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

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Glioblastoma is an aggressive form of brain cancer that kills most patients within two years of diagnosis. In tests on mice last year, a team at the University of North Carolina at Chapel Hill showed that adult skin cells could be transformed into stem cells and used to hunt down the tumors. Building on that, they've now found that the process works with human cells, and can be administered quickly enough to beat the ticking time-bombs.

Treatments for glioblastoma include the usual options of surgery, radiation therapy and chemotherapy, but none of them are particularly effective. The tumors are capable of spreading tendrils out into the brain and it can grow back in a matter of months after being removed. As a result, the median survival rate of sufferers is under 18 months, and there's only a 30 percent chance of living more than two years.

"We desperately need something better," says Shawn Hingtgen, the lead researcher on the study.

To find that something better, last year the scientists took fibroblasts a type of skin cell that generates collagen and connective tissue from mice and reprogrammed them into neural stem cells. These stem cells seek out and latch onto cancer cells in the brain, but alone are powerless to fight the tumor. To give them that ability, the scientists engineered them to express a particular cancer-killing protein. The result was mice that lived between 160 and 220 percent longer.

The next step was to test the process with human cells, and in the year since, the team has found that the results are just as promising. The technique differs slightly when scaled up to humans. The patient would be administered with a substance called a prodrug, which by itself does nothing, until it's triggered. The stem cells are engineered to carry a protein that acts as that trigger, activating the prodrug only in a small halo around itself instead of affecting the entire body. That allows the drug to target only a small desired area, ideally reducing the ill side effects that treatments like chemotherapy can induce.

Importantly, the technique can be administered quickly, to give the patients the best chance at survival.

"Speed is essential," says Hingtgen. "It used to take weeks to convert human skin cells to stem cells. But brain cancer patients don't have weeks and months to wait for us to generate these therapies. The new process we developed to create these stem cells is fast enough and simple enough to be used to treat a patient."

The treatment is an important step, but there's still a long way to go.

"We're one to two years away from clinical trials, but for the first time, we showed that our strategy for treating glioblastoma works with human stem cells and human cancers," says Hingtgen. "This is a big step toward a real treatment and making a real difference."

The research was published in the journal Science Translational Medicine.

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Brain cancers can be really tricky to treat. Some, such as glioblastomas, spread roots through the brain tissue, meaning they are often impossible to remove surgically, leading to tragically low survival rates. But researchers are working on a way touse stem cells to track down the cancer, kill it, and then melt it away. By doing this, theyve managed to shrink brain tumors in mice to2 to 5 percent of their original size.

The trick has already been tried before using neural stem cells to hunt down and deliver cancer-killing drugs to tumors in mice. But there is a problem: It's tricky to getneural stem cells from humans. The safest way of doing this would be to take adult cells and then induce them in a two-step process to become neural stem cells. This, however, takes time.

Speed is essential, saysShawn Hingtgen, who led the research published in Science Translational Medicine. It used to take weeks to convert human skin cells to stem cells. But brain cancer patients dont have weeks and months to wait for us to generate these therapies. The new process we developed to create these stem cells is fast enough and simple enough to be used to treat a patient.

The researchers found a way to speed the process up byremoving one of the steps entirely, allowing them to produce the neural stem cells from adult skin cells in just four days. Usually, researchers would need to take the skin cell, induce it to become a generic stem cell, and then push it towards becoming a neural stem cell.

But by treating the skin cells with a cocktail of biochemicals, they were able to get the cells to turn straight into neural stem cells. They then tested these to see if they still had the same properties as original neutral stem cells and home in on tumors both in a petri dish and in animals models. They found they behaved exactly the same.

The final step was to see if they could somehow engineer these newly created cells to deliver drugs that are targeted at the cancer. They therefore got the stem cells to carry a particular protein that activates what is called a prodrug, which the researchers describe as forming a halo of drugs around the stem cell.

Were one to two years away from clinical trials, but for the first time, we showed that our strategy for treating glioblastoma works with human stem cells and human cancers, says Hingtgen. This is a big step toward a real treatment and making a real difference.

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Scientists Reprogram Skin Cells To Hunt Down And Shrink Brain Tumors - IFLScience

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The Scientist

Regulators OK Clinical Trials Using Donor Stem Cells The Scientist WIKIPEDIA, TMHLEEResearchers in Japan who have been developing a cell therapy for macular degeneration received support from health authorities this week (February 1) to begin a clinical trial using donor-derived induced pluripotent stem (IPS) cells ...

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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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Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem celllike state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. Although these cells meet the defining criteria for pluripotent stem cells, it is not known if iPSCs and embryonic stem cells differ in clinically significant ways. Mouse iPSCs were first reported in 2006, and human iPSCs were first reported in late 2007. Mouse iPSCs demonstrate important characteristics of pluripotent stem cells, including expressing stem cell markers, forming tumors containing cells from all three germ layers, and being able to contribute to many different tissues when injected into mouse embryos at a very early stage in development. Human iPSCs also express stem cell markers and are capable of generating cells characteristic of all three germ layers.

Although additional research is needed, iPSCs are already useful tools for drug development and modeling of diseases, and scientists hope to use them in transplantation medicine. Viruses are currently used to introduce the reprogramming factors into adult cells, and this process must be carefully controlled and tested before the technique can lead to useful treatment for humans. In animal studies, the virus used to introduce the stem cell factors sometimes causes cancers. Researchers are currently investigating non-viral delivery strategies. In any case, this breakthrough discovery has created a powerful new way to "de-differentiate" cells whose developmental fates had been previously assumed to be determined. In addition, tissues derived from iPSCs will be a nearly identical match to the cell donor and thus probably avoid rejection by the immune system. The iPSC strategy creates pluripotent stem cells that, together with studies of other types of pluripotent stem cells, will help researchers learn how to reprogram cells to repair damaged tissues in the human body.

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Stem Cell Basics VI. | stemcells.nih.gov

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Cardiac muscle cells or cardiomyocytes (also known as myocardiocytes[1] or cardiac myocytes[2]) are the muscle cells (myocytes) that make up the cardiac muscle. Each myocardial cell contains myofibrils, which are specialized organelles consisting of long chains of sarcomeres, the fundamental contractile units of muscle cells. Cardiomyocytes show striations similar to those on skeletal muscle cells. Unlike multinucleated skeletal cells, the majority of cardiomyocytes contain only one nucleus, although they may have as many as four.[3] Cardiomyocytes have a high mitochondrial density, which allows them to produce adenosine triphosphate (ATP) quickly, making them highly resistant to fatigue.

There are two types of cells within the heart: the cardiomyocytes and the cardiac pacemaker cells. Cardiomyocytes make up the atria (the chambers in which blood enters the heart) and the ventricles (the chambers where blood is collected and pumped out of the heart). These cells must be able to shorten and lengthen their fibers and the fibers must be flexible enough to stretch. These functions are critical to the proper form during the beating of the heart.[4]

Cardiac pacemaker cells carry the impulses that are responsible for the beating of the heart. They are distributed throughout the heart and are responsible for several functions. First, they are responsible for being able to spontaneously generate and send out electrical impulses. They also must be able to receive and respond to electrical impulses from the brain. Lastly, they must be able to transfer electrical impulses from cell to cell.[5]

All of these cells are connected by cellular bridges. Porous junctions called intercalated discs form junctions between the cells. They permit sodium, potassium and calcium to easily diffuse from cell to cell. This makes it easier for depolarization and repolarization in the myocardium. Because of these junctions and bridges the heart muscle is able to act as a single coordinated unit.[6][7]

The cardiomyocytes are about 100 to 150 micrometers long and 15 to 20 micrometers in diameter.[citation needed]

Humans are born with a set number of heart muscle cells, or cardiomyocytes, which increase in size as heart grows larger during childhood development. Recent evidence suggests that cardiomyocytes are actually slowly turned over as we age, but that less than 50% of the cardiomyocytes we are born with are replaced during a normal life span.[8] The growth of individual cardiomyocytes not only occurs during normal heart development, it also occurs in response to extensive exercise (athletic heart syndrome), heart disease, or heart muscle injury such as after a myocardial infarction. A healthy adult cardiomyocyte has a cylindrical shape that is approximately 100m long and 10-25m in diameter. Cardiomyocyte hypertrophy occurs through sarcomerogenesis, the creation of new sarcomere units in the cell. During heart volume overload, cardiomyocytes grow through eccentric hypertrophy.[9] The cardiomyocytes extend lengthwise but have the same diameter, resulting in ventricular dilation. During heart pressure overload, cardiomyocytes grow through concentric hypertrophy.[9] The cardiomyocytes grow larger in diameter but have the same length, resulting in heart wall thickening.

Cardiac action potential consists of two cycles, a rest phase and an active phase. These two phases are commonly understood as systole and diastole. The rest phase is considered polarized. The resting potential during this phase of the beat separates the ions such as sodium, potassium and calcium. Myocardial cells possess the property of automaticity or spontaneous depolarization. This is the direct result of a membrane which allows sodium ions to slowly enter the cell until the threshold is reached for depolarization. Calcium ions follow and extend the depolarization even further. Once calcium stops moving inward, potassium ions move out slowly to produce repolarization. The very slow repolarization of the CMC membrane is responsible for the long refractory period.[10][11]

Myocardial infarction, commonly known as a heart attack, occurs when the heart's supplementary blood vessels are obstructed by an unstable build-up of white blood cells, cholesterol, and fat. With no blood flow, the cells die, causing whole portions of cardiac tissue to die. Once these tissues are lost, they cannot be replaced, thus causing permanent damage. Current research indicates, however, that it may be possible to repair damaged cardiac tissue with stem cells,[12] as human embryonic stem cells can differentiate into cardiomyocytes under appropriate conditions.[13]

The cardiomyopathies are a group of diseases characterized by disruptions to cardiac muscle cell growth and / or organization. Presentation can range from asymptomatic to sudden cardiac death.

Cardiomyopathy can be caused by genetic, endocrine, environmental, or other factors.

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Stem cells have tremendous promise to help us understand and treat a range of diseases, injuries and other health-related conditions. Their potential is evident in the use of blood stem cells to treat diseases of the blood, a therapy that has saved the lives of thousands of children with leukemia; and can be seen in the use of stem cells for tissue grafts to treat diseases or injury to the bone, skin and surface of the eye. Important clinical trials involving stem cells are underway for many other conditions and researchers continue to explore new avenues using stem cells in medicine.

There is still a lot to learn about stem cells, however, and their current applications as treatments are sometimes exaggerated by the media and other parties who do not fully understand the science and current limitations, and also by clinics looking to capitalize on the hype by selling treatments to chronically ill or seriously injured patients. The information on this page is intended to help you understand both the potential and the limitations of stem cells at this point in time, and to help you spot some of the misinformation that is widely circulated by clinics offering unproven treatments.

It is important to discuss these Nine Things to Know and any research or information you gather with your primary care physician and other trusted members of your healthcare team in deciding what is right for you.

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Nine Things to Know About Stem Cell Treatments

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While a number of companies have dabbled in this space, the following players are facilitating the development of iPS cell therapies: Cellular Dynamics International (CDI), RIKEN, Cynata Therapeutics, and Astellas (previously Ocata Therapeutics).

While each iPS cell therapy group is considered in detail below, Cellular Dynamics International (CDI) is featured first, because it dominates the iPSC industry. CDI also recently split into two business units, a Life Science Unit and a Therapeutics Unit, demonstrating a commercial strategy for its iPS cell therapy development.

Cellular Dynamics International (CDI) is headquartered in Madison, Wisconsin, although it provides technical support and sales information from both the United States and Japan. CDI was founded in 2004 and listed on NASDAQ in July 2013. The company had global revenues of $16.7 million in 2014 and currently has 150+ employees. It also has an extremely robust patent portfolio containing more than 800 patents, of which 130 pertain to iPSCs.

According to the company, CDI is the worlds largest producer of fully functional human cells derived from induced pluripotent stem (iPS) cells.[1] Their trademarked, iCell Cardiomyocytes, derived from iPSCs, are human cardiac cells used to aid drug discovery, improve the predictability of a drugs worth, and screen for toxicity. In addition, CDI provides: iCell Endothelial Cells for use in vascular-targeted drug discovery and tissue regeneration, iCell Hepatocytes, and iCell Neurons for pre-clinical drug discovery, toxicity testing, disease prediction, and cellular research.[2] As such, CDIs main role with regard to iPCS therapy development is the production of industrial-scale, clinical-grade iPSCs.

As mentioned previously, induced pluripotent stem cells were first produced in 2006 from mouse cells and in 2007 from human cells, by Shinya Yamanaka at Kyoto University,[3] who also won the Nobel Prize in Medicine or Physiology for his work on iPSCs.[4] Yamanaka has ties toCellular Dynamics International as a member of the scientific advisory board of iPS Academia Japan.

IPS Academia Japan was originally established to manage the patents and technology of Yamanakas work, and is now the distributor of several of Cellular Dynamics products, including iCell Neurons, iCell Cardiomyocytes, and iCell Endothelial Cells.[5] Importantly, in 2010 Cellular Dynamics became the first foreign company to be granted rights to use Yamanakas iPSC patent portfolio.Not only has CDI licensed rights to Yamanakas patents, but it also has a license to use Otsu, Japan-based Takara Bios RetroNectin product, which it uses as a tool to produce its iCell and MyCell products.[6] Through its licenses and intellectual property, CDI currently uses induced pluripotent stem cells to produce human heart cells (cardiomyocytes), brain cells (neurons), blood vessel cells (endothelial cells), and liver cells (hepatocytes), manufacturing them in high quantity, quality, and purity.

These human cells produced by the company are used for both in vitro and in vivo applications that range from basic and applied research to drug discovery research that includes target identification and validation, toxicity testing, safety and efficacy testing, and more. As such, CDI has emerged as a global leader with the ability to generate iPSCs that have the potential to be used for a wide range of research and possibly therapeutic purposes.

In a landmark event with the iPSC market, the company had an initial public offering (IPO) in July of 2013, in which it sold 38,460,000 shares of common stock to the public at $12.00 per share, to raise proceeds of approximately $43 million.[7] This event secured the companys position as the global leader in producing high-quality human iPSCs and differentiated cells in industrial quantities.

In addition, in March of 2013, Celullar Dynamics International and the Coriell Institute for Medical Research announced receiving multi-million dollars grants from the California Institute for Regenerative Medicine (CIRM) for the creation of iPSC lines from 3,000 healthy and diseased donors, a result that will create the worlds largest human iPSC bank.

Not surprisingly, Cellular Dynamics International has continued its innovation, announcing in February of 2015 that it would be manufacturing cGMP HLA Superdonor stem cell lines that will support cellular therapy applications through genetic matching.[8] Currently, CDI has two HLA superdonor cell lines that provide a partial HLA match to approximately 19% of the population within the U.S., and it aims to expand its master stem cell bank by collecting more donor cell lines that will cover 95% of the U.S. population.[9]

The HLA superdonor cell lines were manufactured using blood samples, and used to produce pluripotent iPSC lines, giving the cells the capacity to differentiate into nearly any cell within the human body.

CDI also leads the iPSC market in terms of supporting drug development and discovery. For example, CDIs MyCell products are created using custom iPSC reprogramming and differentiation methods, thereby providing biologically relevant human cells from patients with unique disease-associated genotypes and phenotypes.[10] The companys iCell and MyCell cells can also be adapted to screening platforms and are matched to function with common readout technologies.[11] CDIs products are also used for high-throughput screening,[12] and have been used as supporting data for Investigational New Drug (IND) applications submitted to the Federal Drug Administration (FDA).[13]

On March 30, 2015, Fujifilm Holdings Corporation announced that it was acquiring CDI, in which Fujifilm will acquire CDI through all-cash offer followed by a second step merger. Specifically, Fujifilm will acquire all issued and outstanding shares of CDIs common stock for $16.5 per share or approximately $ 307 million, after which CDI will continue to run its operations in Madison, Wisconsin, and Novato, California as a consolidated subsidiary of Fujifilm.[14]

CDIs technology platform enables the production of high-quality fully functioning iPSCs (and other human cells) on an industrial scale, while Fujifilm has developed highly-biocompatible recombinant peptidesthat can be shaped into a variety of forms for use as a cellular scaffoldin regenerative medicinewhen used in conjunction with CDIs products.[15] Fujifilm has been strengthening its presence in the regenerative medicine field over several years, including by acquiring a majority of shares of Japan Tissue Engineering Co. in December 2014, so while the acquisition was unexpected, it as not fully suprising.

In summary, the acquisition of CDI will allow Fujifilm to gaindominance in the areaof iPS cell-based drug discovery services and will position it to strategically combine CDIs iPS cell technologywithFujifilms expertise in material science and engineering systems, creating a powerhouse within the iPSC market. It is yet to be seen whether Fujifilm will try to commercialize CDIs iPS cell production technologies by making the cells available for clinical use or whether they will choose to focus their attention on iPS cell-based drug discovery services.

In November 2015 Astellas Pharma announced it was acquiring Ocata Therapeutics for $379M. Ocata Therapeutics is a biotechnology company that specializes in the development of cellular therapies, using both adult and human embryonic stem cells to develop patient-specific therapies. The companys main laboratory and GMP facility is in Marlborough, Massachusetts, and its corporate offices are in Santa Monica, California.

When a number of private companies began to explore the possibility of using artificially re-manufactured iPSCs for therapeutic purposes, one such company that was ready to capitalize on the breakthrough technology was Ocata Therapeutics (at the time called Advanced Cell Technology or ACT). In 2010, the company announced that it had discovered several problematic issues while conducting experiments for the purpose of applying for U.S. Food and Drug Administration approval to use iPSCs in therapeutic applications. Concerns such as premature cell death, mutation into cancer cells, and low proliferation rates were some of the problems that surfaced. [16]

As a result, the company has since shifted its induced pluripotent stem cell approach to producingiPS cell-derived human platelets, as one of the benefits of a platelet-based product is that platelets do not contain nuclei, and therefore, cannot divide or carry genetic information. Although nothing is completely safe, iPS cell-derived platelets are likely to be much safer than other iPSC therapies, in which uncontrolled proliferation is a major concern.

While the companys Induced Pluripotent Stem Cell-Derived Human Platelet Program received a great deal of media coverage in late 2012, including being awarded the December 2012 honor of being named one of the 10 Ideas that Will Shape the Yearby New Scientist Magazine,[17] unfortunately the company did not succeed in moving the concept through to clinical testing in 2013.

Nonetheless, in a November 2015 presentation by Astellas President and CEO, Yoshihiko Hatanaka, he indicated that the company will aim to develop an Ophthalmic Disease Cell Therapy Franchise based around its embryonic stem cells (ESCs) and induced pluripotent stem cell (iPS cells) technology. [18]

On June 22, 2016, RIKEN announced that it is resuming its retinal induced pluripotent stem cell (iPSC) study in partnership with Kyoto University.

2013 was the first time in which clinical research involving transplant of iPSCs into humans was initiated, led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB)in Kobe, Japan. Dr. Takahashi and her team wereinvestigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration. Althoughthe trial was initiated in 2013 and production of iPSCs from patients began at that time, it was not until August of 2014 that the first patient, a Japanese woman, was implanted with retinal tissue generated using iPSCs derived from her own skin cells.

A team of three eye specialists, led by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, implanted a 1.3 by 3.0mm sheet of iPSC-derived retinal pigment epithelium cells into the patients retina.[19]Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanakas team identified two small genetic changes in the patients iPSCs and the retinal pigment epithelium (RPE) cells derived from them. Therefore, it is major news that theRIKEN Institute will now be resuming the worlds first clinical study involving the use of iPSC-derived cells in humans.

According to the Japan Times, this attempt at the clinical studywill involve allogeneic rather than autologous iPSC-derived cells for purposes of cost and time efficiency.Specifically,the researchers will be developing retinal tissues from iPS cells supplied by Kyoto Universitys Center for iPS Cell Research and Application, an institution headed by Nobel prize winner Shinya Yamanaka. To learn about this announcement, view this article fromAsahi Shimbun, aTokyo- based newspaper.

Australian stem cell company Cynata Therapeutics (ASX:CYP) is taking a unique approach. It is creating allogeneic iPS cell derived mesenchyal stem cell (MSCs).Cynatas Cymerus technology utilizes iPSCs originating from an adult donor as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-gradeMSCs.

One of the key inventors of the approach is Igor Slukvin, who has released more than 70 publications about stem cell topics, including the landmark article in Cell describing the now patented Cymerus technique. Dr. Slukvins co-inventor is James Thomson, the first person to isolate an embryonic stem cell (ESC) and one of the first people to create a human-induced, pluripotent stem cell (hiPSC).

Recently, Cynata received advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) that its Phase I clinical trial application has been approved, titledAn Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease. It will be the worlds first clinical trial involving a therapeutic product derived from allogeneic (unrelated to the patient) induced pluripotent stem cells (iPSCs).

Participants for Cynatas upcoming Phase I clinical trial will be adults who have undergone an allogeneic haematopoietic stem cell transplant (HSCT) to treat a haematological disorder and subsequently been diagnosed with steroid-resistant Grade II-IV GvHD.The primary objective of the trial is to assess safety and tolerability, while the secondary objective is to evaluate the efficacy of two infusions of CYP-001 in adults with steroid-resistant GvHD.

There are four key advantages of Cynatas proprietary Cymerus MSC manufacturing platform, as described below.

Unlimited Quantities Cynatas Cymerus technology utilizes iPSCs originating from an adult donor as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-gradeMSCs. According to Cynatas Executive Chairman Stewart Washer who was recently interviewed by The Life Sciences Report, The Cymerus technology gets around the loss of potency with the unlimited iPS cellor induced pluripotent stem cellwhich is basically immortal.

Uniform Batches Because the proprietary Cymerus technology allows nearly unlimited production of MSCs from a single iPSC donor, there is batch-to-batch uniformity. Utilizing a consistent starting material allows for a standardized cell manufacturing process and a consistent cell therapy product.

Single Donor As described previously, Cynatas Cymerus technology creates iPSC-derived mesenchymoangioblasts (MCAs), which are differentiated into MSCs. Unlike other companies involved with MSC manufacturing, Cynata does not require a constant stream of new donors in order to source fresh stem cells for its cell manufacturing process, nor does it require the massive expansion of MSCs necessitated by reliance on freshly isolated donations.

Economic Manufacture at Commercial Scale (Low Cost) Finally, Cynata has achieved a cost-savings advantage through its uniqueapproach to MSCmanufacturing. Its proprietary Cymerus technology addresses a critical shortcoming in existing methods of production of MSCs for therapeutic use, which is the ability to achieve economic manufacture at commercial scale.

Footnotes [1] CellularDynamics.com (2014). About CDI. Available at: http://www.cellulardynamics.com/about/index.html. Web. 1 Apr. 2015. [2] Ibid. [3] Takahashi K, Yamanaka S (August 2006).Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell126(4): 66376. [4] 2012 Nobel Prize in Physiology or Medicine Press Release. Nobelprize.org. Nobel Media AB 2013. Web. 7 Feb 2014. Available at: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html. Web. 1 Apr. 2015. [5] Striklin, D (Jan 13, 2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet. Retrieved Feb 1, 2014 from, http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. [6] Striklin, D (2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet [Online]. Available at: http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. Web. 1 Apr. 2015. [7] Cellular Dynamics International (July 30, 2013). Cellular Dynamics International Announces Closing of Initial Public Offering [Press Release]. Retrieved from http://www.cellulardynamics.com/news/pr/2013_07_30.html. [8] Investors.cellulardynamics.com,. Cellular Dynamics Manufactures Cgmp HLA Superdonor Stem Cell Lines To Enable Cell Therapy With Genetic Matching (NASDAQ:ICEL). N.p., 2015. Web. 7 Mar. 2015. [9] Ibid. [10] Cellulardynamics.com,. Cellular Dynamics | Mycell Products. N.p., 2015. Web. 7 Mar. 2015. [11]Sirenko, O. et al. Multiparameter In Vitro Assessment Of Compound Effects On Cardiomyocyte Physiology Using Ipsc Cells.Journal of Biomolecular Screening18.1 (2012): 39-53. Web. 7 Mar. 2015. [12] Sciencedirect.com,. Prevention Of -Amyloid Induced Toxicity In Human Ips Cell-Derived Neurons By Inhibition Of Cyclin-Dependent Kinases And Associated Cell Cycle Events. N.p., 2015. Web. 7 Mar. 2015. [13] Sciencedirect.com,. HER2-Targeted Liposomal Doxorubicin Displays Enhanced Anti-Tumorigenic Effects Without Associated Cardiotoxicity. N.p., 2015. Web. 7 Mar. 2015. [14] Cellular Dynamics International, Inc. Fujifilm Holdings To Acquire Cellular Dynamics International, Inc.. GlobeNewswire News Room. N.p., 2015. Web. 7 Apr. 2015. [15] Ibid. [16] Advanced Cell Technologies (Feb 11, 2011). Advanced Cell and Colleagues Report Therapeutic Cells Derived From iPS Cells Display Early Aging [Press Release]. Available at: http://www.advancedcell.com/news-and-media/press-releases/advanced-cell-and-colleagues-report-therapeutic-cells-derived-from-ips-cells-display-early-aging/. [17] Advanced Cell Technology (Dec 20, 2012). New Scientist Magazine Selects ACTs Induced Pluripotent Stem (iPS) Cell-Derived Human Platelet Program As One of 10 Ideas That Will Shape The Year [Press Release]. Available at: http://articles.latimes.com/2009/mar/06/science/sci-stemcell6. Web. 9 Apr. 2015. [18] Astellas Pharma (2015). Acquisition of Ocata Therapeutics New Step Forward in Ophthalmology with Cell Therapy Approach. Available at: https://www.astellas.com/en/corporate/news/pdf/151110_2_Eg.pdf. Web. 29 Jan. 2017. [19]Cyranoski, David. Japanese Woman Is First Recipient Of Next-Generation Stem Cells. Nature (2014): n. pag. Web. 6 Mar. 2015.

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One of the current challenges for stem cell researchers is to understand how all the skin appendages are regenerated. This could lead to improved treatments for burn patients, or others with severe skin damage.

Researchers are also working to identify new ways to grow skin cells in the lab. Epidermal stem cells are currently cultivated on a layer of cells from rodents, called murine cells. These cell culture conditions have been proved safe, but it would be preferable to avoid using animal products when cultivating cells that will be transplanted into patients. So, researchers are searching for effective cell culture conditions that will not require the use of murine cells.

Scientists are also working to treat genetic diseases affecting the skin. Since skin stem cells can be cultivated in laboratories, researchers can genetically modify the cells, for example by inserting a missing gene. The correctly modified cells can be selected, grown and multiplied in the lab, then transplanted back onto the patient. Epidermolysis Bullosa is one example of a genetic skin disease that might benefit from this approach. Work is underway to test the technique.

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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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This article is about birth in humans. For birth in other mammals, see birth.

Childbirth, also known as labour and delivery, is the ending of a pregnancy by one or more babies leaving a woman's uterus.[1] In 2015 there were about 135 million births globally.[2] About 15 million were born before 37 weeks of gestation,[3] while between 3 and 12% were born after 42 weeks.[4] In the developed world most deliveries occur in hospital,[5][6] while in the developing world most births take place at home with the support of a traditional birth attendant.[7]

The most common way of childbirth is a vaginal delivery.[8] It involves three stages of labour: the shortening and opening of the cervix, descent and birth of the baby, and the pushing out of the placenta.[9] The first stage typically lasts twelve to nineteen hours, the second stage twenty minutes to two hours, and the third stage five to thirty minutes.[10] The first stage begins with crampy abdominal or back pains that last around half a minute and occur every ten to thirty minutes.[9] The crampy pains become stronger and closer together over time.[10] During the second stage pushing with contractions may occur.[10] In the third stage delayed clamping of the umbilical cord is generally recommended.[11] A number of methods can help with pain such as relaxation techniques, opioids, and spinal blocks.[10]

Most babies are born head first; however about 4% are born feet or buttock first, known as breech.[10][12] During labour a women can generally eat and move around as she likes, pushing is not recommended during the first stage or during delivery of the head, and enemas are not recommended.[13] While making a cut to the opening of the vagina is common, known as an episiotomy, it is generally not needed.[10] In 2012, about 23 million deliveries occurred by a surgical procedure known as Caesarean section.[14] Caesarean sections may be recommended for twins, signs of distress in the baby, or breech position.[10] This method of delivery can take longer to heal from.[10]

Each year complications from pregnancy and childbirth result in about 500,000 maternal deaths, 7 million women have serious long term problems, and 50 million women have health negative outcomes following delivery.[15] Most of these occur in the developing world.[15] Specific complications include obstructed labour, postpartum bleeding, eclampsia, and postpartum infection.[15] Complications in the baby include birth asphyxia.[16]

The most prominent sign of labour is strong repetitive uterine contractions. The distress levels reported by labouring women vary widely. They appear to be influenced by fear and anxiety levels, experience with prior childbirth, cultural ideas of childbirth and pain,[17][18] mobility during labour, and the support received during labour. Personal expectations, the amount of support from caregivers, quality of the caregiver-patient relationship, and involvement in decision-making are more important in women's overall satisfaction with the experience of childbirth than are other factors such as age, socioeconomic status, ethnicity, preparation, physical environment, pain, immobility, or medical interventions.[19]

Pain in contractions has been described as feeling similar to very strong menstrual cramps. Women are often encouraged to refrain from screaming, but moaning and grunting may be encouraged to help lessen pain. Crowning may be experienced as an intense stretching and burning. Even women who show little reaction to labour pains, in comparison to other women, show a substantially severe reaction to crowning.

Back labour is a term for specific pain occurring in the lower back, just above the tailbone, during childbirth.[20]

Childbirth can be an intense event and strong emotions, both positive and negative, can be brought to the surface. Abnormal and persistent fear of childbirth is known as tokophobia.

During the later stages of gestation there is an increase in abundance of oxytocin, a hormone that is known to evoke feelings of contentment, reductions in anxiety, and feelings of calmness and security around the mate.[21] Oxytocin is further released during labour when the fetus stimulates the cervix and vagina, and it is believed that it plays a major role in the bonding of a mother to her infant and in the establishment of maternal behavior. The act of nursing a child also causes a release of oxytocin.[22]

Between 70% and 80% of mothers in the United States report some feelings of sadness or "baby blues" after giving birth. The symptoms normally occur for a few minutes up to few hours each day and they should lessen and disappear within two weeks after delivery. Postpartum depression may develop in some women; about 10% of mothers in the United States are diagnosed with this condition. Preventive group therapy has proven effective as a prophylactic treatment for postpartum depression.[23][24]

Humans are bipedal with an erect stance. The erect posture causes the weight of the abdominal contents to thrust on the pelvic floor, a complex structure which must not only support this weight but allow, in women, three channels to pass through it: the urethra, the vagina and the rectum. The infant's head and shoulders must go through a specific sequence of maneuvers in order to pass through the ring of the mother's pelvis.

Six phases of a typical vertex (head-first presentation) delivery:

Station refers to the relationship of the fetal presenting part to the level of the ischial spines. When the presenting part is at the ischial spines the station is 0 (synonymous with engagement). If the presenting fetal part is above the spines, the distance is measured and described as minus stations, which range from 1 to 4cm. If the presenting part is below the ischial spines, the distance is stated as plus stations ( +1 to +4cm). At +3 and +4 the presenting part is at the perineum and can be seen.[25]

The fetal head may temporarily change shape substantially (becoming more elongated) as it moves through the birth canal. This change in the shape of the fetal head is called molding and is much more prominent in women having their first vaginal delivery.[26]

There are various definitions of the onset of labour, including:

In order to avail for more uniform terminology, the first stage of labour is divided into "latent" and "active" phases, where the latent phase is sometimes included in the definition of labour,[30] and sometimes not.[31]

Some reports note that the onset of term labour more commonly takes place in the late night and early morning hours. This may be a result of a synergism between the nocturnal increase in melatonin and oxytocin.[32]

The latent phase of labour is also called the quiescent phase, prodromal labour, or pre-labour. It is a subclassification of the first stage.[33]

The latent phase is generally defined as beginning at the point at which the woman perceives regular uterine contractions.[34] In contrast, Braxton Hicks contractions, which are contractions that may start around 26 weeks gestation and are sometimes called "false labour", should be infrequent, irregular, and involve only mild cramping.[35] The signaling mechanisms responsible for uterine coordination are complex. Electrical propagation is the primary mechanism used for signaling up to several centimeters. Over longer distances, however, signaling may involve a mechanical mechanism.[36]

Cervical effacement, which is the thinning and stretching of the cervix, and cervical dilation occur during the closing weeks of pregnancy and is usually complete or near complete, by the end of the latent phase.[citation needed] The degree of cervical effacement may be felt during a vaginal examination. A 'long' cervix implies that effacement has not yet occurred. Latent phase ends with the onset of active first stage, and this transition is defined retrospectively.

The active stage of labour (or "active phase of first stage" if the previous phase is termed "latent phase of first stage") has geographically differing definitions. In the US, the definition of active labour was changed from 3 to 4cm, to 5cm of cervical dilation for multiparous women, mothers who had given birth previously, and at 6cm for nulliparous women, those who had not given birth before.[37] This has been done in an effort to increase the rates of vaginal delivery.[38]

A definition of active labour in a British journal was having contractions more frequent than every 5 minutes, in addition to either a cervical dilation of 3cm or more or a cervical effacement of 80% or more.[39]

In Sweden, the onset of the active phase of labour is defined as when two of the following criteria are met:[40]

Health care providers may assess a labouring mother's progress in labour by performing a cervical exam to evaluate the cervical dilation, effacement, and station. These factors form the Bishop score. The Bishop score can also be used as a means to predict the success of an induction of labour.

During effacement, the cervix becomes incorporated into the lower segment of the uterus. During a contraction, uterine muscles contract causing shortening of the upper segment and drawing upwards of the lower segment, in a gradual expulsive motion.[citation needed] The presenting fetal part then is permitted to descend. Full dilation is reached when the cervix has widened enough to allow passage of the baby's head, around 10cm dilation for a term baby.

The duration of labour varies widely, but the active phase averages some 8 hours[41] for women giving birth to their first child ("primiparae") and shorter for women who have already given birth ("multiparae"). Active phase prolongation is defined as in a primigravid woman as the failure of the cervix to dilate at a rate of 1.2cm/h over a period of at least two hours. This definition is based on Friedman's Curve, which plots the typical rate of cervical dilation and fetal descent during active labour.[42] Some practitioners may diagnose "Failure to Progress", and consequently, propose interventions to optimize chances for healthy outcome.[43]

The expulsion stage (stimulated by prostaglandins and oxytocin) begins when the cervix is fully dilated, and ends when the baby is born. As pressure on the cervix increases, women may have the sensation of pelvic pressure and an urge to begin pushing. At the beginning of the normal second stage, the head is fully engaged in the pelvis; the widest diameter of the head has passed below the level of the pelvic inlet. The fetal head then continues descent into the pelvis, below the pubic arch and out through the vaginal introitus (opening). This is assisted by the additional maternal efforts of "bearing down" or pushing. The appearance of the fetal head at the vaginal orifice is termed the "crowning". At this point, the woman will feel an intense burning or stinging sensation.

When the amniotic sac has not ruptured during labour or pushing, the infant can be born with the membranes intact. This is referred to as "delivery en caul".

Complete expulsion of the baby signals the successful completion of the second stage of labour.

The second stage of birth will vary by factors including parity (the number of children a woman has had), fetal size, anesthesia, and the presence of infection. Longer labours are associated with declining rates of spontaneous vaginal delivery and increasing rates of infection, perineal laceration, and obstetric hemorrhage, as well as the need for intensive care of the neonate.[44]

The period from just after the fetus is expelled until just after the placenta is expelled is called the third stage of labour or the involution stage. Placental expulsion begins as a physiological separation from the wall of the uterus. The average time from delivery of the baby until complete expulsion of the placenta is estimated to be 1012 minutes dependent on whether active or expectant management is employed[45] In as many as 3% of all vaginal deliveries, the duration of the third stage is longer than 30 minutes and raises concern for retained placenta.[46]

Placental expulsion can be managed actively or it can be managed expectantly, allowing the placenta to be expelled without medical assistance. Active management is described as the administration of a uterotonic drug within one minute of fetal delivery, controlled traction of the umbilical cord and fundal massage after delivery of the placenta, followed by performance of uterine massage every 15 minutes for two hours.[47] In a joint statement, World Health Organization, the International Federation of Gynaecology and Obstetrics and the International Confederation of Midwives recommend active management of the third stage of labour in all vaginal deliveries to help to prevent postpartum hemorrhage.[48][49][50]

Delaying the clamping of the umbilical cord until at least one minute after birth improves outcomes as long as there is the ability to treat jaundice if it occurs.[51] In some birthing centers, this may be delayed by 5 minutes or more, or omitted entirely. Delayed clamping of the cord decreases the risk of anemia but may increase risk of jaundice. Clamping is followed by cutting of the cord, which is painless due to the absence of nerves.

The "fourth stage of labour" is the period beginning immediately after the birth of a child and extending for about six weeks. The terms postpartum and postnatal are often used to describe this period.[52] It is the time in which the mother's body, including hormone levels and uterus size, return to a non-pregnant state and the newborn adjusts to life outside the mother's body. The World Health Organization (WHO) describes the postnatal period as the most critical and yet the most neglected phase in the lives of mothers and babies; most deaths occur during the postnatal period.[53]

Following the birth, if the mother had an episiotomy or a tearing of the perineum, it is stitched. The mother should have regular assessments for uterine contraction and fundal height,[54] vaginal bleeding, heart rate and blood pressure, and temperature, for the first 24 hours after birth. The first passing of urine should be documented within 6 hours.[53] Afterpains (pains similar to menstrual cramps), contractions of the uterus to prevent excessive blood flow, continue for several days. Vaginal discharge, termed "lochia", can be expected to continue for several weeks; initially bright red, it gradually becomes pink, changing to brown, and finally to yellow or white.[55]

Most authorities suggest the infant be placed in skin-to-skin contact with the mother for 1 2 hours immediately after birth, putting routine cares off till later.

Until recently babies born in hospitals were removed from their mothers shortly after birth and brought to the mother only at feeding times. Mothers were told that their newborn would be safer in the nursery and that the separation would offer the mother more time to rest. As attitudes began to change, some hospitals offered a "rooming in" option wherein after a period of routine hospital procedures and observation, the infant could be allowed to share the mother's room. However, more recent information has begun to question the standard practice of removing the newborn immediately postpartum for routine postnatal procedures before being returned to the mother. Beginning around 2000, some authorities began to suggest that early skin-to-skin contact (placing the naked baby on the mother's chest) may benefit both mother and infant. Using animal studies that have shown that the intimate contact inherent in skin-to-skin contact promotes neurobehaviors that result in the fulfillment of basic biological needs as a model, recent studies have been done to assess what, if any, advantages may be associated with early skin-to-skin contact for human mothers and their babies. A 2011 medical review looked at existing studies and found that early skin-to-skin contact, sometimes called kangaroo care, resulted in improved breastfeeding outcomes, cardio-respiratory stability, and a decrease in infant crying. [56][57][58] A 2007 Cochrane review of studies found that skin-to-skin contact at birth reduced crying, kept the baby warmer, improved mother-baby interaction, and improved the chances for successful breastfeeding.[59]

As of 2014, early postpartum skin-to-skin contact is endorsed by all major organizations that are responsible for the well-being of infants, including the American Academy of Pediatrics.[60] The World Health Organization (WHO) states that "the process of childbirth is not finished until the baby has safely transferred from placental to mammary nutrition." They advise that the newborn be placed skin-to-skin with the mother, postponing any routine procedures for at least one to two hours. The WHO suggests that any initial observations of the infant can be done while the infant remains close to the mother, saying that even a brief separation before the baby has had its first feed can disturb the bonding process. They further advise frequent skin-to-skin contact as much as possible during the first days after delivery, especially if it was interrupted for some reason after the delivery.[61] The National Institute for Health and Care Excellence also advises postponing procedures such as weighing, measuring, and bathing for at least 1 hour to insure an initial period of skin-to-skin contact between mother and infant. [62]

Deliveries are assisted by a number of professions include: obstetricians, family physicians and midwives. For low risk pregnancies all three result in similar outcomes.[63]

Eating or drinking during labour is an area of ongoing debate. While some have argued that eating in labour has no harmful effects on outcomes,[64] others continue to have concern regarding the increased possibility of an aspiration event (choking on recently eaten foods) in the event of an emergency delivery due to the increased relaxation of the esophagus in pregnancy, upward pressure of the uterus on the stomach, and the possibility of general anesthetic in the event of an emergency cesarean.[65] A 2013 Cochrane review found that with good obstetrical anaesthesia there is no change in harms from allowing eating and drinking during labour in those who are unlikely to need surgery. They additionally acknowledge that not eating does not mean there is an empty stomach or that its contents are not as acidic. They therefore conclude that "women should be free to eat and drink in labour, or not, as they wish."[66]

At one time shaving of the area around the vagina, was common practice due to the belief that hair removal reduced the risk of infection, made an episiotomy (a surgical cut to enlarge the vaginal entrance) easier, and helped with instrumental deliveries. It is currently less common, though it is still a routine procedure in some countries. A 2009 Cochrane review found no evidence of any benefit with perineal shaving. The review did find side effects including irritation, redness, and multiple superficial scratches from the razor.[67][needs update] Another effort to prevent infection has been the use of the antiseptic chlorhexidine or providone-iodine solution in the vagina. Evidence of benefit with chlorhexidine is lacking.[68] A decreased risk is found with providone-iodine when a cesarean section is to be performed.[69]

Active management of labour consists of a number of care principles, including frequent assessment of cervical dilatation. If the cervix is not dilating, oxytocin is offered. This management results in a slightly reduced number of caesarean births, but does not change how many women have assisted vaginal births. 75% of women report that they are very satisfied with either active management or normal care.[70]

In many cases and with increasing frequency, childbirth is achieved through induction of labour or caesarean section. Caesarean section is the removal of the neonate through a surgical incision in the abdomen, rather than through vaginal birth.[71] Childbirth by C-Sections increased 50% in the U.S. from 1996 to 2006, and comprise nearly 32% of births in the U.S. and Canada.[71][72] Induced births and elective cesarean before 39 weeks can be harmful to the neonate as well as harmful or without benefit to the mother. Therefore, many guidelines recommend against non-medically required induced births and elective cesarean before 39 weeks.[73] The rate of labour induction in the United States is 22%, and has more than doubled from 1990 to 2006.[74][75]

Health conditions that may warrant induced labour or cesarean delivery include gestational or chronic hypertension, preeclampsia, eclampsia, diabetes, premature rupture of membranes, severe fetal growth restriction, and post-term pregnancy. Cesarean section too may be of benefit to both the mother and baby for certain indications including maternal HIV/AIDS, fetal abnormality, breech position, fetal distress, multiple gestations, and maternal medical conditions which would be worsened by labour or vaginal birth.

Pitocin is the most commonly used agent for induction in the United States, and is used to induce uterine contractions. Other methods of inducing labour include stripping of the amniotic membrane, artificial rupturing of the amniotic sac (called amniotomy), or nipple stimulation. Ripening of the cervix can be accomplished with the placement of a Foley catheter or the use of synthetic prostaglandins such as misoprostol.[74] A large review of methods of induction was published in 2011.[76]

The American Congress of Obstetricians and Gynecologists (ACOG) guidelines recommend a full evaluation of the maternal-fetal status, the status of the cervix, and at least a 39 completed weeks (full term) of gestation for optimal health of the newborn when considering elective induction of labour. Per these guidelines, the following conditions may be an indication for induction, including:

Induction is also considered for logistical reasons, such as the distance from hospital or psychosocial conditions, but in these instances gestational age confirmation must be done, and the maturity of the fetal lung must be confirmed by testing.

The ACOG also note that contraindications for induced labour are the same as for spontaneous vaginal delivery, including vasa previa, complete placenta praevia, umbilical cord prolapse or active genital herpes simplex infection.[77]

Some women prefer to avoid analgesic medication during childbirth. Psychological preparation may be beneficial. A recent Cochrane overview of systematic reviews on non-drug interventions found that relaxation techniques, immersion in water, massage, and acupuncture may provide pain relief. Acupuncture and relaxation were found to decrease the number of caesarean sections required.[78] Immersion in water has been found to relieve pain during the first stage of labor and to reduce the need for anesthesia and shorten the duration of labor, however the safety and efficacy of immersion during birth, water birth, has not been established or associated with maternal or fetal benefit.[79]

Some women like to have someone to support them during labour and birth; such as a midwife, nurse, or doula; or a lay person such as the father of the baby, a family member, or a close friend. Studies have found that continuous support during labor and delivery reduce the need for medication and a caesarean or operative vaginal delivery, and result in an improved Apgar score for the infant.[80][81]

The injection of small amounts of sterile water into or just below the skin at several points on the back has been a method tried to reduce labour pain, but no good evidence shows that it actually helps.[82]

Different measures for pain control have varying degrees of success and side effects to the woman and her baby. In some countries of Europe, doctors commonly prescribe inhaled nitrous oxide gas for pain control, especially as 53% nitrous oxide, 47% oxygen, known as Entonox; in the UK, midwives may use this gas without a doctor's prescription. Opioids such as fentanyl may be used, but if given too close to birth there is a risk of respiratory depression in the infant.

Popular medical pain control in hospitals include the regional anesthetics epidurals (EDA), and spinal anaesthesia. Epidural analgesia is a generally safe and effective method of relieving pain in labour, but is associated with longer labour, more operative intervention (particularly instrument delivery), and increases in cost.[83] Generally, pain and stress hormones rise throughout labour for women without epidurals, while pain, fear, and stress hormones decrease upon administration of epidural analgesia, but rise again later.[84] Medicine administered via epidural can cross the placenta and enter the bloodstream of the fetus.[85] Epidural analgesia has no statistically significant impact on the risk of caesarean section, and does not appear to have an immediate effect on neonatal status as determined by Apgar scores.[86]

Augmentation is the process of facilitating further labour. Oxytocin has been used to increase the rate of vaginal delivery in those with a slow progress of labour.[87]

Administration of antispasmodics (e.g. hyoscine butylbromide) is not formally regarded as augmentation of labour; however, there is weak evidence that they may shorten labour.[88] There is not enough evidence to make conclusions about unwanted effects in mothers or babies.[88]

Vaginal tears can occur during childbirth, most often at the vaginal opening as the baby's head passes through, especially if the baby descends quickly. Tears can involve the perineal skin or extend to the muscles and the anal sphincter and anus. The midwife or obstetrician may decide to make a surgical cut to the perineum (episiotomy) to make the baby's birth easier and prevent severe tears that can be difficult to repair. A 2012 Cochrane review compared episiotomy as needed (restrictive) with routine episiotomy to determine the possible benefits and harms for mother and baby. The review found that restrictive episiotomy policies appeared to give a number of benefits compared with using routine episiotomy. Women experienced less severe perineal trauma, less posterior perineal trauma, less suturing and fewer healing complications at seven days with no difference in occurrence of pain, urinary incontinence, painful sex or severe vaginal/perineal trauma after birth, however they found that women experienced more anterior perineal damage with restrictive episiotomy.[89]

Obstetric forceps or ventouse may be used to facilitate childbirth.

In cases of a cephalic presenting twin (first baby head down), twins can often be delivered vaginally. In some cases twin delivery is done in a larger delivery room or in an operating theatre, in the event of complication e.g.

Historically women have been attended and supported by other women during labour and birth. However currently, as more women are giving birth in a hospital rather than at home, continuous support has become the exception rather than the norm. When women became pregnant any time before the 1950s the husband would not be in the birthing room. It did not matter if it was a home birth; the husband was waiting downstairs or in another room in the home. If it was in a hospital then the husband was in the waiting room. "Her husband was attentive and kind, but, Kirby concluded, Every good woman needs a companion of her own sex."[90] Obstetric care frequently subjects women to institutional routines, which may have adverse effects on the progress of labour. Supportive care during labour may involve emotional support, comfort measures, and information and advocacy which may promote the physical process of labour as well as women's feelings of control and competence, thus reducing the need for obstetric intervention. The continuous support may be provided either by hospital staff such as nurses or midwives, doulas, or by companions of the woman's choice from her social network. There is increasing evidence to show that the participation of the child's father in the birth leads to better birth and also post-birth outcomes, providing the father does not exhibit excessive anxiety.[91]

A recent Cochrane review involving more than 15,000 women in a wide range of settings and circumstances found that "Women who received continuous labour support were more likely to give birth 'spontaneously', i.e. give birth with neither caesarean nor vacuum nor forceps. In addition, women were less likely to use pain medications, were more likely to be satisfied, and had slightly shorter labours. Their babies were less likely to have low five-minute Apgar scores."[80]

For monitoring of the fetus during childbirth, a simple pinard stethoscope or doppler fetal monitor ("doptone") can be used. A method of external (noninvasive) fetal monitoring (EFM) during childbirth is cardiotocography, using a cardiotocograph that consists of two sensors: The heart (cardio) sensor is an ultrasonic sensor, similar to a Doppler fetal monitor, that continuously emits ultrasound and detects motion of the fetal heart by the characteristic of the reflected sound. The pressure-sensitive contraction transducer, called a tocodynamometer (toco) has a flat area that is fixated to the skin by a band around the belly. The pressure required to flatten a section of the wall correlates with the internal pressure, thereby providing an estimate of contraction[92] Monitoring with a cardiotocograph can either be intermittent or continuous.

A mother's water has to break before internal (invasive) monitoring can be used. More invasive monitoring can involve a fetal scalp electrode to give an additional measure of fetal heart activity, and/or intrauterine pressure catheter (IUPC). It can also involve fetal scalp pH testing.

It is currently possible to collect two types of stem cells during childbirth: amniotic stem cells and umbilical cord blood stem cells.[93] They are being studied as possible treatments of a number of conditions.[93]

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The "natural" maternal mortality rate of childbirthwhere nothing is done to avert maternal deathhas been estimated at 1500 deaths per 100,000 births.[95] (See main articles: neonatal death, maternal death). Each year about 500,000 women die due to pregnancy, 7 million have serious long term complications, and 50 million have negative outcomes following delivery.[15]

Modern medicine has decreased the risk of childbirth complications. In Western countries, such as the United States and Sweden, the current maternal mortality rate is around 10 deaths per 100,000 births.[95]:p.10 As of June 2011, about one third of American births have some complications, "many of which are directly related to the mother's health."[96]

Birthing complications may be maternal or fetal, and long term or short term.

Newborn mortality at 37 weeks may be 2.5 times the number at 40 weeks, and was elevated compared to 38 weeks of gestation. These "early term" births were also associated with increased death during infancy, compared to those occurring at 39 to 41 weeks ("full term").[73] Researchers found benefits to going full term and "no adverse effects" in the health of the mothers or babies.[73]

Medical researchers find that neonates born before 39 weeks experienced significantly more complications (2.5 times more in one study) compared with those delivered at 39 to 40 weeks. Health problems among babies delivered "pre-term" included respiratory distress, jaundice and low blood sugar.[73][97] The American Congress of Obstetricians and Gynecologists and medical policy makers review research studies and find increased incidence of suspected or proven sepsis, RDS, Hypoglycemia, need for respiratory support, need for NICU admission, and need for hospitalization > 4 5 days. In the case of cesarean sections, rates of respiratory death were 14 times higher in pre-labour at 37 compared with 40 weeks gestation, and 8.2 times higher for pre-labour cesarean at 38 weeks. In this review, no studies found decreased neonatal morbidity due to non-medically indicated (elective) delivery before 39 weeks.[73]

The second stage of labour may be delayed or lengthy due to:

Secondary changes may be observed: swelling of the tissues, maternal exhaustion, fetal heart rate abnormalities. Left untreated, severe complications include death of mother and/or baby, and genitovaginal fistula.

Obstructed labour, also known as labor dystocia, is when, even though the uterus is contracting normally, the baby does not exit the pelvis during childbirth due to being physically blocked.[98] Prolonged obstructed labor can result in obstetric fistula, a complication of childbirth where tissue death preforates the rectum or bladder.

Vaginal birth injury with visible tears or episiotomies are common. Internal tissue tearing as well as nerve damage to the pelvic structures lead in a proportion of women to problems with prolapse, incontinence of stool or urine and sexual dysfunction. Fifteen percent of women become incontinent, to some degree, of stool or urine after normal delivery, this number rising considerably after these women reach menopause. Vaginal birth injury is a necessary, but not sufficient, cause of all non hysterectomy related prolapse in later life. Risk factors for significant vaginal birth injury include:

There is tentative evidence that antibiotics may help prevent wound infections in women with third or fourth degree tears.[99]

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Childbirth - Wikipedia

Spinal Cord Stem Cells Comments Off on Childbirth – Wikipedia | January 13th, 2017

CCR5 Identifiers Aliases CCR5, CC-CKR-5, CCCKR5, CCR-5, CD195, CKR-5, CKR5, CMKBR5, IDDM22, C-C motif chemokine receptor 5 (gene/pseudogene) External IDs OMIM: 601373 MGI: 107182 HomoloGene: 37325 GeneCards: CCR5 Targeted by Drug aplaviroc, cenicriviroc, maraviroc, vicriviroc[1] Orthologs Species Human Mouse Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) Chr 3: 46.37 46.38 Mb Chr 9: 124.12 124.15 Mb PubMed search [2] [3] Wikidata View/Edit Human View/Edit Mouse

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. This is the process by which T cells are attracted to specific tissue and organ targets. Many forms of HIV, the virus that causes AIDS, initially use CCR5 to enter and infect host cells. Certain individuals carry a mutation known as CCR5-32 in the CCR5 gene, protecting them against these strains of HIV.

In humans, the CCR5 gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.[4][5][6][7][8][9]

The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins.[10][11] It is a G proteincoupled receptor[10] which functions as a chemokine receptor in the CC chemokine group.

CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1 and 1, respectively), and CCL3L1.[12][13] CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).[12][14][15]

CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, functional response of the receptor, and HIV co-receptor activity.[16]

HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells.[17] These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell.[18] The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell.[18] The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 env gene: the Gp120 external subunit, and the Gp41 transmembrane subunit.[18] This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of three Gp120-Gp41 hetero-dimers.[18] The Gp120 envelope protein is a chemokine mimic.[17] It lacks the unique structure of a chemokine, however it is still capable of binding to the CCR5 and CXCR4 chemokine receptors.[17] During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell- forming a heterotrimeric complex.[17] The formation of this complex stimulates the release of a fusogenic peptide inducing the fusion of the viral membrane with the membrane of the target host cell.[17] Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein.[19] Co-receptor recognition also include the V1-V2 region of gp120, and the bridging sheet (an antiparallel, 4-stranded sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity.[19] The normal ligands for this receptor, RANTES, MIP-1, and MIP-1, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,[20] suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.

CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, to be released from its metastable conformation and insert itself into the membrane of the host cell. Although it hasn't been finalized as a proven theory yet, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains [19]

CCR5 is essential for the spread of the R5-strain of the HIV-1 virus.[21] Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function.[22] A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with the associative binding between the Gp120 envelope protein and the HIV co-receptor CCR5.[21] These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). Maraviroc was approved for use by the FDA in August 2007.[21] It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor.[19] A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. However, because there is still another co-receptor available, this indicates that lacking the CCR5 gene doesn't make one immune to the virus; it simply implies that it would be more challenging for the individual to contract it. Also, the virus still has access to the CD4. Unlike CCR5, which the body apparently doesn't really need due to those still living healthy lives even with the lack of/or absence of the gene (as a result of the delta 32 mutation), CD4 is critical in the bodies defense system (fighting against infection).[23] Even without the availability of either co-receptors (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail), resulting in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.[24]

CCR5-32 (or CCR5-D32 or CCR5 delta 32) is an allele of CCR5.[25][26]

CCR5 32 is a 32-base-pair deletion that introduces a premature stop codon into the CCR5 receptor locus, resulting in a nonfunctional receptor.[27][28] CCR5 is required for M-tropic HIV-1 virus entry.[29] Individuals homozygous for CCR5 32 do not express functional CCR5 receptors on their cell surfaces and are resistant to HIV-1 infection, despite multiple high-risk exposures.[29] Individuals heterozygous for the mutant allele have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface.[30] Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced viral loads and a 2-3-year-slower progression to AIDS relative to wild types.[27][29][31] Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment.[32] CCR5 32 has an (heterozygote) allele frequency of 10% in Europe, and a homozygote frequency of 1%.

The CCR5 32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution,[33] which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.

Two studies have used linkage analysis to estimate the age of the CCR5 32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 32 deletion would be proportional to the age of the deletion.[26][34] Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-32 deletion occurred 700 years ago (275-1875, 95% confidence interval). Another group, Libert et al. (1998), estimated the age of the CCR5 32 mutation is based on the microsatellite mutations to be 2100 years (700-4800, 95% confidence interval). On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900-4700, 95% confidence interval).[34] A third hypothesis relies on the north-to-south gradient of allele frequency in Europe which shows that the highest allele frequency occurred in Nordic regions such as Iceland, Norway and Sweden and lowest allele frequency in the south. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe was due to the Viking dispersal in the 8th to 10th century.[35] Vikings were later replaced by the Varangians in Russia, which migrated East which may have contributed to the observed east-to-west cline of allele frequency.[33][35]

HIV-1 was initially transmitted from chimpanzees (Pan troglodytes) to humans in the early 1900s in Southeast Cameroon, Africa,[36] through exposure to infected blood and body fluids while butchering bushmeat.[37] However, HIV-1 was effectively absent from Europe until the late 1980s.[38] Therefore, given the average age of roughly 1000 years for the CCR5-32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies.[33] Hence, other pathogens have been suggested agents of positive selection for CCR5 32. The first major one being bubonic plague (Yersinia pestis), and later, smallpox (Variola major). Other data suggest that the allele frequency resulted as a negative selection pressure as a result of pathogens that became more widespread during Roman expansion.[39] The idea that negative selection played a role in its low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.[40][41]

Several lines of evidence suggest that the CCR5 32 allele evolved only once.[33] First, CCR5 32 has a relatively high frequency in several different Caucasian populations but is comparatively absent in Asian, Middle Eastern and American Indian populations,[26] suggesting that a single mutation occurred after divergence of Caucasians from their African ancestor).[26][27][42] Second, genetic linkage analysis indicates that the mutation occurs on a homogenous genetic background, implying that inheritance of the mutation occurred from a common ancestor.[34] This was demonstrated by showing that the CCR5 32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele.[34] This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 32 alleles arose from a single mutational event. Finally, the CCR5 32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).[34]

In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%.[26] Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.

It is estimated that HIV-1 entered the human population in Africa in the early 1900s,[36] symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 32 from zero to 10% in 2000 years. In 1998, Stephens et al. suggested that bubonic plague (Yersinia pestis) had exerted positive selective pressure on CCR5 32.[26] This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352.[43] After the Black Death, there were less severe, intermittent, epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent.[43][44][45] In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of Europes population.[43][46] Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents and spread by fleas and only occasionally infecting humans.[47] Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs.[48] Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur.[47] Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 32 to 10% in Europe.[25]

To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox.[25] Plague was modeled according to historical accounts,[49][50] while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812.[44] Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague.[25] Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human.[51][52] The authors calculated that if plague were selecting for CCR5 32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.

The hypothesis that smallpox exerted positive selection for CCR5 32 is also biologically plausible, since poxviruses, like HIV, are viruses that enter white blood cells by using chemokine receptors.[53] By contrast, Yersinia pestis is a bacterium with a very different biology.

Although Caucasians are the only population with a high frequency of CCR5 32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980. The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia.[52] By contrast, the CCR5 32 mutation is found only in European, West Asian, and North African populations.[54] The anomalously high frequency of CCR5 32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.

Research has not yet revealed a cost of carrying the CCR5 null mutation that is as dramatic as the benefit conferred in the context of HIV-1 exposure. In general, research suggests that the CCR5 32 mutation protects against diseases caused by certain pathogens but may also play a deleterious role in postinfection inflammatory processes, which can injure tissue and create further pathology.[55] The best evidence for this proposed antagonistic pleiotropy is found in flavivirus infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (a flavivirus).[56] In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.[57]

This finding in humans confirmed a previously-observed experiment in an animal model of CCR5 32 homozygosity. After infection with West Nile Virus, CCR5 32 mice had markedly increased viral titers in the central nervous system and had increased mortality[58] compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.

CCR5 32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., tick-borne encephalitis, West Nile virus). Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.

A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals.[59] When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 eventually take over the culture, as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus-resistant cell pool in infected individuals.[59]

This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with 2 copies of CCR5-32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[5][60] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.[5] However, this is consistent with the observation that cells expressing the CCR5-32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[61] After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.[6]

Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a zinc finger nuclease to carry the CCR5-32 trait and then reintroduced into the body as a potential HIV treatment.[62][63] Results reported in 2014 were promising.[9]

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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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Session Tracks

Conference Series invites all the participants from all over the world to attend"8th European Immunology Conference, June 29-July 01, 2017 Madrid, Spain, includesprompt keynote presentations, Oral talks, Poster presentations and Exhibitions.

European ImmunologyConferenceis to gathering people in academia and society interested inimmunologyto share the latest trends and important issues relevant to our field/subject area.Immunology Conferencesbrings together the global leaders in Immunology and relevant fields to present their research at this exclusive scientific program. TheImmunology Conferencehosting presentations from editors of prominent refereed journals, renowned and active investigators and decision makers in the field of Immunology.European Immunology ConferenceOrganizing Committee also invites Young investigators at every career stage to submit abstracts reporting their latest scientific findings in oral and poster sessions.

Track:1Cellular Immunology

The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science ofimmunology. The immune system has been divided into a more primitive innate immune system and, in vertebrates, an acquired oradaptive immune system

The field concerning the interactions among cells and molecules of the immunesystem,and how such interactions contribute to the recognition and elimination of pathogens. Humans possess a range of non-specific mechanical and biochemical defences against routinely encountered bacteria, parasites, viruses, and fungi. The skin, for example, is an effective physical barrier to infection. Basic chemical defences are also present in blood, saliva, and tears, and on mucous membranes. True protection stems from the host's ability to mount responses targeted to specific organisms, and to retain a form of memory that results in a rapid, efficient response to a given organism upon a repeat encounter. This more formal sense of immunity, termed adaptive immunity, depends upon the coordinated activities of cells and molecules of the immune system.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland

Track: 2Inflammatory/Autoimmune Diseases

Autoimmune diseasescan affect almost any part of the body, including the heart, brain, nerves, muscles, skin, eyes, joints, lungs, kidneys, glands, the digestive tract, and blood vessels.

The classic sign of an autoimmune disease is inflammation, which can cause redness, heat, pain, and swelling. How an autoimmune disease affects you depends on what part of the body is targeted. If the disease affects the joints, as inrheumatoid arthritis, you might have joint pain, stiffness, and loss of function. If it affects the thyroid, as in Graves disease and thyroiditis, it might cause tiredness, weight gain, and muscle aches. If it attacks the skin, as it does in scleroderma/systemic sclerosis, vitiligo, andsystemic lupus erythematosus(SLE), it can cause rashes, blisters, and colour changes. Many autoimmune diseases dont restrict themselves to one part of the body. For example, SLE can affect the skin, joints, kidneys, heart, nerves, blood vessels, and more. Type 1 diabetes can affect your glands, eyes, kidneys, muscles, and more.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 3T-Cells and B-Cells

T cell: A type of white blood cell that is of key importance to the immune system and is at the core of adaptive immunity, the system that tailors the body's immune response to specific pathogens. The T cells are like soldiers who search out and destroy the targeted invaders. Immature T cells (termed T-stem cells) migrate to the thymus gland in the neck, where they mature and differentiate into various types of mature T cells and become active in the immune system in response to a hormone called thymosin and other factors. T-cells that are potentially activated against the body's own tissues are normally killed or changed ("down-regulated") during this maturational process.There are several different types of mature T cells. Not all of their functions are known. T cells can produce substances called cytokines such as the interleukins which further stimulate the immune response. T-cell activation is measured as a way to assess the health of patients withHIV/AIDSand less frequently in other disorders. T cell are also known as T lymphocytes. The "T" stands for "thymus" -- the organ in which these cells mature. As opposed to B cells which mature in the bone marrow.B cells, also known asBlymphocytes, are a type of white bloodcellof the lymphocyte subtype. They function in thehumoral immunitycomponent of the adaptive immune system by secreting antibodies. Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells. All of the plasma cells descended from a single B cell produce the same antibody which is directed against the antigen that stimulated it to mature. The same principle holds with memory B cells. Thus, all of the plasma cells and memory cells "remember" the stimulus that led to their formation. The maturation of B cells takes place in birds in an organ called the bursa of Fabricus. B cells in mammals mature largely in the bone marrow. The B cell, or B lymphocyte, is thus an immunologically important cell. It is not thymus-dependent, has a short lifespan, and is responsible for the production ofimmunoglobulins.It expresses immunoglobulins on its surface.

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 4Cancer and Tumor Immunobiology

The tumour is an important aspect of cancer biology that contributes to tumour initiation, tumour progression and responses to therapy. Cells and molecules of the immune system are a fundamental component of the tumour microenvironment. Importantly,therapeutic strategies for cancer treatmentcan harness the immune system to specifically target tumour cells and this is particularly appealing owing to the possibility of inducing tumour-specific immunological memory, which might cause long-lasting regression and prevent relapse in cancer patients.The composition and characteristics of the tumour microenvironment vary widely and are important in determining the anti-tumour immune response.Immunotherapyis a new class ofcancer treatmentthat works to harness the innate powers of the immune system to fight cancer. Because of the immune system's unique properties, these therapies may hold greater potential than current treatment approaches to fight cancer more powerfully, to offer longer-term protection against the disease, to come with fewer side effects, and to benefit more patients with more cancer

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 5 Vaccines

A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters. There are two basictypes of vaccines: live attenuated and inactivated. The characteristics of live and inactivatedvaccinesare different, and these characteristics determine how thevaccineis used. Liveattenuatedvaccinesare produced by modifying a disease-producing (wild) virus or bacteria in a laboratory.

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 6Immunotherapy

Immunotherapy,also called biologic therapy, is a type of cancer treatment designed to boost the body's natural defences to fight the cancer. It uses materials either made by the body or in a laboratory to improve, target, or restore immune system function. Immunotherapy is treatment that uses certain parts of a persons immune system to fight diseases such as cancer. This can be done in a couple of ways:1)Stimulating your own immune system to work harder or smarter to attack cancer cells2)Giving you immune system components, such as man-made immune system proteins. Some types of immunotherapy are also sometimes called biologic therapy or biotherapy.

In the last few decadesimmunotherapyhas become an important part of treating some types of cancer. Newer types of immune treatments are now being studied, and theyll impact how we treat cancer in the future. Immunotherapy includes treatments that work in different ways. Some boost the bodys immune system in a very general way. Others help train the immune system to attack cancer cells specifically. Immunotherapy works better for some types of cancer than for others. Its used by itself for some of these cancers, but for others it seems to work better when used with other types of treatment.

Many different types of immunotherapy are used to treat cancer. They include:Monoclonal antibodies,Adoptive cell transfer,Cytokines, Treatment Vaccines, BCG,

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 7Neuro Immunology

Neuroimmunology, a branch of immunologythat deals especially with the inter relationships of the nervous system and immune responses andautoimmune disorders. It deals with particularly fundamental and appliedneurobiology,meetings onneurology,neuropathology, neurochemistry,neurovirology, neuroendocrinology, neuromuscular research,neuropharmacologyand psychology, which involve either immunologic methodology (e.g. immunocytochemistry) or fundamental immunology (e.g. antibody and lymphocyte assays).

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 8Infectious Diseases and Immune System

Infectious diseases are caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi; the diseases can be spread, directly or indirectly, from one person to another.Zoonotic diseasesare infectious diseases of animals that can cause disease when transmitted to humans. Some infectious diseases can be passed from person to person. Some are transmitted by bites from insects or animals. And others are acquired by ingesting contaminated food or water or being exposed to organisms in the environment. Signs and symptoms vary depending on the organism causing the infection, but often include fever and fatigue. Mild complaints may respond to rest and home remedies, while some life-threatening infections may require hospitalization.

Many infectious diseases, such as measles andchickenpox, can be prevented by vaccines. Frequent and thorough hand-washing also helps protect you from infectious diseases

There are four main kinds of germs:

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 9Reproductive Immunology,

Reproductive immunologyrefers to a field of medicine that studies interactions (or the absence of them) between the immune system and components related to thereproductivesystem, such as maternal immune tolerance towards the fetus, orimmunologicalinteractions across the blood-testis barrier. The immune system refers to all parts of the body that work to defend it against harmful enemies. In people with immunological fertility problems their body identifies part of reproductive function as an enemy and sendsNatural Killer (NK) cellsto attack. A healthy immune response would only identify an enemy correctly and attack only foreign invaders such as a virus, parasite, bacteria, ect.

The concept of reproductive immunology is not widely accepted by all physicians.Those patients who have had repeated miscarriages and multiple failed IVF's find themselves exploring it's possibilities as the reason. With an increased amount of success among treating any potential immunological factors, the idea of reproductive immunology can no longer be overlooked.The failure to conceive is often due to immunologic problems that can lead to very early rejection of the embryo, often before the pregnancy can be detected by even the most sensitive tests. Women can often produce perfectly healthy embryos that are lost through repeated "mini miscarriages." This most commonly occurs in women who have conditions such asendometriosis, an under-active thyroid gland or in cases of so called "unexplained infertility." It has been estimated that an immune factor may be involved in up to 20% of couples with otherwiseunexplained infertility. These are all conditions where abnormalities of the womans immune system may play an important role.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology (C7), March 19 - 23, 2017, Whistler, British Columbia, Canada

Track:10Auto Immunity,

Autoimmunityis the system ofimmuneresponses of an organism against its own cells and tissues. Any disease that results from such an aberrantimmuneresponse is termed an autoimmune disease.

Autoimmunity is present to some extent in everyone and is usually harmless. However, autoimmunity can cause a broad range of human illnesses, known collectively as autoimmune diseases. Autoimmune diseases occur when there is progression from benign autoimmunity to pathogenicautoimmunity. This progression is determined by genetic influences as well as environmental triggers. Autoimmunity is evidenced by the presence of autoantibodies (antibodies directed against the person who produced them) and T cells that are reactive with host antigens.

Autoimmune disorders

An autoimmune disorder occurs whenthe bodys immune systemattacks and destroys healthy body tissue by mistake. There are more than 80 types of autoimmune disorders.

Causes

The white blood cells in the bodys immune system help protect against harmful substances. Examples include bacteria, viruses,toxins,cancercells, and blood and tissue from outside the body. These substances contain antigens. The immune system producesantibodiesagainst these antigens that enable it to destroy these harmful substances. When you have an autoimmune disorder, your immune system does not distinguish between healthy tissue and antigens. As a result, the body sets off a reaction that destroys normal tissues. The exact cause of autoimmune disorders is unknown. One theory is that some microorganisms (such as bacteria or viruses) or drugs may trigger changes that confuse the immune system. This may happen more often in people who have genes that make them more prone toautoimmune disorders.

An autoimmune disorder may result in:

A person may have more than one autoimmune disorder at the same time. Common autoimmune disorders include:

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology (C7), March 19 - 23, 2017, Whistler, British Columbia, Canada

Track: 11Costimmulatory pathways in multiple sclerosis

Costimulatory moleculescan be categorized based either on their functional attributes or on their structure. The costimulatory molecules discussed in this review will be divided into (1)positive costimulatory pathways:promoting T cell activation, survival and/or differentiation; (2)negative costimulatory pathways:antagonizing TCR signalling and suppressing T cell activation; (3) as third group we will discuss themembers of the TIM family, a rather new family of cell surface molecules involved in the regulation of T cell differentiation and Treg function.Costimulatory pathways have a critical role in the regulation of alloreactivity. A complex network of positive and negative pathways regulates T cell responses. Blocking costimulation improves allograft survival in rodents and non-human primates. The costimulation blocker belatacept is being developed asimmunosuppressivedruginrenal transplantation.

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3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 12Autoimmunity and Therapathies

Autoimmunityis the system ofimmuneresponsesof an organism against its own cells and tissues. Any disease that results from such an aberrantimmuneresponse is termed an autoimmune disease.

Autoimmunity is present to some extent in everyone and is usually harmless. However, autoimmunity can cause a broad range of human illnesses, known collectively as autoimmune diseases.Autoimmune diseasesoccur when there is progression from benign autoimmunity to pathogenic autoimmunity. This progression is determined by genetic influences as well as environmental triggers. Autoimmunity is evidenced by the presence of autoantibodies (antibodies directed against the person who produced them) and T cells that are reactive with host antigens.

Current treatments for allergic and autoimmune disease treat disease symptoms or depend on non-specific immune suppression. Treatment would be improved greatly by targeting the fundamental cause of the disease, that is the loss of tolerance to an otherwise innocuous antigen in allergy or self-antigen in autoimmune disease (AID). Much has been learned about the mechanisms of peripheral tolerance in recent years. We now appreciate that antigen presenting cells (APC) may be either immunogenic or tolerogenic, depending on their location, environmental cues and activation state

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3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 13DiagnosticImmunology

Diagnostic Immunology. Immunoassays are laboratory techniques based on the detection of antibody production in response to foreign antigens. Antibodies, part of the humoral immune response, are involved in pathogen detection and neutralization.

Diagnostic immunology has considerably advanced due to the development of automated methods.New technology takes into account saving samples, reagents, and reducing cost.The future of diagnosticimmunologyfaces challenges in the vaccination field for protection against HIV and asanti-cancer therapy. Modern immunology relies heavily on the use of antibodies as highly specific laboratory reagents. The diagnosis of infectious diseases, the successful outcome of transfusions and transplantations, and the availability of biochemical and hematologic assays with extraordinary specificity and sensitivity capabilities all attest to the value of antibody detection.Immunologic methods are used in the treatment and prevention ofinfectious diseasesand in the large number of immune-mediated diseases. Advances in diagnostic immunology are largely driven by instrumentation, automation, and the implementation of less complex and more standardized procedures.

Examples of such processes are as follows:

These methods have facilitated the performance of tests and have greatly expanded the information that can be developed by a clinical laboratory. The tests are now used for clinical diagnosis and the monitoring of therapies and patient responses. Immunology is a relatively young science and there is still so much to discover. Immunologists work in many different disease areas today that include allergy, autoimmunity, immunodeficiency, transplantation, and cancer.

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3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 14Allergy and Therapathies

Although medications available for allergy are usually very effective, they do not cure people of allergies. Allergenimmunotherapyis the closest thing we have for a "cure" for allergy, reducing the severity of symptoms and the need for medication for many allergy sufferers. Allergen immunotherapy involves the regular administration of gradually increasing doses of allergen extracts over a period of years. Immunotherapy can be given to patients as an injection or as drops or tablets under the tongue (sublingual).Allergen immunotherapy changes the way the immune system reacts to allergens, by switching off allergy. The end result is that you become immune to the allergens, so that you can tolerate them with fewer or no symptoms. Allergen immunotherapy is not, however, a quick fix form of treatment. Those agreeing to allergen immunotherapy need to be committed to 3-5 years of treatment for it to work, and to cooperate with your doctor to minimize the frequency of side effects.Allergen immunotherapyis usually recommended for the treatment of potentially life threatening allergic reactions to stinging insects. Published data on allergen immunotherapy injections shows that venom immunotherapy can reduce the risk of a severe reaction in adults from around 60 % per sting, down to less than 10%. In Australia and New Zealand,venom immunotherapyis currently available for bee and wasp allergy. Jack Jumper Ant immunotherapy is available in Tasmania for Tasmanian residents. Allergen immunotherapy is often recommended for treatment ofallergic rhinitis

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 15Technological Innovations inImmunology

Immunology is the branch of biomedical sciences concerned with all aspects of the immune system in all multicellular organisms. Immunology deals with physiological functioning of the immune system in states of both health and disease as well as malfunctions of the immune system in immunological disorders like allergies, hypersensitivities, immune deficiency, transplant rejection andautoimmune disorders.

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track:16Antigen Processing

Antigen processingis an immunologicalprocessthat prepares antigensfor presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage ofantigenpresentation pathways. The process by which antigen-presenting cells digest proteins from inside or outside the cell and display the resulting antigenic peptide fragments on cell surface MHC molecules for recognition by T cells is central to the body's ability to detect signs of infection or abnormal cell growth. As such, understanding the processes and mechanisms of antigen processing and presentation provides us with crucial insights necessary for the design ofvaccines and therapeutic strategiesto bolster T-cell responses.

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 17Immunoinformatics and Systems Immunology

Immunoinformaticsis a branch ofbioinformaticsdealing with in silico analysis and modelling of immunological data and problems Immunoinformatics includes the study and design of algorithms for mapping potential B- andT-cell epitopes, which lessens the time and cost required for laboratory analysis of pathogen gene products. Using this information, an immunologist can explore the potential binding sites, which, in turn, leads to the development of newvaccines. This methodology is termed reversevaccinology and it analyses the pathogen genome to identify potential antigenic proteins.This is advantageous because conventional methods need to cultivate pathogen and then extract its antigenic proteins. Although pathogens grow fast, extraction of their proteins and then testing of those proteins on a large scale is expensive and time consuming. Immunoinformatics is capable of identifying virulence genes and surface-associated proteins.

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology (C7), March 19 - 23, 2017, Whistler, British Columbia, Canada

Track: 18Rheumatology

Rheumatology represents a subspecialty in internal medicine and pediatrics, which is devoted to adequate diagnosis andtherapy of rheumatic diseases(including clinical problems in joints, soft tissues, heritable connective tissue disorders, vasculitis and autoimmune diseases). This field is multidisciplinary in nature, which means it relies on close relationships with other medical specialties.The specialty of rheumatology has undergone a myriad of noteworthy advances in recent years, especially if we consider the development of state-of-the-art biological drugs with novel targets, made possible by rapid advances in the basic science of musculoskeletal diseases and improved imaging techniques.

RelatedImmunology Conferences|Immunologists Meetings|Conference Series LLC:

Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 19Nutritional Immunology

Nutritional immunologyis an emerging discipline that evolved with the study of the detrimental effect of malnutrition on the immune system. The clinical and public health importance of nutritional immunology is also receiving attention. Immune system dysfunctions that result from malnutrition are, in fact, NutritionallyAcquired Immune Deficiency Syndromes(NAIDS). NAIDS afflicts millions of people in the Third World, as well as thousands in modern centers, i.e., patients with cachexia secondary to serious disease, neoplasia or trauma. The human immune system functions to protect the body against foreign pathogens and thereby preventing infection and disease. Optimal functioning of the immune system, both innate and adaptive immunity, is strongly influenced by an individuals nutritional status, with malnutrition being the most common cause of immunodeficiency in the world. Nutrient deficiencies result in immunosuppression and dysregulation of the immune response including impairment of phagocyte function and cytokine production, as well as adversely affecting aspects of humoral and cell-mediated immunity. Such alterations in immune function and the resulting inflammation are not only associated with infection, but also with the development of chronic diseases including cancer, autoimmune disease, osteoporosis, disorders of the endocrine system andcardiovascular disease.

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8 th European Immunology Conference June 29-July 01, 2017 ...

Bone Marrow Stem Cells Comments Off on 8 th European Immunology Conference June 29-July 01, 2017 … | January 11th, 2017

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The Journal of Cell Science & Therapy is an Open Access, peer-reviewed, academic journal with a wide range of fields within the discipline creates a platform for the authors to publish their comprehensive and most reliable source of information on the discoveries and current developments in the mode of original articles, review articles, case reports, short communications, etc, making them freely available through online without any restrictions or any other subscriptions to researchers worldwide.

The journal is using Editorial Manager System for quality in peer review process. Editorial Manager is an online manuscript submission, review and tracking systems. Review processing is performed by the editorial board members of Journal of Cell Science & Therapy or outside experts; at least two independent reviewers approval followed by editor approval is required for acceptance of any citable manuscript. Authors may submit manuscripts and track their progress through the system, hopefully to publication. Reviewers can download manuscripts and submit their opinions to the editor. Editors can manage the whole submission/review/revise/publish process.

Journal of Cell Science & Therapy is a peer reviewed scientific journal known for rapid dissemination of high-quality research. This Cell Science journal with highest impact factor offers an Open Access platform to the authors in academia and industry to publish their novel research. It serves the International Scientific Community with its standard research publications.

Cells are small compartments that hold the biological equipment necessary to keep an organism alive and successful. Living things may be unicellular or multicellular such as a human being. According to cell theory, cells are the fundamental unit of structure and function in all living organisms and come from preexisting cells, and that all cells contain the hereditary information necessary for regulating cell functions and for transmitting information to the next generation of cells.

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The cytokines produced by expression from suitable cloning vectors containing the desired cytokine gene, can be expressed in yeast (Saccharomyces cerevisiae expression system), bacteria (Escherichia coli expression system), mammalian cells (BHK, CHO, COS, Namalwa), or insect cell systems. Cytokines are designed for demanding applications such as cell culture, differentiation studies, and functional assays mainly in the fields of immunology, neurology, and stem cell research.

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Hematology is the investigation of blood, the blood-framing organs, and blood diseases in which the specialists deal with the diagnosis, treatment and overall management of people with blood disorders ranging from anemia to blood cancer. Some of the diseases treated by haematologists include Iron deficiency anaemia, Sickle cell anemia, Polycythemia or excess production of red blood cells, Myelofibrosis, Leukemia, hemophilia, myelodysplastic syndromes, Malignant lymphomas, Blood transfusion and bone marrow stem cell transplantation

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Cell biology (cytology) is a branch of biology that studies cells their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division, death and cell function. Research in cell biology is closely related to genetics, biochemistry, molecular biology, immunology, and developmental biology.

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A hair follicle is part of the skin that grows hair by packing old cells together. Attached to the follicle is a sebaceous gland, a tiny sebum-producing gland found everywhere except on the palms, lips and soles of the feet. The follicle cells that extrude hairs from just below the surface of the skin are simply too hard to bring back to life, and even preventative therapies didnt seem to be able to do much to keep them alive. But research on inducing stem cells to grow into follicle cells could change that forever.

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Mesenchymal stem cells (MSCs), the major stem cells for cell therapy. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. Cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinical research field.

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Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy.

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Cell Science & Therapy, Insights in Cell Science, Cellular and Molecular Biology, Cell Biology: Research & Therapy, Hematology/Oncology and Stem Cell Therapy, Journal of Cosmetic and Laser Therapy, Cancer Biology and Therapy, Cancer Gene Therapy, Cytotherapy

Rejuvenation and regeneration are two key processes that define cell therapy. Cellular Therapy is a form of non-toxic, holistic medicine in which the entire organism is being treated. Cellular Therapies are an integral part of complimentary treatment regimens. They are extremely versatile and can be used for a wide range of disorders.

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Cell & Developmental Biology, Archives in Cancer Research,Cancer Clinical Trials, Cancer Science & Therapy, Cancer Biology and Therapy, Cancer Gene Therapy, Cytotherapy, Journal of Cancer Science and Therapy, Stem Cell Research and Therapy

Dendritic cells (DCs) cells are the most potent antigen-producing cells, represent unique antigen-producing cells capable of sensitizing T cells to both new and recall antigens. Dendritic Cell Vaccines, or Dendritic cell therapy, is another Alternative Cancer Therapy or newly emerging and potent form of immune therapy used to treat cancer.

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Clinical & Experimental Neuroimmunology, Immunochemistry & Immunopathology: Open Access, Clinical & Cellular Immunology, Immunooncology, Dendrobiology, Genes and Cancer, International Journal of Cancer, Journal of Cancer Science and Therapy, Molecular Cancer Research, Molecular Cancer Therapeutics

The cells are most commonly immune-derived, with the goal of transferring immune functionality and characteristics along with the cells. Transferring autologous cells minimizes GVHD issues. The adaptive transfer of autologous tumor infiltrating lymphocytes (TIL) or genetically re-directed peripheral blood mononuclear cells has been used to treat patients with advanced solid tumors, including melanoma and colorectal carcinoma, as well as patients with CD19-expressing hematologic malignancies. As of 2015 the technique had expanded to treat cervical cancer, lymphoma, leukemia, bile duct cancer and neuroblastoma.

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Cell Signaling, Cellular & Molecular Pathology, Cell Biology: Research & Therapy, Stem Cell Research & Therapy, Antiviral Chemistry and Chemotherapy, Cancer Biotherapy and Radiopharmaceuticals, Cancer Biology and Therapy, Cytotherapy, Japanese Journal of Cancer and Chemotherapy, Oncology and Stem Cell Therapy

The ability to convert one cell type into another has caused great excitement in the stem cell field. iPS Reprogramming and transdifferentiation are the two approaches which makes cells in to another type of cells. In iPS procedure, it make possible to convert essentially any cell type in the body back into pluripotent stem cells that are almost identical to embryonic stem cells. And another approach uses transcription factors to convert a given cell type directly into another specialized cell type, without first forcing the cells to go back to a pluripotent state.

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Autologous stem cell transplants are done using peripheral blood stem cell transplantation (PBSCT). With PBSCT, the stem cells are taken from blood. The growth factor G-CSF may be used to stimulate the growth of new stem cells so they spill over into the blood.

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Cellular and Molecular Biology, Single Cell Biology, Molecular Biology, Stem Cell Research & Therapy, Insights in Stem Cells, Current Stem Cell Research and Therapy, Journal of Stem Cells, Journal of Stem Cells and Regenerative Medicine, Stem Cell Research, Stem Cell Research and Therapy, Stem Cells

Advance Cell & Gene Thearpy practical, experienced guidance in development, GMP/GTP manufacturing, and regulatory compliance, as well as comprehensive scientific and technical strategic analysis of business opportunities in cell therapy, gene therapy and tissue therapies.

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Immunotherapy involves engineering patients own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer. .Adoptive T cell therapy for cancer is a form of transfusion therapy consisting of the infusion of various mature T cell subsets with the goal of eliminating a tumor and preventing its recurrence.

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Commercialization of the first cell-based therapeutics, including cartilage repair products; tissue-engineered skin; and the first personalized, cellular immunotherapy for cancer. Production, storage, and delivery of living cell-based pharmaceuticals presents several unique challenges. Novel, innovative technologies and strategies will be required to bring cell therapies to commercial success.

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Cellular therapy products include cellular immunotherapies, and other types of both autologous and allogeneic cells for certain therapeutic indications, including adult and embryonic stem cells. Human gene therapy refers to products that introduce genetic material into a persons DNA to replace faulty or missing genetic material, thus treating a disease or abnormal medical condition.

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Journal of Cell Science and Therapy is associated with our international conference "6th World Congrss on Cell & Stem Cell Research" during Feb 29- March 2, 2016 Philadelphia, USA with a theme "Novel Therapies in Cell Science and Stem Cell Research. Stem Cell Therapy-2016 will encompass recent researches and findings in stem cell technologies, stem cell therapies and transplantations, current understanding of cell plasticity in cancer and other advancements in stem cell research and cell science.

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Cell Science & Therapy - omicsonline.org

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What is a bone marrow transplant?

Bone marrow transplant (BMT) is a special therapy for patients with certain cancers or other diseases. A bone marrow transplant involves taking cells that are normally found in the bone marrow (stem cells), filtering those cells, and giving them back either to the donor (patient) or to another person. The goal of BMT is to transfuse healthy bone marrow cells into a person after their own unhealthy bone marrow has been treated to kill the abnormal cells.

Bone marrow transplant has been used successfully to treat diseases such as leukemias, lymphomas, aplastic anemia, immune deficiency disorders, and some solid tumor cancers since 1968.

What is bone marrow?

Bone marrow is the soft, spongy tissue found inside bones. It is the medium for development and storage of most of the body's blood cells.

The blood cells that produce other blood cells are called stem cells. The most primitive of the stem cells is called the pluripotent stem cell, which is different than other blood cells with regards to the following properties:

It is the stem cells that are needed in bone marrow transplant.

Why is a bone marrow transplant needed?

The goal of a bone marrow transplant is to cure many diseases and types of cancer. When the doses of chemotherapy or radiation needed to cure a cancer are so high that a person's bone marrow stem cells will be permanently damaged or destroyed by the treatment, a bone marrow transplant may be needed. Bone marrow transplants may also be needed if the bone marrow has been destroyed by a disease.

A bone marrow transplant can be used to:

The risks and benefits must be weighed in a thorough discussion with your doctor and specialists in bone marrow transplants prior to procedure.

What are some diseases that may benefit from bone marrow transplant?

The following diseases are the ones that most commonly benefit from bone marrow transplant:

However, patients experience diseases differently, and bone marrow transplant may not be appropriate for everyone who suffers from these diseases.

What are the different types of bone marrow transplants?

There are different types of bone marrow transplants depending on who the donor is. The different types of BMT include the following:

How are a donor and recipient matched?

Matching involves typing human leukocyte antigen (HLA) tissue. The antigens on the surface of these special white blood cells determine the genetic makeup of a person's immune system. There are at least 100 HLA antigens; however, it is believed that there are a few major antigens that determine whether a donor and recipient match. The others are considered "minor" and their effect on a successful transplant is not as well-defined.

Medical research is still investigating the role all antigens play in the process of a bone marrow transplant. The more antigens that match, the better the engraftment of donated marrow. Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin producing new blood cells.

Most of the genes that "code" for the human immune system are on one chromosome. Since we only have two of each chromosome, one we received from each of our parents, a full sibling of a patient in need of a transplant has a one in four chance of having gotten the same set of chromosomes and being a "full match" for transplantation.

The bone marrow transplant team

The group of specialists involved in the care of patients going through transplant is often referred to as the transplant team. All individuals work together to provide the best chance for a successful transplant. The team consists of the following:

An extensive evaluation is completed by the bone marrow transplant team. The decision for you to undergo a bone marrow transplant will be based on many factors, including the following:

For a patient receiving the transplant, the following will occur in advance of the procedure:

Preparation for the donor

How are the stem cells collected?

A bone marrow transplant is done by transferring stem cells from one person to another. Stem cells can either be collected from the circulating cells in the blood (the peripheral system) or from the bone marrow.

If the donor is the person himself or herself, it is called an autologous bone marrow transplant. If an autologous transplant is planned, previously collected stem cells, from either peripheral (apheresis) or harvest, are counted, screened, and ready to infuse.

The bone marrow transplant procedure

The preparations for a bone marrow transplant vary depending on the type of transplant, the disease requiring transplant, and your tolerance for certain medications. Consider the following:

The days before transplant are counted as minus days. The day of transplant is considered day zero. Engraftment and recovery following the transplant are counted as plus days. For example, a patient may enter the hospital on day -8 for preparative regimen. The day of transplant is numbered zero. Days +1, +2, etc., will follow. There are specific events, complications, and risks associated with each day before, during, and after transplant. The days are numbered to help the patient and family understand where they are in terms of risks and discharge planning.

During infusion of bone marrow, the patient may experience the following:

After infusion, the patient may:

After leaving the hospital, the recovery process continues for several months or longer, during which time the patient cannot return to work or many previously enjoyed activities. The patient must also make frequent follow-up visits to the hospital or doctor's office.

When does engraftment occur?

Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin producing new blood cells. Depending on the type of transplant and the disease being treated, engraftment usually occurs around day +15 or +30. Blood counts will be checked frequently during the days following transplant to evaluate initiation and progress of engraftment. Platelets are generally the last blood cell to recover.

Engraftment can be delayed because of infection, medications, low donated stem cell count, or graft failure. Although the new bone marrow may begin making cells in the first 30 days following transplant, it may take months, even years, for the entire immune system to fully recover.

What complications and side effects may occur following BMT?

Complications may vary, depending on the following:

The following are complications that may occur with a bone marrow transplant. However, each individual may experience symptoms differently. These complications may also occur alone, or in combination:

Long-term outlook for a bone marrow transplantation

Prognosis greatly depends on the following:

As with any procedure, in bone marrow transplant the prognosis and long-term survival can vary greatly from person to person. The number of transplants being done for an increasing number of diseases, as well as ongoing medical developments, have greatly improved the outcome for bone marrow transplant in children and adults. Continuous follow-up care is essential for the patient following a bone marrow transplant. New methods to improve treatment and to decrease complications and side effects of a bone marrow transplant are continually being discovered.

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Bone Marrow Transplantation | Hematology and Oncology

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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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Pia mater - Wikipedia

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Bone marrow is a soft, spongy material found in your large bones. It makes more than 200 billion new blood cells every day, including red blood cells, white blood cells, and platelets. But for people with bone marrow disease, including several types of cancer, the process doesnt work properly. Often, a bone marrow transplant is a persons best chance of survival and a possible cure. The good news is that donating bone marrow can be as easy and painless as giving blood.

A bone marrow transplant replaces diseased bone marrow with healthy tissue, usually stem cells found in the blood. Thats why bone marrow transplants are also called stem cell transplants. In an allogeneic transplantation (ALLO transplant), blood stem cells from the bone marrow are transplanted from a donor into the patient. The donor stem cells can come from either the blood that circulates throughout another persons body or from umbilical cord blood.

But theres a catch. Before a person receives an ALLO transplant, a matching donor must be found using human leukocyte antigen (HLA) typing. This special blood test analyzes HLAs, which are specific proteins on the surface of white blood cells and other cells that make each persons tissue type unique. HLA-matched bone marrow is less likely to cause a possible side effect of transplantation called graft vs. host disease (GVHD). GVHD is when immune cells in the transplanted tissue recognize the recipients body as foreign and attack it.

Only about 30% of people who need a transplant can find an HLA-matched donor in their immediate family. For the remaining 70% of people, doctors need to find HLA-matched bone marrow from other donors. In 2016, that equals about 14,000 people from very young children up to older adults in the United States who need to find a donor outside of their close family.

The National Marrow Donor Program (NMDP) has a registry of potential donors that might be the match a patient needs. Heres how the donation process works:

You register with the NMDP online or in person at a donor center. You can find a center by calling the toll-free number 1-800-MARROW2.

You collect cells from your cheek with a cotton swab or provide a small blood sample. This is done by following directions in a mail-in kit or at a donor center. The sample is analyzed to determine your HLA type, which is recorded in the NMDP national database.

If an HLA match is made with a patient in need, the NMDP contacts you. A donor center takes a new sample of your blood, which is sent to the patients transplant center to confirm the HLA match. Once doctors confirm the match, youd meet with a counselor from the NMDP to talk about the procedures, benefits, and risks of the donation process. You then decide whether youre comfortable with donating.

If you agree to donate bone marrow, youll likely do whats called a peripheral blood stem cell (PBSC) collection. Heres how it works:

For 5 days leading up to the donation, youll get a daily 5-minute injection of granulocyte colony-stimulating factor (G-CSF), a white blood cell growth hormone.

On day 5, a trained health care provider will place a needle in each of your arms. One needle will remove blood, and a machine circulates the blood and collects the stem cells. Your blood then is returned to your body through the second needle. The process takes about 3 hours and may be repeated on a second donation day. Side effects include headaches, bone soreness, and discomfort from the needles during the process.

Although less common, some donors may be asked to undergo a bone marrow harvest, during which doctors take bone marrow from the back of a donors hip bone during surgery. Donors usually go home the same day of the surgery and can return to normal activity within 1 week. Common side effects include nausea, headache, and fatigue, most often related to the anesthesia. Bruising or discomfort in the lower back is also common.

The end result? You could help cure someones disease.

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Donating Bone Marrow | Cancer.Net

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