmosphere.

It turned out well, he said. The cells were alive and functioning.

Zubair was supported in that effort as he is being supported in sending cells to the space station by the Center for Applied Science Technology. Its chief executive is Lee Harvey, a retired Navy pilot and former astronaut candidate who lives in Orange Park.

While stem cells have myriad potential medical applications, one that particularly interests Zubair is the use of them in treating stroke patients. Its a personal cause to Zubair, whose mother died of a stroke in 1997.

Weve shown that an infusion of stem cells at the site of stroke improves the inflammation and also secretes factors for the regeneration of neurons and blood vessels, he said.

Zubair hasnt entirely given up on his old dream of being an astronaut. Hes applied for the civilian astronaut program. But he doesnt expect that to happen.

Im not sure I made a cut, he said. I just wanted to apply.

And he realizes what a long, strange trip hes made.

I have come so far from Africa to here, he said, and now Im sending stem cells into space.

Charlie Patton: (904) 359-4413

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Mayo researcher Abba Zubair is sending stem cells for study on the International Space Station - Florida Times-Union

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Stem cell therapy treatment gives new lease of life to 5-year-old Jamshedpur February 17, 2017 , by Desk 1

Ranchi : Till very recently, it was believed that brain damage is irreversible. However, now with emerging research; we understand that it is possible to repair the damaged brain tissue using cell therapy.

Again, today there are still many people in India who have not preserved their stem cells through cord blood banks. For all those patients, who have lost their hopes in finding a new treatment for neurological related disorders, adult stem cell therapy offers a new hope for such kind of patients.

Dr Alok Sharma, Director, NeuroGen Brain and Spine Institute, Professor and Head of Neurosurgery, LTMG Hospital & LTM Medical College, Sion said Stem cell therapy is emerging as one of the newer treatment options for conditions like Autism, Cerebral Palsy, Mental retardation, Muscular Dytrophy, Spinal Cord Injury, Paralysis, Brain Stroke, Cerebellar Ataxia and Other Neurological Disorders. This treatment has the potential to repair the damaged neural tissue at molecular, structural and functional level.

Dr. NandiniGokulchandran, Deputy Director, Neurogen Brain and Spine Institute saidStem Cell Therapy (SCT) done at NeuroGen Brain and Spine Institute is a very simple and safe procedure. Stem Cells are taken from patients own bone marrow with the help of one needle and are injected back in their Spinal Fluid after processing.

Since they are taken from the patients own body there is no rejection, no side effects, hence making SCT a completely safe procedure.

Today, we are presenting a case study of Ranchi based 5 yrs old Master Dhairya Singh. He is a known case of brain damage due to lack of oxygen but not during birth. Dhairya was born in a normal manner, cried immediately after birth also his birth weight was appropriate.

There were no immediate post-natal complications reported. Dhariya was a normal child till the age of one and half years old. Then one day he suffered from an episode of pneumonia for which he was hospitalized for 6 days.

Last updated:Friday, February 17, 2017

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Stem cell therapy treatment gives new lease of life to 5-year-old - Avenue Mail

Spinal Cord Stem Cells Comments Off on Stem cell therapy treatment gives new lease of life to 5-year-old – Avenue Mail | February 16th, 2017

Wyoming resident and pediatric nurse Elizabeth Groter has partnered with DKMS (Dynamic Kernel Module Support), the nonprofit leading the fight against blood cancer, to host a bone marrow registration drive in Toulon Friday. The event will be held from 3 to 7 p.m. at the Stark County High School cafeteria, and will help register potential lifesaving donors. Anyone in good general health who is between 18 and 55 can register. The process involves filling out a simple form, understanding the donation methods and swabbing the inside of each cheek for 30 seconds. There is no charge to register. Donations help DKMS cover the $65 registration processing fee but are not required. Groter is a pediatric nurse at Childrens Hospital of Illinois, and a DKMS representative. She was inspired to host a drive with DKMS after experiencing first-hand how simple it is to be added to the KDMS bone marrow registry. With her job experience, Groter has met countless children battling leukemia and other blood cancers who are in need of bone marrow transplants, and wanted to make a difference by helping to grow the registry to find lifesaving matches for patients. Groters uncle is a leukemia survivor and another source of her inspiration. Becoming a part of the bone marrow registry to be a possible match for someone with blood cancer is so incredibly easy, and Im going to make it even easier for you. By doing something as simple as this, you could possibly change someones life in an instant, said Groter. According to DKMS, 70 percent of people suffering from blood-related illnesses must rely on donors outside their families to save their life. Swabbing your cheek is all it takes to register as a potential donor. Anyone who wishes to register as a potential donor but is unable to attend Fridays drive can register online at http://www.dkms.org. DKMS is an international nonprofit organization dedicated to eradicating blood cancers like leukemia and other blood-related illnesses. The organization inspires men and woman around to the world to register as bone marrow and blood stem cell donors.

Original post:
Nurse asking people to sign up as bone-marrow donors - Kewanee Star Courier

Bone Marrow Stem Cells Comments Off on Nurse asking people to sign up as bone-marrow donors – Kewanee Star Courier | February 15th, 2017

Submit the press release

Transparency Market Research, in a report titled Stem Cells Market Global Industry Analysis, Size, Share, Growth, Trends and Forecast, 2012 2018, states that the global stem cells market is projected to witness remarkable growth from 2012 to 2018, fueled by increasing government support, unmet medical needs, rising stem cell banking services, and growing medical tourism. Driven by these factors, the global stem cells market is anticipated to expand at a 24.20% CAGR during the forecast period, rising from a value of US$26.2 bn in 2013 to US$119.5 bn by 2018.

Browse the full Stem Cells Market (Adult, Human Embryonic , Induced Pluripotent, Rat-Neural, Umbilical Cord, Cell Production, Cell Acquisition, Expansion, Sub-Culture) Global Industry Analysis, Size, Share, Growth, Trends and Forecast, 2012 2018 report at http://www.transparencymarketresearch.com/stem-cells-market.html

Rise in disposable income in emerging economies, the increasing prevalence of neurodegenerative disorders, development of the contract research industry, and replacement of animal tissue in drug discovery are also anticipated to contribute towards the overall growth of the stem cells market.By product, the stem cells market is categorized into adult stem cells, induced pluripotent stem cells, very small embryonic-like stem cells, human embryonic stem cells, and rat neural stem cells. Adult stem cells, which dominated the overall market in 2011, include mesenchymal stem cells, dental stem cells, neuronal stem cells, hematopoietic stem cells, and umbilical cord stem cells.

On the basis of technology, the stem cells market is segmented into stem cell acquisition, production, cryopreservation, and expansion and sub-culture. Stem cell acquisition is the largest as well as the most rapidly developing technological segment and includes bone marrow harvesting, umbilical cord blood, and apheresis. The segment of stem cell production includes cloning, isolation, in-vitro fertilization, and cell culture.

On the basis of application, the stem cells market is bifurcated into regenerative medicine and drug discovery and development. Regenerative medicine, which holds the larger share in the stem cells market, covers major disciplines such as orthopedics, hematology, wound care, diabetes, incontinence, neurology, oncology, cardiovascular and myocardial infarction, spinal cord injuries, and liver disorders.

Geographically, the global stem cells market is divided into Europe, Asia Pacific, North America, and Rest of the World. North America dominates the overall market, followed by Europe owing to increased prevalence of neurological and cardiac disorders, state initiatives and provision of grants from several organizations, development of innovative therapies, strong research activities, and effective marketing solutions. The Asia Pacific stem cells market is anticipated to witness impressive growth over the next two years thanks to rapidly growing contract research outsourcing and booming medical tourism.

The leading companies profiled in the stem cells market report are Osiris Therapeutics, Advanced Cell Technology, Cellartis AB, Bioheart, Cellular Engineering Technologies, Biotime Inc., Cytori Therapeutics Inc., Angel Biotechnology, Stemcelltechnologies Inc., California Stem Cell Inc., Brainstorm Cell Therapeutics, and Celgene Corporation Inc. These players are analyzed based on aspects such as company and financial overview, product portfolio, business strategies, and recent developments.

Global Stem Cells Market, By Product

Adult Stem Cells Hematopoietic Stem Cells Mesenchymal Stem Cells Neuronal Stem Cells Dental Stem Cells Umbilical Cord Stem Cells Human Embryonic Stem Cells Induced Pluripotent Stem Cells Rat Neural Stem Cells Very Small Embryonic-Like Stem Cells Global Stem Cells Market, By Technology

Stem Cell Acquisition Bone Marrow Harvest for Stem Cells Apheresis for Stem Cells Umbilical Cord Blood Stem Cell Production Therapeutic Cloning for Stem Cells Stem Cells Production By In Vitro Fertilization Stem Cell Isolation Stem Cell Culture Stem Cell Cryopreservation Stem Cells Expansion and Sub-Culture Global Stem Cells Market, By Application

Regenerative Medicine Neurology Orthopedics Oncology Hematology Cardiovascular and Myocardial Infarction Injuries Diabetes Liver Disorders Incontinence Others Drug Discovery and Development Global Stem Cells Market, By Geography

North America Asia Pacific Europe Rest of the World

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Transparency Market Research (TMR) is a global market intelligence company providing business information reports and services. The companys exclusive blend of quantitative forecasting and trend analysis provides forward-looking insight for thousands of decision makers. TMRs experienced team of analysts, researchers, and consultants use proprietary data sources and various tools and techniques to gather and analyze information.

TMRs data repository is continuously updated and revised by a team of research experts so that it always reflects the latest trends and information. With extensive research and analysis capabilities, Transparency Market Research employs rigorous primary and secondary research techniques to develop distinctive data sets and research material for business reports.

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Stem Cells Market Share, Size, Growth & Forecast 2018 Illuminated by New Report - Satellite PR News (press release)

Spinal Cord Stem Cells Comments Off on Stem Cells Market Share, Size, Growth & Forecast 2018 Illuminated by New Report – Satellite PR News (press release) | February 15th, 2017

Growing stem cells on carbon nitride sheets not only activates bone-related genes, but also releases calcium ions when exposed to red light.

Asian Scientist Newsroom | February 15, 2017 | In the Lab

AsianScientist (Feb. 15, 2017) - Light absorbing nanosheets could help bone regrowth, according to a study by researchers at the Ulsan National Institute of Science and Technology published in ACS Nano.

Human bone marrow-derived mesenchymal stem cells (hBMSCs) have been successfully used to treat fractures by regenerating lost bone tissue. To increase the area of bone regeneration, scientists have attempted to enhance the function of stem cells using carbon nanotubes, graphenes and nano-oxides.

In the present study, Professors Kim Kwang S. and Suh Pann-Ghill examined the bone regenerative abilities of carbon nitride (C3N4) nanosheets. Firstly, Kim's team synthesized carbon nitrogen derivatives from melamine compounds. Then, they analyzed the light-absorbing characteristics of C3N4 sheets at a wavelength range of 455-635 nanometers (nm).

They found that the C3N4 sheets emit fluorescence at the wavelength of 635 nm when exposed to red light in a liquid state. The released electrons induced calcium to accumulate in the cytoplasm, thereby speeding up bone regeneration.

Suh's team then conducted studies investigating biomedical applications of this material. To do so, they cultured stem cells and cancer cells in a medium containing 200 g/ml of C3N4 sheets. The material showed no cytotoxicity after two days of testing, suggesting that it is biocompatible.

They also confirmed that C3N4 sheets induce stem cells to differentiate into osteoblasts to promote mineral formation, turning on osteogenic differentiation marker genes such as ALP, BSP, and OCN. Moreover, Runx2 (Runt-related transcription factor 2), a key transcription factor in osteoblast differentiation was also activated. This gene activation resulted in the increased osteoblast differentiation and accelerated bone formation.

This research has opened up the possibility of developing a new medicine that effectively treats skeletal injuries, such as fractures and osteoporosis, said co-author Professor Seo Young-Kyo. It will be a very useful tool for making artificial joints and teeth with the use of 3D printing.

This is an important milestone in the analysis of biomechanical functions needed for the development of biomaterials, including adjuvants for hard tissues such as damaged bones and teeth.

The research team expects that their findings affirm the potential of C3N4 sheets in developing bone formation and directing hBMSCs toward bone regeneration.

The article can be found at: Tiwari et al. (2016) Accelerated Bone Regeneration by Two-Photon Photoactivated Carbon Nitride Nanosheets.

Source: Ulsan National Institute of Science and Technology. Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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Lights, Carbon Nitride, Bone Regeneration! - Asian Scientist Magazine

Bone Marrow Stem Cells Comments Off on Lights, Carbon Nitride, Bone Regeneration! – Asian Scientist Magazine | February 15th, 2017

A 45-year-old Salina man who was diagnosed with leukemia in November is being honored by a bone marrow registration drive Saturday being held at his church.

This is open to the whole community we want to stress that, said Linda Ourada, a member of the health ministry committee at St. Mary Queen of the Universe Catholic Church Parish Center, 230 E. Cloud. The drive will be held from 10 a.m. to 2 p.m. Saturday at the parish center.

Its possible that Phong Vos sister is a match for him, said Vos wife, Mary Pham.

More blood work is planned to determine if the match is close enough. In the meanwhile, the effort to sign up possible donors for Vo or anyone else who needs a bone marrow or peripheral blood stem cell donation is planned.

Pam Welsh, of Salina, said that more than a decade ago, she had her cheek swabbed during a bone marrow registration drive when a Bennington woman needed a match. She said she was called about a year later and told she was one of three people who were a possible match for a patient. She said she went to Salina Regional Health Center to have blood drawn for further testing.

I was given a choice if I wanted to continue in the process, she said. There was never any pressure.

She said that after the blood tests showed she was a good match for the patient, a nurse came to her house to give her shots to boost her stem cell count. Then she and a friend drove to a Wichita hospital, where she underwent an outpatient procedure during which her blood was drawn from one arm and passed through a machine that filtered out blood stem cells before the blood was returned to her other arm. Welsh said the procedure took one day, and then she took the next day off to recover. All expenses were paid by DKMS, an international organization that fights blood cancer and blood disorders, she said.

She said she found out that her blood was given to a 55-year-old man with some form of leukemia. She was told he was still alive when DKMS contacted her for a five-year checkup.

Although she never met him, Welsh said that for her there was a huge reward in knowing that I was able to help this man knowing that I gave him more years.

Its just a good feeling, she said.

Pham said Vo started feeling ill in October and has since undergone chemotherapy at Via Christi Hospital in Wichita and the University of Kansas Medical Center in Kansas City. However, the leukemia has persisted.

Pham, who works for Schwans, has lived in Salina since her grandparents and an aunt, who had lived here since 1975, acted as her sponsors when she immigrated from Vietnam about 21 years ago. She met Vo, who moved here in the late 1990s, at work, and they were married at St. Marys. They have four sons, ages 11, 11, 10 and 8, who have missed their father during his long hospital stays.

When my husband got sick, I was panicked, and I was like, What do I need to do? I dont know what to do, Pham said. Soon she was told about DKMS, which will attempt to match potential donors who register at the Salina drive with Vo and other patients.

The bone marrow registration process for DKMS is simple, said Linda Ourada, who is helping to organize the event.

Its not like drawing blood, Ourada said. People get this mixed up with a blood drive. Theres no blood involved.

A swab is taken from the inside of the cheek, which is then sent for DNA analysis and entered into a global donor computer registry that already includes information about 7 million potential donors.

Every day in the United States, there are 14,000 people waiting for this blood stem cell donation, and only 30 percent get a family match, so that leaves 70 percent out there looking for a suitable donation from someone like us, Ourada said.

Ourada said that in 2012, more than 250 people registered and nine potential matches were contacted for further testing during a bone marrow drive at the church to honor a St. Louis family with Salina ties who had four boys with a rare form of blood cancer.

There is no cost to register as a donor, although monetary donations are being accepted to cover the approximately $65 in costs associated with registering each possible donor.

Potential donors must be between the ages of 18 and 55, in general good health and be willing to donate should their marrow be matched with a person who needs it. Further details about weight and height requirements or other limiting factors can be found at dkmsamericas.org.

The donation process may be accomplished one of two ways, depending on the patients needs. The preferred method is a blood transfusion, but for some patients, an actual bone marrow graft is necessary. The marrow is harvested through a hollow needle from a hip bone in an outpatient surgical procedure.

Bone marrow could be used to treat blood cancers, anemias, genetic disorders and other life-threatening ailments.

The rest is here:
Bone marrow registration drive planned to honor Salina man - Salina Journal (subscription)

Bone Marrow Stem Cells Comments Off on Bone marrow registration drive planned to honor Salina man – Salina Journal (subscription) | February 11th, 2017

When Becky's baby girl started sweating, vomiting and struggling to breathe while breastfeeding , she knew something was wrong.

But despite taking her daughter, Kirsty, to the GP numerous times, she was dismissed as "neurotic" and "unable to cope", a new book reveals.

Even when the six-month-old was finally referred to hospital for X-Rays, paediatricians wrongly diagnosed her condition as bronchitis.

It was only when she was close to death, lying limp and grey in her terrified mum's arms, that the true cause of her illness was diagnosed.

She had severe heart failure after "multiple heart attacks" - which she had suffered from 'silently', unable to communicate or understand them.

Kirsty wasnt gaining weight," writes world-famous cardiac surgeon Stephen Westaby in his remarkable book, Fragile Lives , published today.

"She had a pasty, washed-out look and a cough like a dogs bark.

In reality, this baby was suffering repeated small heart attacks with excruciating chest pain that she could neither communicate nor understand.

"The human body can be outlandishly cruel.

Stephen, from Oxford, operated on Kirsty following her ALCAPA (anomalous left coronary artery from the pulmonary artery) diagnosis.

He found the situation "even worse" than he had thought and, at one point, Becky and her husband were warned they would likely lose their baby.

However, in a desperate, last-ditch attempt to save the youngster's life, Stephen carried out a procedure that had never been done before in a child.

He made her heart smaller by removing almost a third of it, before stitching the organ back up until it looked like a "quivering black banana".

Amazingly, he saved his tiny patient's life.

Today, Kirsty is an 18-year-old, athletic student. She has been able to attend school, go to prom and spend time with her friends.

Her incredible story is one of many featured in Stephen's new book, which details some of the surgeon's most extraordinary and poignant cases.

Others include a woman who lived the horror of locked-in syndrome, and a man whose life was powered by a battery for more than seven years

They all include drama, emotion and blood (lots of it).

Having grown up on a council estate in Scunthorpe, North Lincolnshire, Stephen went into cardiac surgery after watching his granddad die of heart failure.

He tells Mirror Online that, despite his passion for the speciality and his determination, he "never anticipated" he would even get to medical school.

But over the past nearly 40 years, he has become an acclaimed heart surgeon and pioneer, responsible for a number of significant developments in the field.

He invented a T-Y stent - dubbed the "Westaby" tube - to bypass damaged airways, and became the first surgeon to fit a patient with a new type of artificial heart.

The patient, Peter, died aged 69 after over seven years of "extra life". "He was the first to reveal the true potential of blood pump technology," writes Stephen in his book.

The surgeon, who has worked in hospitals in the UK and abroad, says he learned "very early on" that a lot of patients were being turned away for heart transplants.

"Although transplants were great for patients, a lot of others were being turned away," he says. "Very few people can have heart transplants.

"They need someone else to die to get their heart.

He says that, even as a trainee, he was interested in alternative options for the unfortunate patients who could not receive a transplant.

In his book, he describes how, as a student, he was called to assist an operation on a young car crash victim after drinking pints in the pub.

"Bad problem, both the injury and the beer," he writes in his book.

"Not so much the amount of alcohol - we were used to that - more the volume of urine to pass during a four-hour operation."

To get through the surgery without losing concentration or having to leave, he reveals how he used rubber tubing so his urine would run into his surgical boots.

He admits, at one point, he had to cough loudly to disguise the "squelching sound".

When you start doing any surgery, it is scary. It takes you a few months to get into," says the dad-of-two. "Its very taxing."

In subsequent decades, Stephen went on to save hundreds of lives, repeatedly taking chances and pushing the boundaries of heart surgery.

This was all part of being a pioneer, pushing the profession to its limit," he says.

Far from working nine-to-five, the surgeon spent his mornings, afternoons and evenings dedicated to his "day job".

To become a heart surgeon I believe you have to work continuously in the way I did in the old days," he tells Mirror Online.

"We had ward rounds at 5am, then wed operate at 7am.

Stephen would spend the rest of the day operating on patients, before going to the research lab. In the evenings, he'd return to intensive care.

"It needs that sort of dedication," he says.

Indeed, it was this dedication that saw him cut a conference in Australia short to rush back to perform life-saving surgery on Kirsty.

Stephen had been in the country for just 13 hours when he received a call from Nick Archer, his paediatric cardiology colleague at Oxfords John Radcliffe Hospital.

No one calls with good news at night, he notes in his book.

And he was right.

He was told that there was a sick baby with ALCAPA - a rare but serious cardiac anomaly - who desperately needed his help.

He later discovered that Kirsty - in whom fate had installed a lethal self-destruct mechanism" - had shown signs of distress within days of her birth.

Her mum Becky, who already had a three-year-old son, noticed beads of sweat were trickling from her baby's nose whenever she tried to breastfeed her.

However, a paediatrician dismissed the infant's symptoms, Stephen writes in his book, deeming the move an example of "p***-poor medicine".

Within a matter of weeks, Kirsty was sweating, vomiting and struggling to breathe during feeds. However, she had no temperature.

Her concerned mum repeatedly took her to visit the doctor, but was "deemed neurotic and unable to cope", according to Fragile Lives.

At the time, Becky's husband was working abroad, away from their daughter who had a "pasty look" and a "cough like a dog's bark".

After eventually managing to get Kirsty referred to a hospital for X-Rays, Becky was told that her baby was suffering from bronchitis.

Feeling desperate and certain that something "dreadful" was going to happen, she later took the "grey" youngster to another hospital.

But there, she was diagnosed with the same condition.

Now late at night, Becky demanded a further X-Ray. Shockingly, she was "told off for her unreasonable attitude," Stephen writes in his moving book.

However, after the scan, the mum finally had her fears confirmed.

Her daughter was found to have a massive heart, with medics having reportedly misinterpreted heart shadows on her X-Rays as fluid.

Kirsty was rushed to Oxford's specialist childrens heart unit. By then, she was very cold and suffering from severe heart failure, Stephen says.

While flying back from Australia, the surgeon devised an alternative technique for the operation in a bid to increase the baby's chance of survival.

After landing in the UK, however, he was shocked by Kirsty's condition.

"She was emaciated, with virtually no body fat, her heaving ribs and rapid breathing a consequence of her congested lungs, and her abdomen swollen with fluid," he writes.

He adds: Without immediate surgery, shed be dead within days.

Joined by his surgical team, Stephen opened up the baby's small body with a scalpel blade, an electrical saw and a rib retractor while her parents faced an anxious wait.

He describes in his book how he found her heart to be the size of a lemon.

Babies' hearts are typically the size of a walnut.

Stephen then goes on to explain how he replumbed Kirsty's heart's blood supply and removed up to 30 per cent of her organ in an attempt to save her.

Incredibly, the surgery was a success.

The operation "provided some of the first evidence that an infants own cardiac stem cells can regenerate heart muscle and actually remove fibrous tissue," Stephen says.

"Adult hearts cannot recover in the same way," he writes.

Speaking to the Mirror Online, the surgeon describes how he "always put the patient first", even if it meant the possibility of being sacked.

He admits he did things "off piste" and, when he didn't have the money to perform certain procedures, he would raise charitable funds.

I used to operate on everyone from premature babies in their cots to people all the way through to their nineties," he says.

"Every one is precious."

He adds that it takes a "special sort of person" - one who is extremely skilled, gutsy and empathetic - to operate on babies and children.

"I think you find it difficult every time you lose a patient, no matter how high risk they are," he says.

"I used to really hate having to go out of an operating theatre and telling [relatives] their loved one had died.

Stephen, who describes his own story as one of "grim determination", worked on around 12,000 patients during his career.

He estimates between 300 and 400 died earlier than they would have.

I did lose an awful lot of patients," he says.

"There are lots of cases that have stuck with me.

But he adds: "Very few heart patients die because the surgeon doesnt do a good job.

He says some patients suffer complications which aren't managed well, while the quality of the intensive care team can also have an impact.

Nowadays, surgeons' death rates are published. There is also a risk of legal action by grief-stricken and angry relatives, Stephen says.

This 'naming and shaming' culture, he claims, is having a negative effect on the profession and putting graduates off from going into heart surgery.

"It's a worrying time for trainees," he says, describing how there are "serious weaknesses" with the system. "Surgeons now have their death rates published."

He adds that this also means it's difficult to maintain consistent intensive care teams.

"There's a lot of agency nurses, people not familiar with protocol," he says.

Stephen, who established the Oxford Heart Centre in the 1980s, recently retired from surgery after developing Dupuytren's contracture, or a 'claw hand'.

"My hand was warped into the position in which I held the scissors, the needle holder, the sternal saw," the 68-year-old writes in his book.

Now, he is working in two "very exciting" roles, one of which involves a proposed Wellness and Life Science Village in Llanelli, Wales.

He is also medical director at the regenerative medicine firm, Celixir , which he says has made "very important" developments for people with heart failure.

Reflecting on his incredible career, Stephen, who lives with his wife, Sarah, 63, acknowledges that he "didn't give enough time" to his family.

He met his spouse - a "free spirit from Africa" - over an open chest in Accident & Emergency, where she was working as a sister.

Stephen has a 38-year-old daughter - by his first wife, Jane - and a 28-year-old son - by Sarah, as well as two young granddaughters.

I never gave enough time to my kids and my grandchildren," he admits.

But he adds that one of the reasons he wrote his book, "was so they could see why I wasnt with them as much as I could be".

Stephen appeared on ITV's This Morning today, along with Kirsty and Becky.

Viewers have since taken to social media to praise his "amazing" and "remarkable" work, with some calling for him to be knighted.

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Mum dismissed as 'neurotic and unable to cope' after baby girl ... - Mirror.co.uk

Cardiac Stem Cells Comments Off on Mum dismissed as ‘neurotic and unable to cope’ after baby girl … – Mirror.co.uk | February 9th, 2017

Mouse and human skin cells can be reprogrammed to hunt down tumors and deliver anticancer therapies.

Imagine cells that can move through your brain, hunting down cancer and destroying it before they themselves disappear without a trace. Scientists have just achieved that in mice, creating personalized tumor-homing cells from adult skin cells that can shrink brain tumors to 2% to 5% of their original size. Althoughthe strategy has yet to be fully tested in people, the new method could one day give doctors a quick way to develop a custom treatment for aggressive cancers like glioblastoma, which kills most human patients in 1215 months. It only took 4 days to create the tumor-homing cells for the mice.

Glioblastomas are nasty: They spread roots and tendrils of cancerous cells through the brain, making them impossible to remove surgically. They, and other cancers, also exude a chemical signal that attracts stem cellsspecialized cells that can produce multiple cell types in the body. Scientists think stem cells might detect tumors as a wound that needs healing and migrate to help fix the damage. But that gives scientists a secret weaponif they can harness stem cells natural ability to home toward tumor cells, the stem cells could be manipulated to deliver cancer-killing drugs precisely where they are needed.

Other research has already exploited this methodusing neural stem cellswhich give rise to neurons and other brain cellsto hunt down brain cancer in mice and deliver tumor-eradicating drugs. But few have tried this in people, in part because getting those neural stem cells is hard, says Shawn Hingtgen, a stem cell biologist at the University of North Carolina inChapel Hill. Right now, there are three main ways. Scientists can either harvest the cells directly from the patient, harvest them from another patient, or they can genetically reprogram adult cells. But harvesting requires invasive surgery, and bestowing stem cell properties on adult cells takes a two-step process that can increase the risk of the final cells becoming cancerous. And using cells from someone other than the cancer patient being treated might trigger an immune response against the foreign cells.

To solve these problems, Hingtgens group wanted to see whetherthey could skip a step in the genetic reprogramming process, which first transforms adult skin cells into standard stem cells and then turns those into neural stem cells. Treating the skin cells with a biochemical cocktail to promote neural stem cell characteristics seemed to do the trick, turning it into a one-step process, he and his colleague report today in Science Translational Medicine.

But the next big question was whether these cells could home in on tumors in lab dishes, and in animals, like neural stem cells. We were really holding our breath, Hingtgen says. The day we saw the cells crawling across the [Petri] dish toward the tumors, we knew we had something special. The tumor-homing cells moved 500 micronsthe same width as five human hairsin 22 hours, and they could burrow into lab-grown glioblastomas. This is a great start, says Frank Marini, a cancer biologist at the Wake Forest Institute forRegenerative Medicine in Winston-Salem, North Carolina,who was not involved with the study. Incredibly quick and relatively efficient.

The team also engineered the cells to deliver common cancer treatments to glioblastomas in mice. Mouse tumors injected directly with the reprogrammed stem cells shrank 20- to 50-fold in 2428 days compared withnontreated mice. In addition, the survival times of treated rodents nearly doubled. In some mice, the scientists removed tumors after they were established, and injected treatment cells into the cavity. Residual tumors, spawned from the remaining cancer cells, were 3.5 times smaller in the treated mice than in untreated mice.

Marini notes that more rigorous testing is needed to demonstrate just how far the tumor-targeting cells can migrate. In a human brain, the cells would need to travel a matter of millimeters or centimeters, up to 20 times farther than the 500 microns tested here, he says. And other researchers question the need to use cells from the patients own skin. An immune response, triggered by foreign neural stem cells, could actually help attack tumors, says Evan Snyder, a stem cell biologist at Sanford Burnham Prebys Medical Discovery Institute in San Diego, California, and one of the early pioneers of the idea of using stem cells to attack tumors.

Hingtgens group is already testing how far their tumor-homing cells can migrate using larger animal models. They are also getting skin cells from glioblastoma patients to make sure the new method works for the people they hope to help, he says. Everything were doing is to get this to the patient as quickly as we can.

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Reprogrammed skin cells shrink brain tumors in mice | Science | AAAS - Science Magazine

Skin Stem Cells Comments Off on Reprogrammed skin cells shrink brain tumors in mice | Science | AAAS – Science Magazine | February 7th, 2017

The red shows rat cells in the developing heart of a mouse embryo.

A team of scientists from the Salk Institute in the United States created a stir last week with the announcement that they had created hybrid human-pig foetuses.

The story was widely reported, although some outlets took a more hyperbolic or alarmed tone than others.

One might wonder why scientists are even creating human-animal hybrids often referred to as chimeras after the Greek mythological creature with features of lion, goat and snake.

The intention is not to create new and bizarre creatures. Chimeras are incredibly useful for understanding how animals grow and develop. They might one day be used to grow life-saving organs that can be transplanted into humans.

The chimeric pig foetuses produced by Juan Izpisua Belmonte, Jun Wu and their team at the Salk Institute were not allowed to develop to term, and contained human cells in multiple tissues.

The actual proportion of human cells in the chimeras was quite low and their presence appeared to interfere with development. Even so, the study represents a first step in a new avenue of stem cell research which has great promise. But it also raises serious ethical concerns.

A chimera is an organism containing cells from two or more individuals and they do occur in nature, albeit rarely.

Marmoset monkeys often display chimerism in their blood and other tissues as a result of transfer of cells between twins while still in the womb. Following a successful bone marrow transplantation to treat leukaemia, patients have cells in their bone marrow from the donor as well as themselves.

Chimeras can be generated artificially in the laboratory through combining the cells from early embryos of the same or different species. The creation of chimeric mice has been essential for research in developmental biology, genetics, physiology and pathology.

This has been made possible by advances in gene targeting in mouse embryonic stem cells, allowing scientists to alter the cells to express or silence certain genes. Along with the ability to use those cells in the development of chimeras, this has enabled researchers to produce animals that can be used to study how genes influence health and disease.

The pioneers of this technology are Oliver Smithies, Mario Cappechi and Martin Evans, who received a Nobel Prize in Physiology or Medicine in 2007 for their work.

More recently, researchers have become interested in investigating the ability of human pluripotent stem cells master cells obtained from human embryos or created in the laboratory from body cells, to contribute to the tissues of chimeric animals.

Human pluripotent stem cells can be grown indefinitely in the laboratory, and like their mouse counterparts, they can form all the tissues of the body.

Many researchers have now shown they can make functional human tissues of medical significance from human pluripotent cells, such as nerve, heart, liver and kidney cells.

Indeed, cellular therapeutics derived from human pluripotent stem cells are already in clinical trials for spinal cord injury, diabetes and macular degeneration.

However, since 2007 it has been clear that there is not one type of pluripotent stem cell. Rather, a range of different types of pluripotent stem cells have been generated in mice and humans using different techniques.

These cells appear to correspond to cells at different stages of embryonic development, and therefore are likely to have different properties, raising the question about which source of cells is best.

Creating a chimeras has long been the gold standard used by researchers to determine the potential of pluripotent stem cells. While used extensively in animal stem cell research, chimeric studies using human pluripotent stem cells have proved challenging as few human cells survive in human-animal chimeras.

Although the number of human cells in the chimera was low, the findings by the Salk Institute researchers provide a new avenue to address two important goals. The first is the possibility of creating humanised animals for use in biomedical research.

While it is already possible to produce mice with human blood, providing an invaluable insight into how our blood and immune system functions, these animals rely on the use of human fetal tissue and are difficult to make.

The use of pluripotent stem cells in human-animal chimeras might facilitate the efficient production of mice with human blood cells, or other tissues such as liver or heart, on a larger scale. This could greatly enhance our ability to study the development of diseases and to develop new drugs to treat them.

The second potential application of human-animal chimeras comes from some enticing studies performed in Japan in 2010. These studies were able to generate interspecies chimeras following the introduction of rat pluripotent stem cells into a mouse embryo that lacked a key gene for pancreas development.

As a result, the live born mice had a fully functional pancreas comprised entirely of rat cells. If a similar outcome could be achieved with human stem cells in a pig chimera, this would represent a new source of human organs for transplantation.

While scientifically achieving such goals remains a long way off, it is almost certain that progress in pluripotent stem cell biology will enable successful experimentation along these lines. But how much of this work is ethically acceptable, and where do the boundaries lie?

Many people condone the use of pigs for food or as a source of replacement heart valves. They might also be content to use pig embryos and foetuses as incubators to manufacture human pancreas or hearts for those waiting on the transplant list. But the use of human-monkey chimeras may be more contested.

Studies have shown that early cells of the central nervous system made from human embryonic stem cells can engraft and colonise the brain of a newborn mouse. This provides a proof of concept for possible cellular therapies.

But what if human cells were injected into monkey embryos? What would be the ethical and cognitive status of a newborn rhesus monkey whose brain consists of predominantly human nerves?

It may be possible to genetically engineer the cells so that human cells can effectively grow into replacement parts. But what safeguards do we need to ensure that the human cells dont also contribute to other organs of the host, such as the reproductive organs?

While the announcement of a human-pig chimera may have taken many by surprise, regulators and medical researchers well recognise that chimeric research may raise issues in addition to the those already posed by animal research.

However, rather than call for a blanket ban or restricting funding for this area of medical research, it requires careful case-by-case consideration by independent oversight committees fully aware of animal welfare considerations and recognising existing standards.

For example, The 2016 Guidelines for Clinical Research and Translation from the International Society for Stem Cell Research call for research where human gametes could be generated from human-animal chimeras to be prohibited, but supports research using human-animal chimeras conducted under appropriate review and oversight.

Chimeric research will and needs to continue. But equally scientists involved in this field need to continue to discuss and consider the implications of their research with the broader community. Chimeras can all too readily be dismissed as mythological monsters engendering fear.

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Actin is a family of globular multi-functional proteins that form microfilaments. It is found in essentially all eukaryotic cells (the only known exception being nematode sperm), where it may be present at a concentration of over 100 M. An actin protein's mass is roughly 42-kDa, with a diameter of 4 to 7nm, and it is the monomeric subunit of two types of filaments in cells: microfilaments, one of the three major components of the cytoskeleton, and thin filaments, part of the contractile apparatus in muscle cells. It can be present as either a free monomer called G-actin (globular) or as part of a linear polymer microfilament called F-actin (filamentous), both of which are essential for such important cellular functions as the mobility and contraction of cells during cell division.

Actin participates in many important cellular processes, including muscle contraction, cell motility, cell division and cytokinesis, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with cellular membranes.[2] In vertebrates, three main groups of actin isoforms, alpha, beta, and gamma have been identified. The alpha actins, found in muscle tissues, are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton, and as mediators of internal cell motility. It is believed that the diverse range of structures formed by actin enabling it to fulfill such a large range of functions is regulated through the binding of tropomyosin along the filaments.[3]

A cells ability to dynamically form microfilaments provides the scaffolding that allows it to rapidly remodel itself in response to its environment or to the organisms internal signals, for example, to increase cell membrane absorption or increase cell adhesion in order to form cell tissue. Other enzymes or organelles such as cilia can be anchored to this scaffolding in order to control the deformation of the external cell membrane, which allows endocytosis and cytokinesis. It can also produce movement either by itself or with the help of molecular motors. Actin therefore contributes to processes such as the intracellular transport of vesicles and organelles as well as muscular contraction and cellular migration. It therefore plays an important role in embryogenesis, the healing of wounds and the invasivity of cancer cells. The evolutionary origin of actin can be traced to prokaryotic cells, which have equivalent proteins.[4] Actin homologs from prokaryotes and archaea polymerize into different helical or linear filaments consisting of one or multiple strands. However the in-strand contacts and nucleotide binding sites are preserved in prokaryotes and in archaea.[5] Lastly, actin plays an important role in the control of gene expression.

A large number of illnesses and diseases are caused by mutations in alleles of the genes that regulate the production of actin or of its associated proteins. The production of actin is also key to the process of infection by some pathogenic microorganisms. Mutations in the different genes that regulate actin production in humans can cause muscular diseases, variations in the size and function of the heart as well as deafness. The make-up of the cytoskeleton is also related to the pathogenicity of intracellular bacteria and viruses, particularly in the processes related to evading the actions of the immune system.[6]

Actin was first observed experimentally in 1887 by W.D. Halliburton, who extracted a protein from muscle that 'coagulated' preparations of myosin that he called "myosin-ferment".[7] However, Halliburton was unable to further refine his findings, and the discovery of actin is credited instead to Brun Ferenc Straub, a young biochemist working in Albert Szent-Gyrgyi's laboratory at the Institute of Medical Chemistry at the University of Szeged, Hungary.

In 1942, Straub developed a novel technique for extracting muscle protein that allowed him to isolate substantial amounts of relatively pure actin. Straub's method is essentially the same as that used in laboratories today. Szent-Gyorgyi had previously described the more viscous form of myosin produced by slow muscle extractions as 'activated' myosin, and, since Straub's protein produced the activating effect, it was dubbed actin. Adding ATP to a mixture of both proteins (called actomyosin) causes a decrease in viscosity. The hostilities of World War II meant Szent-Gyorgyi and Straub were unable to publish the work in Western scientific journals. Actin therefore only became well known in the West in 1945, when their paper was published as a supplement to the Acta Physiologica Scandinavica.[8] Straub continued to work on actin, and in 1950 reported that actin contains bound ATP[9] and that, during polymerization of the protein into microfilaments, the nucleotide is hydrolyzed to ADP and inorganic phosphate (which remain bound to the microfilament). Straub suggested that the transformation of ATP-bound actin to ADP-bound actin played a role in muscular contraction. In fact, this is true only in smooth muscle, and was not supported through experimentation until 2001.[9][10]

The amino acid sequencing of actin was completed by M. Elzinga and co-workers in 1973.[11] The crystal structure of G-actin was solved in 1990 by Kabsch and colleagues.[12] In the same year, a model for F-actin was proposed by Holmes and colleagues following experiments using co-crystallization with different proteins.[13] The procedure of co-crystallization with different proteins was used repeatedly during the following years, until in 2001 the isolated protein was crystallized along with ADP. However, there is still no high-resolution X-ray structure of F-actin. The crystallization of F-actin was possible due to the use of a rhodamine conjugate that impedes polymerization by blocking the amino acid cys-374.[1] Christine Oriol-Audit died in the same year that actin was first crystallized but she was the researcher that in 1977 first crystallized actin in the absence of Actin Binding Proteins (ABPs). However, the resulting crystals were too small for the available technology of the time.[14]

Although no high-resolution model of actins filamentous form currently exists, in 2008 Sawayas team were able to produce a more exact model of its structure based on multiple crystals of actin dimers that bind in different places.[15] This model has subsequently been further refined by Sawaya and Lorenz. Other approaches such as the use of cryo-electron microscopy and synchrotron radiation have recently allowed increasing resolution and better understanding of the nature of the interactions and conformational changes implicated in the formation of actin filaments.[16][17][18]

Its amino acid sequence is also one of the most highly conserved of the proteins as it has changed little over the course of evolution, differing by no more than 20% in species as diverse as algae and humans. It is therefore considered to have an optimised structure.[4] It has two distinguishing features: it is an enzyme that slowly hydrolizes ATP, the "universal energy currency" of biological processes. However, the ATP is required in order to maintain its structural integrity. Its efficient structure is formed by an almost unique folding process. In addition, it is able to carry out more interactions than any other protein, which allows it to perform a wider variety of functions than other proteins at almost every level of cellular life.[4]Myosin is an example of a protein that bonds with actin. Another example is villin, which can weave actin into bundles or cut the filaments depending on the concentration of calcium cations in the surrounding medium.[19]

Actin is one of the most abundant proteins in eukaryotes, where it is found throughout the cytoplasm.[19] In fact, in muscle fibres it comprises 20% of total cellular protein by weight and between 1% and 5% in other cells. However, there is not only one type of actin, the genes that code for actin are defined as a gene family (a family that in plants contains more than 60 elements, including genes and pseudogenes and in humans more than 30 elements).[4][20] This means that the genetic information of each individual contains instructions that generate actin variants (called isoforms) that possess slightly different functions. This, in turn, means that eukaryotic organisms express different genes that give rise to: -actin, which is found in contractile structures; -actin, found at the expanding edge of cells that use the projection of their cellular structures as their means of mobility; and -actin, which is found in the filaments of stress fibres.[21] In addition to the similarities that exist between an organisms isoforms there is also an evolutionary conservation in the structure and function even between organisms contained in different eukaryotic domains: in bacteria the actin homologue MreB has been identified, which is a protein that is capable of polymerizing into microfilaments;[4][17] and in archaea the homologue Ta0583 is even more similar to the eukaryotic actins.[22]

Cellular actin has two forms: monomeric globules called G-actin and polymeric filaments called F-actin (that is, as filaments made up of many G-actin monomers). F-actin can also be described as a microfilament. Two parallel F-actin strands must rotate 166 degrees to lie correctly on top of each other. This creates the double helix structure of the microfilaments found in the cytoskeleton. Microfilaments measure approximately 7 nm in diameter with the helix repeating every 37nm. Each molecule of actin is bound to a molecule of adenosine triphosphate (ATP) or adenosine diphosphate (ADP) that is associated with a Mg2+ cation. The most commonly found forms of actin, compared to all the possible combinations, are ATP-G-Actin and ADP-F-actin.[23][24]

Scanning electron microscope images indicate that G-actin has a globular structure; however, X-ray crystallography shows that each of these globules consists of two lobes separated by a cleft. This structure represents the ATPase fold, which is a centre of enzymatic catalysis that binds ATP and Mg2+ and hydrolyzes the former to ADP plus phosphate. This fold is a conserved structural motif that is also found in other proteins that interact with triphosphate nucleotides such as hexokinase (an enzyme used in energy metabolism) or in Hsp70 proteins (a protein family that play an important part in protein folding).[25] G-actin is only functional when it contains either ADP or ATP in its cleft but the form that is bound to ATP predominates in cells when actin is present in its free state.[23]

The X-ray crystallography model of actin that was produced by Kabsch from the striated muscle tissue of rabbits is the most commonly used in structural studies as it was the first to be purified. The G-actin crystallized by Kabsch is approximately 67 x 40 x 37 in size, has a molecular mass of 41,785 Da and an estimated isoelectric point of 4.8. Its net charge at pH = 7 is -7.[11][26]

Elzinga and co-workers first determined the complete peptide sequence for this type of actin in 1973, with later work by the same author adding further detail to the model. It contains 374 amino acid residues. Its N-terminus is highly acidic and starts with an acetyled aspartate in its amino group. While its C-terminus is alkaline and is formed by a phenylalanine preceded by a cysteine, which has a degree of functional importance. Both extremes are in close proximity within the I-subdomain. An anomalous N-methylhistidine is located at position 73.[26]

The tertiary structure is formed by two domains known as the large and the small, which are separated by a cleft centred around the location of the bond with ATP-ADP+Pi. Below this there is a deeper notch called a groove. In the native state, despite their names, both have a comparable depth.[11]

The normal convention in topological studies means that a protein is shown with the biggest domain on the left-hand side and the smallest domain on the right-hand side. In this position the smaller domain is in turn divided into two: subdomain I (lower position, residues 1-32, 70-144 and 338-374) and subdomain II (upper position, residues 33-69). The larger domain is also divided in two: subdomain III (lower, residues 145-180 and 270-337) and subdomain IV (higher, residues 181-269). The exposed areas of subdomains I and III are referred to as the barbed ends, while the exposed areas of domains II and IV are termed the pointed" ends. This nomenclature refers to the fact that, due to the small mass of subdomain II actin is polar; the importance of this will be discussed below in the discussion on assembly dynamics. Some authors call the subdomains Ia, Ib, IIa and IIb, respectively.[27]

The most notable supersecondary structure is a five chain beta sheet that is composed of a -meander and a -- clockwise unit. It is present in both domains suggesting that the protein arose from gene duplication.[12]

The classical description of F-actin states that it has a filamentous structure that can be considered to be a single stranded levorotatory helix with a rotation of 166 around the helical axis and an axial translation of 27.5 , or a single stranded dextrorotatory helix with a cross over spacing of 350-380 , with each actin surrounded by four more.[29] The symmetry of the actin polymer at 2.17 subunits per turn of a helix is incompatible with the formation of crystals, which is only possible with a symmetry of exactly 2, 3, 4 or 6 subunits per turn. Therefore, models have to be constructed that explain these anomalies using data from electron microscopy, cryo-electron microscopy, crystallization of dimers in different positions and diffraction of X-rays.[17][18] It should be pointed out that it is not correct to talk of a structure for a molecule as dynamic as the actin filament. In reality we talk of distinct structural states, in these the measurement of axial translation remains constant at 27.5 while the subunit rotation data shows considerable variability, with displacements of up to 10% from its optimum position commonly seen. Some proteins, such as cofilin appear to increase the angle of turn, but again this could be interpreted as the establishment of different "structural states". These could be important in the polymerization process.[30]

There is less agreement regarding measurements of the turn radius and filament thickness: while the first models assigned a longitude of 25 , current X-ray diffraction data, backed up by cryo-electron microscopy suggests a longitude of 23.7 . These studies have shown the precise contact points between monomers. Some are formed with units of the same chain, between the "barbed" end on one monomer and the "pointed" end of the next one. While the monomers in adjacent chains make lateral contact through projections from subdomain IV, with the most important projections being those formed by the C-terminus and the hydrophobic link formed by three bodies involving residues 39-42, 201-203 and 286. This model suggests that a filament is formed by monomers in a "sheet" formation, in which the subdomains turn about themselves, this form is also found in the bacterial actin homologue MreB.[17]

The F-actin polymer is considered to have structural polarity due to the fact that all the microfilaments subunits point towards the same end. This gives rise to a naming convention: the end that possesses an actin subunit that has its ATP binding site exposed is called the "(-) end", while the opposite end where the cleft is directed at a different adjacent monomer is called the "(+) end".[21] The terms "pointed" and "barbed" referring to the two ends of the microfilaments derive from their appearance under transmission electron microscopy when samples are examined following a preparation technique called "decoration". This method consists of the addition of myosin S1 fragments to tissue that has been fixed with tannic acid. This myosin forms polar bonds with actin monomers, giving rise to a configuration that looks like arrows with feather fletchings along its shaft, where the shaft is the actin and the fletchings are the myosin. Following this logic, the end of the microfilament that does not have any protruding myosin is called the point of the arrow (- end) and the other end is called the barbed end (+ end).[31] A S1 fragment is composed of the head and neck domains of myosin II. Under physiological conditions, G-actin (the monomer form) is transformed to F-actin (the polymer form) by ATP, where the role of ATP is essential.[32]

The helical F-actin filament found in muscles also contains a tropomyosin molecule, which is a 40 nanometre long protein that is wrapped around the F-actin helix.[18] During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction. There are other protein molecules bound to the tropomyosin thread, these are the troponins that have three polymers: troponin I, troponin T and troponin C.[33]

Actin can spontaneously acquire a large part of its tertiary structure.[35] However, the way it acquires its fully functional form from its newly synthesized native form is special and almost unique in protein chemistry. The reason for this special route could be the need to avoid the presence of incorrectly folded actin monomers, which could be toxic as they can act as inefficient polymerization terminators. Nevertheless, it is key to establishing the stability of the cytoskeleton, and additionally, it is an essential process for coordinating the cell cycle.[36][37]

CCT is required in order to ensure that folding takes place correctly. CCT is a group II cytosolic molecular chaperone (or chaperonin, a protein that assists in the folding of other macromolecular structures). CCT is formed of a double ring of eight different subunits (hetero-octameric) and it differs from other molecular chaperones, particularly from its homologue GroEL which is found in the Archaea, as it does not require a co-chaperone to act as a lid over the central catalytic cavity. Substrates bind to CCT through specific domains. It was initially thought that it only bound with actin and tubulin, although recent immunoprecipitation studies have shown that it interacts with a large number of polypeptides, which possibly function as substrates. It acts through ATP-dependent conformational changes that on occasion require several rounds of liberation and catalysis in order to complete a reaction.[38]

In order to successfully complete their folding, both actin and tubulin need to interact with another protein called prefoldin, which is a heterohexameric complex (formed by six distinct subunits), in an interaction that is so specific that the molecules have coevolved[citation needed]. Actin complexes with prefoldin while it is still being formed, when it is approximately 145 amino acids long, specifically those at the N-terminal.[39]

Different recognition sub-units are used for actin or tubulin although there is some overlap. In actin the subunits that bind with prefoldin are probably PFD3 and PFD4, which bind in two places one between residues 60-79 and the other between residues 170-198. The actin is recognized, loaded and delivered to the cytosolic chaperonin (CCT) in an open conformation by the inner end of prefoldins "tentacles (see the image and note).[35] The contact when actin is delivered is so brief that a tertiary complex is not formed, immediately freeing the prefoldin.[34]

The CCT then causes actin's sequential folding by forming bonds with its subunits rather than simply enclosing it in its cavity.[40] This is why it possesses specific recognition areas in its apical -domain. The first stage in the folding consists of the recognition of residues 245-249. Next, other determinants establish contact.[41] Both actin and tubulin bind to CCT in open conformations in the absence of ATP. In actins case, two subunits are bound during each conformational change, whereas for tubulin binding takes place with four subunits. Actin has specific binding sequences, which interact with the and -CCT subunits or with -CCT and -CCT. After AMP-PNP is bound to CCT the substrates move within the chaperonins cavity. It also seems that in the case of actin, the CAP protein is required as a possible cofactor in actin's final folding states.[37]

The exact manner by which this process is regulated is still not fully understood, but it is known that the protein PhLP3 (a protein similar to phosducin) inhibits its activity through the formation of a tertiary complex.[38]

Actin is an ATPase, which means that it is an enzyme that hydrolyzes ATP. This group of enzymes is characterised by their slow reaction rates. It is known that this ATPase is active, that is, its speed increases by some 40,000 times when the actin forms part of a filament.[30] A reference value for this rate of hydrolysis under ideal conditions is around 0.3 s1. Then, the Pi remains bound to the actin next to the ADP for a long time, until it is liberated next to the end of the filament.[42]

The exact molecular details of the catalytic mechanism are still not fully understood. Although there is much debate on this issue, it seems certain that a "closed" conformation is required for the hydrolysis of ATP, and it is thought that the residues that are involved in the process move to the appropriate distance.[30] The glutamic acid Glu137 is one of the key residues, which is located in subdomain 1. Its function is to bind the water molecule that produces a nucleophilic attack on the ATPs -phosphate bond, while the nucleotide is strongly bound to subdomains 3 and 4. The slowness of the catalytic process is due to the large distance and skewed position of the water molecule in relation to the reactant. It is highly likely that the conformational change produced by the rotation of the domains between actins G and F forms moves the Glu137 closer allowing its hydrolysis. This model suggests that the polymerization and ATPases function would be decoupled straight away.[17][18]

Principal interactions of structural proteins are at cadherin-based adherens junction. Actin filaments are linked to -actinin and to the membrane through vinculin. The head domain of vinculin associates to E-cadherin via -catenin, -catenin, and -catenin. The tail domain of vinculin binds to membrane lipids and to actin filaments.

Actin has been one of the most highly conserved proteins throughout evolution because it interacts with a large number of other proteins. It has 80.2% sequence conservation at the gene level between Homo sapiens and Saccharomyces cerevisiae (a species of yeast), and 95% conservation of the primary structure of the protein product.[4]

Although most yeasts have only a single actin gene, higher eukaryotes, in general, express several isoforms of actin encoded by a family of related genes. Mammals have at least six actin isoforms coded by separate genes,[43] which are divided into three classes (alpha, beta and gamma) according to their isoelectric points. In general, alpha actins are found in muscle (-skeletal, -aortic smooth, -cardiac, and 2-enteric smooth), whereas beta and gamma isoforms are prominent in non-muscle cells (- and 1-cytoplasmic). Although the amino acid sequences and in vitro properties of the isoforms are highly similar, these isoforms cannot completely substitute for one another in vivo.[44]

The typical actin gene has an approximately 100-nucleotide 5' UTR, a 1200-nucleotide translated region, and a 200-nucleotide 3' UTR. The majority of actin genes are interrupted by introns, with up to six introns in any of 19 well-characterised locations. The high conservation of the family makes actin the favoured model for studies comparing the introns-early and introns-late models of intron evolution.

All non-spherical prokaryotes appear to possess genes such as MreB, which encode homologues of actin; these genes are required for the cell's shape to be maintained. The plasmid-derived gene ParM encodes an actin-like protein whose polymerized form is dynamically unstable, and appears to partition the plasmid DNA into its daughter cells during cell division by a mechanism analogous to that employed by microtubules in eukaryotic mitosis.[45] Actin is found in both smooth and rough endoplasmic reticulums.

Actin polymerization and depolymerization is necessary in chemotaxis and cytokinesis. Nucleating factors are necessary to stimulate actin polymerization. One such nucleating factor is the Arp2/3 complex, which mimics a G-actin dimer in order to stimulate the nucleation (or formation of the first trimer) of monomeric G-actin. The Arp2/3 complex binds to actin filaments at 70 degrees to form new actin branches off existing actin filaments. Also, actin filaments themselves bind ATP, and hydrolysis of this ATP stimulates destabilization of the polymer.

The growth of actin filaments can be regulated by thymosin and profilin. Thymosin binds to G-actin to buffer the polymerizing process, while profilin binds to G-actin to exchange ADP for ATP, promoting the monomeric addition to the barbed, plus end of F-actin filaments.

F-actin is both strong and dynamic. Unlike other polymers, such as DNA, whose constituent elements are bound together with covalent bonds, the monomers of actin filaments are assembled by weaker bonds. The lateral bonds with neighbouring monomers resolve this anomaly, which in theory should weaken the structure as they can be broken by thermal agitation. In addition, the weak bonds give the advantage that the filament ends can easily release or incorporate monomers. This means that the filaments can be rapidly remodelled and can change cellular structure in response to an environmental stimulus. Which, along with the biochemical mechanism by which it is brought about is known as the "assembly dynamic".[6]

Studies focusing on the accumulation and loss of subunits by microfilaments are carried out in vitro (that is, in the laboratory and not on cellular systems) as the polymerization of the resulting actin gives rise to the same F-actin as produced in vivo. The in vivo process is controlled by a multitude of proteins in order to make it responsive to cellular demands, this makes it difficult to observe its basic conditions.[46]

In vitro production takes place in a sequential manner: first, there is the "activation phase", when the bonding and exchange of divalent cations occurs in specific places on the G-actin, which is bound to ATP. This produces a conformational change, sometimes called G*-actin or F-actin monomer as it is very similar to the units that are located on the filament.[27] This prepares it for the "nucleation phase", in which the G-actin gives rise to small unstable fragments of F-actin that are able to polymerize. Unstable dimers and trimers are initially formed. The "elongation phase" begins when there are a sufficiently large number of these short polymers. In this phase the filament forms and rapidly grows through the reversible addition of new monomers at both extremes.[47] Finally, a "stationary equilibrium" is achieved where the G-actin monomers are exchanged at both ends of the microfilament without any change to its total length.[19] In this last phase the "critical concentration Cc" is defined as the ratio between the assembly constant and the dissociation constant for G-actin, where the dynamic for the addition and elimination of dimers and trimers does not produce a change in the microfilament's length. Under normal in vitro conditions Cc is 0.1 M,[48] which means that at higher values polymerization occurs and at lower values depolymerization occurs.[49]

As indicated above, although actin hydrolyzes ATP, everything points to the fact that ATP is not required for actin to be assembled, given that, on one hand, the hydrolysis mainly takes place inside the filament, and on the other hand the ADP could also instigate polymerization. This poses the question of understanding which thermodynamically unfavourable process requires such a prodigious expenditure of energy. The so-called actin cycle, which couples ATP hydrolysis to actin polymerization, consists of the preferential addition of G-actin-ATP monomers to a filaments barbed end, and the simultaneous disassembly of F-actin-ADP monomers at the pointed end where the ADP is subsequently changed into ATP, thereby closing the cycle, this aspect of actin filament formation is known as treadmilling.

ATP is hydrolysed relatively rapidly just after the addition of a G-actin monomer to the filament. There are two hypotheses regarding how this occurs; the stochastic, which suggests that hydrolysis randomly occurs in a manner that is in some way influenced by the neighbouring molecules; and the vectoral, which suggests that hydrolysis only occurs adjacent to other molecules whose ATP has already been hydrolysed. In either case, the resulting Pi is not released, it remains for some time noncovalently bound to actins ADP, in this way there are three species of actin in a filament: ATP-Actin, ADP+Pi-Actin and ADP-Actin.[42][50] The amount of each one of these species present in a filament depends on its length and state: as elongation commences the filament has an approximately equal amount of actin monomers bound with ATP and ADP+Pi and a small amount of ADP-Actin at the (-) end. As the stationary state is reached the situation reverses, with ADP present along the majority of the filament and only the area nearest the (+) end containing ADP+Pi and with ATP only present at the tip.[51]

If we compare the filaments that only contain ADP-Actin with those that include ATP, in the former the critical constants are similar at both ends, while Cc for the other two nucleotides is different: At the (+) end Cc+=0.1 M, while at the (-) end Cc=0.8 M, which gives rise to the following situations:[21]

It is therefore possible to deduce that the energy produced by hydrolysis is used to create a true stationary state, that is a flux, instead of a simple equilibrium, one that is dynamic, polar and attached to the filament. This justifies the expenditure of energy as it promotes essential biological functions.[42] In addition, the configuration of the different monomer types is detected by actin binding proteins, which also control this dynamism, as will be described in the following section.

Microfilament formation by treadmilling has been found to be atypical in stereocilia. In this case the control of the structure's size is totally apical and it is controlled in some way by gene expression, that is, by the total quantity of protein monomer synthesized in any given moment.[52]

The actin cytoskeleton in vivo is not exclusively composed of actin, other proteins are required for its formation, continuance and function. These proteins are called actin-binding proteins (ABP) and they are involved in actins polymerization, depolymerization, stability, organisation in bundles or networks, fragmentation and destruction.[19] The diversity of these proteins is such that actin is thought to be the protein that takes part in the greatest number of protein-protein interactions.[54] For example, G-actin sequestering elements exist that impede its incorporation into microfilaments. There are also proteins that stimulate its polymerization or that give complexity to the synthesizing networks.[21]

Other proteins that bind to actin regulate the length of the microfilaments by cutting them, which gives rise to new active ends for polymerization. For example, if a microfilament with two ends is cut twice, there will be three new microfilaments with six ends. This new situation favors the dynamics of assembly and disassembly. The most notable of these proteins are gelsolin and cofilin. These proteins first achieve a cut by binding to an actin monomer located in the polymer they then change the actin monomers conformation while remaining bound to the newly generated (+) end. This has the effect of impeding the addition or exchange of new G-actin subunits. Depolymerization is encouraged as the (-) ends are not linked to any other molecule.[60]

Other proteins that bind with actin cover the ends of F-actin in order to stabilize them, but they are unable to break them. Examples of this type of protein are CapZ (that binds the (+) ends depending on a cells levels of Ca2+/calmodulin. These levels depend on the cells internal and external signals and are involved in the regulation of its biological functions).[61] Another example is tropomodulin (that binds to the (-) end). Tropomodulin basically acts to stabilize the F-actin present in the myofibrils present in muscle sarcomeres, which are structures characterized by their great stability.[62]

The Arp2/3 complex is widely found in all eukaryotic organisms.[64] It is composed of seven subunits, some of which possess a topology that is clearly related to their biological function: two of the subunits, "ARP2 and "ARP3, have a structure similar to that of actin monomers. This homology allows both units to act as nucleation agents in the polymerization of G-actin and F-actin. This complex is also required in more complicated processes such as in establishing dendritic structures and also in anastomosis (the reconnection of two branching structures that had previously been joined, such as in blood vessels).[65]

There are a number of toxins that interfere with actins dynamics, either by preventing it from polymerizing (latrunculin and cytochalasin D) or by stabilizing it (phalloidin):

Actin forms filaments ('F-actin' or microfilaments) that are essential elements of the eukaryotic cytoskeleton, able to undergo very fast polymerization and depolymerization dynamics. In most cells actin filaments form larger-scale networks which are essential for many key functions in cells:[69]

The actin protein is found in both the cytoplasm and the cell nucleus.[70] Its location is regulated by cell membrane signal transduction pathways that integrate the stimuli that a cell receives stimulating the restructuring of the actin networks in response. In Dictyostelium, phospholipase D has been found to intervene in inositol phosphate pathways.[71] Actin filaments are particularly stable and abundant in muscle fibres. Within the sarcomere (the basic morphological and physiological unit of muscle fibres) actin is present in both the I and A bands; myosin is also present in the latter.[72]

Microfilaments are involved in the movement of all mobile cells, including non-muscular types, and drugs that disrupt F-actin organization (such as the cytochalasins) affect the activity of these cells. Actin comprises 2% of the total amount of proteins in hepatocytes, 10% in fibroblasts, 15% in amoebas and up to 50-80% in activated platelets.[73] There are a number of different types of actin with slightly different structures and functions. This means that -actin is found exclusively in muscle fibres, while types and are found in other cells. In addition, as the latter types have a high turnover rate the majority of them are found outside permanent structures. This means that the microfilaments found in cells other than muscle cells are present in two forms:[74]

Actins cytoskeleton is key to the processes of endocytosis, cytokinesis, determination of cell polarity and morphogenesis in yeasts. In addition to relying on actin these processes involve 20 or 30 associated proteins, which all have a high degree of evolutionary conservation, along with many signalling molecules. Together these elements allow a spatially and temporally modulated assembly that defines a cells response to both internal and external stimuli.[76]

Yeasts contain three main elements that are associated with actin: patches, cables and rings that, despite being present for long, are subject to a dynamic equilibrium due to continual polymerization and depolymerization. They possess a number of accessory proteins including ADF/cofilin, which has a molecular weight of 16kDa and is coded for by a single gene, called COF1; Aip1, a cofilin cofactor that promotes the disassembly of microfilaments; Srv2/CAP, a process regulator related to adenylate cyclase proteins; a profilin with a molecular weight of approximately 14 kDa that is associated with actin monomers; and twinfilin, a 40 kDa protein involved in the organization of patches.[76]

Plant genome studies have revealed the existence of protein isovariants within the actin family of genes. Within Arabidopsis thaliana, a dicotyledon used as a model organism, there are ten types of actin, nine types of -tubulins, six -tubulins, six profilins and dozens of myosins. This diversity is explained by the evolutionary necessity of possessing variants that slightly differ in their temporal and spatial expression.[4] The majority of these proteins were jointly expressed in the tissue analysed. Actin networks are distributed throughout the cytoplasm of cells that have been cultivated in vitro. There is a concentration of the network around the nucleus that is connected via spokes to the cellular cortex, this network is highly dynamic, with a continuous polymerization and depolymerization.[77]

Even though the majority of plant cells have a cell wall that defines their morphology and impedes their movement, their microfilaments can generate sufficient force to achieve a number of cellular activities, such as, the cytoplasmic currents generated by the microfilaments and myosin. Actin is also involved in the movement of organelles and in cellular morphogenesis, which involve cell division as well as the elongation and differentiation of the cell.[79]

The most notable proteins associated with the actin cytoskeleton in plants include:[79]villin, which belongs to the same family as gelsolin/severin and is able to cut microfilaments and bind actin monomers in the presence of calcium cations; fimbrin, which is able to recognize and unite actin monomers and which is involved in the formation of networks (by a different regulation process from that of animals and yeasts);[80]formins, which are able to act as an F-actin polymerization nucleating agent; myosin, a typical molecular motor that is specific to eukaryotes and which in Arabidopsis thaliana is coded for by 17 genes in two distinct classes; CHUP1, which can bind actin and is implicated in the spatial distribution of chloroplasts in the cell; KAM1/MUR3 that define the morphology of the Golgi apparatus as well as the composition of xyloglucans in the cell wall; NtWLIM1, which facilitates the emergence of actin cell structures; and ERD10, which is involved in the association of organelles within membranes and microfilaments and which seems to play a role that is involved in an organisms reaction to stress.

Nuclear actin was first noticed and described in 1977 by Clark and Merriam.[81] Authors describe a protein present in the nuclear fraction, obtained from Xenopus laevis oocytes, which shows the same features such skeletal muscle actin. Since that time there have been many scientific reports about the structure and functions of actin in the nucleus (for review see: Hofmann 2009.[82]) The controlled level of actin in the nucleus, its interaction with actin-binding proteins (ABP) and the presence of different isoforms allows actin to play an important role in many important nuclear processes.

The actin sequence does not contain a nuclear localization signal. The small size of actin (about 43 kDa) allows it to enter the nucleus by passive diffusion.[83] Actin however shuttles between cytoplasm and nucleus quite quickly, which indicates the existence of active transport. The import of actin into the nucleus (probably in a complex with cofilin) is facilitated by the import protein importin 9.[84]

Low level of actin in the nucleus seems to be very important, because actin has two nuclear export signals (NES) into its sequence. Microinjected actin is quickly removed from the nucleus to the cytoplasm. Actin is exported at least in two ways, through exportin 1 (EXP1) and exportin 6 (Exp6).[85][86]

Specific modifications, such as SUMOylation, allows for nuclear actin retention. It was demonstrated that a mutation preventing SUMOylation causes rapid export of beta actin from the nucleus.[87]

Based on the experimental results a general mechanism of nuclear actin transport can be proposed:[87][88]

Nuclear actin exists mainly as a monomer, but can also form dynamic oligomers and short polymers.[89][90][91] Nuclear actin organization varies in different cell types. For example, in Xenopus oocytes (with higher nuclear actin level in comparison to somatic cells) actin forms filaments, which stabilize nucleus architecture. These filaments can be observed under the microscope thanks to fluorophore-conjugated phalloidin staining.[81][83]

In somatic cell nucleus however we cannot observe any actin filaments using this technique.[92] The DNase I inhibition assay, so far the only test which allows the quantification of the polymerized actin directly in biological samples, have revealed that endogenous nuclear actin occurs indeed mainly in a monomeric form.[91]

Precisely controlled level of actin in the cell nucleus, lower than in the cytoplasm, prevents the formation of filaments. The polymerization is also reduced by the limited access to actin monomers, which are bound in complexes with ABPs, mainly cofilin.[88]

Little attention is paid to actin isoforms, however it has been shown that different isoforms of actin are present in the cell nucleus. Actin isoforms, despite of their high sequence similarity, have different biochemical properties such as polymerization and depolymerization kinetic.[93] They also shows different localization and functions.

The level of actin isoforms, both in the cytoplasm and the nucleus, may change for example in response to stimulation of cell growth or arrest of proliferation and transcriptional activity.[94]

Research concerns on nuclear actin are usually focused on isoform beta.[95][96][97][98] However the use of antibodies directed against different actin isoforms allows identifying not only the cytoplasmic beta in the cell nucleus, but also:

The presence of different isoforms of actin may have a significant effect on its function in nuclear processes, especially because the level of individual isoforms can be controlled independently.[91]

Functions of actin in the nucleus are associated with its ability to polymerization, interaction with variety of ABPs and with structural elements of the nucleus. Nuclear actin is involved in:

Due to its ability to conformational changes and interaction with many proteins actin acts as a regulator of formation and activity of protein complexes such as transcriptional complex.[105]

In muscle cells, actomyosin myofibrils makeup much of the cytoplasmic material. These myofibrils are made of thin filaments of actin (typically around 7nm in diameter), and thick filaments of the motor-protein myosin (typically around 15nm in diameter).[121] These myofibrils use energy derived from ATP to create movements of cells, such as muscle contraction.[121] Using the hydrolysis of ATP for energy, myosin heads undergo a cycle during which they attach to thin filaments, exert a tension, and then, depending on the load, perform a power stroke that causes the thin filaments to slide past, shortening the muscle.

In contractile bundles, the actin-bundling protein alpha-actinin separates each thin filament by ~35nm. This increase in distance allows thick filaments to fit in between and interact, enabling deformation or contraction. In deformation, one end of myosin is bound to the plasma membrane, while the other end "walks" toward the plus end of the actin filament. This pulls the membrane into a different shape relative to the cell cortex. For contraction, the myosin molecule is usually bound to two separate filaments and both ends simultaneously "walk" toward their filament's plus end, sliding the actin filaments closer to each other. This results in the shortening, or contraction, of the actin bundle (but not the filament). This mechanism is responsible for muscle contraction and cytokinesis, the division of one cell into two.

The helical F-actin filament found in muscles also contains a tropomyosin molecule, a 40-nanometre protein that is wrapped around the F-actin helix. During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction (the interaction gives rise to a movement between the two proteins that, because it is repeated many times, produces a contraction). There are other protein molecules bound to the tropomyosin thread, these include the troponins that have three polymers: troponin I, troponin T, and troponin C.[33] Tropomyosins regulatory function depends on its interaction with troponin in the presence of Ca2+ ions.[122]

Both actin and myosin are involved in muscle contraction and relaxation and they make up 90% of muscle protein.[123] The overall process is initiated by an external signal, typically through an action potential stimulating the muscle, which contains specialized cells whose interiors are rich in actin and myosin filaments. The contraction-relaxation cycle comprises the following steps:[72]

The traditional image of actins function relates it to the maintenance of the cytoskeleton and, therefore, the organization and movement of organelles, as well as the determination of a cells shape.[74] However, actin has a wider role in eukaryotic cell physiology, in addition to similar functions in prokaryotes.

The majority of mammals possess six different actin genes. Of these, two code for the cytoskeleton (ACTB and ACTG1) while the other four are involved in skeletal striated muscle (ACTA1), smooth muscle tissue (ACTA2), intestinal muscles (ACTG2) and cardiac muscle (ACTC1). The actin in the cytoskeleton is involved in the pathogenic mechanisms of many infectious agents, including HIV. The vast majority of the mutations that affect actin are point mutations that have a dominant effect, with the exception of six mutations involved in nemaline myopathy. This is because in many cases the mutant of the actin monomer acts as a cap by preventing the elongation of F-actin.[27]

ACTA1 is the gene that codes for the -isoform of actin that is predominant in human skeletal striated muscles, although it is also expressed in heart muscle and in the thyroid gland.[141] Its DNA sequence consists of seven exons that produce five known transcripts.[142] The majority of these consist of point mutations causing substitution of amino acids. The mutations are in many cases associated with a phenotype that determines the severity and the course of the affliction.[27][142]

The mutation alters the structure and function of skeletal muscles producing one of three forms of myopathy: type 3 nemaline myopathy, congenital myopathy with an excess of thin myofilaments (CM) and Congenital myopathy with fibre type disproportion (CMFTD). Mutations have also been found that produce core myopathies).[144] Although their phenotypes are similar, in addition to typical nemaline myopathy some specialists distinguish another type of myopathy called actinic nemaline myopathy. In the former, clumps of actin form instead of the typical rods. It is important to state that a patient can show more than one of these phenotypes in a biopsy.[145] The most common symptoms consist of a typical facial morphology (myopathic faces), muscular weakness, a delay in motor development and respiratory difficulties. The course of the illness, its gravity and the age at which it appears are all variable and overlapping forms of myopathy are also found. A symptom of nemalinic myopathy is that Nemaline rods appear in differing places in Type 1 muscle fibres. These rods are non-pathognomonic structures that have a similar composition to the Z disks found in the sarcomere.[146]

The pathogenesis of this myopathy is very varied. Many mutations occur in the region of actins indentation near to its nucleotide binding sites, while others occur in Domain 2, or in the areas where interaction occurs with associated proteins. This goes some way to explain the great variety of clumps that form in these cases, such as Nemaline or Intranuclear Bodies or Zebra Bodies.[27] Changes in actins folding occur in nemaline myopathy as well as changes in its aggregation and there are also changes in the expression of other associated proteins. In some variants where intranuclear bodies are found the changes in the folding masks the nucleuss protein exportation signal so that the accumulation of actin's mutated form occurs in the cell nucleus.[147] On the other hand, it appears that mutations to ACTA1 that give rise to a CFTDM have a greater effect on sarcomeric function than on its structure.[148] Recent investigations have tried to understand this apparent paradox, which suggests there is no clear correlation between the number of rods and muscular weakness. It appears that some mutations are able to induce a greater apoptosis rate in type II muscular fibres.[36]

There are two isoforms that code for actins in the smooth muscle tissue:

ACTG2 codes for the largest actin isoform, which has nine exons, one of which, the one located at the 5' end, is not translated.[149] It is an -actin that is expressed in the enteric smooth muscle. No mutations to this gene have been found that correspond to pathologies, although microarrays have shown that this protein is more often expressed in cases that are resistant to chemotherapy using cisplatin.[150]

ACTA2 codes for an -actin located in the smooth muscle, and also in vascular smooth muscle. It has been noted that the MYH11 mutation could be responsible for at least 14% of hereditary thoracic aortic aneurisms particularly Type 6. This is because the mutated variant produces an incorrect filamentary assembly and a reduced capacity for vascular smooth muscle contraction. Degradation of the aortic media has been recorded in these individuals, with areas of disorganization and hyperplasia as well as stenosis of the aortas vasa vasorum.[151] The number of afflictions that the gene is implicated in is increasing. It has been related to Moyamoya disease and it seems likely that certain mutations in heterozygosis could confer a predisposition to many vascular pathologies, such as thoracic aortic aneurysm and ischaemic heart disease.[152] The -actin found in smooth muscles is also an interesting marker for evaluating the progress of liver cirrhosis.[153]

The ACTC1 gene codes for the -actin isoform present in heart muscle. It was first sequenced by Hamada and co-workers in 1982, when it was found that it is interrupted by five introns.[154] It was the first of the six genes where alleles were found that were implicated in pathological processes.[155]

A number of structural disorders associated with point mutations of this gene have been described that cause malfunctioning of the heart, such as Type 1R dilated cardiomyopathy and Type 11 hypertrophic cardiomyopathy. Certain defects of the atrial septum have been described recently that could also be related to these mutations.[157][158]

Two cases of dilated cardiomyopathy have been studied involving a substitution of highly conserved amino acids belonging to the protein domains that bind and intersperse with the Z discs. This has led to the theory that the dilation is produced by a defect in the transmission of contractile force in the myocytes.[29][155]

The mutations inACTC1 are responsible for at least 5% of hypertrophic cardiomyopathies.[159] The existence of a number of point mutations have also been found:[160]

Pathogenesis appears to involve a compensatory mechanism: the mutated proteins act like toxins with a dominant effect, decreasing the hearts ability to contract causing abnormal mechanical behaviour such that the hypertrophy, that is usually delayed, is a consequence of the cardiac muscles normal response to stress.[161]

Recent studies have discovered ACTC1 mutations that are implicated in two other pathological processes: Infantile idiopathic restrictive cardiomyopathy,[162] and noncompaction of the left ventricular myocardium.[163]

ACTB is a highly complex locus. A number of pseudogenes exist that are distributed throughout the genome, and its sequence contains six exons that can give rise to up to 21 different transcriptions by alternative splicing, which are known as the -actins. Consistent with this complexity, its products are also found in a number of locations and they form part of a wide variety of processes (cytoskeleton, NuA4 histone-acyltransferase complex, cell nucleus) and in addition they are associated with the mechanisms of a great number of pathological processes (carcinomas, juvenile dystonia, infection mechanisms, nervous system malformations and tumour invasion, among others).[164] A new form of actin has been discovered, kappa actin, which appears to substitute for -actin in processes relating to tumours.[165]

Three pathological processes have so far been discovered that are caused by a direct alteration in gene sequence:

The ACTG1 locus codes for the cytosolic -actin protein that is responsible for the formation of cytoskeletal microfilaments. It contains six exons, giving rise to 22 different mRNAs, which produce four complete isoforms whose form of expression is probably dependent on the type of tissue they are found in. It also has two different DNA promoters.[170] It has been noted that the sequences translated from this locus and from that of -actin are very similar to the predicted ones, suggesting a common ancestral sequence that suffered duplication and genetic conversion.[171]

In terms of pathology, it has been associated with processes such as amyloidosis, retinitis pigmentosa, infection mechanisms, kidney diseases and various types of congenital hearing loss.[170]

Six autosomal-dominant point mutations in the sequence have been found to cause various types of hearing loss, particularly sensorineural hearing loss linked to the DFNA 20/26 locus. It seems that they affect the stereocilia of the ciliated cells present in the inner ears Organ of Corti. -actin is the most abundant protein found in human tissue, but it is not very abundant in ciliated cells, which explains the location of the pathology. On the other hand, it appears that the majority of these mutations affect the areas involved in linking with other proteins, particularly actomyosin.[27] Some experiments have suggested that the pathological mechanism for this type of hearing loss relates to the F-actin in the mutations being more sensitive to cofilin than normal.[172]

However, although there is no record of any case, it is known that -actin is also expressed in skeletal muscles, and although it is present in small quantities, model organisms have shown that its absence can give rise to myopathies.[173]

Some infectious agents use actin, especially cytoplasmic actin, in their life cycle. Two basic forms are present in bacteria:

In addition to the previously cited example, actin polymerization is stimulated in the initial steps of the internalization of some viruses, notably HIV, by, for example, inactivating the cofilin complex.[178]

The role that actin plays in the invasion process of cancer cells has still not been determined.[179]

The eukaryotic cytoskeleton of organisms among all taxonomic groups have similar components to actin and tubulin. For example, the protein that is coded by the ACTG2 gene in humans is completely equivalent to the homologues present in rats and mice, even though at a nucleotide level the similarity decreases to 92%.[149] However, there are major differences with the equivalents in prokaryotes (FtsZ and MreB), where the similarity between nucleotide sequences is between 4050% among different bacteria and archaea species. Some authors suggest that the ancestral protein that gave rise to the model eukaryotic actin resembles the proteins present in modern bacterial cytoskeletons.[4][180]

Some authors point out that the behaviour of actin, tubulin and histone, a protein involved in the stabilization and regulation of DNA, are similar in their ability to bind nucleotides and in their ability of take advantage of Brownian motion. It has also been suggested that they all have a common ancestor.[181] Therefore, evolutionary processes resulted in the diversification of ancestral proteins into the varieties present today, conserving, among others, actins as efficient molecules that were able to tackle essential ancestral biological processes, such as endocytosis.[182]

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The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord. The central nervous system is so named because it integrates information it receives from, and coordinates and influences the activity of all parts of the bodies of bilaterally symmetric animalsthat is, all multicellular animals except sponges and radially symmetric animals such as jellyfishand it contains the majority of the nervous system. Many consider the retina[2] and the optic nerve (2nd cranial nerve),[3][4] as well as the olfactory nerves (1st) and olfactory epithelium[5] as parts of the CNS, synapsing directly on brain tissue without intermediate ganglia. Following this classification[which?] the olfactory epithelium is the only central nervous tissue in direct contact with the environment, which opens up for therapeutic treatments. [5] The CNS is contained within the dorsal body cavity, with the brain housed in the cranial cavity and the spinal cord in the spinal canal. In vertebrates, the brain is protected by the skull, while the spinal cord is protected by the vertebrae, both enclosed in the meninges.[6]

The central nervous system consists of the two major structures: the brain and spinal cord. The brain is encased in the skull, and protected by the cranium.[7] The spinal cord is continuous with the brain and lies caudally to the brain,[8] and is protected by the vertebra.[7] The spinal cord reaches from the base of the skull, continues through[7] or starting below[9] the foramen magnum,[7] and terminates roughly level with the first or second lumbar vertebra,[8][9] occupying the upper sections of the vertebral canal.[4]

Microscopically, there are differences between the neurons and tissue of the central nervous system and the peripheral nervous system.[citation needed] The central nervous system is divided in white and gray matter.[8] This can also be seen macroscopically on brain tissue. The white matter consists of axons and oligodendrocytes, while the gray matter consists of neurons and unmyelinated fibers. Both tissues include a number of glial cells (although the white matter contains more), which are often referred to as supporting cells of the central nervous system. Different forms of glial cells have different functions, some acting almost as scaffolding for neuroblasts to climb during neurogenesis such as bergmann glia, while others such as microglia are a specialized form of macrophage, involved in the immune system of the brain as well as the clearance of various metabolites from the brain tissue.[4]Astrocytes may be involved with both clearance of metabolites as well as transport of fuel and various beneficial substances to neurons from the capillaries of the brain. Upon CNS injury astrocytes will proliferate, causing gliosis, a form of neuronal scar tissue, lacking in functional neurons.[4]

The brain (cerebrum as well as midbrain and hindbrain) consists of a cortex, composed of neuron-bodies constituting gray matter, while internally there is more white matter that form tracts and commissures. Apart from cortical gray matter there is also subcortical gray matter making up a large number of different nuclei.[8]

From and to the spinal cord are projections of the peripheral nervous system in the form of spinal nerves (sometimes segmental nerves[7]). The nerves connect the spinal cord to skin, joints, muscles etc. and allow for the transmission of efferent motor as well as afferent sensory signals and stimuli.[8] This allows for voluntary and involuntary motions of muscles, as well as the perception of senses. All in all 31 spinal nerves project from the brain stem,[8] some forming plexa as they branch out, such as the brachial plexa, sacral plexa etc.[7] Each spinal nerve will carry both sensory and motor signals, but the nerves synapse at different regions of the spinal cord, either from the periphery to sensory relay neurons that relay the information to the CNS or from the CNS to motor neurons, which relay the information out.[8]

The spinal cord relays information up to the brain through spinal tracts through the "final common pathway"[8] to the thalamus and ultimately to the cortex. Not all information is relayed to the cortex, and does not reach our immediate consciousness, but is instead transmitted only to the thalamus which sorts and adapts accordingly. This in turn may explain why we are not constantly aware of all aspects of our surroundings.[citation needed]

Schematic image showing the locations of a few tracts of the spinal cord.

Reflexes may also occur without engaging more than one neuron of the central nervous system as in the below example of a short reflex.

Apart from the spinal cord, there are also peripheral nerves of the PNS that synapse through intermediaries or ganglia directly on the CNS. These 12 nerves exist in the head and neck region and are called cranial nerves. Cranial nerves bring information to the CNS to and from the face, as well as to certain muscles (such as the trapezius muscle, which is innervated by accessory nerves[7] as well as certain cervical spinal nerves).[7]

Two pairs of cranial nerves; the olfactory nerves and the optic nerves[2] are often considered structures of the central nervous system. This is because they do not synapse first on peripheral ganglia, but directly on central nervous neurons. The olfactory epithelium is significant in that it consists of central nervous tissue expressed in direct contact to the environment, allowing for administration of certain pharmaceuticals and drugs. [5]

Myelinated peripheral nerve at top, central nervous neuron at bottom

Rostrally to the spinal cord lies the brain.[8] The brain makes up the largest portion of the central nervous system, and is often the main structure referred to when speaking of the nervous system. The brain is the major functional unit of the central nervous system. While the spinal cord has certain processing ability such as that of spinal locomotion and can process reflexes, the brain is the major processing unit of the nervous system.[citation needed]

The brainstem consists of the medulla, the pons and the midbrain. The medulla can be referred to as an extension of the spinal cord, and its organization and functional properties are similar to those of the spinal cord.[8] The tracts passing from the spinal cord to the brain pass through here.[8]

Regulatory functions of the medulla nuclei include control of the blood pressure and breathing. Other nuclei are involved in balance, taste, hearing and control of muscles of the face and neck.[8]

The next structure rostral to the medulla is the pons, which lies on the ventral anterior side of the brainstem. Nuclei in the pons include pontine nuclei which work with the cerebellum and transmit information between the cerebellum and the cerebral cortex.[8] In the dorsal posterior pons lie nuclei that have to do with breathing, sleep and taste.[8]

The midbrain (or mesencephalon) is situated above and rostral to the pons, and includes nuclei linking distinct parts of the motor system, among others the cerebellum, the basal ganglia and both cerebral hemispheres. Additionally parts of the visual and auditory systems are located in the mid brain, including control of automatic eye movements.[8]

The brainstem at large provides entry and exit to the brain for a number of pathways for motor and autonomic control of the face and neck through cranial nerves,[8] and autonomic control of the organs is mediated by the tenth cranial (vagus) nerve.[4] A large portion of the brainstem is involved in such autonomic control of the body. Such functions may engage the heart, blood vessels, pupillae, among others.[8]

The brainstem also hold the reticular formation, a group of nuclei involved in both arousal and alertness.[8]

The cerebellum lies behind the pons. The cerebellum is composed of several dividing fissures and lobes. Its function includes the control of posture, and the coordination of movements of parts of the body, including the eyes and head as well as the limbs. Further it is involved in motion that has been learned and perfected though practice, and will adapt to new learned movements.[8] Despite its previous classification as a motor structure, the cerebellum also displays connections to areas of the cerebral cortex involved in language as well as cognitive functions. These connections have been shown by the use of medical imaging techniques such as fMRI and PET.[8]

The body of the cerebellum holds more neurons than any other structure of the brain including that of the larger cerebrum (or cerebral hemispheres), but is also more extensively understood than other structures of the brain, and includes fewer types of different neurons.[8] It handles and processes sensory stimuli, motor information as well as balance information from the vestibular organ.[8]

The two structures of the diencephalon worth noting are the thalamus and the hypothalamus. The thalamus acts as a linkage between incoming pathways from the peripheral nervous system as well as the optical nerve (though it does not receive input from the olfactory nerve) to the cerebral hemispheres. Previously it was considered only a "relay station", but it is engaged in the sorting of information that will reach cerebral hemispheres (neocortex).[8]

Apart from its function of sorting information from the periphery, the thalamus also connects the cerebellum and basal ganglia with the cerebrum. In common with the aforementioned reticular system the thalamus is involved in wakefullness and consciousness, such as though the SCN.[8]

The hypothalamus engages in functions of a number of primitive emotions or feelings such as hunger, thirst and maternal bonding. This is regulated partly through control of secretion of hormones from the pituitary gland. Additionally the hypothalamus plays a role in motivation and many other behaviors of the individual.[8]

The cerebrum of cerebral hemispheres make up the largest visual portion of the human brain. Various structures combine forming the cerebral hemispheres, among others, the cortex, basal ganglia, amygdala and hippocampus. The hemispheres together control a large portion of the functions of the human brain such as emotion, memory, perception and motor functions. Apart from this the cerebral hemispheres stand for the cognitive capabilities of the brain.[8]

Connecting each of the hemispheres is the corpus callosum as well as several additional commissures.[8] One of the most important parts of the cerebral hemispheres is the cortex, made up of gray matter covering the surface of the brain. Functionally, the cerebral cortex is involved in planning and carrying out of everyday tasks.[8]

The hippocampus is involved in storage of memories, the amygdala plays a role in perception and communication of emotion, while the basal ganglia play a major role in the coordination of voluntary movement.[8]

This differentiates the central nervous system from the peripheral nervous system, which consists of neurons, axons and Schwann cells. Oligodendrocytes and Schwann cells have similar functions in the central and peripheral nervous system respectively. Both act to add myelin sheaths to the axons, which acts as a form of insulation allowing for better and faster proliferation of electrical signals along the nerves. Axons in the central nervous system are often very short (barely a few millimeters) and do not need the same degree of isolation as peripheral nerves do. Some peripheral nerves can be over 1m in length, such as the nerves to the big toe. To ensure signals move at sufficient speed, myelination is needed.

The way in which the Schwann cells and oligodendrocytes myelinate nerves differ. A Schwann cell usually myelinates a single axon, completely surrounding it. Sometimes they may myelinate many axons, especially when in areas of short axons.[7] Oligodendrocytes usually myelinate several axons. They do this by sending out thin projections of their cell membrane which envelop and enclose the axon.

Top; CNS as seen in a median section of a 5 week old embryo. Bottom; CNS seen in a median section of a 3 month old embryo.

During early development of the vertebrate embryo, a longitudinal groove on the neural plate gradually deepens and the ridges on either side of the groove (the neural folds) become elevated, and ultimately meet, transforming the groove into a closed tube called the neural tube.[10] The formation of the neural tube is called neurulation. At this stage, the walls of the neural tube contain proliferating neural stem cells in a region called the ventricular zone. The neural stem cells, principally radial glial cells, multiply and generate neurons through the process of neurogenesis, forming the rudiment of the central nervous system.[11]

The neural tube gives rise to both brain and spinal cord. The anterior (or 'rostral') portion of the neural tube initially differentiates into three brain vesicles (pockets): the prosencephalon at the front, the mesencephalon, and, between the mesencephalon and the spinal cord, the rhombencephalon. (By six weeks in the human embryo) the prosencephalon then divides further into the telencephalon and diencephalon; and the rhombencephalon divides into the metencephalon and myelencephalon. The spinal cord is derived from the posterior or 'caudal' portion of the neural tube.

As a vertebrate grows, these vesicles differentiate further still. The telencephalon differentiates into, among other things, the striatum, the hippocampus and the neocortex, and its cavity becomes the first and second ventricles. Diencephalon elaborations include the subthalamus, hypothalamus, thalamus and epithalamus, and its cavity forms the third ventricle. The tectum, pretectum, cerebral peduncle and other structures develop out of the mesencephalon, and its cavity grows into the mesencephalic duct (cerebral aqueduct). The metencephalon becomes, among other things, the pons and the cerebellum, the myelencephalon forms the medulla oblongata, and their cavities develop into the fourth ventricle.[12]

Development of the neural tube

Rhinencephalon, Amygdala, Hippocampus, Neocortex, Basal ganglia, Lateral ventricles

Epithalamus, Thalamus, Hypothalamus, Subthalamus, Pituitary gland, Pineal gland, Third ventricle

Tectum, Cerebral peduncle, Pretectum, Mesencephalic duct

Pons, Cerebellum

Planarians, members of the phylum Platyhelminthes (flatworms), have the simplest, clearly defined delineation of a nervous system into a central nervous system (CNS) and a peripheral nervous system (PNS).[13][14] Their primitive brains, consisting of two fused anterior ganglia, and longitudinal nerve cords form the CNS; the laterally projecting nerves form the PNS. A molecular study found that more than 95% of the 116 genes involved in the nervous system of planarians, which includes genes related to the CNS, also exist in humans.[15] Like planarians, vertebrates have a distinct CNS and PNS, though more complex than those of planarians.

In arthropods, the ventral nerve cord, the subesophageal ganglia and the supraesophageal ganglia are usually seen as making up the CNS.

The CNS of chordates differs from that of other animals in being placed dorsally in the body, above the gut and notochord/spine.[16] The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: the telencephalon of reptiles is only an appendix to the large olfactory bulb, while in mammals it makes up most of the volume of the CNS. In the human brain, the telencephalon covers most of the diencephalon and the mesencephalon. Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

Mammals which appear in the fossil record after the first fishes, amphibians, and reptiles are the only vertebrates to possess the evolutionarily recent, outermost part of the cerebral cortex known as the neocortex.[17] The neocortex of monotremes (the duck-billed platypus and several species of spiny anteaters) and of marsupials (such as kangaroos, koalas, opossums, wombats, and Tasmanian devils) lack the convolutions gyri and sulci found in the neocortex of most placental mammals (eutherians).[18] Within placental mammals, the size and complexity of the neocortex increased over time. The area of the neocortex of mice is only about 1/100 that of monkeys, and that of monkeys is only about 1/10 that of humans.[17] In addition, rats lack convolutions in their neocortex (possibly also because rats are small mammals), whereas cats have a moderate degree of convolutions, and humans have quite extensive convolutions.[17] Extreme convolution of the neocortex is found in dolphins, possibly related to their complex echolocation.

There are many central nervous system diseases and conditions, including infections of the central nervous system such as encephalitis and poliomyelitis, early-onset neurological disorders including ADHD and autism, late-onset neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and essential tremor, autoimmune and inflammatory diseases such as multiple sclerosis and acute disseminated encephalomyelitis, genetic disorders such as Krabbe's disease and Huntington's disease, as well as amyotrophic lateral sclerosis and adrenoleukodystrophy. Lastly, cancers of the central nervous system can cause severe illness and, when malignant, can have very high mortality rates.

Specialty professional organizations recommend that neurological imaging of the brain be done only to answer a specific clinical question and not as routine screening.[19]

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Spinal Cord Stem Cells Comments Off on Central nervous system – Wikipedia | January 11th, 2017

Pia mater ( or [1]), often referred to as simply the pia, is the delicate innermost layer of the meninges, the membranes surrounding the brain and spinal cord. Pia mater is medieval Latin meaning "tender mother".[1] The other two meningeal membranes are the dura mater and the arachnoid mater. Both the pia and arachnoid mater are derivatives of the neural crest while the dura is derived from embryonic mesoderm. Pia mater is a thin fibrous tissue that is impermeable to fluid. This allows the pia mater to enclose cerebrospinal fluid. By containing this fluid the pia mater works with the other meningeal layers to protect and cushion the brain. The pia mater allows blood vessels to pass through and nourish the brain. The perivascular space created between blood vessels and pia mater functions as a lymphatic system for the brain. When the pia mater becomes irritated and inflamed the result is meningitis.[2]

Pia mater is the thin, translucent, mesh-like meningeal envelope, spanning nearly the entire surface of the brain. It is absent only at the natural openings between the ventricles, the median aperture, and the lateral aperture. The pia firmly adheres to the surface of the brain and loosely connects to the arachnoid layer.[3] Because of this continuum, the layers are often referred to as the pia arachnoid or leptomeninges. A subarachnoid space exists between the arachnoid layer and the pia, into which the choroid plexus releases and maintains the cerebrospinal fluid (CSF). The subarachnoid space contains trabeculae, or fibrous filaments, that connect and bring stability to the two layers, allowing for the appropriate protection from and movement of the proteins, electrolytes, ions, and glucose contained within the CSF.[4] Romanian biologist Viorel Pais, through recent electron microscopy studies, has demonstrated for the first time in the specialty literature that pia mater is formed by cordocytes and blood vessels.

The thin membrane is composed of fibrous connective tissue, which is covered by a sheet of flat cells impermeable to fluid on its outer surface. A network of blood vessels travels to the brain and spinal cord by interlacing through the pia membrane. These capillaries are responsible for nourishing the brain.[5] This vascular membrane is held together by areolar tissue covered by mesothelial cells from the delicate strands of connective tissue called the arachnoid trabeculae. In the perivascular spaces, the pia mater begins as mesothelial lining on the outer surface, but the cells then fade to be replaced by neuroglia elements.[6]

Although the pia mater is primarily structurally similar throughout, it spans both the spinal cords neural tissue and runs down the fissures of the cerebral cortex in the brain. It is often broken down into two categories, the cranial pia mater (pia mater encephali) and the spinal pia mater (pia mater spinalis).

The section of the pia mater enveloping the brain is known as the cranial pia mater. It is anchored to the brain by the processes of astrocytes, which are glial cells responsible for many functions, including maintenance of the extracellular space. The cranial pia mater joins with the ependyma, which lines the cerebral ventricles to form choroid plexuses that produce cerebrospinal fluid. Together with the other meningeal layers, the function of the pia mater is to protect the central nervous system by containing the cerebrospinal fluid, which cushions the brain and spine.[4]

The cranial pia mater covers the surface of the brain. This layer goes in between the cerebral gyri and cerebellar laminae, folding inward to create the tela chorioidea of the third ventricle and the choroid plexuses of the lateral and third ventricles. At the level of the cerebellum, the pia mater membrane is more fragile due to the length of blood vessels as well as decreased connection to the cerebral cortex.[6]

The spinal pia mater closely follows and encloses the curves of the spinal cord, and is attached to it through a connection to the anterior fissure. The pia mater attaches to the dura mater through 21 pairs of denticulate ligaments that pass through the arachnoid mater and dura mater of the spinal cord. These denticular ligaments help to anchor the spinal cord and prevent side to side movement, providing stability.[7] The membrane in this area is much thicker than the cranial pia mater, due to the two-layer composition of the pia membrane. The outer layer, which is made up of mostly connective tissue, is responsible for this thickness. Between the two layers are spaces which exchange information with the subarachnoid cavity as well as blood vessels. At the point where the pia mater reaches the conus medullaris or medullary cone at the end of the spinal cord, the membrane extends as a thin filament called the filum terminale or terminal filum, contained within the lumbar cistern. This filament eventually blends with the dura mater and extends as far as the coccyx, or tailbone. It then fuses with the periosteum, a membrane found at the surface of all bones, and forms the coccygeal ligament. There it is called the central ligament and assists with movements of the trunk of the body.[6]

In conjunction with the other meningeal membranes, pia mater functions to cover and protect the central nervous system (CNS), to protect the blood vessels and enclose the venous sinuses near the CNS, to contain the cerebrospinal fluid (CSF) and to form partitions with the skull.[8] The CSF, pia mater, and other layers of the meninges work together as a protection device for the brain, with the CSF often referred to as the fourth layer of the meninges.

Cerebrospinal fluid is circulated through the ventricles, cisterns, and subarachnoid space within the brain and spinal cord. About 150mL of CSF is always in circulation, constantly being recycled through the daily production of nearly 500mL of fluid. The CSF is primarily secreted by the choroid plexus; however, about one-third of the CSF is secreted by pia mater and the other ventricular ependymal surfaces (the thin epithelial membrane lining the brain and spinal cord canal) and arachnoidal membranes. The CSF travels from the ventricles and cerebellum through three foramina in the brain, emptying into the cerebrum, and ending its cycle in the venous blood via structures like the arachnoid granulations. The pia spans every surface crevice of the brain other than the foramina to allow the circulation of CSF to continue.[9]

Pia mater allows for the formation of perivascular spaces that help serve as the brains lymphatic system. Blood vessels that penetrate the brain first pass across the surface and then go inwards toward the brain. This direction of flow leads to a layer of the pia mater being carried inwards and loosely adhering to the vessels, leading to the production of a space, namely a perivascular space, between the pia mater and each blood vessel. This is critical because the brain lacks a true lymphatic system. In the remainder of the body, small amounts of protein are able to leak from the parenchymal capillaries through the lymphatic system. In the brain, this ends up in the interstitial space. The protein portions are able to leave through the very permeable pia mater and enter the subarachnoid space in order to flow in the cerebrospinal fluid (CSF), eventually ending up in the cerebral veins. The pia mater serves to create these perivascular spaces to allow passage of certain material, such as fluids, proteins, and even extraneous particulate matter such as dead white blood cells from the blood stream to the CSF, and essentially the brain.[9]

A function of the pia mater is that of the bloodbrain barrier (BBB), which keeps the CSF and brain fluid separate from the blood, allowing limited sodium, chlorine, and potassium through, and absolutely no plasma proteins nor organic molecules. Nearby, the ventricles are lined with the ependyma membrane. The CSF is only kept separate through the pia mater. Due to the ependyma and pia maters high permeability, nearly anything entering the CSF is able to enter the brain interstitial fluid.[9] However, regulation of this permeability is achieved through the abundant amount of astrocyte foot processes which are responsible for connecting the capillaries and the pia mater in a way that helps limit the amount of free diffusion going into the CNS.[10] The permeability of the pia then serves to closely connect the interstitial brain fluid and the CSF and allow them to remain nearly homogenous in terms of composition.[9]

The function of the pia mater is more simply visualized through these ordinary occurrences. This last property is evident in cases of head injury. When the head comes into contact with another object, the brain is protected from the skull due to the similarity in density between these two fluids so that the brain does not simply smash through into the skull, but rather its movement is slowed and stopped by the viscous ability of this fluid. The contrast in permeability between the BBB and pia mater mentioned before is also useful in the application of medicine. Drugs that enter the blood stream can not penetrate and function in the brain, but instead must be administered into the cerebrospinal fluid.[9]

The pia mater also functions to deal with the deformation of the spinal cord under compression. Due to the high elastic modulus of the pia mater, it is able to provide a constraint on the surface of the spinal cord. This constraint stops the elongation of the spinal cord, as well as providing a high strain energy. This high strain energy is useful and responsible for the restoration of the spinal cord to its original shape following a period of decompression.[11]

Ventral root afferents are unmyelinated sensory axons located within the pia mater. These ventral root afferents relay sensory information from the pia mater and allow for the transmission of pain from disc herniation and other spinal injury.[12]

The significant increase in the size of the cerebral hemisphere through evolution has been made possible in part through the evolution of the vascular pia mater, which allows nutrient blood vessels to penetrate deep into the intertwined cerebral matter, providing the necessary nutrients in this larger neural mass. Throughout the course of life on earth, the nervous system of animals has continued to evolve to a more compact and increased organization of neurons and other nervous system cells. This process is most evident in vertebrates and especially mammals in which the increased size of the brain is generally condensed into a smaller space through the presence of sulci or fissures on the surface of the hemisphere divided into gyri allowing more superficies of the cortical grey matter to exist. The development of the meninges and the existence of a defined pia mater was first noted in the vertebrates, and has been more and more significant membrane in the brains of mammals with larger brains.[13]

Meningitis is the inflammation of the pia and arachnoid mater. This is often due to bacteria that have entered the subarachnoid space, but can also be caused by viruses, fungi, as well as non-infectious causes such as certain drugs. It is believed that bacterial meningitis is caused by bacteria that enter the central nervous system through the blood stream. The molecular tools these pathogens would require to cross the meningeal layers and the bloodbrain barrier are not yet well understood. Inside the subarachnoid, bacteria replicate and cause inflammation from released toxins such as hydrogen peroxide (H2O2) . These toxins have been found to damage the mitochondria and produce a large scale immune response. Headache and meningismus are often signs of inflammation relayed via trigeminal sensory nerve fibers within the pia mater. Disabling neuropsychological effects are seen in up to half of bacterial meningitis survivors. Research into how bacteria invade and enter the meningeal layers is the next step in prevention of the progression of meningitis.[14]

A tumor growing from the meninges is referred to as a meningioma. Most meningiomas grow from the arachnoid mater inward applying pressure on the pia mater and therefore the brain or spinal cord. While meningiomas make up 20% of primary brain tumors and 12% of spinal cord tumors, 90% of these tumors are benign. Meningiomas tend to grow slowly and therefore symptoms may arise years after initial tumor formation. The symptoms often include headaches and seizures due to the force the tumor creates on sensory receptors. The treatments available for these tumors include surgery and radiation.[15]

Median sagittal section of brain

Coronal section of inferior horn of lateral ventricle

Diagrammatic representation of a section across the top of the skull, showing the membranes of the brain, etc.

Diagrammatic section of scalp

Ultrastructural diagram of the cerebral cortex (Viorel Pais, 2012)

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Spinal Cord Stem Cells Comments Off on Pia mater – Wikipedia | January 8th, 2017

An isolated cardiac muscle cell, beating

Cardiac muscle (heart muscle) is an involuntary, striated muscle that is found in the walls and histological foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle. These three types of muscle all form in the process of myogenesis. The cells that constitute cardiac muscle, called cardiomyocytes or myocardiocytes, predominantly contain only one nucleus, although populations with two to four nuclei do exist.[1][2][pageneeded] The myocardium is the muscle tissue of the heart, and forms a thick middle layer between the outer epicardium layer and the inner endocardium layer.

Coordinated contractions of cardiac muscle cells in the heart pump blood out of the atria and ventricles to the blood vessels of the left/body/systemic and right/lungs/pulmonary circulatory systems. This complex mechanism illustrates systole of the heart.

Cardiac muscle cells, unlike most other tissues in the body, rely on an available blood and electrical supply to deliver oxygen and nutrients and remove waste products such as carbon dioxide. The coronary arteries help fulfill this function.

Cardiac muscle has cross striations formed by rotating segments of thick and thin protein filaments. Like skeletal muscle, the primary structural proteins of cardiac muscle are myosin and actin. The actin filaments are thin, causing the lighter appearance of the I bands in striated muscle, whereas the myosin filament is thicker, lending a darker appearance to the alternating A bands as observed with electron microscopy. However, in contrast to skeletal muscle, cardiac muscle cells are typically branch-like instead of linear.

Another histological difference between cardiac muscle and skeletal muscle is that the T-tubules in the cardiac muscle are bigger and wider and track laterally to the Z-discs. There are fewer T-tubules in comparison with skeletal muscle. The diad is a structure in the cardiac myocyte located at the sarcomere Z-line. It is composed of a single T-tubule paired with a terminal cisterna of the sarcoplasmic reticulum. The diad plays an important role in excitation-contraction coupling by juxtaposing an inlet for the action potential near a source of Ca2+ ions. This way, the wave of depolarization can be coupled to calcium-mediated cardiac muscle contraction via the sliding filament mechanism. Cardiac muscle forms these instead of the triads formed between the sarcoplasmic reticulum in skeletal muscle and T-tubules. T-tubules play critical role in excitation-contraction coupling (ECC). Recently, the action potentials of T-tubules were recorded optically by Guixue Bu et al.[3]

The cardiac syncytium is a network of cardiomyocytes connected to each other by intercalated discs that enable the rapid transmission of electrical impulses through the network, enabling the syncytium to act in a coordinated contraction of the myocardium. There is an atrial syncytium and a ventricular syncytium that are connected by cardiac connection fibres.[4] Electrical resistance through intercalated discs is very low, thus allowing free diffusion of ions. The ease of ion movement along cardiac muscle fibers axes is such that action potentials are able to travel from one cardiac muscle cell to the next, facing only slight resistance. Each syncytium obeys the all or none law.[5]

Intercalated discs are complex adhering structures that connect the single cardiomyocytes to an electrochemical syncytium (in contrast to the skeletal muscle, which becomes a multicellular syncytium during mammalian embryonic development). The discs are responsible mainly for force transmission during muscle contraction. Intercalated discs consist of three different types of cell-cell junctions: the actin filament anchoring adherens junctions, the intermediate filament anchoring desmosomes , and gap junctions. They allow action potentials to spread between cardiac cells by permitting the passage of ions between cells, producing depolarization of the heart muscle. However, novel molecular biological and comprehensive studies unequivocally showed that intercalated discs consist for the most part of mixed-type adhering junctions named area composita (pl. areae compositae) representing an amalgamation of typical desmosomal and fascia adhaerens proteins (in contrast to various epithelia).[6][7][8] The authors discuss the high importance of these findings for the understanding of inherited cardiomyopathies (such as arrhythmogenic right ventricular cardiomyopathy).

Under light microscopy, intercalated discs appear as thin, typically dark-staining lines dividing adjacent cardiac muscle cells. The intercalated discs run perpendicular to the direction of muscle fibers. Under electron microscopy, an intercalated disc's path appears more complex. At low magnification, this may appear as a convoluted electron dense structure overlying the location of the obscured Z-line. At high magnification, the intercalated disc's path appears even more convoluted, with both longitudinal and transverse areas appearing in longitudinal section.[9]

In contrast to skeletal muscle, cardiac muscle requires extracellular calcium ions for contraction to occur. Like skeletal muscle, the initiation and upshoot of the action potential in ventricular cardiomyocytes is derived from the entry of sodium ions across the sarcolemma in a regenerative process. However, an inward flux of extracellular calcium ions through L-type calcium channels sustains the depolarization of cardiac muscle cells for a longer duration. The reason for the calcium dependence is due to the mechanism of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum that must occur during normal excitation-contraction (EC) coupling to cause contraction. Once the intracellular concentration of calcium increases, calcium ions bind to the protein troponin, which allows myosin to bind to actin and contraction to occur.

Until recently, it was commonly believed that cardiac muscle cells could not be regenerated. However, a study reported in the April 3, 2009 issue of Science contradicts that belief.[10] Olaf Bergmann and his colleagues at the Karolinska Institute in Stockholm tested samples of heart muscle from people born before 1955 who had very little cardiac muscle around their heart, many showing with disabilities from this abnormality. By using DNA samples from many hearts, the researchers estimated that a 4-year-old renews about 20% of heart muscle cells per year, and about 69 percent of the heart muscle cells of a 50-year-old were generated after he or she was born.

One way that cardiomyocyte regeneration occurs is through the division of pre-existing cardiomyocytes during the normal aging process.[11] The division process of pre-existing cardiomyocytes has also been shown to increase in areas adjacent to sites of myocardial injury. In addition, certain growth factors promote the self-renewal of endogenous cardiomyocytes and cardiac stem cells. For example, insulin-like growth factor 1, hepatocyte growth factor, and high-mobility group protein B1 increase cardiac stem cell migration to the affected area, as well as the proliferation and survival of these cells.[12] Some members of the fibroblast growth factor family also induce cell-cycle re-entry of small cardiomyocytes. Vascular endothelial growth factor also plays an important role in the recruitment of native cardiac cells to an infarct site in addition to its angiogenic effect.

Based on the natural role of stem cells in cardiomyocyte regeneration, researchers and clinicians are increasingly interested in using these cells to induce regeneration of damaged tissue. Various stem cell lineages have been shown to be able to differentiate into cardiomyocytes, including bone marrow stem cells. For example, in one study, researchers transplanted bone marrow cells, which included a population of stem cells, adjacent to an infarct site in a mouse model. Nine days after surgery, the researchers found a new band of regenerating myocardium.[13] However, this regeneration was not observed when the injected population of cells was devoid of stem cells, which strongly suggests that it was the stem cell population that contributed to the myocardium regeneration. Other clinical trials have shown that autologous bone marrow cell transplants delivered via the infarct-related artery decreases the infarct area compared to patients not given the cell therapy.[14]

Occlusion (blockage) of the coronary arteries by atherosclerosis and/or thrombosis can lead to myocardial infarction (heart attack), where part of the myocardium is injured due to ischemia (not receiving enough oxygen). This occurs because coronary arteries are functional end arteries - i.e. there is almost no overlap in the areas supplied by different arteries (anastomoses) so that if one fails, others cannot adequately perfuse the region, unlike in other tissues.

Certain viruses lead to myocarditis (inflammation of the myocardium). Cardiomyopathies are inherent diseases of the myocardium, many of which are caused by genetic mutations.

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Cardiac Stem Cells Comments Off on Cardiac muscle – Wikipedia | November 27th, 2016