The gender gap in math perceived to exist between girls and boys has long been contested. New research published in the journal Science sheds clarity on the debate and demonstrates that girls perform better in mathematics in more gender equal societies, in some cases besting male peers.The research, led in part by Kellogg School of Management Professor Paola Sapienza, sought to address the issue of whether social and cultural factors influence women’s success in math and science. Sapienza and her colleagues Luigi Guiso (Instituto Universitario Europeo) and Ferdinando Monte and Luigi Zingales (University of Chicago), empirically investigated whether a global gender gap exists in math to understand the relative importance of biology and culture on the development of basic mental attributes that are valuable for conducting math and science.

“The so-called gender gap in math skills seems to be at least partially correlated to environmental factors” says Sapienza. “The gap doesn’t exist in countries in which men and women have access to similar resources and opportunities.”

In search of bridges across the math gender gap, Sapienza and her colleagues analyzed data from more than 276,000 children in 40 countries. The large number of subjects and broad range of social systems represented were key to the validity of the study. Each child took the 2003 Organisation for Economic Co-operation and Development Programme for International Student Assessment (PISA), an internationally standardized assessment of math, reading, science and problem-solving ability.

Based on the PISA analysis, Sapienza and her colleagues determined that while the global pattern shows that boys tended to outperform girls in math (on average girls score 10.5 points lower than boys), this advantage was not always the case. In a few countries, including Iceland, Sweden and Norway, girls scored as well as boys or better.

Sapienza and colleagues examined social features that might explain the variance from country to country. The team used four tools to measure how well women were integrated into each society compared with men. These tools were the 2006 Gender Gap Index (GGI) developed by the World Economic Forum (WEF); the World Values Survey; the percentage of women aged 15 or older who are eligible to work in each country’s labor force; and the WEF political empowerment index, which measures the representation of women in government.

Sapienza’s team found that, in more gender equal societies, the gender gap in math disappears. For example, the math gender gap almost disappeared in Sweden (GGI = 0.81), while girls scored 23 points below boys in math in Turkey (GGI = 0.59). Not only did average girls’ scores improve as equality improved, but the number of girls reaching the highest levels of performance also increased.

Math and science rates for girls in the U.S., which ranks 23rd on the GGI scale with a score of 0.7, fell in the middle of the pack. On average, U.S. girls score almost 10 points lower than U.S. boys in mathematics, which is around the average for all countries analyzed in the study.

The research also found a striking gender gap in reading skills. In every country girls perform better than boys in reading In more gender equal societies, the girls’ advantage in reading over boys increases further. On average, girls have reading scores that are 32.7 points higher than those of boys (6.6 percent higher than the mean average score for boys). In Turkey, this amounts to 25.1 points higher and in Iceland, girls score 61.0 points higher.

Said Sapienza, “Our research indicates that in more gender equal societies, girls will gain an absolute advantage relative to boys.”

In 1999, when Dr. Huda Zoghbi and her Baylor College of Medicine colleagues identified a mutation of the gene MeCP2 as the culprit in Rett syndrome, a neurodevelopmental disorder, the discovery was only the prelude to understanding a symphony of neurological missteps.

Unraveling the story of MeCP2 demonstrates the finicky nature of neurons that work best when the recipe for the proteins affecting them is followed exactly. Zoghbi and her collaborators describe the role MeCP2 plays in the brain in a report that appears in the current issue of the journal Science.

“Whether you lose the protein or gain too much, the symptoms in the brain overlap quite a bit,” said Zoghbi, who is a BCM professor of pediatrics, neurology, neuroscience, molecular and human genetics and a Howard Hughes Medical Institute investigator. “The brain is very sensitive to its physiological equilibrium.”

Yet the brain or neurons in it can demonstrate a problem with only a limited range of symptoms: autism, seizures or mental retardation.

“The symptoms are those of an unhappy neuron,” said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.

Zoghbi and her colleagues found that MeCP2 is a key regulator that can turn on and off genes that govern activities in the neurons of the hypothalamus. While MeCP2 can turn off a gene, it is more likely to turn it on.

As infants, girls with Rett syndrome seem normal for at least six months. Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk. Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior. Many of their symptoms mirror those of autism. Zoghbi’s laboratory was the first to identify a mutation in the MeCP2 gene that results in too little of this protein, causing girls to develop Rett. Boys who suffer from a disorder linked to an excess of MeCP2 have impaired motor function, seizures and mental retardation with autism-like behavior.

In trying to find out how the alterations in MeCP2 affect the brain, the scientists began their studies in the hypothalamus because symptoms of Rett syndrome such as anxiety, sleep disturbance and slowed growth can all be attributed to problems in that part of the brain. Previous studies of the whole brain proved inconclusive, and by targeting a very specific area of the brain, Zoghbi and her collaborators hoped to zero in on the problem.

“Loss of function of the MeCP2 gene causes Rett syndrome,” said Maria Chahrour, a BCM graduate student and first author of the report. Doubling or tripling MeCP2 levels causes other neurological disorders. To better understand the protein, the scientists decided to study mice that either lacked MeCP2 or had too much of it.

They dissected the hypothalamus in both kinds of mice and looked at changes in the genes compared to the same genes in normal mice.

“There are thousands of genes changed by MeCP2,” said Chahrour. In both the mice who had no MeCP2 and those who had too much of the dysfunctional gene, they found changes in expression of thousands of genes. Surprisingly, they found that in at least 85 percent of the genes, MeCP2 turned the gene on. In fact, they found that it associates with CREB1, another gene tasked with turning on genes.

Interestingly, although the two diseases share many features, having no protein versus having too much caused opposite effects on gene expression, suggesting again that “the symptoms are those of an unhappy neuron,” said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.

“Because MeCP2 regulates thousands of genes, it does not make sense to target each of them individually in designing treatments,” Chahrour said. “We are going to have to find a therapeutic strategy that can bypass MeCP2 and restore the normal order in the brain,” she said.

Long viewed as straitlaced spinsters, sexless freshwater invertebrate animals known as bdelloid rotifers may actually be far more promiscuous than anyone had imagined: Scientists at Harvard University have found that the genomes of these common creatures are chock-full of DNA from plants, fungi, bacteria, and animals.The finding, described this week in the journal Science, could take the sex out of sexual reproduction, showing that bdelloid rotifers, all of which are female, can exchange genetic material via other means.

“Our result shows that genes can enter the genomes of bdelloid rotifers in a manner fundamentally different from that which, in other animals, results from the mating of males and females,” says Matthew S. Meselson, Thomas Dudley Cabot Professor of the Natural Sciences in Harvard’s Faculty of Arts and Sciences.

In essence, Meselson and colleagues say, bdelloids may acquire DNA by habitually disintegrating their genomes — something these unusual animals do regularly during periods of desiccation, which fractures their genetic material and ruptures cellular membranes. Miraculously, bdelloids can then spring back to life upon rehydration of their habitats, readily reconstituting their genomes and their membranes.

In the process of rebuilding their shattered DNA, though, they may adopt shreds of genetic material from other bdelloids in the same puddle, as well as from unrelated species.

Meselson and co-authors Eugene A. Gladyshev and Irina R. Arkhipova believe the findings may solve the longstanding mystery of bdelloids’ sexless ways, and may shed light on their ability to adapt to new environments.

“These fascinating animals not only have relaxed the barriers to incorporation of foreign genetic material, but, more surprisingly, they even managed to keep some of these alien genes functional,” says Arkhipova, a staff scientist in Harvard’s Department of Molecular and Cellular Biology.

“In principle, this gives them an opportunity to take advantage of the entire environmental metagenome,” adds Gladyshev, a graduate student in molecular and cellular biology at Harvard.

While the scientists have yet to pinpoint the exact sources of the invasive DNA, they have ascertained that the foreign genes are concentrated in bdelloid telomeres, the regions at the ends of DNA thought to prevent its strands from unraveling — much like the plastic cap on the end of a shoelace.

A next step, Meselson says, is to determine whether bdelloid genomes also contain homologous genes imported from other bdelloids. He and his colleagues also hope to examine whether the animals actually use any of the hundreds of snippets of foreign DNA they appear to vacuum up.

Nearly all other multicellular animals have strong safeguards against foreign DNA, but bdelloids’ seeming embrace of genetic detritus is in keeping with their general quirkiness: Shunning sex and entirely lacking males, the ubiquitous creatures are also extraordinarily resistant to radiation, as Meselson and Gladyshev demonstrated earlier this year in a paper published in the Proceedings of the National Academy of Sciences.

With nearly 500 recognized species worldwide, bdelloid rotifers were discovered in 1702, when the renowned Dutch scientist and microscopy pioneer Antony van Leeuwenhoek added water to dust retrieved from a rain gutter on his house and observed the organisms in the resulting fluid. He subsequently described the creatures in a letter to Britain’s Royal Society, which still counts an envelope of van Leeuwenhoek’s rain-gutter dust among its holdings.

A new analysis of the Martian rock that gave hints of water on the Red Planet — and, therefore, optimism about the prospect of life — now suggests the water was more likely a thick brine, far too salty to support life as we know it.The finding, by scientists at Harvard University and Stony Brook University, is detailed this week in the journal Science.

“Liquid water is required by all species on Earth and we’ve assumed that water is the very least that would be necessary for life on Mars,” says Nicholas J. Tosca, a postdoctoral researcher in Harvard’s Department of Organismic and Evolutionary Biology. “However, to really assess Mars’ habitability we need to consider the properties of its water. Not all of Earth’s waters are able to support life, and the limits of terrestrial life are sharply defined by water’s temperature, acidity, and salinity.”

Together with co-authors Andrew H. Knoll and Scott M. McLennan, Tosca analyzed salt deposits in four-billion-year-old Martian rock explored by NASA’s Mars Exploration Rover, Opportunity, and by orbiting spacecraft. It was the Mars Rover whose reports back to Earth stoked excitement over water on the ancient surface of the Red Planet.

The new analysis suggests that even billions of years ago, when there was unquestionably some water on Mars, its salinity commonly exceeded the levels in which terrestrial life can arise, survive, or thrive.

“Our sense has been that while Mars is a lousy environment for supporting life today, long ago it might have more closely resembled Earth,” says Knoll, Fisher Professor of Natural Sciences and professor of Earth and planetary sciences at Harvard. “But this result suggests quite strongly that even as long as four billion years ago, the surface of Mars would have been challenging for life. No matter how far back we peer into Mars’ history, we may never see a point at which the planet really looked like Earth.”

Tosca, Knoll, and McLennan studied mineral deposits in Martian rock to calculate the “water activity” of the water that once existed on Mars. Water activity is a quantity affected by how much solute is dissolved in water; since water molecules continuously adhere to and surround solute molecules, water activity reflects the amount of water that remains available for biological processes.

The water activity of pure water is 1.0, where all of its molecules are unaffected by dissolved solute and free to mediate biological processes. Terrestrial seawater has a water activity of 0.98. Decades of research, largely from the food industry, have shown that few known organisms can grow when water activity falls below 0.9, and very few can survive below 0.85.

Based on the chemical composition of salts that precipitated out of ancient Martian waters, Tosca and his colleagues project that the water activity of Martian water was at most 0.78 to 0.86, and quite possibly reaching below 0.5 as evaporation continued to concentrate the brines, making it an environment uninhabitable by terrestrial species.

“This doesn’t rule out life forms of a type we’ve never encountered,” Knoll says, “but life that could originate and persist in such a salty setting would require biochemistry distinct from any known among even the most robust halophiles on Earth.”

The scientists say that the handful of terrestrial halophiles — species that can tolerate high salinity — descended from ancestors that first evolved in purer waters. Based on what we know about Earth, they say that it’s difficult to imagine life arising in acidic, oxidizing brines like those inferred for ancient Mars.

“People have known for hundreds of years that salt prevents microbial growth,” Tosca says. “It’s why meat was salted in the days before refrigeration.”

Tosca and Knoll say it’s possible there may have been more dilute waters earlier in Mars’ history, or elsewhere on the planet. However, the area whose rocks they studied — called Meridiani Planum — is believed, based on Mars Rover data, to have been one of the wetter, more hospitable areas of ancient Mars.

In this week’s issue of Science, a team of researchers from the United States and Sweden report on a newly identified factor that controls the natural input of new nitrogen into boreal forest ecosystems. Nitrogen is the primary nutrient that dictates productivity (and thus carbon consumption) in boreal forests. In pristine boreal ecosystems, most new nitrogen enters the forest through cyanobacteria living on the shoots of feather mosses, which grows in dense cushions on the forest floor. These bacteria convert nitrogen from the atmosphere to a form that can be used by other living organisms, a process referred to as “nitrogen-fixation.” The researchers showed that this natural fertilization process appears to be partially controlled by trees and shrubs that sit above the feather mosses.

In the summer of 2006, the researchers placed small tubes, called resin lysimeters, in the moss layer to catch nitrogen deposited on the feather moss carpets from the above canopy and then monitored nitrogen fixation rates in the mosses. The studies revealed that when high levels of nitrogen were deposited on the moss cushion from above, a condition typical of young forests, nitrogen fixation was extremely low. In older, low-productivity forests, very little nitrogen was deposited on the moss cushion, resulting in extremely high nitrogen fixation rates.

Nitrogen fixation is an energy demanding process. Thus, when mosses are exposed to high concentrations of bioavailable nitrogen, the cyanobacteria will consume this resident nitrogen rather than expending energy on fixing new nitrogen. Thus the nitrogen content of canopy throughfall acts as a regulator of newly fixed nitrogen into these boreal forests. For this same reason, elevated nitrogen deposition from pollution likely reduces moss nitrogen fixation rates. The moss would initially buffer the forest against the effect of nitrogen added as pollution or fertilizer; however, chronic elevated nitrogen inputs would ultimately eliminate this natural source of forest fertility.

The feather moss-cyanobacterial association provides a unique model system in which to study nitrogen feedback mechanisms. The cyanobacteria reside on the leaves, thus the nitrogen status of the canopy throughfall directly influences nitrogen fixation in the feather mosses. This direct expression of a nutrient feedback mechanism could not be detected in other nitrogen fixing plant species, such as legumes, that house their nitrogen fixing bacteria below ground and where soils and decomposing litter intercept and modify the nitrogen from throughfall before it reaches the bacteria.

These findings are important from a global standpoint, because feather mosses (and associated cyanobacteria) are the primary source of biologically fixed nitrogen in the boreal forest biome. The dominating feathermoss Pleurozium schreberi is also found in arctic and temperate biomes and thus may be the widest distributed individual nitrogen-fixing plant species on Earth. Understanding feed back mechanisms among dominating organisms that regulate fundamental ecosystem processes are integral to our ability to predict long term outcomes of global carbon dynamics.

The two studies in the May 30th issue of Cell, a Cell Press publication, uncover the crystal structure and biochemical activity of an enzyme known as XPD helicase taken from Sulfolobus archaea, microbes distinct from bacteria that share many fundamental genes with humans. For reasons that had remained rather mysterious until now, point mutations in human XPD sometimes at neighboring sites can spell the difference between cancer-prone xeroderma pigmentosa, the aging disorder known as Cockayne syndrome and another aging disorder called trichothiodystrophy.

If you consider the linear sequence of XPD and map the [disease-linked] point mutations onto it, there is nothing clear about why they would be causative for one of the three diseases or another, said Jill Fuss of The Scripps Research Institute. By having these structures for XPD, we suddenly see how it is working.

The protein from archaea is a simplified model, but that doesn’t stop us learning a lot about the biology of the human enzyme, said Malcolm White of University of St Andrews, who led the other study. Archaeal protein structures are often very close matches to the equivalent proteins from humans, even though they diverged from one another three billion years ago. We can learn a lot about human health by looking deep into evolutionary time.

Archaea have particular similarities with humans and other eukaryotes in the way in which they process information, including DNA replication, transcription and repair, White explained. One of those common elements is XPD helicase, a component of a fundamental complex (known as TFIIH) with roles in initiating the transcription of genes into the templates for protein and in the repair of damaged DNA. In both instances, the helicase parts the two DNA strands at either the transcription start site or the site of DNA damage.

Defects in XPD are known to underlie xeroderma pigmentosa (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). Although people with all three diseases share a sensitivity to the sun, they differ greatly in their predispositions to cancer or accelerated aging, explained John Tainer, who led the Scripps study. XP patients show several 1000-fold increase in skin cancer, whereas neither CS nor TTD patients show an increase in the cancer incidence despite their sun sensitivity. Furthermore, both CS and TTD are premature aging diseases plus developmental disorders, with CS patients being more severely affected and exhibiting severe mental retardation from birth.

Both teams now have evidence to explain what separates the diseases despite their similar molecular causes. They find that XP-causing mutations in XPD all fall in sites where the helicase binds ATP (the energy currency of the cell) or DNA. Those alterations leave the enzyme unable to function in DNA repair. However, the overall effect on the structure of the enzyme is minimal. As such, the enzyme still fills its position in the TFIIH complex, allowing transcription to proceed. That inability to repair defects, leaves those with XP prone to developing cancer as mutations arise and go uncorrected.

In the case of TTD, the defect is quite different, White said. TTD-linked mutations are found all over the protein at points important to its interactions with other proteins. Therefore, those mutations leave the protein floppy, destabilizing the entire TFIIH complex and causing defects in both transcription and repair.

It is thought that the transcription defects protect against cancer, but lead to an increase in cell death and therefore the rapid aging symptoms seen in TTD patients, White said.

As for CS, Tainer’s group suggests it results when defects in XPD lock the protein into a rigid position. As a result, they said, the protein may stick in repair mode and cut out DNA at sites where it should be transcribing.

White agrees that CS seems to result from mutations that influence the XPD protein’s flexibility. However, he’s not yet sure exactly how that leads to the symptoms of CS.The new insights into XPD point to the importance of whole proteins, not just their active sites.

“We’ve been able to characterize three activities together with the structure”, Tainer said. “We’ve shown how mutations in the binding site alone can cause cancer. Scientists often thought it was just the active sites that were important that other changes wouldn’t matter. But we see that other changes can lead to very severe defects.”

The results also hold an important general lesson for the value of protein structure for understanding gene function. The results of the Human Genome Project have revealed associations between sequence mutations and particular diseases or disease risks, but in many cases we don’t know why, Tainer said. As in the case of XPD, the protein structures may hold the key.

Researchers at Duke University Medical Center have uncovered definitive evidence that a small but potent subset of immune system B cells is able to regulate inflammation.Using a new set of scientific tools to identify and count these cells, the team showed that these B cells can block contact hypersensitivity, the type of skin reactions that many people have when they brush against poison ivy.

The findings may have large implications for scientists and physicians who develop vaccines and study immune-linked diseases, including cancer. Once the cells that regulate inflammatory responses are identified, scientists may have a better way to develop treatments for many diseases, particularly autoimmune diseases such as arthritis, type 1 diabetes and multiple sclerosis.

“While the study of regulatory T cells is a hot area with obvious clinical applications, everyone has been pretty skeptical about whether regulatory B cells exist,” said Thomas F. Tedder, Ph.D., chairman of the Immunology Department and lead author of the study published in the May issue of Immunity. “I am converted. They do exist.”

Koichi Yanaba and Jean-David Bouaziz identified this unique subset of small white blood cells, which they call B10 cells, in the Tedder laboratory.

The researchers found that B10 cells produce a potent cytokine, called IL-10 (interleukin-10), a protein that can inhibit immune responses. The B10 cells also can affect the function of T cells, which are immune system cells that generally boost immune responses by producing cytokines. T cells also attack tumors and virus-infected cells.

The study was supported by grants from the NIH, the Association pour la Recherche contre le Cancer (ARC), Foundation Rene Touraine, and the Philippe Foundation.

Depleting B10 cells may enhance some immune responses, Tedder said. Enhancing B10 cell function may inhibit inflammation and immune responses in other diseases, like contact hypersensitivity.

“Now that we have been able to identify this regulatory B cell subset, we have already developed treatments that deplete these cells in mice. We are moving to translate these findings to benefit people,” he said.

“The discovery of the ability to identify this potent regulatory cell type should provide important clues to how the immune system regulates itself in response to vaccines as well as infectious agents,” says Barton F. Haynes, M.D., leader of the international Center for HIV/AIDS Vaccine Immunology (CHAVI), a consortium of universities and academic medical centers, and director of the Duke Human Vaccine Institute. “This information should enable researchers to design ways to help the immune system control infections more effectively, and could be a useful advance as we refine approaches to preventing HIV infection.”

There’s a huge initiative underway to look at regulatory T cells in autoimmune disease, HIV infection, and cancer therapy,” Tedder said. “What we have also shown is that it is not only regulatory T cells, but also regulatory B cells that could prevent a person from making effective immune responses in HIV and many other diseases, particularly cancer.”

The Duke researchers developed a way to mark the B10 cells so that they could see that just these cells were producing IL-10. Previously, scientists could only purify a population of B cells and see whether IL-10 could be produced by some of these cells in the population.

In this study, they found that the B10 cells represented only 1-2 percent of all of the B cells in the spleen of a normal mouse. Before this, no one had definitively identified this B cell subset or such regulatory B cells in normal mice, although B cell regulatory function had been described in some genetically altered mice with chronic inflammation.

“In this study, we could directly look at the B cells that were producing IL-10, and figure out what their cell surface molecules looked like, so that we could isolate them. This allowed us to show that this rare subset of B cells controlled immune responses by producing IL-10, which inhibits T cell inflammatory responses,” Tedder said.

The scientists studied a special mouse (CD19-deficient) with altered genes that give them an increased contact hypersensitivity reaction. As it turned out, these mice lacked B10 cells, which resulted in exaggerated inflammation reaction. “This allowed us to show that giving CD19-deficient mice a few B10 cells had a big effect on reducing inflammation,” Tedder said.

They found that depleting all B cells in the mice also resulted in worse inflammation. Since total B cell depletion therapies are now being used to treat people with B cell cancers and autoimmune disease, these findings help to further explain how these therapies treat disease. They also open the door to creating new therapies that take advantage of the power of B10 cells.

This is the first of several papers that will describe cases in which regulatory B10 cells help control immune responses, Tedder said.

With improved resolution, tissue-specific molecular markers and precise timing, University of Oregon biologist James A. Weston and colleagues have possibly overturned a long-standing assumption about the origin of embryonic cells that give rise to connective and skeletal tissues that form the base of the skull and facial structures in back-boned creatures from fish to humans.

Weston and co-authors from the Max Planck Institute of Immunology in Germany and the French National Scientific Research Centre at the Curie Institute document their potentially textbook-changing case in an article appearing online this week (May 19-23) ahead of regular publication in the Proceedings of the National Academy of Sciences.

The cells in question, they argue, do not come from a portion of embryonic neural epithelium called the neural crest, as widely believed, but rather from a distinct thin layer of epidermal epithelial cells next to it. “Our results,” Weston said, “could lead to a better understanding of the etiology of craniofacial defects, as well as the evolution of the head that distinguishes vertebrates from other creatures.”

The neural crest was first identified by classical embryologists in the late 19th and early 20th centuries and has been one of the most studied embryonic tissues. Conventional wisdom says that the neural crest gives rise to skeletal and connective tissue of the head and face, as well as a wide diversity of other stem cells that migrate to many places in the vertebrate embryo, where they spawn the cells that create the peripheral nervous system, and pigment cells in skin and hair (or scales and feathers).

The new study is part of research done over 25 years in Weston’s quest to understand early development of the neural crest and explore alternative explanations for sometimes differing findings involving its assumed cell lineages. Weston noted that mutations in mice that adversely affected development of the peripheral nervous system or pigmentation did not affect craniofacial structures, whereas mutations that caused abnormal development of skeletal and connective tissue of the head and face did not alter neural crest-derived pigment or peripheral nervous system cells.

This paradox, he said, led him to wonder if different genetic programs were required to function in distinct embryonic precursors of these tissues. “In our new paper,” he said, “we finally were able to re-examine some of the underlying assumptions that have led to the conventional wisdom about the source of the embryonic cell lineages that give rise to the skeleton and connective tissue of the head and face.”

In the mouse embryo at eight days gestation, Weston and collaborators used high-resolution imaging and immunostaining techniques to identify and track the dispersal of cells known to jump start connective and skeletal tissue development. They were able to see clearly that these cells came from the non-neural layer of cells rather than from the neural crest. The same distinction also exists in chicken embryos during the first few days of gestation, Weston noted. “Looking at the right time is very important,” he said.

Weston argues that this non-neural epithelium is indeed distinct from the neural crest, because its cells contain characteristically different molecules. He and colleagues dispute suggestions that this non-neural structure is simply a sub-domain of the neural crest. “These cells emerge at a different time in development and disperse in the embryo before neural crest cells begin to migrate,” Weston said.

“New technologies let us see cell types more clearly than ever before,” said Weston, a member of the UO’s Institute of Neuroscience. “We previously had discovered that a molecule that marks cell surfaces in the non-neural epithelium reveals a very sharp boundary between this non-neural epithelium and the neural tissue connected to the neural crest. In this study, we took a closer look.”

They located a population of cells in the non-neural epithelium that express other molecules that “do not appear to originate from the neural crest,” said Weston, who retired in 2001 but continued to teach in the College of Arts and Sciences until 2006. He still collaborates in some research with colleagues at the UO and at various labs around the world.

“I think our results have two important messages,” he said. “First, it is important to identify and validate — rather than ignore — assumptions; and second, because we identified an alternative embryonic cell lineage as the source of the head and facial structures, we can now more effectively analyze and understand the molecular-genetic mechanisms that regulate the normal and abnormal development of these structures.”

Magnetic nanoparticles (with a size of some few to several hundred nanometres) are a new, promising means of fighting cancer. The particles serve as a carrier for drugs: “loaded” with the drugs, the nanoparticles are released into the blood stream, where they move until they come under the influence of a targeting magnetic field which holds them on to the tumour - until the drug has released its active agent. Besides this pharmaceutical effect, also a physical action can be applied: an electromagnetic a.c. field heats up the accumulated particles so much that they destroy the tumour. Both therapeutic concepts have the advantage of largely avoiding undesired side effects on the healthy tissue.

These procedures have already been successfully been applied in the animal model and have, in part, already been tested on patients. Here it is important to know before application whether the particles tend to aggregate and thus might occlude blood vessels. Information about this can be gained by magnetorelaxometry developed at the PTB. In this procedure, the particles are shortly magnetised by a strong magnetic field in order to measure their relaxation after the switch-off of the field by means of superconducting quantum interferometers, so-called “SQUIDs”. Conclusions on their aggregation behaviour in these media can be drawn from measurements of suspensions of nanoparticles in the serum or in whole blood. As an example, it could be shown in this way that certain nanoparticles in the blood serum form clusters with a diameter of up to 200 nm - a clear indication of aggregation, so that these nanoparticles do not appear to be suitable for therapy.

At present, the high technical effort connected with the use of helium-cooled magnetic field sensors is still standing in the way of using this method routinely in practice. In a joint project with Braunschweig Technical University supported by the Ministry of Education and Research (BMBF), the procedure is currently being transferred to a simpler technology based on fluxgate magnetometers.

The results of the first orders from customers have served, for example, to optimise the paint drying process in the automobile industry, the thermal design of furnaces as well as the monitoring of glass forming processes.

Another measuring facility is currently being set up in the PTB which will allow emissivity measurements to be performed under vacuum conditions in an extended temperature and wavelength range - in particular for space applications.

For the first time, researchers at Delft University of Technology have witnessed the spontaneous repair of damage to DNA molecules in real time. They observed this at the level of a single DNA molecule. Insight into this type of repair mechanism is essential as errors in this process can lead to the development of cancerous cells. Researchers from the Kavli Institute of Nanoscience Delft are to publish an article on this in the leading scientific journal Molecular Cell.

Cells have mechanisms for repairing the continuous accidental damage occurring in DNA. These damages can vary from a change to a single part of the DNA to a total break in the DNA structure. These breaks can, for instance, be caused by ultraviolet light or X-rays, but also occur during cell division, when DNA molecules split and form two new DNA molecules. If this type of break is not properly repaired it can be highly dangerous to the functioning of the cell and lead to the creation of a cancerous cell.

One major DNA-repair mechanism involved in repairing these breaks is known as homologous recombination. This mechanism has been observed for the first time by Delft University of Technology researchers in real time and at the level of a single DNA molecule.

To observe this, a DNA molecule is stretched between a magnetic bead and a glass surface. A force is exerted on the magnetic bead using a magnetic field, enabling researchers to pull and rotate a single DNA molecule in a controlled fashion. As the position of the bead changes when the DNA molecule is repaired, researchers are able to observe the repair process in detail.

Expanding on prior research performed at the University of Pennsylvania, Penn biologists have determined that faulty RNA, the blueprint that creates mutated, toxic proteins, contributes to a family of neurodegenerative disorders in humans.

Nancy Bonini, professor in the Department of Biology at Penn and an investigator of the Howard Hughes Medical Institute, and her team previously showed that the gene that codes for the ataxin-3 protein, responsible for the inherited neurodegenerative disorder Spinocerebellar ataxia type 3, or SCA3, can cause the disease in the model organism Drosophila. SCA3 is one of a class of human diseases known as polyglutamine repeat diseases, which includes Huntington’s disease. Previous studies had suggested that the disease is caused largely by the toxic polyglutamine protein encoded by the gene.

The current study, which appears in the journal Nature, demonstrates that faulty RNA, the blueprint for the toxic polyglutamine protein, also assists in the onset and progression of disease in fruit fly models.

“The challenge for many researchers is coupling the power of a simple genetic model, in this case the fruit fly, to the enormous problem of human neurodegenerative disease,” Bonini said. “By recreating in the fly various human diseases, we have found that, while the mutated protein is a toxic entity, toxicity is also going on at the RNA level to contribute to the disease.”

To identify potential contributors to ataxin-3 pathogenesis, Bonini and her team performed a genetic screen with the fruit fly model of ataxin-3 to find genes that could change the toxicity. The study produced one new gene that dramatically enhanced neurodegeneration. Molecular analysis showed that the gene affected was muscleblind, a gene previously implicated as a modifier of toxicity in a different class of human disease due to a toxic RNA. These results suggested the possibility that RNA toxicity may also occur in the polyglutamine disease situation.

The findings indicated that an RNA containing a long CAG repeat, which encodes the polyglutamine stretch in the toxic polyglutamine protein, may contribute to neurodegeneration beyond being the blueprint for that protein. This raised the possibility that expression of the RNA alone may be damaging.

Long CAG repeat sequences can bind together to form hairpins, dangerous molecular shapes. The researchers therefore tested the role of the RNA by altering the CAG repeat sequence to be an interrupted CAACAG repeat that could no longer form a hairpin. Such an RNA strand, however, would still be a blueprint for an identical protein. The researchers found that this altered gene caused dramatically reduced neurodegeneration, indicating that altering the RNA structure mitigated toxicity. To further implicate the RNA in the disease progression, the researchers then expressed just a toxic RNA alone, one that was unable to code for a protein at all. This also caused neuronal degeneration. These findings revealed a toxic role for the RNA in polyglutamine disease, highlighting common components between different types of human triplet repeat expansion diseases. Such diseases include not only the polyglutamine diseases but also diseases like myotonic dystrophy and fragile X.

The family of diseases called polyglutamine repeat disorders arise when the genetic code of a CAG repeat for the amino acid glutamine stutters like a broken record within the gene, becoming very long. This leads to an RNA — the blueprint for the protein — with a similar long run of CAG. During protein synthesis, the long run of CAG repeats are translated into a long uninterrupted run of glutamine residues, forming what is known as a polyglutamine tract. The expanded polyglutamine tract causes the errant protein to fold improperly, leading to a glut of misfolded protein collecting in cells of the nervous system, much like what occurs in Alzheimer’s and Parkinson’s diseases.

Polyglutamine disorders are genetically inherited ataxias, neurodegenerative disorders marked by a gradual decay of muscle coordination, typically appearing in adulthood. They are progressive diseases, with a correlation between the number of CAG repeats within the gene, the severity of disease and age at onset.

In addition to Bonini, researchers whose work contributed to this study are Ling-Bo Li, formerly in the Department of Biology at Penn and now with the Department of Biochemistry at the University of Utah, and Zhenming Yu and Xiuyin Teng of the Department of Biology at Penn and the Howard Hughes Medical Institute.

Funding for this study was provided by the National Institute of Neurological Disorders and Stroke.

Montana State University scientists in the Department of Chemistry and Biochemistry published new research this week that could one day affect the lives of millions around the world who suffer from blood iron disorders.
Martin Lawrence (left) and Anoop Sendamarai (MSU photo by Kelly Gorham)
The paper, which will appear in the Proceedings of the National Academy of Sciences, details the work of Associate Professor Martin Lawrence and doctoral candidate Anoop Sendamarai. The pair have spent the past two years studying Steap3, a protein involved in regulating the body’s absorption of iron.

The results of their studies - the first three-dimensional maps of the atoms that make up Steap3 - could allow pharmaceutical companies to someday design drugs to regulate iron levels in the blood.

“Iron is essential,” Lawrence said. “You can’t live without it, but it’s a double-edged sword. Too much of a good thing can kill you.”

Iron serves several important functions in the bloodstream. It carries oxygen, transports electrons within cells and plays an important role in enzyme systems.

Iron irregularities are some of the most common blood disorders in the world. According to the World Health Organization, iron deficiency, which can lead to anemia, affects more than a billion people around the world and can cause developmental and immune system problems.

Conversely, having too much iron, a condition called hemochromatosis, can also hurt the body by releasing destructive free radicals, Lawrence said. Hemochromatosis affects about one in every 300 people and is most common in people of northern European ancestry. Left untreated, it can lead to early death, often by age 50.

“We’re struck by how many people have too much or too little iron,” Lawrence said.

To understand Steap3’s role in transporting and maintaining balanced levels of iron, Lawrence and Sendamarai first had find and purify samples of the protein and then turn those samples into crystals.

Lawrence said the result of the crystallization process, if done correctly, is analogous to the rigid structure of a brick wall. If done incorrectly, it more closely resembles a pile of bricks.

“It’s kind of a black art really more than a science,” Lawrence said. “You can’t always predict the kind of witch’s brew that needs to be around to get it to crystallize.”

He said only a handful of labs in the country are crystallizing iron transport proteins like Steap3, a fact that places MSU on the same shelf as places like Harvard Medical School.

Once crystallized, the samples are shot with a powerful X-ray beam. Electrons in the sample diffract the X-rays, creating patterns on a digital sensor. The technique, called X-ray crystallography, has been used since the 1950s to de-termine the structure of different substances.

In their basement lab in the campus’s New Chemistry Building, Lawrence and Sendamarai then examined the diffraction patterns created by Steap3.

“It’s kind of like a contour map,” Sendamarai said. “Whenever we see the peaks, we know there are atoms.”

Working backward, they can mathematically determine the position of atoms in the protein and display them in three dimensions.

The computer-drawn result, a three-dimensional image that resembles tangled ribbons and strings, is an picture of what the atoms of Steap3 look like.

Sendamarai said having that picture, which depicts all the nooks and crannies on the protein’s surface, could allow drug companies to design drugs to fit those spots like puzzle pieces.

If a future drug fits those nooks just right, it could help treat hemochromatosis. From there, Sendamarai said it would be conceivable to work backward and possibly treat iron deficiencies or anemia.

Lawrence said that Steap3 is only one in a family of proteins that affect iron transport. This summer, in addition to continuing to study Steap3, Lawrence and Sendamarai hope to learn whether the lab will receive a grant from the National Institutes of Health to work on other iron transport proteins.

“It’s a critical step towards toward learning to modulate iron levels in patients with too much or too little iron,” Sendamarai said. “But, there are a lot of question marks left in iron transport. It’s a big field.”

How does a stem cell decide what specialized identity to adopt – or simply to remain a stem cell? A new study suggests that the conventional view, which assumes that cells are “instructed” to progress along prescribed signaling pathways, is too simplistic. Instead, it supports the idea that cells differentiate through the collective behavior of multiple genes in a network that ultimately leads to just a few endpoints – just as a marble on a hilltop can travel a nearly infinite number of downward paths, only to arrive in the same valley.

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When exposed to a growth factor, a blood stem cell, represented by a blue marble, falls into a new “attractor state,” depicted as a valley in a landscape, to become a red blood cell. Different influences, such as differentiation factors, can lead stem cells to the same attractor state, but each cell can take very different paths though the landscape to get there (just as a marble might take a different path each time it rolls down a hill).Credit: Graham Paterson, Children’s Hospital Boston

The findings, published in the May 22 issue of Nature, give a glimpse into how that collective behavior works, and show that cell populations maintain a built-in variability that nature can harness for change under the right conditions. The findings also help explain why the process of differentiating stem cells into specific lineages in the laboratory has been highly inefficient.

Led by Sui Huang, MD, PhD, a Visiting Associate Professor in the Children’s Hospital Boston Vascular Biology Program (now also on the faculty of the University of Calgary), and Hannah Chang, an MD/PhD student in Children’s Vascular Biology Program, the researchers examined how blood stem cells “decide” to become white blood cell progenitors or red blood cell progenitors.

They began by examining populations of seemingly identical blood stem cells, and found that a cell marker of “stemness,” a protein called Sca-1, was actually present in highly variable amounts from cell to cell – in fact, they found a 1,000-fold range. One might think that low Sca-1 cells are simply those cells that have spontaneously differentiated. However, when Huang and Chang divided the cells expressing low, medium and high levels of Sca-1 and cultured them, each descendent cell population recapitulated the same broad range of Sca-1 levels over nine days or more, regardless of what levels they started with.

“We then asked, are these cells also biologically different?” says Huang, the paper’s senior author. “And it turned out they were dramatically different in differentiation.”

The green balls represent blood stem cells in a stable “basin” on the landscape, where they remain stem cells. Each position on the landscape that the balls occupy corresponds to a gene expression state and can be assigned an “energy.” An increase in the balls’ energy or movement within the basin enhances the likelihood that a ball will escape from the basin, but does not bias it towards a particular fate (in this case, red or white blood cells). Only a change in the landscape induced by a differentiation factor may tip the balance toward another stable state, causing the stem cells to “roll down the valleys” and differentiate to either red or white blood cells.Credit: Courtesy Sui Huang, MD, PhD, Children’s Hospital Boston and University of Calgary

Blood stem cells with low levels of Sca-1 differentiated into red blood cell progenitors seven times more often than cells high in Sca-1 when exposed to erythropoietin, a growth factor that promotes red blood cell production. Conversely, when stem cells were exposed to granulocyte–macrophage colony-stimulating factor, which stimulates white blood cell formation, those that were highest in Sca-1 were the most likely to become white cells. Yet, in both experiments, all three groups of cells retained characteristics of stem cells.

Huang and Chang then looked at the proteins GATA1 and PU.1, transcription factors that normally favor differentiation into red and white blood cells, respectively. Blood stem cells that were low in Sca-1 (and most prone to become red blood cells) had much more GATA1 than did the high- and medium-Sca-1 cells. Stem cells high in Sca-1 (and least prone to become red blood cells) had the highest levels of PU.1.

But most important, the differences in Sca-1, GATA1 and PU.1 levels across the three cell groups became less pronounced over time, as did the variability in the cells’ propensity to differentiate, suggesting that the differences are transient.

In a final step, Huang and Chang used microarrays to look at the cells’ entire genome. Again, they found tremendous variability within the apparently uniform cell population: more than 3,900 genes were differentially expressed (turned “on” or “off”) between the low- and high-Sca-1 cells. And again, this variability was dynamic: the differences diminished over time, with gene activity in both the low- and high-Sca-1 cells becoming more like that in the middle group.

Together, the findings make the case that a slow fluctuation or cycling of gene activity tends to maintain cells in a stable state, while also priming them to differentiate when conditions are right.

“Even if cells are officially genetically identical and belong to the same clone, individual members of that population are quite different at any given time,” says Huang. “This heterogeneity has usually been seen as random ‘measurement noise,’ and, more recently, as ‘gene expression noise.’ But it turns out to be very important, and is the basis for stem cells’ multipotency – their ability to differentiate into multiple lineages.”

“Nature has created an incredibly elegant and simple way of creating variability, and maintaining it at a steady level, enabling cells to respond to changes in their environment in a systematic, controlled way,” adds Chang, first author on the paper.

Practically speaking, the work suggests that stem cell biologists may need to change their approach to differentiating stem cells in the laboratory for therapeutic applications.

(A) The concentration Sca-1 protein, a marker of “stemness,” varies greatly in a population of stem cells, though the most common concentration is toward the middle of the range. (B) If the population of stem cells is divided into three groups (low, medium and high Sca-1 level), and those cells are allowed to divide and grow, (C) each group of descendents will reproduce the original range of Sca-1 concentrations. This suggests that populations of stem cells, though genetically identical, have an innate variability that may provide the basis for stem-cell differentiation. This variability could be tapped to increase the efficiency of stem-cell differentiation for therapeutic purposes.Credit: Graham Paterson, Children’s Hospital Boston

“So far the process has been highly inefficient – only 10 to 50 percent of cells respond to the hormone or whatever is given to make them differentiate,” Huang says. “That is because of the cells’ inherent heterogeneity. People have been finding more and more sophisticated stimulator cocktails, but we could make the process more efficient by harnessing the heterogeneity and identifying cells that are already highly poised to differentiate.”

Chang has already done follow-up experiments showing that stem cell differentiation can be made dramatically more efficient by choosing the right subpopulation of stem cells and stimulating them promptly, while they are most apt to differentiate. “I’m not doing anything complicated – just using what nature already has,” she says.

But the findings also challenge biologists to change how they think about biological processes. The work supports the idea of biological systems moving toward a stable “attractor state,” a concept borrowed from physics. In this case, blood stem cells tend to remain blood stem cells, yet they experience inherent fluctuations in gene activity and protein production that can sometimes be enough to tip the balance and cause them to fall into other attractor states – namely, red or white blood cell progenitors. Specific growth factors can tip the balance, but these factors are part of an overall landscape that guides cells toward different destinies. A marble going downhill will eventually end up in a valley, but which valley it falls into depends on the shape of the landscape.

“Growth or differentiation factors merely increases the probability that a cell will grow or differentiate,” says Donald Ingber, MD, PhD, a co-author on the paper who, with Huang, served as Chang’s mentor on the project. “Cell differentiation is an ensemble property, a collective behavior, inherent in the system’s architecture and set of regulatory interactions.”

A previous study by Huang established, for the first time, that a given cell can exhibit a very different pattern of gene activity from its neighbor, taking a very different path through the landscape, yet end up in the same valley. He and his colleagues exposed precursor cells to two completely different drugs (DMSO and retinoic acid) and closely monitored the cells’ gene expression. Both groups of cells eventually differentiated to become neutrophils (a type of white blood cell), but the molecular paths they took and their patterns of gene expression were completely different until day seven, when they finally converged.

The landscape analogy and collective “decision-making” are concepts unfamiliar to biologists, who have tended to focus on single genes acting in linear pathways. This made the work initially difficult to publish, notes Huang. “It’s hard for biologists to move from thinking about single pathways to thinking about a landscape, which is the mathematical manifestation of the entirety of all the possible pathways,” he says. “A single pathway is not a good way to understand a whole process. Our goal has been to understand the driving force behind it.”

You went to a wedding yesterday. The service was beautiful, the food and drink flowed and there was dancing all night. But people tell you that you are in hospital, that you have been in hospital for weeks, and that you didn’t go to a wedding yesterday at all.The experience of false memories like this following neurological damage is known as confabulation. The reasons why patients experience false memories such as these has largely remained a mystery. Now a new study conducted by Dr Martha Turner and colleagues at University College London, published in the May 2008 issue of Cortex offers some clues as to what might be going on.

The authors studied 50 patients who had damage to different parts of the brain, and found that those who confabulated all shared damage to the inferior medial prefrontal cortex, a region in the centre of the front part of the brain just behind the eyes.

“The patients who confabulated had varying levels of memory ability, and varying levels of “executive functioning” (the set of cognitive abilities overseen by the prefrontal cortex that control and regulate other abilities and behaviours), so confabulation cannot be as simple as a combination of these deficits. Instead it must be due to a specific function controlled by the inferior medial prefrontal cortex. Damage to this region appears to lead to the convincing experience of false memories” says Martha Turner, corresponding author for this study.

This study has implications for our understanding of how the human brain controls memory, and how most of us are able to easily tell apart true memories from things we have imagined, dreamed or invented.

A new medication appears to offer significant relief to patients with severe chronic constipation while minimizing the likelihood of cardiac-related side effects, according to results of a study published this week in the New England Journal of Medicine.The trial involved 38 medical centers and was led by Michael Camilleri, M.D., a Mayo Clinic gastroenterologist. Patients who met the study criteria were randomly assigned to receive either of two dosage levels of prucalopride, a medication that stimulates protein receptors involved in contraction of the colon, or a placebo.

“Many more of the patients taking prucalopride were able to have spontaneous bowel movements without having enemas or taking laxatives, as compared to those who were given placebo,” says Dr. Camilleri. “The time it took to have a first bowel movement was much shorter, and quality of life and other abdominal symptoms also were improved for those taking the study drug.”

Constipation is a common medical problem, affecting about 15 percent of Americans who spend several billion dollars each year on laxatives and other treatments. Prevalence is higher among women and African-Americans and is particularly increased in the elderly. This study involved patients with an extreme but common version of constipation called severe chronic constipation. To participate, patients had to have at least six months of constipation, defined as an average of fewer than three bowel movements a week. Those who had more than four bowel movements during the two-week “run-in” period before treatment began were not eligible.

“The normal range of bowel movements is anywhere from three per day to three per week,” explains Dr. Camilleri. “The 620 patients studied in this trial were severely constipated, averaging only one bowel movement during the two weeks before entering treatment, and most had struggled with the problem for several years, not merely months.”

The 2 milligram (mg) and 4 mg doses of prucalopride appeared roughly equal in benefit, with about 30 percent of patients averaging three bowel movements per week during the 12-week study. Only 12 percent of patients on placebo averaged three bowel movements per week. Nearly half (47.3 and 46.6 percent, respectively) of the patients taking prucalopride increased their bowel movements by at least one per week, while about a quarter (25.8 percent) of those on placebo had a similar improvement.

The most common adverse effect from the drug was diarrhea, which tended to occur in the early stages of treatment, but most patients later settled into a more normal routine of bowel movements. Increased bowel movements and diarrhea are expected effects of the drug. Only 1.5 percent and 4.4 percent of patients treated with 2 mg and 4 mg of prucalopride, respectively, stopped the drug due to diarrhea. “This suggests that the diarrhea was less bothersome than the constipation had been,” Dr. Camilleri says. Headaches were a less frequent side effect.

Dr. Camilleri says the cardiac risk issues that have been raised about related drugs for constipation including tegaserod, appear to be less of a concern for prucalopride. “Prucalopride is highly selective in its effect, and doesn’t interact significantly with other protein receptors, such as those involved in regulating heart rhythm,” he explains. “We conducted electrocardiogram testing during the study and did not find heart rhythm issues, although two of the three patients who withdrew from the study did have symptoms, palpitations and dizziness that may have been attributable to an effect on the cardiovascular system.”

Prucalopride is not yet approved for use in the United States or in any other country.

Dr. Camilleri says results from other studies will need to be compiled and published, and safety and efficacy data submitted to the Food and Drug Administration for review, before it can be approved in the United States as a treatment for chronic constipation.