Cientistas dos EUA transformam 'gordura ruim' em 'gordura boa'

Cientistas norte-americanos dizem ter encontrado uma maneira de transformar gordura corporal em um tipo de gordura que queima calorias e diminui o peso.

A informação foi publicada nesta terça-feira no site da "BBC News".

A equipe de Johns Hopkins realizou o experimento em ratos, mas acredita que o mesmo poderia ser feito em seres humanos, o que acende a esperança de uma nova ferramenta para combater a obesidade.

A modificação da expressão de uma proteína ligada ao apetite não só reduziu o consumo de calorias e o peso dos animais, como também transformou a composição de gordura corporal dos ratos.

A gordura "má" branca transformou-se em gordura "boa" marrom, segundo relatório publicado na revista "Cell Metabolism".

A gordura marrom é abundante em bebês, que a usam como fonte de energia para gerar calor corporal, gastando calorias ao mesmo tempo.

Mas à medida que as pessoas envelhecem, grande parte da gordura marrom desaparece e é substituída pela gordura branca, "ruim", que se manifesta como um pneu sobressalente em torno da cintura.

Especialistas acreditam que estimular o organismo a produzir mais gordura marrom em vez de gordura branca pode ser uma maneira útil para controlar o peso e prevenir a obesidade, além de outros problemas relacionados à saúde, como diabetes tipo 2.

EXPERIMENTO

Sheng Bi e seus colegas da Universidade Johns Hopkins School of Medicine realizaram um experimento para averiguar a supressão de uma proteína estimuladora do apetite, chamada NPY, diminuiria o peso de ratos.

Quando silenciaram a proteína no cérebro dos roedores, descobriram a diminuição do seu apetite e ingestão alimentar.

Mesmo quando os ratos foram alimentados com uma dieta muito rica em gordura, ainda conseguiram perder mais peso que os roedores que tinham pleno funcionamento da NPY.

Os cientistas compararam então a composição da gordura dos animais e encontraram uma mudança interessante.

Nos ratos com a NPY silenciada, um pouco da gordura ruim branca tinha sido substituída pela gordura boa marrom.

Os pesquisadores estão esperançosos com a possibilidade do experimento ser realizado em pessoas, injetando células-tronco de gordura marrom sob a pele para queimar a gordura branca e estimular a perda de peso.

De acordo com Bi, "se o corpo humano conseguisse transformar gordura ruim em boa, que queima calorias em vez de armazená-las, poderíamos acrescentar uma ferramenta séria para enfrentar a epidemia de obesidade. "Somente mais pesquisas nos dirão se isso é possível."

Anjo da guarda cardíaco emite alerta antes de ataque do coração

Socorro cardíaco

Quando um ataque do coração começa, um cronômetro é disparado.

A cada minuto que passa, mais tecido cardíaco é privado de sangue, o que o faz deteriorar-se ou mesmo morrer.

A fim de minimizar os danos ao coração, o fluxo de sangue deve ser restaurado o mais rapidamente possível, ou os efeitos podem ser graves, muitas vezes até fatais.

Pesquisas mostram que o período de tempo entre o início de um ataque cardíaco e o início do tratamento é fundamental para aumentar as chances de sobrevida.

Alarme de ataque cardíaco

Então, que tal se um alarme soasse no início de um ataque cardíaco, sinalizando a necessidade imediata de assistência médica, antes até que o próprio paciente possa pedir socorro?

É justamente isto que estão desenvolvendo pesquisadores da Universidade Northwestern, nos Estados Unidos.

Um sensor aciona um pager que os pacientes carregam consigo quando ocorrem alterações no coração ou quando o médico desconfia que o risco de ataque cardíaco de um paciente está elevado demais.

O objetivo dos pesquisadores é tornar a tecnologia capaz de reconhecer os primeiros sinais de ataque cardíaco, até duas horas antes que ele se manifeste clinicamente.

Assim, os pacientes poderão procurar ajuda mais rapidamente.

"Embora as taxas de sobrevivência tenham melhorado ao longo dos últimos anos, muitos pacientes ainda morrem de ataques cardíacos a cada ano," comenta Liviu Klein, um dos cardiologistas participantes da pesquisa. "Se pudermos identificar um ataque cardíaco mais cedo, poderemos ser capazes de salvar mais vidas."

Antes dos sintomas

Ao todo, são 50 centros nos Estados Unidos participando dos testes do ALERTS, um dispositivo implantável destinado a detectar um ataque cardíaco antes que ele se manifeste na forma de sintomas sentidos pelo paciente.

Do tamanho de uma moeda de um dólar, o aparelho monitora a atividade do coração 24 horas por dia, sete dias por semana, usando um fio inserido no músculo cardíaco para monitorar constantemente a sua atividade elétrica.

Quando ocorrem mudanças, como a falta de oxigênio no coração, uma antena envia um sinal para um pager que o paciente carrega, avisando que um ataque cardíaco é iminente.

"Sintomas de ataques cardíacos são frequentemente mal interpretados, fazendo com que os pacientes retardem o tratamento," diz Klein. "Este dispositivo deixa claro que a atenção médica é necessária, permitindo que o paciente procure ajuda de forma rápida e proporcionando-nos uma oportunidade de iniciar o tratamento antes que um ataque de coração resulte em danos irreversíveis."

Minimamente invasivo

O dispositivo é primariamente projetado para pacientes que já sofreram um ataque cardíaco e estão em alto risco de sofrer outro ataque cardíaco.

Ele é implantado como um marca-passo, mas através de um procedimento cirúrgico minimamente invasivo, e tem o potencial de detectar um ataque cardíaco nos seus estágios mais iniciais.

Technique Developed for Measuring Stressed Molecules in Cells

ScienceDaily (May 3, 2011) — Biophysicists at the University of Pennsylvania have helped develop a new technique for studying how proteins respond to physical stress and have applied it to better understand the stability-granting structures in normal and mutated red blood cells.

Rendering of red blood cells. Biophysicists at the University of Pennsylvania have helped develop a new technique for studying how proteins respond to physical stress and have applied it to better understand the stability-granting structures in normal and mutated red blood cells. 

The research was conducted by Dennis Discher and Christine Krieger in the Molecular and Cell Biophysics Lab in Penn's School of Engineering and Applied Science, along with researchers from the New York Blood Center and the Wistar Institute.

Discher's research was published online in the journal Proceedings of the National Academy of Sciences.

In stark contrast with much of the architecture people interact with every day, the internal architecture of the human body is predominantly soft. Other than bones, all of the organs, tissues and structures in the body are pliable and flexible and need to be that way in order to work.

The Discher lab's research aims to understand what keeps these flexible structures stable, especially when they are under constant physical stress. Discher selected red blood cells as a model for this stress, as they make a complete lap of the turbulent circulatory system every few minutes but survive for months.

"Red blood cells are disks, and they have proteins right below the membrane that give it resilience, like a car tire," Discher said. "The cells are filled with hemoglobin like the tires are filled with air, but where the rubber meets the road is the exterior."

To measure stress in that membrane on an atomic level, the Discher team needed a way to track changes to the shape of those supporting proteins. They found an ideal proxy for that stress in the amino acid cysteine.

Proteins are long chain of amino acids that are tightly folded in on themselves. The order and chemical properties of the acids determine the locations of the folds, which in turn determine the function of the protein. Cysteine is "hydrophobic"; it interacts poorly with water and so it is usually on the inside of a protein. And because stress changes the shape of these folded proteins, Discher reasoned that measuring the degree to which cysteine is exposed would in effect measure how stressed the protein and cells containing it are.

Discher's team simulated the shear forces originating from the beating heart, which forcefully pumps blood and ultimately pulls apart the folds that keep cysteine on the inside of proteins at the red blood cell membrane, allowing it to bind with a fluorescent marker dye. The team could visually confirm that more stressed cells were more fluorescent under the microscope but actually tested the levels of marked cysteine using mass spectrometry.

"Just like a polymer engineer designing a tire, we're looking at the relationship between the chemical makeup and the physical stability of the structure and how it performs," Discher said. "We can use this technique to look at the relationship between structure, flexibility and function."

Investigating the structural elements of blood cells could pave the way to breakthroughs for human health.

"How long can blood be stored? Why are there no good blood substitutes? There are a lot of things we don't understand about the forces cells can sustain before fragmenting and falling apart, especially when we consider age and mutations," he said.

The Discher team studied the mutated blood cells that result in disorders known as elliptocytosis; cells are elliptical, rather than round, and therefore have shorter functional lifespans. These elliptical cells are often missing a chemical "rivet" that anchors the support proteins to the outer membrane, which means that stress causes them to "disassociate," or disconnect, rather than unfold.

That kind of structural change is crippling to the function of anatomical structures like blood cells. The flexibility provided by unfolding is therefore key to their overall stability.

"At least for this cell, the first mechanism of response is to unfold proteins and keep the interactions between proteins the same," Discher said. "That constant back and forth with unfolding within these cells as the cells flow and distort while in the blood stream, allows their architecture to be maintained."

Discher and his colleagues plan to use their cysteine-mass-spectometry technique to investigate the role of softness and flexibility in responding to stress in other biological systems, particularly stem cells, and to better understand why those traits are intrinsic to life on this planet.

Along with Discher and Krieger, the research was conducted by Xiuli An and Narla Mohandas of the New York Blood Center and Hsin-Yao Tang and David W. Speicher of the Wistar Institute.

The research was supported by the National Institutes of Health.

Removable 'Cloak' for Nanoparticles Helps Them Target Tumors

ScienceDaily (May 3, 2011) — MIT chemical engineers have designed a new type of drug-delivery nanoparticle that exploits a trait shared by almost all tumors: They are more acidic than healthy tissues.

The outer layer of this nanoparticle (in yellow) falls off in an acidic environment.

Such particles could target nearly any type of tumor, and can be designed to carry virtually any type of drug, says Paula Hammond, a member of the David H. Koch Institute for Integrative Cancer Research at MIT and senior author of a paper describing the particles in the journal ACS Nano.

Like most other drug-delivering nanoparticles, the new MIT particles are cloaked in a polymer layer that protects them from being degraded by the bloodstream. However, the MIT team, including lead author and postdoctoral associate Zhiyong Poon, designed this outer layer to fall off after entering the slightly more acidic environment near a tumor. That reveals another layer that is able to penetrate individual tumor cells.

In the ACS Nano paper, which went online April 23, the researchers reported that, in mice, their particles can survive in the bloodstream for up to 24 hours, accumulate at tumor sites and enter tumor cells.

A new target

The new MIT approach differs from that taken by most nanoparticle designers. Typically, researchers try to target their particles to a tumor by decorating them with molecules that bind specifically to proteins found on the surface of cancer cells. The problem with that strategy is that it's difficult to find the right target -- a molecule found on all of the cancer cells in a particular tumor, but not on healthy cells. Also, a target that works for one type of cancer might not work for another.

Hammond and her colleagues decided to take advantage of tumor acidity, which is a byproduct of its revved-up metabolism. Tumor cells grow and divide much more rapidly than normal cells, and that metabolic activity uses up a lot of oxygen, which increases acidity. As the tumor grows, the tissue becomes more and more acidic.

To build their targeted particles, the researchers used a technique called "layer-by-layer assembly." This means each layer can be tailored to perform a specific function.

When the outer layer (made of polyethylene glycol, or PEG) breaks down in the tumor's acidic environment, a positively charged middle layer is revealed. That positive charge helps to overcome another obstacle to nanoparticle drug delivery: Once the particles reach a tumor, it's difficult to get them to enter the cells. Particles with a positive charge can penetrate the negatively charged cell membrane, but such particles can't be injected into the body without a "cloak" of some kind because they would also destroy healthy tissues.

The nanoparticles' innermost layer can be a polymer that carries a cancer drug, or a quantum dot that could be used for imaging, or virtually anything else that the designer might want to deliver, says Hammond, who is the Bayer Professor of Chemical Engineering at MIT.

Layer by layer

Other researchers have tried to design nanoparticles that take advantage of tumors' acidity, but Hammond's particles are the first that have been successfully tested in living animals.

Jinming Gao, professor of oncology and pharmacology at the University of Texas Southwestern Medical Center, says it is "quite clever" to use layer-by-layer assembly to create particles with a protective layer that can be shed when the particles reach their targets. "It is a nice proof of concept," says Gao, who was not part of the research team. "This could serve as a general strategy to target acidic tumor microenvironment for improved drug delivery."

The researchers are planning to further develop these particles and test their ability to deliver drugs in animals. Hammond says she expects it could take five to 10 years of development before human clinical trials could begin.

Hammond's team is also working on nanoparticles that can carry multiple payloads. For example, the outer PEG layer might carry a drug or a gene that would "prime" the tumor cells to be susceptible to another drug carried in the particle's core.

Protein Identified as Enemy of Vital Tumor Suppressor PTEN

ScienceDaily (May 3, 2011) — A protein known as WWP2 appears to play a key role in tumor survival, a research team headed by a scientist at The University of Texas MD Anderson Cancer Center reports in an advance online publication of Nature Cell Biology.

Their research suggests that the little-studied protein binds to the tumor-suppressing protein PTEN (phosphatase and tensin homologue deleted on chromosome 10), marking it for destruction by proteasomes, which degrade proteins and recycle their components.

PTEN plays a role regulating the cellular reproduction cycle and prevents rapid cell growth, a hallmark of malignant cells. Its gene is mutated or deleted in many types of cancer, the researchers noted.

The WWP2 (atrophin-1 interacting protein 2) protein was discovered in the laboratory of Junjie Chen, Ph.D., professor and chair in MD Anderson's Department of Experimental Radiation Oncology and senior author of the paper.

"We were trying to find regulators of PTEN when we isolated the protein WWP2 as a putative PTEN-associated protein," Chen said. He noted that WWP2 caught the researchers' attention because it is similar to the NEDD4-1 protein, which has been proposed as a regulator of PTEN function.

First suspect doesn't affect PTEN

WWP2 is an E3 ubiquitin ligase in the NEDD4-like protein family. Ubiquitins attach to other proteins, labeling them for degradation by proteasomes. NEDD4-like proteins play important roles regulating gene transcription, embryonic stem cells, cellular transport and activation of T cells.

"But when NEDD4-1 is deleted in mice, researchers have not seen a clear change in PTEN protein level," Chen noted. "These findings suggest that there may be other PTEN regulators.

"Because WWP2 is part of the NEDD4-like family, we decided to take a look at it to see if it's the real regulator of PTEN," Chen continued. "When you knock down WWP2, you see an increase in PTEN level, whereas with WWP2 overexpression you can see a decrease in PTEN. This finding indicates that WWP2 may be involved in PTEN's regulation."

Overall, the study results suggest that WWP2 can regulate PTEN stability, Chen said.

Possibly a cancer-driving gene

The team uncovered evidence that WWP2 is a potential oncogene -- a driver in tumor formation and growth. In one experiment, mice with normal WWP2 developed prostate cancer tumors after nine weeks that were more than three times the size of tumors in mice with WWP2 silenced.

Chen noted that more research is needed to determine whether WWP2 is functionally important in tumors or in tumor formation. "We need to look at real tumor samples to determine whether tumors with reduced PTEN expression could result from the overexpression of WWP2."

He added that some early studies suggest that WWP2 may operate in tumors, but a correlation between WWP2 overexpression and PTEN downregulation in tumors has not been established.

This work was supported in part by a grant from the Department of Biotechnology, Ministry of Science and Technology, India, a U.S. Department of Defense Era of Hope Research Scholar Award, an NIH Specialized Program of Research Excellence award to Mayo Clinic, and a National Cancer Institute grant to MD Anderson. Also, fellowship support came from the Department of Biotechnology, Council of Scientific and Industrial Research and University Grants Commission, India, and support from the Institute of Life Sciences, Hyderabad, India.

Co-authors with Chen are first author Subbareddy Maddika, Ph.D, Sridhar Kavela, Neelam Rani, and Vivek Reddy Palicharla, all of the Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics in Nampally, Hyderabad, India; Jenny Pokorny and Jann Sarkaria, M.D., of the Mayo Clinic, Rochester, Minn.

Scientists Identify Genetic Risk for Major Depression

ScienceDaily (May 3, 2011) — A new study reveals a novel gene associated with major depression. The research, published in the April 28 issue of the journal Neuron, suggests a previously unrecognized mechanism for major depression and may guide future therapeutic strategies for this debilitating mood disorder.

Depressive patients carrying the risk allele show volume reduction in certain regions of the hippocampus. 

Major depression is a psychiatric disorder that is responsible for a substantial loss in work productivity and can even lead to suicide in some individuals. "Current treatments for major depression are indispensible but their clinical efficacy is still unsatisfactory, as reflected by high rates of treatment resistance and side effects," explains study author Dr. Martin A. Kohli from the Max Planck Institute of Psychiatry in Munich, Germany. "Identification of mechanisms causing depression is pertinent for discovery of better antidepressants."

While is likely that a combination of genetic and environmental risk factors contribute to major depression, identification of risk-conferring genes has been challenging due to the complexity of the genetics and the considerable environmental factors associated with the disease. Dr. Kohli and colleagues performed a stringent genome-wide association study of patients diagnosed with major depression and matched control subjects with no history of psychiatric illness. They identified SLC6A15, a gene that codes for a neuronal amino acid transporter protein, as a novel susceptibility gene for major depression. The finding was confirmed in an expanded study examining over 15,000 individuals.

The researchers examined the functional relevance of the genetic association between SLC6A15 and major depression. Already nondepressed subjects carrying the risk-conferring genetic variants showed lower expression of SLC6A15 in the hippocampus, a brain region implicated in major depression. Moreover, using human brain imaging, risk variant carriers with a positive life history of major depression showed smaller hippocampi. Finally, in a mouse model, lower hippocampal SLC6A15 expression was linked to the effects of chronic social stress, a proven risk factor for depression.

The authors suggest that reduced SLC6A15 expression might lead to perturbation of neuronal circuits related to susceptibility for major depression. "Our results support the notion that lower SLC6A15 expression, especially in the hippocampus, could increase an individual's stress susceptibility by altering neuronal integrity and excitatory neurotransmission in this key brain region," says senior author Dr. Elisabeth B. Binder. "Because SLC6A15 appears amenable to drug targeting, our results may incite the discovery of a novel class of antidepressant drugs."

Research Opens Door to Vaccines That Can Circumvent Maternal Antibodies

ScienceDaily (May 3, 2011) — New research that reveals how maternal antibodies block an immune response to the measles virus is a first step toward improving current childhood vaccination practices, scientists say.

Maternal antibodies are passed to fetuses during pregnancy and to newborns in their mothers' milk. The antibodies protect infants against disease in the first months of life, but that protection comes at a cost: Their presence also interferes with the generation of a natural immune response to vaccination. As a result, most babies receive measles immunizations at the age of 12 to 15 months, when maternal antibodies are gone.

Years of studies have advanced the theory that maternal antibodies shield the measles virus so that cells that generate an immune response can't see the pathogen. If that were the case, little could be done to intervene.

But Ohio State University researchers have demonstrated an entirely different mechanism in an animal model, showing that maternal antibodies bind to a specific receptor that sends a message to stop activation of an immune response to vaccination. The scientists also determined that signals to the immune response can be manipulated, and they are already devising ways that vaccines could be designed to circumvent this natural process.

"In effect, we have found how maternal antibodies affect the off-switch in the immune response, and we have found a potential on-switch," said Stefan Niewiesk, associate professor of veterinary biosciences at Ohio State University and senior author of the study.

The research is published in the online First Edition of the journal Blood.

Under current pediatric practices, children receive measles vaccinations at age 12 to 15 months, and again when they are 5 years old. Maternal antibodies can be active in babies for up to nine months; this schedule is designed to offer protection after the decline of maternal antibodies.

"The maternal antibodies are high at birth, and go down over time. By age 1 year, the maternal antibodies are gone. So this vaccine schedule works quite well if protection is not so urgent. But there is a window of opportunity for measles to come in and infect. So we would like to be able to immunize earlier," said Niewiesk, also an investigator in Ohio State's Center for Microbial Interface Biology.

Niewiesk has been a leader in developing the cotton rat as an animal model for infectious diseases. The animal is susceptible to common human pathogens that affect the respiratory system, and Niewiesk's lab has developed antibodies and other substances that help to evaluate the immune response, which is similar to that found in humans.

As a result, researchers around the world have consulted with Niewiesk for years, using the animals to test vaccine candidates. Often, the experimental vaccines do not work in the presence of maternal antibodies. And even for the one vaccine that did work, the researchers couldn't explain why at the time.

So Niewiesk changed direction, setting aside vaccine testing and instead studying how the maternal antibodies influence the immune response to an antigen -- in this case, the measles virus. With this new information, he and colleagues now have better information to guide the design of a measles vaccine that will be effective even while maternal antibodies are present.

In a normal immune response, white blood cells known as B cells grow and release antibodies that are prepared to fight a specific invader, known as an antigen. The B cells are called to action by B cell receptors on their surface; when the antigen binds to these B cell receptors, the cells get the message to proliferate and then secrete antibodies that are made strictly for the task of fending off the attacking virus.

But the Ohio State researchers determined that when maternal antibodies are active, and then an antigen comes along, their presence triggers a different receptor on the B cell surface -- a receptor known as Fc-gamma RIIB. And because this particular receptor's job is to regulate the immune response, preventing it from going out of control, the receptor tells the B cell to stop -- don't grow, and don't secrete antigen-specific antibodies.

"The problem is that maternal antibodies come in, and will go away, but this Fc receptor doesn't know it. The receptor reacts -- 'Hey, there is antibody already, let's not make too much of an immune response.' This binding leads to a negative signal, and it blocks the receptor's positive signal to the B cell," Niewiesk said.

Further investigation of the multiple signals received by B cells suggests that there are ways to work around this effect that the maternal antibodies have on the immune response, said Dhohyung Kim, first author of the paper and a doctoral candidate in Ohio State's graduate program in Molecular, Cellular and Developmental Biology.

Maternal antibodies are immunoglobulin G (IgG) molecules, a designation based on their structure, and IgG antibodies are among the most potent players in the immune response. In this current work, Kim showed that another type of antibody, an immunoglobulin M molecule, can be used with a measles vaccine and that these IgM antibodies can activate B cells, even when maternal antibodies are present.

The IgM antibodies bind to yet another type of receptor on the B cell surface, Niewiesk explained. "So we are looking at the various ways B cells are being activated, and we already see that we can improve the positive signal to B cells by stimulating them with IgM antibodies," he said.

As part of the study, the researchers disproved the previous theory about how maternal antibodies work -- a process called epitope masking. This theory suggested that maternal antibodies would bind to specific areas on the measles virus needed for immune response recognition -- called epitopes -- and effectively shield the virus so that B cells could neither see the virus nor activate an immune response.

Niewiesk said the scientists knew that the measles virus surface has numerous epitopes, making it highly unlikely that maternal antibodies could block so many different areas of recognition on a single virus. In addition, they showed that suppression of the immune response did not occur if maternal antibody structures were manipulated to prevent them from binding to the Fc-gamma RIIB receptor. That meant that this Fc receptor was key to the mechanism that allowed maternal antibodies to suppress the immune response.

The National Institute of Allergy and Infectious Diseases supported this research.

Versatility of Stem Cells Controlled by Alliances, Competitions of Proteins

ScienceDaily (May 3, 2011) — Because they can change into any other cell, stem cells are the subject of intense research, but how they "decide" to specialize, or differentiate, hasn't been understood. A new study using a unique technology shows that proteins must jostle and join behind the scenes to make it happen, as well as to restore flexibility to cells that already had made their choice.

More like globs of proteins Transcription factors may compete or cooperate within cells, producing complex bindings across hundreds of nucleotides, determing what kind of cells stem cells become. William Fairbrother, center, postdoctoral researcher Alec DeSimone and technician Luciana Ferraris analyzed hundreds of thousands of DNA letters and found previously unspotted patterns of protein interactions. 

Like people with a big choice to make, stem cells have a process to "decide" whether to transform into a specific cell type or to stay flexible, a state that biologists call "pluripotency." Using a technology he invented, Brown researcher William Fairbrother and colleagues have discovered new molecular interactions in the process that will help regenerative medicine researchers better understand pluripotency.

In a paper published in advance online in the journal Genome Research, Fairbrother's team showed that different proteins called transcription factors compete and cooperate in the cells to produce complex bindings along crucial sequences of DNA. This game of molecular "capture the flag," played in teams and amid shifting alliances, appears to be a necessary part of what determines whether stem cells retain their pluripotency and whether specialized, or differentiated, cells can regain it.

In recent years scientists have reported spectacular successes in turning fully differentiated cells back into pluripotent stem cells, a process called reprogramming. But the animals derived from these cells often suffer higher rates of tumors and other problems, Fairbrother said. The reason may be because the complex details of the reprogramming process haven't been fully understood. He said there are many misconceptions about how reprogramming transcription factors interact with DNA.

"Most people think of a protein binding to DNA as a single, surgical thing where you have this isolated binding event," Fairbrother said. "But in fact we show that sometimes these binding events occur over hundreds of nucleotides so they seem more like great greasy globs of proteins that are forming. In addition, the proteins interact with each other, diversifying their function by appearing in complexes with with different partners at different places."

By employing a high-throughput, high-resolution binding assay that he's dubbed MEGAShift, Fairbrother and his colleagues, who include pathology researchers from the University of Utah School of Medicine, were able to analyze the interactions of several key transcription factors in a region of 316,000 letters of DNA with a resolution as low as 10 base pairs. Through hundreds of thousands of array measurements, lead authors Luciana Ferraris and Allan Stewart, Fairbrother, Alec DeSimone, and the other authors learned previously unspotted patterns of protein interactions.

"How do stem cells stay in the state where they can keep their options open?" Fairbrother said. "A key player is POU5F1. But what are the key players that could interact with it and modulate its function? We've developed technology to look at that question."

One of several findings in the paper concerned POU5F1 and its archrival, POU2F1, which binds to exactly the same eight-letter DNA sequence. Which protein binds to the sequence first influences whether a stem cell specializes or remains pluripotent. Experiments showed that a determining factor was a third protein called SOX2. SOX2 helped both proteins bind, but it helps POU2F1 more than POU5F1. In contrast, the team found that another player, NANOG, exclusively helps POU5F1.

"Who binds next to a protein is a determinant of who ends up binding to a sequence," Fairbrother said.

With support from the National Institutes of Health, Fairbrother's group is also applying MEGAShift to other questions, including how protein-protein interactions affect the formation of RNA-protein complexes, which can be even more complicated than binding DNA.

They will also look at the problem of narrowing the field of hundreds of genomic sequence variations that exist naturally in the population down to the real genetic "causal variants" of disease risk. MEGAShift can sort through which variants associated with disease result in an altered binding event that results in a clinical manifestation, such as diabetes or lupus.

In addition to Fairbrother, DeSimone, Ferraris and Stewart, other authors on the paper Matthew Gemberling at Brown, Dean Tantin at the University of Utah, and Jinsuk Kang also at the University of Utah.

The research was funded by the National Human Genome Research Institute.

Device Measures Brain Temperature Non-Invasively: Monitoring Could Be Critical in Life-Saving Cooling Therapy

ScienceDaily (May 3, 2011) — Doctors have long sought a way to directly measure the brain's temperature without inserting a probe through the skull. Now researchers have developed a way to get the brain's precise temperature with a device the diameter of a poker-chip that rests on a patient's head, according to findings presented May 1 at the annual meeting of the Pediatric Academic Societies in Denver.

"This is the first time that anyone has presented data on the brain temperature of a human obtained non-invasively," said principal researcher Dr, Thomas Bass, a neonatologist at Children's Hospital of The King's Daughters in Norfolk, Va., and a professor of pediatrics at the hospital's academic partner, Eastern Virginia Medical School.

The research also suggests that an injured brain can be significantly warmer than the body, a finding critical to cooling therapies that reduce brain damage in everyone from elderly heart attack victims to hypoxic newborns.

"Knowing the actual brain temperature may allow us to improve outcomes by keeping the brain at an optimum temperature," said Dr. Bass.

With the help of a $750,000 National Institutes of Health grant, a research team led by Dr. Bass adapted an instrument that calculates temperatures by detecting microwave emissions produced by all human tissue.

Those microwaves pass unimpeded through the skull, like light passing through a sheet of glass. As tissue temperatures increase, the emissions grow more intense. Engineers calibrated the device to measure the temperature of brain tissue 1.5 centimeters beneath the skull.

In the trial whose results were presented, the device was placed on the heads of infants undergoing cooling therapy at CHKD. The device's brain temperature readings were correlated with rectal and esophageal temperatures. The difference in temperature between the brain and the body recorded by other means was as high as 5.4% Fahrenheit.

"That's difference is larger than we expected," Dr. Bass said.

Dr. Bass, who pioneered research on cooling therapy for hypoxic newborns, and set about this research because he believed the therapy could be improved if doctors knew precise temperature of the damaged organ, the brain.

Hypoxic brain damage in infants occurs most often in full-term births when the child suffers oxygen loss either immediately before or during delivery. Because of a quirk in the brain, a child can be revived but brain cells continue to die over several days, resulting in brain damage or death. Doctors could do little to stop this progression; parents often watched helplessly as their sons and daughters literally died before their eyes.

Based on the observation that children rescued from freezing ponds after extended periods of time suffered little or no brain damage, cooling therapy involves chilling an infant's body to 92 degrees for 72 hours after brain injury.

A clinical trial on the therapy showed that cooling the child stops or reduces the progression of brain cell death, drastically reducing brain damage and death. The results were so positive that the therapy is now standard in advanced neonatal intensive-care units worldwide.

Cooling therapy is now used with other patients as well, including heart attack victims whose brains have suffered oxygen deprivation.

Because cooling therapy's success relies on the temperature of the brain, precise readings of the brain's temperature is likely to improve a therapy that's already proven remarkably effective.

Children's Hospital of The King's Daughters is the only freestanding pediatric hospital in Virginia.

Brain Enlargement in Autism Due to Brain Changes Occurring Before Age 2

ScienceDaily (May 3, 2011) — In 2005, researchers from the University of North Carolina at Chapel Hill found that 2-year-old children with autism have brains up to 10 percent larger than children of the same age without autism.

These images show brain maturation measured by cortical thickness for a representative subject with autism at age 2 (left) and age 4 (right). Thicker areas of cortex are shown in red, while thinner cortical areas are displayed in green.

Now a follow-up study by UNC researchers has found that the children who had enlarged brains at age 2 continued to have enlarged brains at ages 4 and 5, but the amount of the enlargement was to the same degree found at age 2. This increased brain growth did not continue beyond 2 years of age and the changes detected at age 2 were due to overgrowth prior to that time point. In addition, the study found that the cortical enlargement was associated with increased folding on the surface of the brain (or increased surface area) and not an increase in the thickness of outer layer of the brain (or gray matter).

"Brain enlargement resulting from increased folding on the surface of the brain is most likely genetic in origin and a result of an increase in the proliferation of neurons in the developing brain," said Heather Cody Hazlett, PhD, assistant professor in the Department of Psychiatry, who is the lead author of the new study, which is published in the May 2011 issue of Archives of General Psychiatry.

In both the 2005 study and the new study, Hazlett and colleagues analyzed magnetic resonance imaging (MRI) scans of the children's brains using computer software developed for that purpose by Martin Styner, PhD, an assistant professor of computer science and psychiatry at UNC, and Guido Gerig, PhD, formerly at UNC and now at the University of Utah.

"From earlier work by our group on head circumference or head size in children with autism, we think that brain overgrowth in many children with autism may actually be happening around the first birthday. Together these findings suggest that we should be searching for genes that may underlie the over-proliferation of neurons in this early post-natal period," said Joseph Piven, MD, senior author of the new study and director of the Carolina Institute for Developmental Disabilities.

UNC is currently leading two separate studies aimed at that goal. Hazlett leads the Brain Development in School Age Children with Autism study, which is funded by Autism Speaks. "It was important to continue to follow these children to track their brain development to see if the brain and behavioral differences we observed were maintained as the children matured," said Hazlett.

UNC is also leading the Infant Brain Imaging Study (IBIS), a National Institutes of Health-funded multi-center study which includes four sites around the U.S. "We are studying infant children at high genetic risk for autism, by virtue of their having an older brother or sister with autism -- somewhere around 20 percent of those children will develop autism. We are doing brain scans and behavior assessments on those children at 6, 12 and 24 months of age to look at how the brain develops in the subgroup that develop autism before they have symptoms of autism at 6 months of age and over the interval that they develop autism -- between 6 and 24 months of age, in most cases," Piven said. "We are also looking at whether specific gene alterations may be responsible."

More information about IBIS is available athttp://www.ibisnetwork.org/.

Authors of the May 2011 article in Archives of General Psychiatry, in addition to Hazlett, are Michele Poe, PhD, Guido Gerig, PhD, Martin Styner, PhD, Chad Chappell, Rachel Gimpel Smith, Clement Vachet, MS, and Piven.

The UNC authors are all affiliated with one or more of the following: The Department of Psychiatry in the School of Medicine, the Carolina Institute for Developmental Disabilities, the Frank Porter Graham Child Development Institute, and the Department of Computer Science in the College of Arts and Sciences.