BIOCHEMISTS SOLVE ADDRESS PROBLEM IN CELLS THAT LEADS TO LETHAL KIDNEY DISEASE

Research by UCLA biochemists may lead to a new treatment -- or even a cure -- for PH1, a rare and potentially deadly genetic kidney disease that afflicts children. Their findings also may provide important insights into treatments for Parkinson's disease, Alzheimer's disease and other degenerative diseases.

Led by Carla Koehler, a professor of chemistry and biochemistry in the UCLA College, the researchers identified a compound called dequalinium chloride, or DECA, that can prevent a metabolic enzyme from going to the wrong location within a cell. Ensuring that the enzyme -- called alanine: glyoxylate aminotransferase, or AGT -- goes to the proper "address" in the cell prevents PH1.

The findings were published online in the Proceedings of the National Academy of Sciences and will appear later in the journal's print edition.

In humans, AGT is supposed to go to an organelle inside the cell called the peroxisome, but for people with a particular genetic mutation, the enzyme mistakenly goes instead to the mitochondria -- tiny power generators in cells that burn food and produce most of the cells' energy -- which causes PH1.

Koehler's team demonstrated that adding small amounts of DECA, which is FDA-approved, to cells in a Petri dish prevents AGT from going to the mitochondria and sends it to its proper destination, the peroxisome.

"In many mutations that cause diseases, the enzyme doesn't work," Koehler said. "In PH1 the enzyme does work, but it goes to the wrong part of the cell. We wanted to use DECA in a cell model to block AGT from going to the wrong address and send it back to the right address. DECA blocks the mitochondria 'mailbox' and takes it to the peroxisome address instead."

How often did it work?

"All the time," said Koehler, a member of UCLA's Jonsson Comprehensive Cancer Center, Molecular Biology Institute and Brain Research Institute.

For people with the mutation, the correct peroxisome address is present in AGT, but it is ignored because it is accompanied by the address of the mitochondria, which the cell reads first, Koehler said.

Koehler, who also is a member of the scientific and medical advisory board of the United Mitochondrial Disease Foundation, hopes to find out whether a similar "correct address" strategy can slow cancer down. Her laboratory has identified approximately 100 other small molecules, which she calls MitoBloCKs, that she and her colleagues are testing for their ability to combat Parkinson's, Alzheimer's and other diseases.

PH1 -- short for primary hyperoxaluria 1 -- starts at birth and is usually fatal for patients who do not receive both kidney and liver transplants. Approximately half of those with the disease have kidney failure by age 15. Koehler has presented her findings to the Oxalosis and Hyperoxaluria Foundation, which provides support for PH1 patients and their families.

Scientists' ability to diagnose rare diseases has improved in recent years because technological advances in genomics have made it easier to identify more genetic mutations, Koehler said.

According to Koehler, to treat diseases, scientists must first understand how proteins like AGT move inside the cell. Her research, which encompasses biochemistry, genetics and cell biology, studies how mitochondria are assembled and function, how proteins enter the mitochondria and reach the right location inside cells, and how mitochondria communicate with the rest of the cell.

Her laboratory uses model systems that enable them to study the biochemistry in a way that is not possible with humans. Much of the work is conducted in yeast.

"It's exciting that our studies in baker's yeast, a typical laboratory model, might be able to help kids with a complicated disease," Koehler said.

How Nerve Cells Map Themselves

Today's post from sciencedaily.com (see link below) is a fascinating look at how nerve cells map their own position and either block or allow other embryonic nerve cells from moving into their right position in the nervous system. Apparently the axons have a lot to do with this (the axons are the 'wires' you see connecting one nerve to another in images of nerve cells) and act as corridors for both information and nerve development. If the axons are disrupted, it can lead to all sorts of conditions, due to nerve signals being diverted, or prevented from reaching their destination. It just shows how complex and amazing the nervous system is and highlights how little we appreciate how things get done in our bodies. The question is: although scientists can deliberately interfere with axons to prove a point, can they effectively repair them in the future so that normals nerve signals are restored to their normal function?

Nerve cells use each other as maps
Date:May 19, 2015 Source: Umeå universitet 

Summary:

When nerve cells form in an embryo they don't start off in the right place but have to be guided to their final position by navigating a kind of molecular and cellular "map" in order to function properly. In a recent research study published in Nature Communications neurobiologist Sara Wilson, Umeå University, found that during embryonic development different parts of the nerve cell are important for guiding other nerve cells into their physical positions.

"We found nerve cells do this in two ways, either acting as barriers preventing cell bodies to move further than they need to, or by acting as guides opening a corridor that the cell bodies can travel along," she says.

The nervous system is analogous to a biological "computer" with different nerve cells forming connections that continuously send neural information around the spinal cord, brain and body and back again. Each nerve cell has a kind of "GPS coordinate" and exactly where nerve cells are physically located is very important so they can connect correctly with other nerve cells.

When nerve cells are in the wrong place neural information is not transmitted properly and it results in dysfunction and neurodevelopmental disorders such as lissencephaly, Kallmann syndrome and periventricular heterotopia. These misplacements can also happen in very common developmental disorders such as dyslexia and autistic spectrum disorders but it is not fully clear what role such misplacements play in these cases.

"Because nerve cell position is so important in normal nervous system function and dysfunction we wanted to find out how nerve cells position themselves in the first place. This study uncovered an exciting new mechanism for how this happens" Sara Wilson says.

Two of the main parts of a nerve cell are the central part (called the cell body) and a very long part like a "wire" (called the axon) that connects with and sends information to other nerve cells. It is important for both of these parts to be in the right place to get the nervous system to work properly.

The axons usually group together and form structures similar to corridors heading in a certain direction. Using genetic changes in mouse embryos to disrupt these axonal corridors (make them head in a different direction), her research group at Umeå Centre of Molecular Medicine, now at the Department of Molecular Biology, Umeå University, found that cell bodies from nerve cells also end up in the wrong place.

"This means the axons from some nerve cells are influencing the position of the cell bodies of other nerve cells meaning that the nerve cells are creating a "map" for other nerve cells to find their way" Sara Wilson says.

"This is the first time that axons have been shown to act as barriers and it could have important implications for understanding how the nervous system forms in all animals, including humans" Sara Wilson concludes.

Overall, this work and other work from the group focuses on understanding the mechanisms (genetic, cellular and molecular) of how the precise "anatomy" of the nervous system first forms and how that influences neuronal function and dysfunction. This basic science research has important medical implications for understanding the cause of some neurodevelopmental disorders: For example do the genes that are associated with such disorders generally control cell body guidance and is that what leads to dysfunction?

"It can also give clues as to how to grow axons during regeneration following damage or disease of the nervous system. Can we "force" regenerating neurons to connect properly? In the future, we plan to continue this basic research and find medical research teams to collaborate with to see if our findings are beneficial in these medical contexts" Sara Wilson says.

Story Source:

The above story is based on materials provided by Umeå universitet. Note: Materials may be edited for content and length.

Journal Reference:
Christophe Laumonnerie, Yong Guang Tong, Helena Alstermark, Sara I. Wilson. Commissural axonal corridors instruct neuronal migration in the mouse spinal cord. Nature Communications, 2015; 6: 7028 DOI: 10.1038/ncomms8028
 
http://www.sciencedaily.com/releases/2015/05/150519084229.htm

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HOMOEOPATHIC REMEDIES FOR PUS CELLS IN URINE

Presence of pus cells in urine is a definite indication of some type of infection. Pus is a whitish or yellowish or slightly green substance which is thick like glue. Pus in urine signifies that the body is fighting an infection in the lower or upper urinary tract.  Pus contains dead skin cells, bacteria and white blood cells. The medical term for the pus in urine condition is known as Pyuria and it is a common symptom for various medical conditions. The most common reason for Pyuria is the existence of urinary tract infection.  Women are more prone to urinary tract infections. The condition can be quite severe if it affects a man.  The urinary tract infections are caused by bacteria entering the urinary tract. The tract consists of the kidneys, urinary bladder, ureters and urethra. The infection can occur at any part of the tract and commonly infections occur in the lower portions such as the urethra and urinary bladder.

Causes-The two most common causes for the presence of pus cells in urine are

·        Urinary tract infection or UTI

·        Sexually transmitted diseasesSome of the other causes for pus seen in urine are

• Viral infections
• Anaerobic bacterial infection
• Fungal infections
• Chemical poisoning
• Kidney stones
• Fastidious bacteria
• Tuberculosis of the urinary tract
• Infection in prostate glands in men
• Cancer of the urinary organs or genital organs
• Sometimes pus cells in urine also result from old age and pregnancy. Certain medications also cause the condition of pus in urine.

Symptoms-- Sometimes there won’t be any symptoms of urinary tract infection or the presence of pus in the urine. When the symptoms occur they are as follows

·        Foul smelling urine

·        Cloudy urine

·        Fever

·        Frequent urination

·        Pain or discomfort while urinating

·        Vomiting

·        Abdominal cramps

If the pus in urine is caused by UTI the pain may be felt deep inside the bladder or at the tip of the urethra through which the pus cells exits the body.  If the pus is formed by STD’s, there will be fever, weakness and there will be an overall feeling of being ill.

HOMOEOPATHIC REMEDIES

CANTHARIS VESICATORIA 30-Cantharis Vesicatoria is one of the top Homeopathic medicines for pus cells in urine. Burning during urination is a sure sign that Cantharis Vesicatoria is the ideal choice among Homeopathic medicines for pus cells in urine. The burning may continue after urination. In some cases, burning in urethra before urination may also be felt. This is attended with a constant desire to urinate. Tenesmus of bladder is marked.  Urine passing drop by drop is also a sure indication of  Cantharis Vesicatoria .

APIS MELLIFICA 30-Apis mellifica is prescribed when  burning, scalding sensation in urethra while passing the last drops of urine is present.  Urine flow is slow. Stinging pain in urethra while passing urine is another key symptom guiding use of Apis Mellifica . Urgency to pass urine is also marked.

BAROSMA CRENATA Q- Barosma crenata has marked action on genito urinary system. Urine contains more pus. Irritable bladder, with vesical catarrh.

BERBERIS VULGARIS Q-Berberis Vulgaris is prescribed when  burning in urethra  is present even when not urinating. Along with this, pain in kidney region and thighs may also be present. Constant urge to urinate, with scanty urine, is another indication that Homeopathic medicine . There is the sensation of some urine remaining in the bladder after urinating. Cramping or aching pain in the bladder while urinating is another symptom showing Berberis Vulgaris .

EQUISETUM Q—Equisetum is a near specific for UTI. There is frequent and intolerable urge to urinate.Dull pain in the bladder is constantly present.There is a shrap cutting burning sensation in the urethra when urinating.Much pus and albumin in urine.

COPAIVA OFF Q- Copaiva is an effective remedy for pus in urine. Urine has a bad smell. Discharge of a greenish , turbid colour with a pungent odour. Painful urination, urine passes by drop by drop.

CHIMAPHILA  UMBELLATA Q-In Chimaphila umbellate urine is turbid , offensive , containing ropy or bloody mucus and depositing a copious sediment. Burning and scalding during urination and straining afterwards .

SARASAPARILLA 30-Sarasaparilla is indicated when  the person experiences severe pain at the conclusion of urination.  Pain in urethra may extend to abdomen. Painful distension and tenderness in bladder may also be present. Urine stream is also feeble and thin. Sarsaparilla Officinalis is also the most suitable among Homeopathic medicines for pus cells in urine among children. The child screams from pain before and while passing urine in such cases.

CLEMATIS ERECTA 30--Clemetis Erecta is very effective for UTI in patients who have suffered from Sexual transmitted disesaes . It is indicated when the symptoms are – Frequent scanty urine with burning at the orifice of urethra. The patient has an unusual desire to pass urine , urine is passed drop by drop , dribbling of urine even after passing of urine.Urine is mixed with pus.

MERC COR. 30--Merc Cor is an  effective remedy  for pus in urine due to UTI.  This medicine can be thought of in cases where the patient  is unable to pass urine or has to put in a lot of effort  for the same. The urine is very little and most often the patient passes dark flesh like pieces of mucus in the urine. The urine is very hot and passes drop by drop and with great pain. Another feature of a Merc cor patient is that he/she experiences a lot  of sweating  immediately after passing urine. This usually happens because the patient has to strain a lot to pass urine.    This medicine can also be expected to give good results in recurrent UTIs in advanced stages of pregnancy.

SOLIDAGO VIRGA Q-Solidago is another effective drug for pus in urine.  Albumin , blood and pus in  urine. Pain in kidney extend to abdomen and bladder.

NITRIC ACID 30-Nitric Acid is an excellent remedy   for pus cells in urine where the urine passed is very offensive. The urine is also scanty and dark in colour. It may also be turbid or cloudy in some cases. Burning and stinging sensation on passing urine may be present.

PAREIRA BRAVA 3-Pareira brava is very effective for UTI. The leading symptoms are—constant urging to urinate , great straining . Pain down thighs during efforts to urinate. Urine is black, bloody with thick pus. Urine is passed with great difficulty. In worst cases urine is passed only by going on hand and knees position.

UVA URSI 3X-Uva Ursi is another remedy   for pus cells where blood is passed along with pus cells in urine. Urine may also contain tenacious mucus. There is frequent urging for urination. Irritation in the bladder is observed. Cutting pain in the urethra may also be present along with the above features.

COLI BACILLINUM 30-- Coli Bacillinum is a near specific medicine for treating e-coli infection. It helps in treating the recurrence of E coli Infection. There is pain and burning while urination.

CORONARY ARTERIES HOLD HEART REGENERATING CELLS

Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue, Vanderbilt University investigators have discovered.

The findings, published recently in Cell Reports, offer insights into how the heart maintains itself and could lead to new strategies for repairing the heart when it fails after a heart attack.

The heart has long been considered to be an organ without regenerative potential, said Antonis Hatzopoulos, Ph.D., associate professor of Medicine and Cell and Developmental Biology.

"People thought that the same heart you had as a young child, you had as an old man or woman as well," he said.

Recent findings, however, have demonstrated that new heart muscle cells are generated at a low rate, suggesting the presence of cardiac stem cells. The source of these cells was unknown.

Hatzopoulos and colleagues postulated that the endothelial cells that line blood vessels might have the potential to generate new heart cells. They knew that endothelial cells give rise to other cell types, including blood cells, during development.

Now, using sophisticated technologies to "track" cells in a mouse model, they have demonstrated that endothelial cells in the coronary arteries generate new cardiac muscle cells in healthy hearts. They found two populations of cardiac stem cells in the coronary arteries -- a quiescent population in the media layer and a proliferative population in the adventitia (outer) layer.

The finding that coronary arteries house a cardiac stem cell "niche" has interesting implications, Hatzopoulos said. Coronary artery disease -- the No. 1 killer in the United States -- would impact this niche.

"Our study suggests that coronary artery disease could lead to heart failure not only by blocking the arteries and causing heart attacks, but also by affecting the way the heart is maintained and regenerated," he said.

The current research follows a previous study in which Hatzopoulos and colleagues demonstrated that after a heart attack, endothelial cells give rise to the fibroblasts that generate scar tissue.

"It looks like the same endothelial system generates myocytes (muscle cells) during homeostasis and then switches to generate scar tissue after a myocardial infarction. After injury, regeneration turns to fibrosis," he said.

Understanding this switch could lead to new strategies for restoring regeneration and producing new heart muscle after a heart attack, during aging or in disease conditions such as diabetes and high blood pressure, he said.

"If we can understand the molecular mechanisms that regulate the fate switch that happens after injury, perhaps we can use some sort of chemical or drug to restore regeneration and make muscle instead of scar," Hatzopoulos said. "We think there is an opportunity here to improve the way we treat people who come into the clinic after myocardial infarction."

BACTERIAL COMMUNICATION SYSTEM COULD BE USED TO STOP CANCER CELLS

Cancer, while always dangerous, truly becomes life-threatening when cancer cells begin to spread to different areas throughout the body. Now, researchers at the University of Missouri have discovered that a molecule used as a communication system by bacteria can be manipulated to prevent cancer cells from spreading. Senthil Kumar, an assistant research professor and assistant director of the Comparative Oncology and Epigenetics Laboratory at the MU College of Veterinary Medicine, says this communication system can be used to "tell" cancer cells how to act, or even to die on command.

"During an infection, bacteria release molecules which allow them to 'talk' to each other," said Kumar, the lead author of the study. "Depending on the type of molecule released, the signal will tell other bacteria to multiply, escape the immune system or even stop spreading. We found that if we introduce the 'stop spreading' bacteria molecule to cancer cells, those cells will not only stop spreading; they will begin to die as well."

In the study published in PLOS ONE, Kumar, and co-author Jeffrey Bryan, an associate professor in the MU College of Veterinary Medicine, treated human pancreatic cancer cells grown in culture with bacterial communication molecules, known as ODDHSL. After the treatment, the pancreatic cancer cells stopped multiplying, failed to migrate and began to die.

"We used pancreatic cancer cells, because those are the most robust, aggressive and hard-to-kill cancer cells that can occur in the human body," Kumar said. "To show that this molecule can not only stop the cancer cells from spreading, but actually cause them to die, is very exciting. Because this treatment shows promise in such an aggressive cancer like pancreatic cancer, we believe it could be used on other types of cancer cells and our lab is in the process of testing this treatment in other types of cancer."

Kumar says the next step in his research is to find a more efficient way to introduce the molecules to the cancer cells before animal and human testing can take place.

"Our biggest challenge right now is to find a way to introduce these molecules in an effective way," Kumar said. "At this time, we only are able to treat cancer cells with this molecule in a laboratory setting. We are now working on a better method which will allow us to treat animals with cancer to see if this therapy is truly effective. The early-stage results of this research are promising. If additional studies, including animal studies, are successful then the next step would be translating this application into clinics."

IMMUNE CELLS IN LIVER DRIVE FATTY LIVER DISEASE LIVER CANCER

Fatty liver disease -- alongside fatty liver due to massive alcohol consumption -- is mainly caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary life style. This is referred to as non-alcoholic fatty liver disease (NAFLD). If NAFLD becomes chronic -- e.g. through the constant uptake of high lipids and high sugar combined with lack of excercise a chronic inflammatory response is triggered in the liver tissue in addition. This can lead to non-alcoholic steatohepatitis (NASH) -- a liver disease with clear detectable pathologic alteratons of the tissue.

These liver diseases (NAFLD and NASH), along with chronic viral infections, are the most common causes of liver cancer, or hepatocellular carcinoma (HCC). In the United States, about 90 million people suffer from NAFLD. In Europe, the figure is more than 40 million, and even in threshold countries like India and China, the number of people affected is rising due to increasingly unhealthy lifestyles. More worrying, in all of the above mentioned states the numbers of NAFLD and NASH patients is constantly increasing. Consequently, the incidence of HCC resulting from NASH and NAFLD is also rising worldwide. In the United States, HCC is the fastest-growing form of cancer at the moment. No efficient causal therapy exists for HCC patients of which approximately 800,000 die every year.

T cells involved in the development of fatty liver disease, NASH and HCC

The mechanisms that cause diseases such as fatty liver disease, steatohepatitis and HCC are still not widely understood. However, immune cells, particularly CD8+ T cells and NK T cells seem to play an important role. This finding was made by a team of scientists led by Prof. Mathias Heikenwälder, Prof. Matthias Tschöp, Dr. Kerstin Stemmer, Dr. Kristian Unger, Prof. Ulrike Protzer and the working group of Dr. Hans Zischka from the Helmholtz Zentrum München together with a team headed by Prof. Percy Knolle of the Technische Universität München (TUM), Prof. Achim Weber from Zurich University Hospital and Dr. Monika Wolf, Institute of Surgical Pathology, University Hospital Zurich. The animal model which was used to examine the long-term effects of metabolic syndrome* enabled the scientists to elucidate new mechanisms that cause fatty liver disease and also show how it can develop into liver cancer.

Inflammatory events offer starting point for prevention and treatment

The scientists assume that an existing metabolic imbalance results in the activation and migration of immune cells to the liver. There, the immune cells interact with liver cells and trigger an inflammatory response that damages the liver tissue and also destabilizes the metabolic activity of the liver cells. "Initially it immune cells promote fatty liver degeneration. The inflammation, which is triggered by specific immune cells, encourages the progression of fatty liver pathology and causes NASH to develop. These processes are the basis for liver cell degeneration, which can cause HCC," explains Prof. Heikenwälder, who led the study. "Our results provide completely new insights into the development of these serious liver diseases. Building on this knowledge, we now want to develop new, preventive and therapeutic strategies to combat these diseases." The initial studies are already under way in the preclinical model.

*Metabolic syndrome: a combination of obesity / abdominal adiposity, insulin resistance, raise levels of lipids in the blood and raised blood pressure.

ARTIFICIAL CELLS TAKE THEIR STEPS MOVABLE CYTOSKELETON MEMBRANE FABRICATED FOR THE FIRST TIME

 Using only a few ingredients, the biophysicist Prof. Andreas Bausch and his team at the Technische Universität München (TUM) have successfully implemented a minimalistic model of the cell that can change its shape and move on its own. They describe how they turned this goal into reality in the current edition of the journal Science, where their research is featured as cover story

Cells are complex objects with a sophisticated metabolic system. Their evolutionary ancestors, the primordial cells, were merely composed of a membrane and a few molecules. These were minimalistic yet perfectly functioning systems.

Thus, "back to the origins of the cell" became the motto of the group of TUM-Prof. Andreas Bausch, who is member of the cluster of excellence "Nanosystems Initiative Munich (NIM)" and his international partners. Their dream is to create a simple cell model with a specific function using a few basic ingredients. In this sense they are following the principle of synthetic biology in which individual cellular building blocks are assembled to create artificial biological systems with new characteristics.

The vision of the biophysicists was to create a cell-like model with a biomechanical function. It should be able to move and change its shape without external influences. They explain how they achieved this goal in their latest publication in Science.

The magic ball

The biophysicists' model comprises a membrane shell, two different kinds of biomolecules and some kind of fuel. The envelope, also known as a vesicle, is made of a double-layered lipid membrane, analogous of natural cell membranes. The scientists filled the vesicals with microtubules, tube-shaped components of the cytoskeleton, and kinesin molecules. In cells, kinesins normally function as molecular motors that transport cellular building blocks along the microtubules. In the experiment, these motors permanently push the tubules alongside each other. For this, kinesins require the energy carrier ATP, which was also available in the experimental setup.

From a physical perspective, the microtubules form a two-dimensional liquid crystal under the membrane, which is in a permanent state of motion. "One can picture the liquid crystal layer as tree logs drifting on the surface of a lake," explains Felix Keber, lead author of the study. "When it becomes too congested, they line up in parallel but can still drift alongside each other."

Migrating faults

Decisive for the deformation of the artificial cell construction is that, even in its state of rest, the liquid crystal must always contain faults. Mathematicians explain these kinds of phenomena by way of the Poincaré-Hopf theorem, figuratively also referred to as the "hairy ball problem." Just as one can't comb a hairy ball flat without creating a cowlick, there will always be some microtubules that cannot lay flat against the membrane surface in a regular pattern. At certain locations the tubules will be oriented somewhat orthogonally to each other -- in a very specific geometry. Since the microtubules in the case of the Munich researchers are in constant motion alongside each other due to the activity of the kinesin molecules, the faults also migrate. Amazingly, they do this in a very uniform and periodic manner, oscillating between two fixed orientations.

Spiked extensions

As long as the vesicle has a spherical shape, the faults have no influence on the external shape of the membrane. However, as soon as water is removed through osmosis, the vesicle starts to change in shape due to the movement within the membrane. As the vesicle loses ever more water, slack in the membrane forms into spiked extensions like those used by single cells for locomotion.

In this process, a fascinating variety of shapes and dynamics come to light. What seems random at first sight is, in fact, following the laws of physics. This is how the international scientists succeeded in deciphering a number of basic principles like the periodic behavior of the vesicles. These principles, in turn, serve as a basis for making predictions in other systems.

"With our synthetic biomolecular model we have created a novel option for developing minimal cell models," explains Bausch. "It is ideally suited to increasing the complexity in a modular fashion in order to reconstruct cellular processes like cell migration or cell division in a controlled manner. That the artificially created system can be comprehensively described from a physical perspective gives us hope that in the next steps we will also be able to uncover the basic principles behind the manifold cell deformations."

DYING BRAIN CELLS CUE NEW BRAIN CELLS TO GROW IN SONGBIRD

Brain cells that multiply to help birds sing their best during breeding season are known to die back naturally later in the year. For the first time researchers have described the series of events that cues new neuron growth each spring, and it all appears to start with a signal from the expiring cells the previous fall that primes the brain to start producing stem cells

If scientists can further tap into the process and understand how those signals work, it might lead to ways to exploit these signals and encourage replacement of cells in human brains that have lost neurons naturally because of aging, severe depression or Alzheimer's disease, said Tracy Larson, a University of Washington doctoral student in biology. She's lead author of a paper in the Sept. 23 Journal of Neuroscience on brain cell birth that follows natural brain cell death.

Neuroscientists have long known that new neurons are generated in the adult brains of many animals, but the birth of new neurons - or neurogenesis - appears to be limited in mammals and humans, especially where new neurons are generated after there's been a blow to the head, stroke or some other physical loss of brain cells, Larson said. That process, referred to as "regenerative" neurogenesis, has been studied in mammals since the 1990s.

This is the first published study to examine the brain's ability to replace cells that have been lost naturally, Larson said.

"Many neurodegenerative disorders are not injury-induced," the co-authors write, "so it is critical to determine if and how reactive neurogenesis occurs under non-injury-induced neurodegenerative conditions."

The researchers worked with Gambel's white-crowned sparrows, a medium-sized species 7 inches (18 centimeters) long that breeds in Alaska, then winters in California and Mexico. Sometimes in flocks of more than 100 birds, they can be so plentiful in parts of California that they are considered pests. The ones in this work came from Eastern Washington.

Like most songbirds, Gambel's white-crowned sparrows experience growth in the area of the brain that controls song output during the breeding season when a superior song helps them attract mates and define their territories. At the end of the season, probably because having extra cells exacts a toll in terms of energy and steroids they require, the cells begin dying naturally and the bird's song degrades.

Gambel's white-crowned sparrows are particularly good to work with because their breeding cycle is closely tied to the amount of sunlight they receive. Give them 20 hours of light in the lab, along with the right increase of steroids, and they are ready to breed. Cut the light to eight to 12 hours and taper the steroids, the breeding behavior ends.

"As the hormone levels decrease, the cells in the part of the brain controlling song no longer have the signal to 'stay alive,'" Larson said. "Those cells undergo programmed cell death - or cell suicide as some call it. As those cells die it is likely they are releasing some kind of signal that somehow gets transmitted to the stem cells that reside in the brain. Whatever that signal is then triggers those cells to divide and replace the loss of the cell that sent the signal to begin with."

The next spring, all that's needed is for steroids to ramp up and new cells start to proliferate in the song center of the brain.

"This paper doesn't describe the exact nature of the signals that stimulate proliferation," Larson said. "We're just describing the phenomenon that there is this connection between cells dying and this stem cell proliferation. Finding the signal is the next step."

"Tracy really nailed this down by going in and blocking cell death at the end of the breeding season," said Eliot Brenowitz, UW professor of psychology and of biology, and co-author on the paper. "There are chemicals you can use to turn off the cell suicide pathway. When this was done, far fewer stem cells divided. You don't get that big uptick in new neurons being born. That's important because it shows there's something about the cells dying that turns on the replacement process.'

"There's no reason to think what goes on in a bird brain doesn't also go on in mammal brains, in human brains," Brenowitz says. "As far as we know, the molecules are the same, the pathways are the same, the hormones are the same. That's the ultimate purpose of all this, to identify these molecular mechanisms that will be of use in repairing human brains."

In mammals, the area of the brain that controls the sense of smell and the one that is thought to have a role in memories can produce tiny numbers of new brain cells but it is not understood how or why. The numbers of new cells is so low that trying to identify and quantify if dying cells are being replaced and if so, the steps that are involved, is much more difficult than when using a songbird like Gambel's white-crowned sparrow, Larson and Brenowitz said.

The other co-authors on the paper are Nivretta Thatra, who started working with Larson while still in high school, continued while earning her UW undergraduate degree and is now at the Allen Institute for Brain Science; and Brian Lee, who worked in Brenowitz's UW lab while earning his undergraduate degree from Johns Hopkins University. The work was supported by the National Institutes of Health and the UW Department of Biology.

Stem Cells To Treat Nerve Pain

Today's post from emaxhealth.com (see link below), talks about something that has been in the news (well neuropathy news!) for some time now and that concerns the use of stem cell therapy to treat nerve pain. By transplanting nerve cells from the brain into the spine, these cells theoretically go on to form healthy synapses and reconnect with other cells nearby. It's an interesting development but they have only tested it on mice so far and the treatment may well be years away for human subjects. The scientific theory behind it looks promising, so hopefully this will be one of the new advances in the study of neuropathy that actually ends up being a viable option.

Stem cells may treat and cure chronic nerve pain

By Jenny Decker RN on May 23, 2012

In a new study from the UCSF it was found that stem cells may treat and cure chronic pain caused by nerve injury.

In the study from University of California San Francisco that was published in the May 24th 2012 issue of Neuron, scientists found that they may not only be able to treat chronic nerve pain, but a cure is possible for some types of neuropathic conditions. Using immature embryonic stem cells from the brain, the scientists then transplanted them into adult mouse spinal cords. A small number of these cells survived and matured, then headed off to form synapses and signaling patterns with other neighboring neurons.

This decreased pain hypersensitivity, and in many cases, almost completely eliminated it. Although the stem cells worked in cases with peripheral nerve damage and chronic neuropathy, the same transplantation did not work with inflammatory pain. More research will need to be done in this area.

Peripheral nerve damage can be caused from shingles, among other things. Pain hypersensitivity occurs as a result. Pain hypersensitivity can be explained as the person getting a very light touch and the result is perceived as very painful, according to Senior Author, Allan Basbaum PhD, Chair of the Department of Anatomy at UCSF. He explains that this type of chronic pain is often debilitating for the person.

In a world where there is little relief for those with chronic neuropathic pain, it can be extremely frustrating that there is very little that helps. Even the medications do not work well. Neurontin, or gabapentin, is a drug that was first used to treat epilepsy, is also used to treat chronic neuropathy. It only helps about 30 percent of people and of those 30 percent, it only relieves about 30 percent of their pain.

This research brings new hope. The goal for the scientists now is to find the possibilities that are inherent with their current findings. They must find where the potential treatments are that are much more effective than current treatments.

The research is in very early stages. The researchers advise that they are a long way from any human trials. But with the very focused effects minus any of the adverse effects usually noted with medications such as Neurontin, stem cell transplants are a very real possibility in the treatment for chronic nerve pain. Not only treatment is possible, but a cure may also be possible as well. The stem cells began new networks with other nerve cells and brought hope to those who suffer each day from chronic neuropathy.

The work for the scientists has just started. Being able to be treated with the stem cells and not have to worry about the movement disturbances that are caused by medications like gabapentin is a true hope for those who suffer everyday from the chronic debiliatating nerve pain. The hope that a cure may be coming sometime in the future gives even more hope.

http://www.emaxhealth.com/1272/stem-cells-may-treat-and-cure-chronic-nerve-pain

OBESITY BREAKTHROUGH METABOLIC MASTER SWITCH PROMPTS FAT CELLS TO STORE OR BURN FAT

Obesity is one of the biggest public health challenges of the 21st century. Affecting more than 500 million people worldwide, obesity costs at least $200 billion each year in the United States alone, and contributes to potentially fatal disorders such as cardiovascular disease, type 2 diabetes, and cancer.

But there may now be a new approach to prevent and even cure obesity, thanks to a study led by researchers at MIT and Harvard Medical School and published today in the New England Journal of Medicine. By analyzing the cellular circuitry underlying the strongest genetic association with obesity, the researchers have unveiled a new pathway that controls human metabolism by prompting our adipocytes, or fat cells, to store fat or burn it away.

"Obesity has traditionally been seen as the result of an imbalance between the amount of food we eat and how much we exercise, but this view ignores the contribution of genetics to each individual's metabolism," says senior author Manolis Kellis, a professor of computer science and a member of MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and of the Broad Institute.

New mechanism found

The strongest association with obesity resides in a gene region known as "FTO," which has been the focus of intense scrutiny since its discovery in 2007. However, previous studies have failed to find a mechanism to explain how genetic differences in the region lead to obesity.

"Many studies attempted to link the FTO region with brain circuits that control appetite or propensity to exercise," says first author Melina Claussnitzer, a visiting professor at CSAIL and instructor in medicine at Beth Israel Deaconess Medical Center and Harvard Medical School. "Our results indicate that the obesity-associated region acts primarily in adipocyte progenitor cells in a brain-independent way."

To recognize the cell types where the obesity-associated region may act, the researchers used annotations of genomic control switches across more than 100 tissues and cell types. They found evidence of a major control switchboard in human adipocyte progenitor cells, suggesting that genetic differences may affect the functioning of human fat stores.

To study the effects of genetic differences in adipocytes, the researchers gathered adipose samples from healthy Europeans carrying either the risk or the non-risk version of the region. They found that the risk version activated a major control region in adipocyte progenitor cells, which turned on two distant genes, IRX3 and IRX5.

Control of thermogenesis

Follow-up experiments showed that IRX3 and IRX5 act as master controllers of a process known as thermogenesis, whereby adipocytes dissipate energy as heat, instead of storing it as fat. Thermogenesis can be triggered by exercise, diet, or exposure to cold, and occurs both in mitochondria-rich brown adipocytes that are developmentally related to muscle, and in beige adipocytes that are instead related to energy-storing white adipocytes.

"Early studies of thermogenesis focused primarily on brown fat, which plays a major role in mice, but is virtually nonexistent in human adults," Claussnitzer says. "This new pathway controls thermogenesis in the more abundant white fat stores instead, and its genetic association with obesity indicates it affects global energy balance in humans."

The researchers predicted that a genetic difference of only one nucleotide is responsible for the obesity association. In risk individuals, a thymine (T) is replaced by a cytosine (C) nucleobase, which disrupts repression of the control region and turns on IRX3 and IRX5. This then turns off thermogenesis, leading to lipid accumulation and ultimately obesity.

By editing a single nucleotide position using the CRISPR/Cas9 system -- a technology that allows researchers to make precise changes to a DNA sequence -- the researchers could switch between lean and obese signatures in human pre-adipocytes. Switching the C to a T in risk individuals turned off IRX3 and IRX5, restored thermogenesis to non-risk levels, and switched off lipid storage genes.

"Knowing the causal variant underlying the obesity association may allow somatic genome editing as a therapeutic avenue for individuals carrying the risk allele," Kellis says. "But more importantly, the uncovered cellular circuits may allow us to dial a metabolic master switch for both risk and non-risk individuals, as a means to counter environmental, lifestyle, or genetic contributors to obesity."

Success in human and mouse cells

The researchers showed that they could indeed manipulate this new pathway to reverse the signatures of obesity in both human cells and mice.

In primary adipose cells from either risk or non-risk individuals, altering the expression of either IRX3 or IRX5 switched between energy-storing white adipocyte functions and energy-burning beige adipocyte functions.

Similarly, repression of IRX3 in mouse adipocytes led to dramatic changes in whole-body energy balance, resulting in a reduction of body weight and all major fat stores, and complete resistance to a high-fat diet.

"By manipulating this new pathway, we could switch between energy storage and energy dissipation programs at both the cellular and the organismal level, providing new hope for a cure against obesity," Kellis says.

The researchers are currently establishing collaborations in academia and industry to translate their findings into obesity therapeutics. They are also using their approach as a model to understand the circuitry of other disease-associated regions in the human genome.