Trojan Horse Of Viruses Revealed

Source:

http://www.sciencedaily.com/releases/2008/04/080425065354.htm

ScienceDaily (Apr. 28, 2008) — Viruses use various tricks and disguises to invade cells. Researchers have now discovered yet another strategy used by viruses: the vaccinia virus disguises itself as cell waste, triggers the formation of evaginations in cells and is suspected to enter the cell interior before the immune defense even notices. The research results have been published in Science.
The vaccinia virus has a problem: it is a giant among viruses and needs a special strategy in order to infiltrate a cell and reproduce. Professor Ari Helenius and Postdoc Jason Mercer from ETH Zurich's Institute for Biochemistry have now discovered what this strategy is. In the process, they stumbled upon new and surprising findings.
The invasion strategy
In order to infiltrate a cell, the vaccinia virus exploits the cellular waste disposal mechanism. When a cell dies, other cells in the vicinity ingest the remains, without needing waste disposal experts such as macrophages. The cells recognize the waste via a special molecule, phosphatidylserine, which sits on the inner surface of the double membrane of cells. This special molecule is pushed out as soon as the cell dies and is broken into parts. The vaccinia virus itself also carries this official waste tag on its surface. "The substance accumulates on the shell of vaccinia viruses", Jason Mercer explained. The pathogen disguises itself as waste material and tricks cells into digesting it, just as they normally would with the remains of dead cells. As the immune response is simultaneously suppressed, the virus can be ingested as waste without being noticed.
The uptake into the cell itself is via macropinocytosis. The ETH Zurich researchers have demonstrated that the vaccinia virus moves along actin-rich filamentous extensions towards the cell. As soon as they impinge upon the cell membrane, an evagination forms, a bleb. The virus itself is the trigger for the formation of the evagination. Using a messenger substance to "knock on the door", the virus triggers a signaling chain reaction inside the cell so that the bleb forms, catches the virus and smuggles it into the cell.
Proteins as unsuspecting allies
"The viruses are the Trojan horses that want to enter Troy; the Trojans are the many proteins that transmit the signals and open the 'city gates' to the unwelcome guest", Ari Helenius said. Aided by Professor Lukas Pelkmans' team, Jason Mercer examined over 7000 different proteins in order to find out not only which Trojans let the virus in, but which as well are chiefly involved in the supply chain. Using definitive methods, the researchers de-activated each one of the suspected proteins to examine their function,and narrowed the vast number of proteins down to 140 potential culprits. The enzyme kinase PAK1 turned out to be an especially "helpful" citizen of Troy. Without PAK1, the pathogen's trick did not work and the cell did not form any evaginations.
Until now, very little has been known about the mechanism vaccinia viruses use to infiltrate a cell. Professor Helenius, whose research objective is to find out what methods and strategies various different viruses employ to invade somatic cells, clarified "This strategy is a new one". Other viruses, such as herpes, adeno and H1 viruses use macropinocytosis. However the vaccinia virus is the first one identified that uses apoptotic mimicry as an entry strategy.
Knowledge of the virus strategies and the signal proteins involved in the ingestion of a virus by a cell is crucial to finding and developing new agents against the pathogens. Until now, antiviral medication has targeted the virus itself. Ari Helenius, however, is looking for substances that interrupt the signaling chain and halt the communication between the virus and the cell. If the cell does not ingest a virus, the virus cannot reproduce and is quickly eliminated by the immune system. This process also has another big advantage: "Viruses cannot adapt to the obstruction of the signal chain all that quickly", he said.
Smallpox: a bioterrorist attack?
The vaccinia virus belongs to a family of particularly dangerous viruses, namely the pox viruses. The most infamous member, Variola, the casitive agent of smallpox constituted a global pandemic disease in the Middle Ages, causing the deaths of millions of people, especially among the indigenous population of North America who became infected by European settlers. Pox was the first viral disease against which a vaccination was developed. In 1771, the first rudimentary vaccine was produced from cowpox viruses, which protected people from the sequelae of the disease. Since 1978, the disease has been classed as eradicated and officially is preserved in only two laboratories; one in Atlanta, the other in Novosibirsk. US authorities, however, fear bioterrorist attacks with pox viruses. Research on these dangerous pathogens is thus encouraged.
Adapted from materials provided by ETH Zurich/Swiss Federal Institute of Technology.

Fausto Intilla - www.oloscience.com

Major Step Forward In Understanding How Memory Works

Source:

http://www.sciencedaily.com/releases/2008/04/080423121427.htm

ScienceDaily (Apr. 25, 2008) — Our ability to remember the objects, places and people within our environment is essential for everyday life, although the importance of this is only fully appreciated when recognition memory beings to fail, as in Alzheimer's disease.

By blocking certain mechanisms that control the way that nerve cells in the brain communicate, scientists from the University of Bristol have been able to prevent visual recognition memory in rats.
This demonstrates they have identified cellular and molecular mechanisms in the brain that may provide a key to understanding processes of recognition memory.
Zafar Bashir, Professor of Cellular Neuroscience, who led the team at Bristol University said: "This is a major step forward in our understanding of recognition memory. We have been able to show that key processes controlling synaptic communication are also vital in learning and memory."
The ability to recognise elements in the surrounding environment such as faces or places, as well as the ability to learn about that environment, is crucial to our normal functioning in the world. But the actual mechanisms and changes that occur in the brain and allow learning to happen are still not very well understood.
One hypothesis is that changes at the specialised junctions (synapses) between nerve cells in the brain, hold the secrets to learning and memory. The change in the strength of communication between synapses is called synaptic plasticity and, it is believed, the mechanisms of synaptic plasticity may be important for learning and memory. Bashir and his colleagues tested this hypothesis.
Dr Sarah Griffiths, lead author on the paper, explained: "Nerve cells in the perirhinal cortex of the brain are known to be vital for visual recognition memory. Using a combination of biological techniques and behavioural testing, we examined whether the mechanisms involved in synaptic plasticity are also vital for visual recognition memory."
In their experiments, they were able to identify a key molecular mechanism that controls synaptic plasticity in the perirhinal cortex. They then demonstrated that blocking the same molecular mechanism that controls synaptic plasticity also prevented visual recognition memory in rats. This shows that such memory relies on specific molecular processes in the brain.
Professor Bashir added: "The next step is to try to understand the processes that enable visual memories to be held in our brains for such long periods of time, and why these mechanisms begin to break down in old age."
The research is published online April 23 in Neuron.
Adapted from materials provided by University of Bristol.

Fausto Intilla - www.oloscience.com

Mighty Microbes: Bacteria Filaments Can Bundle Together And Move Objects 100,000 Times Bacterium's Body Weight

Source:

http://www.sciencedaily.com/releases/2008/04/080418133406.htm

ScienceDaily (Apr. 20, 2008) — Researchers from The University of Arizona and Columbia University have discovered that tiny filaments on bacteria can bundle together and pull with forces far stronger than experts had previously thought possible.

The team of researchers, including Magdalene "Maggie" So, a member of the BIO5 Institute and the department of immunobiology in the UA College of Medicine, studied Type IV pili -- or filaments -- on the surface of Neisseria gonorrhoeae, the bacterium that causes the infectious disease gonorrhea. The research results help them understand the role that Type IV pili play in initiating a variety of infectious diseases -- including tuberculosis -- and how retracting pili allow bacteria to crawl and to exchange genes with each other.
When a bundle of Type IV pili retracts, it pulls with a force in the nanoNewton range, which is 10 times the force of a single retracting filament. The study demonstrates the power and cooperative nature of the nanomotors that cause Type IV pili to retract.
"The motor that causes these filaments to pull is one of the strongest nanomotors known in biology," So said.
In previous studies, the same group of investigators measured single filament retraction forces in the 50 to 100 picoNewton range. This force allows the bacterium to move an object 10,000 times its own body weight. Retraction forces from a bundle are roughly 10 times higher, allowing the bacterium to move objects 100,000 times its body weight.
Pilus retraction forces are an important factor in how N. gonorrhoeae starts an infection. So, who has studied these microbes for more than 20 years, says N. gonorrhoeae communicates with a human cell by pulling on it. These pulling forces perturb the normal circuitry of the cell. As a result, the infected cell is fooled into lowering its defenses against the infecting microbe.
So said that the team of investigators came up with a new method to measure the tremendous forces applied by retracting pili. They allow bacteria to sit on a dense brushwork of tiny elastic pillars. The pili attach to these pillars. When pili retract, they bend the pillars. By measuring how the pillars bend, the investigators calculate the retraction forces.
An article about the research, titled "Cooperative Retraction of Bundled Type IV Pili Enables Nanonewton Force Generation," was published in the latest issue of PLoS Biology.
Authors of the PLoS Biology article are Nicolas Biais and Mike Sheetz, Columbia University; Benoit Ladoux, Université Paris 7; So and Dustin Higashi, both from the UA.
Adapted from materials provided by University of Arizona.

Fausto Intilla - www.oloscience.com

Are we 10 years away from artificial life?

Source:

http://science.howstuffworks.com/artificial-life-news.htm

by Jacob Silverman

In late August 2007, an Associated Press article put forth the claim that scientists were no more than 10 years away from creating artificial life -- and possibly as few as three. Could such a thing be possible? Scientists have made tremendous strides in decoding human and animal genomes, synthesizing DNA and cloning. Creating artificial, functioning biological organisms seems to present a tremendous leap beyond any of these abilities.

But some of the companies and researchers involved in the quest for artificial life believe that the 10-year time frame is possible. Not only that -- they say that the development of wet artificial life (as it's often called) will radically affect our views of biological life and our place in the universe.

The claims about the impending invention of artificial life may be a tad bold. Among the skeptics is Francis Collins, head of the Human Genome Project, says the 10-year time frame is too ambitious. Even so, the prospect of artificial life holds a lot of appeal, and we'll take a look at it in this article.
Wet artificial life is not a modified or genetically engineered organism. It's life created entirely from basic parts. But as we saw in our article about weird life, scientists don't have a rigorous, standardized definition of what life is. Even so, biologists have some basic ideas about which qualities artificial life needs to possess in order to be considered alive.
First, artificial life needs to have DNA or genetic code. It also needs to be able to reproduce and to pass on its genetic code. The life form then needs somewhere to place its genetic code, a protective casing or membrane, similar to a cell wall, that keeps the DNA and other parts together. The cell wall should also allow for normal biological processes to be carried out. In other words, it should be permeable enough to allow for the absorption of nutrients and relatively impermeable against pathogens. Once its basic parts are together, the organism should be self-sustaining: It should eat and metabolize food. Finally, the life form needs the ability to repair itself and to adapt and evolve.
Developing some of these characteristics presents many challenges to researchers. But one Harvard scientist predicted (in that same AP article) that by early 2007, great advances would be made in creating cell membranes [source: Associated Press]. Keeping an artificial organism alive for more than a few minutes or a few hours is also a challenge, though scientists can focus on strengthening the organisms after some of the initial hurdles are overcome.
To create DNA, some scientists advocate placing nucleotides (the building blocks of DNA) inside the cell casing. The nucleotides could somehow be combined to form DNA. That in itself might pose a challenge, as enzymes may be required to assemble the nucleotides, which might violate the "basic parts" rule for creating artificial life.
On the next page, we'll take a look at more challenges that stand between scientists and artificial life. We'll also consider this question: Will artificial life forms get out of control?

Science fiction books and movies are filled with examples of out-of-control machines, viruses, artificial organisms and artificial intelligences. These fictions represent the worst possible outcome, some people say, in "playing God." Some scientists offer the reassurance that by the time artificial organisms are actually created, more mechanisms would be in place to control them.
It's also important to remember that the wide range of diverse and complex organisms on Earth represents the product of almost four billion years of evolution. Even if the 10-year time frame is correct, scientists in 2017 won't be working with artificially created toxic plants, predatory animals or unstoppable viruses. Early synthetic life forms will be rather simple organisms of a few cells or less. In fact, more danger likely lies in the abuse of genetic engineering techniques to modify existing viruses to make them highly contagious or virulent.
To those who say that scientists don't have the right to "play God," advocates often say that creating artificial life is a natural extension of humanity's desire for progress and discovery. Research into artificial life may yield insights into some of biology's fundamental processes, though again, science fiction depictions of artificial creations run amok has likely not helped the case for artificial life.
Since there is some dispute about what defines both life and artificial life, we may see several premature claims of success from biologists. What would qualify as a success? Does it have to be a functional, complex, self-replicating organism, or would a simple bit of artificially created, self-replicating genetic code suffice? How basic must the ingredients be that are combined to create the organism? Francis Collins says that scientists would be "cheating" by using enzymes, which are themselves derived from life forms [source: PBS].
In what may represent an important first step, some scientists have already produced artificial viruses, but they did so by synthetically reproducing DNA of known viruses. They then injected this DNA into cells that weren't synthetically formed.
Once an artificial organism is created, how (and for how long) will it live? Collins believes that artificial life should be able to survive in a basic environment, perhaps in a simple sugar solution, without humans providing complicated chemicals [source: PBS]. Others might say that, at least at first, making some sort of microbe or organism that can survive briefly qualifies as a success -- even if it requires a lot of outside control or monitoring.
At the very least, some of the initial claims regarding artificial life will face significant scrutiny. In the coming years, expect an ongoing debate about what defines life, both "real" and artificial.
For more information about artificial life and other related topics, please check out the links on the next page.

Fausto Intilla - www.oloscience.com

Bloodless Worm Sheds Light On Human Blood, Iron Deficiency

Source:

http://www.sciencedaily.com/releases/2008/04/080416140912.htm

ScienceDaily (Apr. 19, 2008) — Using a lowly bloodless worm, University of Maryland researchers have discovered an important clue to how iron carried in human blood is absorbed and transported into the body. The finding could lead to developing new ways to reduce iron deficiency, the world's number one nutritional disorder.
With C. elegans , a common microscopic worm that lives in dirt, Iqbal Hamza, assistant professor of animal and avian sciences, and his team identified previously unknown proteins that are key to transporting heme, the molecule that creates hemoglobin in blood and carries iron. It is a critical step in understanding how our bodies process iron. Their findings are published in the April 16 issue of Nature online.
"The structure of hemoglobin has been crystallized over and over," says Hamza, "but no one knows how the heme gets into the globin, or how humans absorb iron, which is mostly in the form of heme.
"To understand the underlying issues of nutritional and genetic causes of iron deficiency, we are looking at the molecules and mechanisms involved in heme absorption. Once you understand transport of heme, you can more effectively deliver it to better absorb iron in the human intestine."
Heme and Blood
Heme is a critical molecule for health in all eukaryotes, organisms whose cells are organized into complex structures enclosed in membranes. Species of eukaryotes range from humans to baker's yeast. Heme makes blood red and binds to oxygen and other gases we need to survive.
Heme is created in the mitochondria, then moves through pathways that connect other cells, where it is synthesized to form blood. Heme on its own, however, is toxic. "We wanted to find out how heme gets carried between and within cells," said Hamza.
A Bloodless Worm
Eight steps are required to generate heme, making it a difficult process to control in the study of heme transport pathways, as Hamza learned when he first studied the question in bacteria and mice.
So Hamza did the non-intuitive thing. He chose a test subject that doesn't make heme, but needs it to survive, that doesn't even have blood, but shares a number of genes with humans - the C. elegans roundworm, a simple nematode.
"We tried to understand how blood is formed in an animal that doesn't have blood, that doesn't turn red, but has globin," Hamza said.
C. elegans gets heme by eating bacteria in the soil where it lives. "C. elegans consumes heme and transports it into the intestine. So now you have a master valve to control how much heme the animal sees and digests via its food," Hamza explains.
C. elegans has several other benefits for studying heme transport. Hamza's team could control the amount of heme the worms were eating. With only one valve controlling the heme transport, the scientists knew exactly where heme was entering the worm's intestine, where, as in humans, it is absorbed.
And C. elegans is transparent, so that under the microscope researchers could see the movement of the heme ingested by the worm.
Genes and Iron Deficiency
The study revealed several findings that could lead to new treatment for iron deficiency. One was the discovery that genes are involved in heme transport. Hamza's group found that HRG-1 genes, which are common to humans and C. elegans , were important regulators of heme transport in the worm.
To test their findings in an animal that makes blood, Hamza's team removed the HRG-1 gene in zebrafish. The fish developed bone and brain defects, much like birth defects. The gene removal also resulted in a severe form of anemia usually caused by iron deficiencies.
When they substituted the zebrafish gene with the worm HRG-1 gene, the mutant fish returned to normal, indicating that the fish and worm genes are interchangeable, irrespective of the animal's ability to make blood.
They also found that too little or too much heme can kill C. elegans , a result that could help researchers find ways to treat people who suffer from iron deficiency caused by parasitic worms.
"More than two billion people are infected with parasites," says Hamza. "Hookworms eat a huge amount of hemoglobin and heme in their hosts. If we can simultaneously understand heme transport pathways in humans and worms, we can exploit heme transport genes to deliver drugs disguised as heme to selectively kill parasites but not harm the host."
Other researchers on the study were Abbhirami Rajagopal, Anita U. Rao, Caitlin Hall, Suji Uhm, University of Maryland ; Julio Amigo, Barry H. Paw, Brigham and Women's Hospital, Boston ; Meng Tian, Mark D. Fleming, Children's Hospital, Boston ; Sanjeev K. Upadhyay, M.K. Mathew, Tata Institute of Fundamental Research, Bangalore , India ; Michael Krause, National Institute of Diabetes and Digestive and Kidney Diseases, NIH.
The research was funded by grants from the National Institutes of Health, the March of Dimes Birth Defects Foundation, Council for Scientific and Industrial Research and Kanwal Rekhi Fellowships, and the Howard Hughes Medical Institute Undergraduate Science Education Program.
Adapted from materials provided by University of Maryland.

Fausto Intilla - www.oloscience.com

'Nanodrop' Test Tubes Created With A Flip Of A Switch

Source:

http://www.sciencedaily.com/releases/2008/04/080415154819.htm

ScienceDaily (Apr. 18, 2008) — Researchers at the National Institute of Standards and Technology (NIST) have demonstrated a new device that creates nanodroplet "test tubes" for studying individual proteins under conditions that mimic the crowded confines of a living cell. "By confining individual proteins in nanodroplets of water, researchers can directly observe the dynamics and structural changes of these biomolecules," says physicist Lori Goldner, a coauthor of the paper* published in Langmuir.

Researchers recently have turned their attention to the role that crowding plays in the behavior of proteins and other biomolecules--there is not much extra space in a cell. NIST's nanodroplets can mimic the crowded environment in cells where the proteins live while providing advantages over other techniques to confine or immobilize proteins for study that may interfere with or damage the protein.
This more realistic setting can help researchers study the molecular basis of disease and supply information for developing new pharmaceuticals. For example, misfolded proteins play a role in many illnesses including Type 2 diabetes, Alzheimer's and Parkinson's diseases. By seeing how proteins fold in these nanodroplets, researchers may gain new insight into these ailments and may find new therapies.
The NIST nanodroplet delivery system uses tiny glass micropipettes to create tiny water droplets suspended in an oily fluid for study under a microscope. An applied pressure forces the water solution containing protein test subjects to the tip of the micropipette as it sits immersed in a small drop of oil on the microscope stage. Then, like a magician whipping a tablecloth off a table while leaving the dinnerware behind, an electronic switch causes the pipette to jerk back, leaving behind a small droplet typically less than a micrometer in diameter.
The droplet is held in place with a laser "optical tweezer," and another laser is used to excite fluorescence from the molecule or molecules in the droplet. In one set of fluorescence experiments, explains Goldner, "The molecules seem unperturbed by their confinement--they do not stick to the walls or leave the container--important facts to know for doing nanochemistry or single-molecule biophysics." Similar to a earlier related work, researchers also demonstrated that single fluorescent protein molecules could be detected inside the droplets.
Fluorescence can reveal the number of molecules within the nanodroplet and can show the motion or structural changes of the confined molecule or molecules, allowing researchers to study how two or more proteins interact. By using only a few molecules and tiny amounts of reagents, the technique also minimizes the need for expensive or toxic chemicals.
* J. Tang, A.M. Jofre, G.M. Lowman, R.B. Kishore, J.E. Reiner, K. Helmerson, L.S. Goldner and M.E. Greene. Green fluorescent protein in inertially injected aqueous nanodroplets. published in Langmuir, ASAP Article, Web release date: March 27, 2008.
Adapted from materials provided by National Institute of Standards and Technology.

Fausto Intilla - www.oloscience.com

First Functional Insulin-binding Protein In Invertebrates

Source:

http://www.sciencedaily.com/releases/2008/04/080414193033.htm

ScienceDaily (Apr. 18, 2008) — Insulin-like growth factor (IGF) signaling that helps to regulate mammals' growth, metabolism, reproduction and longevity is well documented. Now new research describes the genetic identification of the first functional insulin-like growth factor binding protein (IGFBP) ortholog in invertebrates.
Insulin and insulin-like growth factors (IGFs) signal through a highly conserved pathway and control growth and metabolism in both vertebrates and invertebrates. The well-studied mammalian IGF binding proteins (IGFBPs) do not, however, have obvious sequence homologs in the fruit fly Drosophila. The discovery of a functional ortholog transforms Drosophila into a powerful model system in which to explore metabolic regulation and presents a significant advance in our understanding of the mechanisms by which the actions of insulin-like peptides are regulated.
A research team led by Ernst Hafen from the Institute of Molecular Systems Biology at the ETH in Zürich, Switzerland, employed a genetic strategy to search for negative insulin/insulin-like growth factor signaling (IIS) regulators in Drosophila. The team identified a new functional insulin-binding protein that acts as an IIS antagonist. Dubbed imaginal morphogenesis protein-late 2 (Imp-L2), the new antagonist binds the Drosophila insulin-like peptide 2 (Dilp2), inhibiting its growth-promoting function. Imp-L2 not only has a role in growth regulation - it is also essential for the dampening of insulin signaling under adverse conditions.
The authors hope that better understanding of Imp-L2's role in growth control and insulin signaling in Drosophila will ultimately impact on our understanding of the human ortholog IGFBP-7. This has a regulatory role in pathways that impact upon diabetes and cancer. IGFBP-7 acts as a tumor suppressor in a variety of human organs and differs in the C-terminus from the other IGFBPs.
"Since Imp-L2 and the human tumor suppressor IGFBP-7 display sequence homology in their C-terminal immunoglobulin-like domains, we suggest that their common precursor represents an ancestral insulin-binding protein," says Hafen.
Journal reference: Imp-L2, a homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. Basil Honegger, Milos Galic, Katja Kohler, Franz Wittwer, Walter Brogiolo, Ernst Hafen and Hugo Stocker. Journal of Biology (in press)
Adapted from materials provided by BioMed Central/Journal of Biology, via EurekAlert!, a service of AAAS.

Fausto Intilla - www.oloscience.com

Different Mutations In Single Gene Suggest Parkinson's Is Primarily An Inherited Genetic Disorder

Source:

http://www.sciencedaily.com/releases/2008/04/080416104317.htm

ScienceDaily (Apr. 18, 2008) — Two new international studies by researchers at the Mayo Clinic site in Florida are rounding out the notion that Parkinson's disease is largely caused by inherited genetic mutations that pass through scores of related generations over hundreds, if not thousands of years. These genetic influences, which can be small but additive, or large and causative, overturn common beliefs that the neurodegenerative disease mostly occurs in a random fashion or is due to undetermined environmental factors.
These latest studies bring the total of number of disease-related mutations in an as yet poorly understood gene, leucine-rich repeat kinase 2 (LRRK2), to seven, all of which are linked, either weakly or strongly, to typical, late onset development of Parkinson's disease in people around the world. One mutation (R1628P) doubles the risk of Parkinson's disease in ethnic Chinese, according to a study published on April 16, 2008 in the online edition of the Annals of Neurology. The second study, published April 15 in Neurology, demonstrates that another very rare mutation (R1441C), found in people on three continents, increases risk by more than 10-fold.
The R1628P was identified by the strong collaborative effort of researchers from Taiwan, Singapore, Japan, and the U.S. The research institutions included the National Taiwan University Hospital, led by Dr. Ruey-Meei Wu, Chang Gung Memorial Hospital led by Dr. Yih-Ru Wu, National Neuroscience Institute of Singapore led by Dr. Eng-King Tan and Juntendo University, led by Dr. Nobutaka Hattori. This group believes the R1628P mutation arose from a single individual in the Han Chinese population about 2,500 years ago and has since spread through generations of descendants, wherever they live. This is the second common LRRK2 mutation discovered in Asians –a mutation labeled G2385R believed to have originated 4,500 years ago was first reported in the journal 'Neurogenetics' in 2006 and subsequently confirmed by several groups. Lrrk2 G2385R and R1628P predispose over 100 million Chinese people to Parkinson's disease.
"The picture that is emerging of Parkinson's disease is one in which genetic risk factors, passed down through the population for hundreds or thousands of years, add up to substantial susceptibility within a single individual, and, with some possible environmental influences, can result in disease," says Mayo Clinic neuroscientist Owen A. Ross, Ph.D., first author on the Annals of Neurology study.
"These types of mutations are important because the goal of this research is to be able to screen people who are most at risk because of their genetic profiles, and design therapies that interfere with the disease process," Dr. Ross says.
The stronger R1441C mutation, also currently being reported, originated from several different "founders" and is now found in 20 families on three continents. It is relatively causative in nature, meaning the majority of people with the mutation are likely to develop the disease.
"Parkinson's disease is fascinating to study because we can now roughly trace when and where mutations occur, and how they travel through offspring and in populations," says Kristoffer Haugarvoll, M.D., a visiting scientist at Mayo Clinic and lead author on the Neurology study. "It also shows us that disease that appears to be the same in the majority of patients can originate from different genetic mutations – either genes that increase risk substantially, or by several risk factors, genetic and environmental, that each have minor but additive effects."
Same mutations in familial and sporadic forms of the disease
Only about 10 percent of patients diagnosed with Parkinson's disease have a strong family history of the disease, and Mayo Clinic researchers in Florida have been part of a worldwide effort to discover whether common genes may explain the origin of the other 90 percent, the so-called "sporadic" form. In 2004, they were part of a team that discovered that the LRRK2 gene is linked to both familial and non-familial cases of the disease.
Since then, they have found LRRK2 mutations that can cause the same clinical manifestations of Parkinson's disease in people with and without a family history – discoveries that "have caused a paradigm shift in the field," says Dr. Ross. For example, a mutation labeled G2019S causes both familial and non-familial Parkinson's disease in a high number of Berber Arabs and Ashkenazi Jews. "This shows that the effect of mutations in different areas of the Lrrk2 protein lead to the same disease, although it may not manifest in each generation and so did not appear to be familial," he says.
In the latest study, Dr Ross and colleagues studied 1079 ethnic Han Chinese diagnosed with Parkinson's disease, of which 44 reported a family history of the disease. These patients were compared with 907 ethnically matched Han Chinese who did not have Parkinson's disease, and results showed the R1628P variant was approximately twice as frequent in Parkinson's disease patients as in the control population. From this, the researchers estimated that for every 100 Chinese, 3 will have the gene variant. Further research then suggested that the R1628P carriers were related to a single common founder that dated from about 2,500 years ago.
The researchers then searched for evidence of the mutation in Japanese patients and controls – but did not find it. "The theory is that this mutation arose in China after the Japanese and Chinese segregated their populations, which explains why the G2385R mutation, which is 2,000 years older than R1628P, is found in both populations and is more common," Dr. Ross says.
"Inheriting one or both of these mutations doesn't mean that a person will develop Parkinson's disease, but that an individual's risk is increased," he says. "The basis of population genetics is that disease is familial; people are so distantly related that they don't know they may have inherited specific genes. While there may be an environmental component to development of the disease, none have been identified that have risks as large as those seen by the LRRK2 gene mutations."
Generations that carry rare but critical mutations
In the Neurology study, Dr. Haugarvoll, who is from Norway, worked with researchers from a number of countries to collect genetic information from discrete populations of people representing three continents who had previously been found to be carriers of the R1441C mutation. "This was a completely collaborative effort," he says. "Rare mutations affect relatively few patients, but if we join forces in a worldwide initiative, we have larger samples to look at, and that is the only way you can advance the science."
The scientists identified 33 affected and 15 unaffected R1441C mutations from 20 families, including four patients with no family history of Parkinsonism. These patients all developed disease that mimicked the typical, late onset disease normally seen in non-familial, sporadic Parkinson's disease, Haugarvoll says. The scientists believe the same disease-causing mutation has occurred independently on several occasions; however, most patients seem to originate from two different founders. One variant was found in Italian, German, Spanish, and American patients. The second was discovered in patients from Belgium and from a single American family, located in Nebraska.
Dr. Haugarvoll says the region of R1441C appears to be "a hotspot for mutation events" because other mutations occur in this general area. What is most interesting, he says, is that "even though there are familial mutations in different locations of the gene, it produces the same effect, the same disease."
"It seems like mutations are occurring in a few founders, and that these founders have a lot of offspring over generations that carry the mutation. Even in sporadic disease, then, familial genes are inherited but symptoms may skip some generations, making the disease appear sporadic" Dr. Haugarvoll says.
Major funding for both studies came from NIH (including the Morris K. Udall Center for Excellence in Parkinson's Disease Research at the Mayo Clinic) and several international funding agencies.
Adapted from materials provided by Mayo Clinic.

Fausto Intilla - www.oloscience.com

Clues To Ancestral Origin Of Placenta Emerge In Genetics Study

Source:

http://www.sciencedaily.com/releases/2008/04/080414145645.htm

ScienceDaily (Apr. 17, 2008) — Researchers at the Stanford University School of Medicine have uncovered the first clues about the ancient origins of a mother's intricate lifeline to her unborn baby, the placenta, which delivers oxygen and nutrients critical to the baby's health.

The evidence suggests the placenta of humans and other mammals evolved from the much simpler tissue that attached to the inside of eggshells and enabled the embryos of our distant ancestors, the birds and reptiles, to get oxygen.
"The placenta is this amazing, complex structure and it's unique to mammals, but we've had no idea what its evolutionary origins are," said Julie Baker, PhD, assistant professor of genetics. Baker is senior author of the study, which will be published in the May issue of Genome Research.
The placenta grows inside the mother's uterus and serves as a way of exchanging gas and nutrients between mother and fetus; it is expelled from the mother's body after the birth of a baby. It is the only organ to develop in adulthood and is the only one with a defined end date, Baker said, making the placenta of interest to people curious about how tissues and organs develop.
Beyond being a biological curiosity, the placenta also plays a role in the health of both the mother and the baby. Some recent research also suggests that the placenta could be a key barrier in preventing or allowing molecules to pass to the unborn baby that influence the baby's disease risk well into adulthood.
"The placenta seems to be critical for fetal health and maternal heath," Baker said. Despite its major impact, almost nothing was known about how the placenta evolved or how it functions.
Baker and Kirstin Knox, graduate student and the study's first author, began addressing the question of the placenta's evolution by determining which genes are active in cells of the placenta throughout pregnancy in mice.
They found that the placenta develops in two distinct stages. In the first stage, which runs from the beginning of pregnancy through mid-gestation, the placental cells primarily activate genes that mammals have in common with birds and reptiles. This suggests that the placenta initially evolved through repurposing genes the early mammals inherited from their immediate ancestors when they arose more than 120 million years ago.
In the second stage, cells of the mammalian placenta switch to a new wave of species-specific genes. Mice activate newly evolved mouse genes and humans activate human genes.
It makes sense that each animal would need a different set of genes, Baker said. "A pregnant orca has different needs than a mouse and so they had to come up with different hormonal solutions to solve their problems," she said. For example, an elephant's placenta nourishes a single animal for 660 days. A pregnant mouse gestates an average of 12 offspring for 20 days. Clearly, those two pregnancies would require very different placentas.
Baker said these findings are particularly interesting given that cloned mice are at high risk of dying soon after the placenta's genetic transition takes place. "There's obviously a huge regulatory change that takes place," she said. What's surprising is that despite the dramatic shift taking place in the placenta, the tissue doesn't change in appearance.
Understanding the placenta's origins and function could prove useful. Previous studies suggest the placenta may contribute to triggering the onset of maternal labor, and is suspected to be involved in a maternal condition called pre-eclampsia, which is a leading cause of premature births.
Baker intends to follow up on this work by collaborating with Theo Palmer, PhD, associate professor of neurosurgery; Gill Bejerano, PhD, assistant professor of developmental biology, and Anna Penn, MD, PhD, assistant professor of pediatrics. Together, the group hopes to learn how the placenta protects the growing brain of the unborn baby, a protection that seems to extend into adulthood.
The work was funded by the National Institutes of Health, the March of Dimes and Stanford's Medical Scientist Training Program.
Adapted from materials provided by Stanford University Medical Center.

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Are Sacrificial Bacteria Altruistic Or Just Unlucky?

Source:

http://www.sciencedaily.com/releases/2008/04/080415101006.htm

ScienceDaily (Apr. 16, 2008) — An investigation of the genes that govern spore formation in the bacteria B. subtilis shows that chance plays a significant role in determining which of the microbes sacrifice themselves for the colony and which go on to form spores.
B. subtilis, a common soil bacteria, is a well-known survivor. When running short of food, it can alternatively band together in colonies or encase itself in a tough, protective spore to wait for better times. In fact, B. subtilis is so good at making spores that it's often used as a model organism by biologists who study bacterial spore formation.
"It's too early to say whether B. subtilis is truly altruistic," said co-author Oleg Igoshin, assistant professor of bioengineering at Rice University. "What is clear from this is that not all bacteria are going to look and act the same, and that's something that can be overlooked when people either study or attempt to control bacteria with population-wide approaches."
For example, Igoshin said doctors and food safety engineers might need to amend general approaches aimed at controlling bacteria with more targeted methods that also account for the uncharacteristic individual.
The new results appear in the April 15 issue of Molecular Systems Biology. The experimental work, which was done by Jan-Willem Veening, currently at Newcastle University, and by other members of Oscar Kuipers' research group at the University of Groningen in the Netherlands, focused on the B. subtilis genes that regulate both spore formation and the production cycles of two proteins -- subtilisin and bacillopeptidase. These two proteins help break apart dead cells and convert them into food. They are produced and released into the surrounding environment by B. subtilis cells that are running low on food.
From previous studies, scientists know there is some overlap between genes that control the production of the two proteins and those that control spore formation.
"Only a portion of the bacteria in a colony will form spores and only portion of the bacteria produce subtilisin, and we were interested in probing the genetic basis for this," Igoshin said. "How is it decided which cells become spores and which don't?"
Igoshin, a computational biologist, used computer simulations to help decipher and interpret the team's experimental results. He said the team found that fewer than 30 percent of individuals in a colony produce large quantities of the food-converting proteins. Even though the proteins benefit all members of the colony and help some cells to become spores, the cells that produce the proteins in bulk do not form spores themselves.
"There's a feedback loop, so that cells that start producing the proteins early get a reinforced signal to keep making them," Igoshin said. "We found that it's probabilistic events -- chance, if you will -- that dictates who is early and who is late. The early ones start working for the benefit of everyone while the later ones save valuable resources to ensure successful completion of sporulation program. Many cells will end up committing to sporulation before they had a chance to contribute to protease production"
Igoshin said a key piece of evidence confirming modeling predictions came in experiments that tracked genetically identical sister cells, some of which became protein producers and some of which didn't.
The research was supported by the Netherlands Organization of Scientific Research, the Royal Netherlands Academy of Arts and Sciences, the Biotechnology and Biological Sciences Research Council, the Wellcome Trust and Rice University. Co-authors also include Robyn Eijlander and Reindert Nijland of the University of Groningen, and Leendert Hamoen of Newcastle University in Great Britain.
Adapted from materials provided by Rice University, via EurekAlert!, a service of AAAS.

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Researchers Mimic Bacteria To Produce Magnetic Nanoparticles

Source:

http://www.sciencedaily.com/releases/2008/04/080414113207.htm

ScienceDaily (Apr. 15, 2008) — When it comes to designing something, it’s hard to find a better source of inspiration than Mother Nature. Using that principle, a diverse, interdisciplinary group of researchers at the U.S. Department of Energy’s Ames Laboratory is mimicking bacteria to synthesize magnetic nanoparticles that could be used for drug targeting and delivery, in magnetic inks and high-density memory devices, or as magnetic seals in motors.
Commercial room-temperature synthesis of ferromagnetic nanoparticles is difficult because the particles form rapidly, resulting in agglomerated clusters of particles with less than ideal crystalline and magnetic properties. Size also matters. As particles get smaller, their magnetic properties, particularly with regard to temperature, also diminish.
However, several strains of bacteria produce magnetite (Fe3O4) – fine, uniform nanoparticles that have desirable magnetic properties. These magnetotactic bacteria use a protein to form crystalline particles about 50 nanometers in size. These crystals are bound by membranes to form chains of particles which the bacteria use like a compass needle to orient themselves with the Earth’s magnetic field.
To see if researchers could learn from the bacteria, Surya Mallapragada, Ames Laboratory Materials Chemistry and Biomolecular Materials program director pulled together a team that included microbiologists, biochemists, material chemists, chemical engineers, materials scientists and physicists from Ames Laboratory and Iowa State University.
As a starting point, former ISU microbiologist Dennis Bazylinski, now at the University of Nevada-Las Vegas, isolated several strains of magnetotactic bacteria for use in the study.
Based on earlier work by a Japanese research team, Ames Laboratory biochemist Marit Nilsen-Hamilton looked at several proteins known to bind iron, including Mms6 found in magnetotactic bacteria, which she cloned from the bacteria. “This protein is associated with the membranes that surround the magnetite crystals,” Nilsen-Hamilton said, “and each bacterium appears to make particles with their own unique crystal structure.”
Ames Lab chemist Tanya Prozorov tried synthesizing crystals, using the proteins with various concentrations of reagents in an aqueous solution, but the particles formed quickly, were small and lacked specific crystal morphology. At the suggestion of Ames Lab senior physicist and crystal growth expert Paul Canfield, the team used polymer gels developed by Mallapragada and Balaji Narasimhan, who are both Ames Lab scientists as well as ISU chemical engineers, to slow down the reaction and help control formation of the nanocrystals and minimize aggregation.
“It’s simple chemistry,” Prozorov said, “and you can judge the reaction by the color, watching it go from yellow to green to black as the crystals form. Once the crystals precipitate out, we use a magnet to concentrate the particles at the bottom of the flask, then separate them out to study them further.”
Prozorov also conducted electron microscopy analysis of the synthetic nanoparticles which showed that Mms6 produced well-formed, faceted crystals resembling those produced naturally by the bacteria. Powder X-ray diffraction studies verified the crystal structure of the particles.
Ames Lab physicist Ruslan Prozorov, tested the magnetic properties of the synthetic crystals which also showed striking similarities to the bacteria-produced crystals and bulk magnetite. The magnetic studies also showed that the “chains” of particles formed by the bacteria had a much sharper magnetic transition definition at a higher temperature than single crystals.
“Nature found a way to beat the thermodynamics (of crystalline magnetite) by arranging the nanoparticles in such a way that they aren’t affected by temperature the way individual crystals are,” Ruslan Prozorov said.
With this basic understanding of magnetotatic bacteria and the ability to synthesize magnetite nanoparticles, the team proceeded to find out if the bioinspired approach could be used to produce cobalt-ferrite nanoparticles. Cobalt-ferrite, which doesn’t occur in living organisms, has more desirable magnetic properties than magnetite, yet presents the same problems for commercially producing nano-scale particles.
In addition to their previous method, the team took the added step of covalently attaching the Mms6 to a strand of functionalized polymer known to self-assemble and form thermoreversible gels. Because the polymer strands come together in a particular way, the attached proteins had a specific alignment that the researchers hoped would serve as a template for the formation of cobalt-ferrite crystals. And the way in which the gel formed would help control the speed of the reaction.
“It worked rather well,” Tanya Prozorov said, “and we ended up with very nice hexagonal cobalt ferrite crystals” and added that she is studying whether the protein will also work for the other neodymium, gadolinium, and holmium ferrites.
The project is funded by the Department of Energy’s Office of Basic Energy Sciences, the National Science Foundation, and the Alfred P. Sloan Foundation. The research has generated fodder for a number of journal articles, including published works in ACSNano, Physical Review B, and Advanced Functional Materials.
Adapted from materials provided by DOE/Ames Laboratory.

Fausto Intilla
www.oloscience.com

Novel Living System Recreates Predator-prey Interaction

Source:

http://www.sciencedaily.com/releases/2008/04/080414082525.htm

ScienceDaily (Apr. 14, 2008) — The hunter-versus-hunted phenomenon exemplified by a pack of lionesses chasing down a lonely gazelle has been recreated in a Petri dish with lowly bacteria.

Working with colleagues at Caltech, Stanford and the Howard Hughes Medical Institute, a Duke University bioengineer has developed a living system using genetically altered bacteria that he believes can provide new insights into how the population levels of prey influence the levels of predators, and vice-versa.
The Duke experiment is an example of a synthetic gene circuit, where researchers load new "programming" into bacteria to make them perform new functions. Such re-programmed bacteria could see a wide variety of applications in medicine, environmental cleanup and biocomputing. In this particular Duke study, researchers rewrote the software of the common bacteria Escherichia coli (E. coli.) to form a mutually dependent living circuit of predator and prey.
The bacterial predators don't actually eat the prey, however. The two populations control each others' suicide rates.
"We created a synthetic ecosystem made up of two distinct populations of E. coli, each with its own specific set of programming and each with the ability to affect the existence of the other," said Lingchong You, assistant professor of biomedical engineering at Duke's Pratt School of Engineering and member of Duke's Institute for Genome Sciences and Policy. "This ecosystem is quite similar to the traditional predator-prey relationship seen in nature and may allow us to explore the dynamics of interacting populations in a predictable manner."
The results of You's study appear April 15 in the journal Molecular Systems Biology. The research was supported by National Institutes of Health, the Defense Advanced Research Projects Agency, the Howard Hughes Medical Institute, and the David and Lucile Packard Foundation.
This field of study, known as synthetic biology, emerged on the scientific scene around 2000, and many of the systems created since have involved the reprogramming of single bacteria. The current circuit is unique in that two different populations of reprogrammed bacteria live in the same ecosystem and are dependent on each other for survival.
"The key to the success of this kind of circuit is the ability of the two populations to communicate with each other," You said. "We created bacteria representing the predators and the prey, with each having the ability to secrete chemicals into their shared ecosystem that can protect or kill."
Central to the operation of this circuit are the numbers of predator and prey cells relative to each other in their controlled environment. Variations in the number of cells of each type trigger the activation of the reprogrammed genes, stimulating the creation of different chemicals.
In this system, low levels of prey in the environment cause the activation of a "suicide" gene in the predator, causing them to die. However, as the population of prey increases, it secretes into the environment a chemical that, when it achieves a high enough concentration, stimulates a gene in the predator to produce an "antidote" to the suicide gene. This leads to an increase in predators, which in turn causes the predator to produce another chemical which enters the prey cell and activates a "killer" gene, causing the prey to die.
"This system is much like the natural world, where one species -- the prey -- suffers from growth of another species -- the predator," You said. "Likewise, the predator benefits from the growth of the prey."
This circuit is not an exact representation of the predator-prey relationship in nature because the prey stops the programmed suicide of predator instead of becoming food, and both populations compete for the same "food" in their world. Nevertheless, You believes that the circuit will become a useful tool for biologic researchers.
"This system provides clear mapping between genetics and the dynamics of population change, which will help in future studies of how molecular interactions can influence population changes, a central theme of ecology," You said. "There are literally unlimited ways to change variables in this system to examine in detail the interplay between environment, gene regulation and population dynamics.
"With additional control over the mixing or segregating of different populations, we should be able to program bacteria to mimic the development and differentiation of more complex organisms," he said.
The research is a collaboration between the You lab and the laboratories of Frances Arnold at Caltech and Stephen Quake at Stanford and the Howard Hughes Medical Institute. The first author of the study, Frederick Balagadde, is currently establishing a research program at the Lawrence Livermore National Lab. While working in the Quake lab, he developed the technology to enable high-resolution measurements of the circuit dynamics. Other study authors include Duke's Hao Song and Jun Ozaki, as well as Cynthia Collins, Rensselear Polytechnic Institute and Mat Barnet, Caltech.
Adapted from materials provided by Duke University, via EurekAlert!, a service of AAAS.

Fausto Intilla

www.oloscience.com

Fly Is At Home On A Crab, With New Evolutionary Neighbors

Source: http://www.sciencedaily.com/releases/2008/04/080408202041.htm

ScienceDaily (Apr. 14, 2008) — Scientists at the Max Planck Institute for Chemical Ecology, Germany, have rediscovered Drosophila endobranchia, a fly living in the mouth of land crabs. The members of Drosophilidae, a family consisting of about 3000 species, are often referred to as fruit flies although most of the members feed on microbes. As microbes can be found growing on a wide range of substrates, fruit flies can accordingly also be found in a multitude of habitats.

One of the more bizarre choices of breeding substrates comes from Drosophila endobranchia. This species is one out of three known fruit flies that have found a home on (and inside) land-crabs. Although frequently mentioned in biology textbooks, the crab flies have somewhat surprisingly been neglected in active research since their description. D. endobranchia has actually not even been seen since its initial discovery in 1966.
In January 2007, scientists from Bill Hansson's group at the Max Planck Institute for Chemical Ecology, Germany, managed to relocate these elusive flies on Grand Cayman in the Caribbean (the sole known home of this species), where small fragmented populations still persist in the few remaining patches of suitable habitats. Concomitant with the insects' re-exploration, a long-standing question regarding D. endobranchia's evolutionary position within the Drosophilidae, disputed since its discovery due to a conflicting set of morphological characteristics, was resolved, based on a new comprehensive molecular and morphological analysis.
Surprisingly, the Cayman crab flies are quite closely related to the other Caribbean crab fly, Drosophila carcinophila, suggesting that something in their shared ancestry has made these flies more suitable for this most unconventional lifestyle.
A well known species of the Drosophilidae family is the fruit fly, Drosophila melanogaster, model organism for genetic studies since decades. There are also three members of the family, D. endobranchia, D. carcinophila, and Lissocephala powelli, which are known to fulfill all or parts of their life cycle on land crabs, and each of them in different areas of the globe. While Lissocephala powelli seems to be restricted to the Christmas Island in the Indian Ocean, the other two species appear at different locations of the Caribbean. D. endobranchia, the least described of the three, was last seen on the Cayman Islands in 1966. The phylogenetic position of this species, i.e. the place it occupies in the tree of life, has remained disputed.
Therefore, Marcus Stensmyr and colleagues decided to relocate this species in the Cayman Islands in order to re-define the phylogeny of this organism with current molecular techniques and shed light on the evolutionary history of this interesting trait.
A search for the Cayman crab flies in 2007 was successful, leading to the collection of 66 specimens. The phylogeny of this species was determined with the aid of molecular biology, which allowed the Max Planck researchers to place D. endobranchia within the canalinea species group, a little known Neotropical group of forest dwelling flies that belongs to the large repleta radiation that also includes D. carcinophila, the second Caribbean crab fly.
"It is intriguing that two species in the same lineage evolved the same odd choice of breeding substrate," says Marcus Stensmyr, "it makes us wonder which aspects of their shared ancestry allow them to survive and thrive in this most specialized environment."
Further reading: Flies' lives on a crab. Marcus C. Stensmyr, Bill S. Hansson. Current Biology 17, 743-746 (2007).
Journal reference: Stensmyr MC, Stieber R, Hansson BS (2008) The Cayman Crab Fly Revisited--Phylogeny and Biology of Drosophila endobranchia. PLoS One 3(4): e1942. doi:10.1371/journal.pone.0001942
Adapted from materials provided by Public Library of Science, via EurekAlert!, a service of AAAS.

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Stem Cells Offer Cartilage Repair Hope For Arthritis Sufferers

Source: http://www.sciencedaily.com/releases/2008/04/080411085922.htm

ScienceDaily (Apr. 14, 2008) — Research being presented April11 at the UK National Stem Cell Network Annual Science Meeting in Edinburgh could offer hope that bone stem cells may be harnessed to repair the damaged cartilage that is one of the main symptoms of osteoarthritis.
Scientists at Cardiff University have successfully identified stem cells within articular cartilage of adults, which although it cannot become any cell in the body like full stem cells, has the ability to derive into chondrocytes - the cells that make up the body's cartilage -- in high enough numbers to make treatment a realistic possibility. The team have even been able to identify the cells in people over 75 years of age.
Osteoarthritis affects over 2M people in the UK and occurs when changes in the make up of the body's cartilage causes joints to fail to work properly. At its worse it can cause the break up of cartilage, causing the ends of the bones in the joint to rub against each other. This results in severe pain and deformation of the joint. One current treatment to treat damaged cartilage due to trauma in younger patients is to harvest cartilage cells from neighbouring healthy cartilage and transplant them into the damaged area. Unfortunately, only a limited number of cells can be generated.
The research team, funded by the Arthritis Research Campaign and the Swiss AO Foundation, have identified a progenitor, or a partially derived stem cell in bovine cartilage that can be turned into can be turned into a chondrocyte in culture. Their breakthrough came in identifying a similar cell in human cartilage that was more like a stem cell with characteristics that they could be used to treat cartilage lesions due to trauma but also mark the onset of osteoarthritis
Lead researcher Professor Charlie Archer from the Cardiff School of Biosciences said: "We have identified a cell which when grown in the lab can produce enough of a person's own cartilage that it could be effectively transplanted. There are limitations in trying to transplant a patient's existing cartilage cells but by culturing it from a resident stem cell we believe we can overcome this limitation.
"This research could have real benefits for arthritis sufferers and especially younger active patients with cartilage lesions that can progress to whole scale osteoarthritis."
Prof Archer commented: "We have embarked on the next stage which is to conduct and animal trial which is a necessary pre-requisite to a clinical trial which we hope to start next year if the results are positive"
Adapted from materials provided by Biotechnology and Biological Sciences Research Council, via EurekAlert!, a service of AAAS.

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Embryonic Stem Cells Could Help Overcome Immune Rejection Problems

Source: http://www.sciencedaily.com/releases/2008/04/080411082935.htm

ScienceDaily (Apr. 13, 2008) — Tissues derived from embryonic stem (ES) cells could help to pacify the immune system and so prevent recipients from rejecting them, the UK National Stem Cell Network Science Meeting will hear on April 11. Speaking at the conference in Edinburgh, Dr Paul Fairchild from the University of Oxford will tell delegates that although tissues derived from ES cells succumb to rejection, they have an inherent immune-privilege which, if exploited, could have far reaching implications for the treatment of conditions such as diabetes, heart attacks and Parkinson's.

The exciting potential of ES cells for use in regenerative medicine may only be realised by better understanding of how to manage the body's immune response to them. With funding from the Medical Research Council, Dr Fairchild and Dr Nathan Robertson are investigating whether tissues derived from ES cells will be rejected in the conventional manner or whether the recipients will not recognise them as foreign.
So far, their findings suggest that, while ES cells are fully susceptible to rejection, they do display some underlying immune privilege which, with better understanding, could be harnessed to promote the activity of regulatory T-cells to suppress activation of the immune system.
Dr Paul Fairchild, explains: "Our work provides hope that the immune system may be persuaded to accept tissues derived from ES cells more readily than has been the case for tissues and organs from conventional sources. It appears that ES cell-derived tissues contribute to their own acceptance by creating an environment conducive to T cell regulation, which may one day be harnessed therapeutically."
The Oxford team generated a panel of ES cell lines from strains of mice that differed from recipients by increasing levels of genetic disparity and used them as a source of tissues for transplantation. Their results show that while minor differences between the two strains provoke prompt rejection in the absence of immune suppression, ES cells do show an underlying tendency for immune privilege.
The next stage of the team's work is to explore further the molecular and cellular basis of this immune-privilege, whether it might be augmented therapeutically and whether unwanted viruses or tumours could exploit ES cell-derived tissues as a safe-haven where they can evade the normal immune response.
Adapted from materials provided by Biotechnology and Biological Sciences Research Council, via EurekAlert!, a service of AAAS.

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Scientists Find A Fingerprint Of Evolution Across The Human Genome

Source:

http://www.sciencedaily.com/releases/2008/04/080408163236.htm

ScienceDaily (Apr. 9, 2008) — The Human Genome Project revealed that only a small fraction of the 3 billion “letter” DNA code actually instructs cells to manufacture proteins, the workhorses of most life processes. This has raised the question of what the remaining part of the human genome does. How much of the rest performs other biological functions, and how much is merely residue of prior genetic events?

Scientists from Cold Spring Harbor Laboratory (CSHL) and the University of Chicago now report that one of the steps in turning genetic information into proteins leaves genetic fingerprints, even on regions of the DNA that are not involved in coding for the final protein. They estimate that such fingerprints affect at least a third of the genome, suggesting that while most DNA does not code for proteins, much of it is nonetheless biologically important – important enough, that is, to persist during evolution.
Conservation of genetic information
To gauge how critical a particular stretch of DNA is, biologists often look at the detailed sequence of “letters” it consists of, and compare it with a corresponding stretch in related creatures like mice. If the stretch serves no purpose, the thinking goes, the two sequences will differ because of numerous mutations since the two species last shared an ancestor. In contrast, it’s believed that the sequences of important genes will be similar, or “conserved,” in different species, because animals with mutations in these genes did not survive. Biologists therefore regard conserved sequences as a sign of biological importance.
To test for conservation, researchers need to find matching stretches in the two species. This is relatively easy for stretches that “code” for proteins, where scientists long ago learned the meaning of the sequence. For “noncoding” regions, however, the comparison is often ambiguous. Even within a gene, stretches of DNA that code for pieces of the target protein are usually interspersed with much larger noncoding stretches, called introns, that are removed from the RNA working copy of the DNA before the protein is made.
Signs of splicing
Previous researchers assumed that mutations in the middle of introns do not affect the final protein, so they simply accumulate. In the new work, however, the researchers found signs that evolution rejects some types of mutations even in these regions of the genome. Although the selection is weak, “introns are not neutral,” in their effect on survival, says CSHL professor Michael Zhang, a bioinformatics expert who headed the research team.
To look for selection, CSHL researcher Chaolin Zhang, a doctoral candidate at Stony Brook University, looked in the human genome for a subtle statistical imbalance in how often various “letters” appear. The researchers attribute this imbalance to special short stretches of DNA that mark regions to be removed. Unless these signal sequences are sprinkled throughout an intron, the data suggest, it may not be properly spliced out, with potentially fatal consequences. Other sequences must likewise be preserved in the regions to be retained.
The scientists found a preference for some “letters” across intron regions, and the opposite preference in coding regions. Together, these regions make up at least a third of the genome, which is thus under selective pressure during evolution. The result supports other recent studies that suggest that, although most DNA does not code for proteins, much of it is nonetheless biologically important.
In addition to demonstrating how splicing affects genetic evolution, the statistical analysis identified possible signaling sequences, some that were already known and others that are new. According to co-author Adrian Krainer, a CSHL professor and splicing expert, “the exciting thing will be to experimentally test whether these predicted elements are really true.”
The article “RNA landscape of evolution for optimal exon and intron discrimination,” authored by Chaolin Zhang, Wen-Hsiung Li, Adrian R. Krainer, and Michael Q. Zhang, appears in the April 15, 2008 edition of the Proceedings of the National Academy of Sciences.
Adapted from materials provided by Cold Spring Harbor Laboratory.

Fausto Intilla
www.oloscience.com