Discovery of cell memory mechanism

Main Category: Genetics
Also Included In: Biology / Biochemistry
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Discovery of cell memory mechanism

The cells in our bodies can divide as often as once every 24 hours, creating a new, identical copy. DNA binding proteins called transcription factors are required for maintaining cell identity. They ensure that daughter cells have the same function as their mother cell, so that for example muscle cells can contract or pancreatic cells can produce insulin. However, each time a cell divides the specific binding pattern of the transcription factors is erased and has to be restored in both mother and daughter cells. Previously it was unknown how this process works, but now scientists at Karolinska Institutet have discovered the importance of particular protein rings encircling the DNA and how these function as the cell's memory.

The DNA in human cells is translated into a multitude of proteins required for a cell to function. When, where and how proteins are expressed is determined by regulatory DNA sequences and a group of proteins, known as transcription factors, that bind to these DNA sequences. Each cell type can be distinguished based on its transcription factors, and a cell can in certain cases be directly converted from one type to another, simply by changing the expression of one or more transcription factors. It is critical that the pattern of transcription factor binding in the genome be maintained. During each cell division, the transcription factors are removed from DNA and must find their way back to the right spot after the cell has divided. Despite many years of intense research, no general mechanism has been discovered which would explain how this is achieved.

"The problem is that there is so much DNA in a cell that it would be impossible for the transcription factors to find their way back within a reasonable time frame. But now we have found a possible mechanism for how this cellular memory works, and how it helps the cell remember the order that existed before the cell divided, helping the transcription factors find their correct places", explains Jussi Taipale, professor at Karolinska Institutet and the University of Helsinki, and head of the research team behind the discovery.

The results are now being published in the scientific journal Cell. The research group has produced the most complete map yet of transcription factors in a cell. They found that a large protein complex called cohesin is positioned as a ring around the two DNA strands that are formed when a cell divides, marking virtually all the places on the DNA where transcription factors were bound. Cohesin encircles the DNA strand as a ring does around a piece of string, and the protein complexes that replicate DNA can pass through the ring without displacing it. Since the two new DNA strands are caught in the ring, only one cohesin is needed to mark the two, thereby helping the transcription factors to find their original binding region on both DNA strands.

"More research is needed before we can be sure, but so far all experiments support our model," says Martin Enge, assistant professor at Karolinska Institutet.

Transcription factors play a pivotal role in many illnesses, including cancer as well as many hereditary diseases. The discovery that virtually all regulatory DNA sequences bind to cohesin may also end up having more direct consequences for patients with cancer or hereditary diseases. Cohesin would function as an indicator of which DNA sequences might contain disease-causing mutations.

"Currently we analyse DNA sequences that are directly located in genes, which constitute about three per cent of the genome. However, most mutations that have been shown to cause cancer are located outside of genes. We cannot analyse these in a reliable manner - the genome is simply too large. By only analysing DNA sequences that bind to cohesin, roughly one per cent of the genome, it would allow us to analyse an individual's mutations and make it much easier to conduct studies to identify novel harmful mutations," Martin Enge concludes.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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This project was supported by the Center for Biosciences at Karolinska Institutet, Knut and Alice Wallenberg Foundation, the Swedish Research Council, Science for Life Laboratory, the Swedish Cancer Foundation, ERC Advanced Grant GROWTHCONTROL, and the EU FP7 Health project SYSCOL. Publication:

Transcription Factor Binding in Human Cells Occurs in Dense Clusters Formed around Cohesin Anchor Sites

Taipale et al. Cell online 15 August 2013, doi: 10.1016/j.cell.2013.07.034.

Karolinska Institutet

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Metal-catalyzed cross-couplings of carbon bonds could enable creation of libraries of drug candidates to accelerate drug discovery

Main Category: Pharma Industry / Biotech Industry
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Metal-catalyzed cross-couplings of carbon bonds could enable creation of libraries of drug candidates to accelerate drug discovery

James Bond had his reasons for ordering his martinis "shaken, not stirred." Similarly, drug manufacturers need to make sure the molecules in a new drug are arranged in an exact manner, lest there be dire consequences. Specifically, they need to be wary of enantiomers, mirror-image molecules composed of the same atoms, but arranged differently.

"One mirror image could be therapeutic while another could be poisonous," said Dr. Mark R. Biscoe, assistant professor of chemistry at The City College of New York. The classic case is thalidomide, a drug marketed in the 1950s and 1960s to treat morning sickness, which resulted in serious birth defects.

Professor Biscoe led a team of researchers at CCNY that developed a new method for preparing libraries of single-enantiomer molecules for therapeutic and toxicity studies that is faster and potentially less costly than methods now used in the pharmaceutical industry. Their findings were reported in Nature Chemistry.

Currently, drug developers typically rely on a chiral resolution process whereby compounds with roughly equal parts of the two enantiomers are separated into the individual enantiomers. Bioenzymatic processes can also be employed to generate single-enantiomer molecules. These strategies are wasteful and costly, Professor Biscoe explained.

He and colleagues found that a metal such as palladium could be employed to achieve a cross-coupling reaction with a single-enantiomer molecule without impacting the integrity of the mirror image formed in the product. By doing so, they could isolate one mirror image for evaluation as a drug candidate.

"By using a single-enantiomer partner in a cross-coupling reaction, we can rapidly generate a diverse library of biologically active molecules for use in drug screening," he said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pharma industry / biotech industry section for the latest news on this subject.

The research was funded by the National Institutes of Health, City College, the Alfred P. Sloan Foundation and PSC-CUNY, with additional support from the National Science Foundation and the American Chemical Society Petroleum Research Fund.

Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides

Ling Li, Chao-Yuan Wang, Rongcai Huang & Mark R. Biscoe; Nature Chemistry 5, 607–612 (2013) doi:10.1038/nchem.1652

City College of New York

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New brain drugs could follow 'rocking receptor' discovery

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Main Category: Neurology / Neuroscience
Also Included In: Alzheimer's / Dementia;  Schizophrenia;  Pharma Industry / Biotech Industry
Article Date: 17 Aug 2013 - 0:00 PDT Current ratings for:
New brain drugs could follow 'rocking receptor' discovery

John Hopkins biophysicists have identified a "rocking" motion in a protein ensemble, a "back and forth" movement critical in the normal functioning of brain signaling molecules. The work could lead to advancements in neurological treatments.

The newly discovered "rocking receptor" is thought to be critical to the communication between nerve cells in the brain and spinal cord; the back-and-forth motion responsible for fully activating a protein.

The discovery may reveal multiple drug targets within the protein ensemble that could lead to treatments for neurological disorders such as epilepsy, schizophrenia, Parkinson's and Alzheimer's disease.

The researchers - led by Albert Lau, PhD, assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine - believe the research may prove to be a critical.

Dr Lau says of the "rocking motion" discovery:

"We believe that our study is the first to show the molecular architecture and behaviour of a prominent neural receptor protein ensemble in a state of partial activation."

Using a combination of methods, the team were able to tease apart the process of zero and full activation in cells to reveal the critical protein ensemble motion. Their methods included:

Computer modellingBiophysical "imaging"Biochemical analysisElectrical monitoring.

The results of the study have been published in the journal Neuron.

The full activation of certain receptors required in synaptic transmission may be far more complex than previously understood, the researchers say.

Dr Lau explains that glutamate receptors reside within the outer envelope of every nerve cell in the brain and spinal cord. These receptors are responsible for changing chemical information into electrical information.

If these receptors are disabled, communication between nerve cells in the brain is sharply reduced, resulting in thought and normal brain function being severely compromised.

Malfunctioning receptors, Dr Lau says, have been linked with numerous neurological disorders and are therefore potential targets for drug therapies.

Lau continued to explain that each glutamate receptor is a united group of four protein segments that has a pocket for clamping down on glutamate like a Venus fly trap snaring a bug. Below the glutamate-binding segments are four other segments embedded in the cell's outer envelope to form a channel for charged particles to flow through. When no glutamates are bound to the receptor, the channel is closed; full activation of the receptor and full opening of the channel occur when four glutamates are bound, each to a difference pocket.

It was previously thought that the level of receptor activation simply corresponded to the degree to which each glutamate-binding segment changed shape during the glutamate-binding process. However, the John Hopkins team were able to show that the four glutamate-binding segments, in addition to clamping down on glutamate, also rock back and forth in pairs when fewer than four glutamates are bound.

"It isn't clear yet how this rocking motion affects receptor function, but we now know that activation depends on more than how much each glutamate-binding segment clamps down," Albert Lau, Ph.D., assistant professor of biophysics and biophysical chemistry and research lead.

Development of drugs for neurological disorders have previously targeted the receptor focused on the four glutamate-binding pockets, rather than the motion involved within the successful execution of the process.

He adds:

"Our discovery of this molecular motion could aid the development of drugs by revealing additional drug-binding sites on the receptor."

Written by Sally Burr

Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today Visit our neurology / neuroscience section for the latest news on this subject.

A Conformational Intermediate in Glutamate Receptor Activation Albert Y. Lau, et al., Neuron, published online 7 August 2013.

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Discovery of gene function may help prevent kidney stones

Main Category: Genetics
Also Included In: Urology / Nephrology
Article Date: 26 Jul 2013 - 2:00 PDT Current ratings for:
Discovery of gene function may help prevent kidney stones

The discovery of a gene's function in E. coli and other bacteria might lead to a probiotic to prevent the most common type of kidney stone, according to a Purdue University study.

Human cells can't metabolize oxalate, an acidic chemical found in nearly all plants we eat, so any oxalate we absorb from food must be excreted from the body. Calcium-oxalate urinary stones can form when oxalate reaches a high concentration in the kidneys. About 80 percent of kidney stones are composed of insoluble calcium oxalate.

T. Joseph Kappock, assistant professor of biochemistry, and his research team made the discovery during a study of genes in Acetobacter aceti, a harmless bacterium that is typically used to convert wine to vinegar. Acetobacter aceti, which normally lives on plant tissue, thrives in acidic conditions that easily kill most other bacteria, Kappock said.

The researchers were searching for other acids in addition to acetic acid, the acid present in vinegar, that the bacterium can metabolize.

"We were very excited when we realized E. coli has the same genetic setup as Acetobacter aceti," said Kappock, whose findings were published in the journal PLOS ONE.

Kappock and doctoral students Elwood A. Mullins and Kelly L. Sullivan found that Acetobacter aceti and E. coli each contain an enzyme with a previously unknown function, called YfdE in E. coli.

DNA sequencing had identified related genes in each bacterium, but provided little insight about its function.

"When we look at a bacterial genome by DNA sequencing, we can't tell what many of the proteins in the organism do," Kappock said. "I compare it to knowing that a vehicle has an internal combustion engine. You don't know if it's in an Indy car or a diesel truck. DNA sequencing tells us we have an internal combustion engine in this organism, but we don't know what it's for or what it can do."

Many other bacteria have the same genes but don't seem to be capable of using them.

"A few bacteria in the gastrointestinal tract eat oxalate, and we think we know how those work," Kappock said. "But we don't know why so many others are killed by oxalate, even though they have genes that would seem to be able to protect them. Oxalate is a very hard nut to crack. It's a very stable molecule that is difficult to decompose. The enzymes that process it are pretty specialized and don't seem to connect to normal bacterial metabolic pathways in an obvious way."

The researchers determined which chemicals are processed by the YfdE enzyme, following a hunch that it would use oxalate. Their results connected oxalate degradation to the core of bacterial metabolism.

Assigning a function to YfdE may help identify beneficial bacteria that could serve as probiotic agents in the human gastrointestinal tract to reduce the risk of kidney stone formation. Kidney stones, which affect more than 5 percent of the U.S. population, can cause painful blockages of the urinary tract.

"If we understand what bacteria need to degrade oxalate, then we might have a better idea how to identify strains that can do that, and thereby suppress the uptake of dietary oxalate" he said. "There are probably bacteria out there that have engineered themselves to do this for us."

Genome-sequencing information will increase the speed of the search, Kappock said.

"Because we've figured out what the gene product does, we will be able to find it in any organism and can zero in on those that might be beneficial," he said.

The researchers used X-ray crystallography to pinpoint the most important regions of the YfdE enzyme.

Kappock said the information has other applications, as well. Scientists and engineers who are interested in mapping and reprogramming microbial metabolism now know what one more gene product does.

"Our one piece of the puzzle will help others understand other metabolic networks," he said.

Agricultural Research at Purdue, the National Science Foundation and the U.S. Department of Energy funded the research.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject.

Abstract:

Acetyl-CoA:Oxalate CoA-transferase 1 Function and X-ray Crystal Structure of Escherichia coli YfdE

Elwood A. Mullins 1, 2; Kelly L. Sullivan 1; T. Joseph Kappock 1;

1 Dept. of Biochemistry, Purdue University, West Lafayette, Indiana, USA

2 Dept. of Chemistry, Washington University, St. Louis, Missouri, USA

Many food plants accumulate oxalate, which humans absorb but do not metabolize, leading to the formation of urinary stones. The commensal bacterium Oxalobacter formigenes consumes oxalate by converting it to oxalyl-CoA, which is decarboxylated by oxalyl-CoA decarboxylase (OXC). OXC and the class III CoA-transferase formyl-CoA:oxalate CoA-transferase (FCOCT) are widespread among bacteria, including many that have no apparent ability to degrade or to resist external oxalate. The EvgA acid response regulator activates transcription of the Escherichia coli yfdXWUVE operon encoding YfdW (FCOCT), YfdU (OXC), and YfdE, a class III CoA-transferase that is ~30% identical to YfdW. YfdW and YfdU are necessary and sufficient for oxalate-induced protection against a subsequent acid challenge; neither of the other genes has a known function. We report the purification, in vitro characterization, 2.1- A crystal structure, and functional assignment of YfdE. YfdE and UctC, an orthologue from the obligate aerobe Acetobacter aceti, perform the reversible conversion of acetyl-CoA and oxalate to oxalyl-CoA and acetate. The annotation of YfdE as acetyl-CoA:oxalate CoA-transferase (ACOCT) expands the scope of metabolic pathways linked to oxalate catabolism and the oxalate-induced acid tolerance response. FCOCT and ACOCT active sites contain distinctive, conserved active site loops (the glycine-rich loop and the GNxH loop, respectively) that appear to encode substrate specificity.

Purdue University

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Modern dentistry may benefit from discovery of an evolutionary compromise for long tooth preservation

Main Category: Dentistry
Article Date: 27 Jul 2013 - 0:00 PDT Current ratings for:
Modern dentistry may benefit from discovery of an evolutionary compromise for long tooth preservation

Researchers at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and the Senckenberg Research Institute in Frankfurt am Main, Germany, have conducted stress analyses on gorilla teeth of differing wear stages. Their findings show that different features of the occlusal surface antagonize tensile stresses in the tooth to tooth contact during the chewing process. They further show that tooth wear with its loss of dental tissue and the reduction of the occlusal relief decreases tensile stresses in the tooth. The result, however, is that food processing becomes less effective. Thus, when the condition of the occlusal surface changes during an individual's lifetime due to tooth wear, the biomechanical requirements on the existing dental material change as well - an evolutionary compromise for longer tooth preservation.

First, the researchers created 3D digital models of three gorilla lower second molars differing in wear stages. In a second step they applied a Software tool (Occlusal Fingerprint Analyser) developed in the Senckenberg Research Institute to precisely determine tooth to tooth contacts. They then used an engineering approach, finite element analysis (FEA), to evaluate whether some dental traits usually found in hominin and extant great ape molars have important biomechanical implications.

The results show that in unworn and slightly worn molars (with a well-formed occlusal relief that is most effective for processing food) tensile stresses concentrate in the grooves of the occlusal surface. In such a condition, the different crests of a molar carry out important biomechanical functions, for example, by reinforcing the crown against stresses that occur during the chewing process. Due to a loss of tooth tissue and a reduction of the occlusal relief the functionality of these crests diminishes during an individual's lifetime. However, this reduced functionality of the crests in worn teeth is counterbalanced by an increase in contact areas during tooth to tooth contacts, which ultimately contributes to a dispersion of the forces that affect the occlusal surface.

This suggests that the wear process might have a crucial influence in the evolution and structural adaptation of molars enabling to endure bite forces and to reduce tooth failure throughout the lifetime of an individual. "It seems that we observe an evolutionary compromise for long tooth preservation. Even though worn teeth are not as efficient they still fulfill their task. This would not be the case if they were lost prematurely", says Stefano Benazzi of the Max Planck Institute for Evolutionary Anthropology. He adds: "Tooth evolution and dental biomechanics can only be understood, if we further investigate tooth function in respect to the dynamic changes of tooth structures during the lifespan of individuals".

"The results have strong implications for understanding the functional biomechanics of dental traits, for deciphering the evolutionary trend of our masticatory apparatus and might have important implications in modern dentistry for improving dental treatments", says Jean-Jacques Hublin, director of the Department of Human Evolution at the Max Planck Institute for Evolutionary Anthropology.

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Parkinson's discovery yields potential to 'protect' nerve cells

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Main Category: Parkinson's Disease
Also Included In: Neurology / Neuroscience
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
Parkinson's discovery yields potential to 'protect' nerve cells

Biologists at The Scripps Research Institute in California have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.

The findings, recently published online in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson's disease. Precisely how the loss of this enzyme leads to the deaths of neurons had been unclear.

The new report's senior author, Professor Steven Reed, said the Scripps team had now constructed a credible model in which parkin loss sharply reduces the level of another protein, Fbw7ß that normally helps protect neurons from oxidative stress.

Prof. Steven Reed said:

"This also suggests a therapeutic strategy that might work against Parkinson's and other neurodegenerative diseases"

Parkinson's is the world's second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of its characteristic tremor, muscle rigidity and slowness of movements.

These motor symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.

Most cases of Parkinson's disease are "sporadic", caused by a variable mix of factors such aging, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins.

However, 5-15% of cases are genetic, arising specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson's-like symptoms before they turn 40 years of age.

Parkin is one of the ubiquitin ligase family of enzymes, whose main function is to regulate the levels of other proteins by "tagging" their protein targets with ubiquitin molecules, marking them for disposal by roving protein-breakers in cells known as proteasomes. Thus researchers assumed that absence of parkin allowed other protein to accumulate abnormally and harm neurons.

But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's disease, consensus about the identity of this protein culprit has been elusive. "There have been a lot of theories, but no one has come up with a truly satisfactory answer," Prof. Steven Reed said.

In 2005, Prof. Reed and his wife, Susanna Ekholm-Reed, a postdoctoral research associate, decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7.

They found that parkin regulates Fbw7 levels by tagging it with ubiquitin, targeting it for degradation by the proteasome. Therefore loss of parkin leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7ß.

Steven and Suzanna observed elevated levels of Fbw7ß in embryonic mouse neurons from which parkin had been deleted, in transgenic mice born without the parkin gene, and, most importantly, in autopsied brain tissue from Parkinson's patients who had parkin mutations.

Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7ß for destruction. However, without the parkin-driven decrease in Fbw7ß levels, the neurons become more sensitive to this oxidative stress - so that more of them undergo programmed self-destruction (apoptosis). Dopamine-producing substantia nigra neurons may be particularly vulnerable to oxidative stress, which has long been suspected as a contributor to Parkinson's.

"We realized that there must be a downstream target of Fbw7ß that's important for neuronal survival during oxidative stress," Susanna Ekholm-Reed said. A lack of funding, however, slowed the research.

A new breakthrough came after other researchers investigating Fbw7's role in cancer reported in 2011 that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis.

"We were very excited about that finding," Susanna Ekholm-Reed said.

The Scripps team followed up with a series of experiments that confirmed the key chain of events: parkin controls levels of Fbw7ß, which in turn keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress. The report suggests this is the principal explanation for how parkin mutations lead to Parkinson's disease.

The team also believe their discovery points to a broad new "neuroprotective" strategy: reducing the Fbw7ß-mediated destruction of Mcl-1 in neurons, which should make neurons more resistant to oxidative and other stresses.

"If we can find a way to inhibit Fbw7ß in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that's seen not only in Parkinson's but also in other major neurological diseases, such as Huntington's disease and ALS [amyotrophic lateral sclerosis]," Prof. Steven Reed said.

Written by: Nick Valentine

Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today Visit our parkinson's disease section for the latest news on this subject. “Parkin-dependent degradation of the F-box protein Fbw7 ß promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1,” Ekholm-Reed S, Goldberg MS, Schlossmacher MG and Reed SI. Published ahead of print 15 July 2013. DOI: 10.1128/MCB.00535-13. Please use one of the following formats to cite this article in your essay, paper or report:

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PTEN discovery provides knowledge to individualize cancer treatment

Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
PTEN discovery provides knowledge to individualize cancer treatment

Scientists at the Princess Margaret Cancer Centre have discovered a function of the tumor suppressor gene PTEN that helps explain why certain promising therapies fail in many cancer patients, a finding that could aid in delivering tailored, personalized cancer medicine based on an individual's genetics.

The research, published online in Science, "increases understanding of the molecular mechanisms of action of PTEN, which is known to be defective in as many as half of all advanced cancers" says principal investigator Vuk Stambolic, Senior Scientist at the Princess Margaret Cancer Centre. Dr. Stambolic, a specialist in cell signalling, is also an Associate Professor in the Department of Medical Biophysics, University of Toronto.

In the lab, working with cell and animal models of cancer, the research team discovered what happens when the protein product of PTEN is lost or deregulated. Dr. Stambolic says: "We realized that the PTEN nuclear function links this tumor suppressor to the response to conventional cancer treatments, such as chemotherapy or radiation. This new knowledge, combined with our prior understanding of PTEN, provided immediate clues for individualizing therapy for patients with PTEN-deficient tumors."

Medical oncologist Lillian Siu, who leads numerous clinical trials at Princess Margaret, but was not directly involved in this research, says: "For clinicians, this is a significant finding that could help guide treatment decisions, especially considering that we can already test for PTEN deficiency by molecularly analyzing biopsied tissue, providing a biomarker for implementation of combined therapies that may be most effective."

For Dr. Stambolic, the discovery builds on his earlier research (Cell, 1998) which helped explain how PTEN loss promotes cell survival, another key feature of cancerous cells. "We now realize that the PTEN story was only half-told in 1998," says Dr. Stambolic. "The new findings, in conjunction with advances in molecular profiling and access to drugs already available or being tested in clinical development, present a tangible scenario to tailor treatment."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject.

The research was funded by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long-term Care and The Princess Margaret Cancer Foundation.

Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress, Bassi et al., Science 26 July 2013: Vol. 341 no. 6144 pp. 395-399, DOI: 10.1126/science.1236188

University Health Network

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Stem cell discovery: Astrocytes could repair stroke brain damage

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Academic Journal
Main Category: Stroke
Also Included In: Neurology / Neuroscience;  Stem Cell Research
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
Stem cell discovery: Astrocytes could repair stroke brain damage

Stem cell researchers have discovered that astrocytes may prove useful against stroke and other brain disorders.

Astrocytes - neural cells that form the blood-brain barrier and so control what can and cannot enter the brain from the blood supply - have previously been overlooked in this area of stroke research.

A collaborative study published in Nature Communications suggests that astrocytes can do far more than simply support nerve cells (neurons).

Wenbin Deng, senior author of the study and associate professor of biochemistry and molecular medicine at UC Davis in California, told Medical News Today:

"This exciting research uncovers the brain-protective powers of stem cell-derived astrocytes.

Astrocytes may help to limit the spread of damage after an ischemic brain stroke in patients, and may also help to regenerate and repair damaged brain cells.

Both of these actions may lead to better functional recovery in patients."

Dr. Wenbin Deng added that astrocyte-centered therapy "could also be used for many other nervous system disorders." He said the following could be included in a list of potential targets for therapy:

Stem cell research has focused until now on developing stroke treatments using therapeutic neurons to stimulate electrical impulses in the brain, and restore tissue that has been damaged by oxygen deprivation. Dr. Wenbin Deng said astrocytes had often been considered just "housekeeping" cells that merely support nerve cells.

An astrocyte - more useful than previously thought. Courtesy Dr. Peng Jiang

"But they're actually much more sophisticated," Dr. Wenbin Deng explained. "They are critical to several brain functions and are believed to protect neurons from injury and death. They are not excitable cells like neurons and are easier to harness. We wanted to explore their potential in treating neurological disorders, beginning with stroke."

The UC Davis team faced an immediate challenge, however - there was little existing understanding on which specific types of astrocyte might have therapeutic potential in brain disorders. Also, the principal reason astrocytes had not been investigated in this context was the difficulty in producing them to the purity levels needed for stem cell therapies.

The UC Davis team decided to use a transcription factor protein called Olig2 to differentiate human embryonic stem cells into astrocytes. This approach generated a previously undiscovered type of astrocyte called Olig2PC-Astros - it was almost 100% pure.

"In this study, we report a surprising twist of fate," Dr. Wenbin Deng told MNT. He added:

"Our novel findings are that highly purified Olig2+ progenitors can give rise to astrocytes and that these astrocytes derived from highly purified Olig2+ progenitors are different from the astrocytes described in any previous work."

In short, the team's quest for a sufficiently pure astrocyte had, by serendipity, also led them to isolate a previously unknown astrocyte with particularly therapeutic properties.

Researchers used three groups of rats with ischemic brain injuries to compare the effects of Olig2PC-Astros, another type of astrocyte called NPC-Astros, and no treatment. The animals were placed in a water maze to assess their learning and memory.

Two weeks after transplantation, the rats receiving Olig2PC-Astros navigated the maze significantly quicker than the other groups. This group also exhibited higher levels of brain-derived neurotrophic factor (BDNF), a protein associated with nerve growth and resilience.

Cell cultures were also used to measure what protection the astrocytes could provide to neurons against the oxidative stress that contributes to brain injury following stroke.

When exposed to hydrogen peroxide, both types of astrocytes provided some protection but the Olig2PC-Astros showed greater antioxidant effects. Further investigation indicated higher levels of the protein Nrf2, which increases antioxidant activity in mouse neurons.

Additionally, the Olig2PC-Astros cells remained in brain areas where they were transplanted, did not differentiate into neurons or other cell types and formed no tumors.

Jan Nolta, director of the UC Davis Institute for Regenerative Cures, commented: "Dr. Deng's team has shown that this new method for deriving astrocytes from embryonic stem cells creates a cell population that is more pure and functionally superior to the standard method for astrocyte derivation."

Jan Nolta added:

"The functional improvement seen in the brain injury models is impressive, as are the higher levels of BDNF.

I will be excited to see this work extended to other brain disease models such as Huntington's disease and others, where it is known that BDNF has a positive effect."

Written by Nick Valentine

Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today Visit our stroke section for the latest news on this subject. "hESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury," Nature Communications, 23 July 2013. Full text Please use one of the following formats to cite this article in your essay, paper or report:

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Cat allergy discovery promises new treatments

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Academic Journal
Main Category: Allergy
Also Included In: Veterinary;  Immune System / Vaccines
Article Date: 25 Jul 2013 - 3:00 PDT Current ratings for:
Cat allergy discovery promises new treatments

New research led by the University of Cambridge in the UK has discovered the reason for the extreme immune reaction in some people who are allergic to cats. A study published online this week in the Journal of Immunology explains how the cat allergen Fel d 1 triggers an immune receptor that is also involved in allergic responses to dust mites.

Lead author Dr. Clare Bryant, from Cambridge's Department of Veterinary Medicine, told the press:

"We are hopeful that our research will lead to new and improved treatments for cat and possibly dog allergy sufferers."

The idea is that new drugs could target the pathway to the newly discovered receptor so it can't trigger the severe immune response in affected people.

Until this study, scientists were somewhat mystified by the severe reaction of the immune system to cat allergen.

They already knew that the most common culprit was the cat allergen Fel d 1, which is present in cat dander, the microscopic pieces of cat skin that are often accompanied by saliva from grooming and become airborne, landing on furnishings, bedding, carpets, curtains and many other surfaces and objects in the home.

Allergic reactions are the result of the immune system responding to what it perceives as dangers or threats to health and life. Normally these threats are from pathogens like viruses and bacteria. Part of the mechanism of recognizing and reacting to pathogens are proteins called receptors, which behave like unique locks, which can only be released when the correct key comes along.

But sometimes the immune system misidentifies a non-threatening substance, reacts to it as if it were a pathogen and mounts the same inflammatory response. One way this happens is because a "key" that shouldn't release a lock somehow does so. In the case of Fel d 1, the lock that it releases or triggers is the pathogen recognition receptor Toll-like receptor 4 (TLR4).

TLR4 is already known to be involved in allergic reactions to dust mites and the metal nickel.

But Bryant and colleagues discovered that Fel d 1 is aided and abetted by another culprit. It teams up with a bacterial toxin found everywhere in the environment. It only needs very low doses of this toxin, called lipopolysaccharide (LPS) to unleash the severe immune response seen in people with cat allergy.

For their study, the team ran a set of tests where they exposed human cells to cat and dog dander proteins. In some tests they added low levels of LPS, and in the others they did not.

They discovered that the presence of the bacterial toxin LPS somehow increases the signalling to the immune system, intensifying the response to the cat allergen Fel d 1.

In a further set of tests, they then discovered TLR4 was the part of the immune system that was reacting to the combination of LPS and Fel d 1.

And when they used a drug that blocks TLR4 (essentially by occupying the lock so the allergen "key" can't get in to release it), they found the cat dander protein had no effect on human cells: they had prevented the inflammatory immune response. Bryant says:

"Not only did we find out that LPS exacerbates the immune response's reaction to cat dander, we identified the part of immune system that recognises it, the receptor TLR4."

The team also found that the allergen Can f 6, which is present in dog dander, also activates TLR4 when LPS is present.

Drugs to inhibit TLR4 are already available, says Bryant, so they are hopeful that their "research will lead to new and improved treatments for cat and possibly dog allergy sufferers."

Funds from the Wellcome Trust and the Medical Research Council (MRC) helped finance the study.

Written by Catharine Paddock PhD

Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today Visit our allergy section for the latest news on this subject.

"Allergens as Immunomodulatory Proteins: The Cat Dander Protein Fel d 1 Enhances TLR Activation by Lipid Ligands"; Jurgen Herre, Hans Grönlund, Heather Brooks, Lee Hopkins, Lisa Waggoner, Ben Murton, Monique Gangloff, Olaniyi Opaleye, Edwin R. Chilvers, Kate Fitzgerald, Nick Gay, Tom Monie, and Clare Bryant; Journal of Immunology 1300284, published ahead of print 22 July 2013; DOI:10.4049/jimmunol.1300284; Link to Abstract.

Additional source: University of Cambridge Press Release.

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