Sections of proteins previously thought to be disordered may in fact have an unexpected biological role - providing certain proteins room to move - according to a study published by researchers at Fox Chase Cancer Center in this month's issue of the journal Structure (Cell Press).

The researchers published the first comprehensive structural study of the protein NHERF1, which serves as a means of bringing together molecular signals between the outer membrane of a cell and the proteins found in the structures that form the cell's cytoskeleton. NHERF1 is representative of a large class of proteins with an array of biological roles, including signaling pathways implicated in diseases such as cystic fibrosis and breast cancer.

"Here we have a molecule that serves an important role in how cells function and survive, but it contains these puzzling 'junk' sequences that don't seem to have any apparent purpose," says the paper's lead author Heinrich Roder, PhD, a structural biologist and senior member of the Fox Chase Cancer Center faculty. "Our work suggests that this disorder is really a way of creating flexibility, allowing the protein to function as a molecular switch, a process that is thought to go wrong in certain diseases."

The NHERF1 proved particularly puzzling to researchers as it contains both known structures and large disordered regions. The structured sections of the protein are comprised of two so-called PDZ domains - components well known to scientists as anchors that can help the protein connect to other proteins and cellular structures - and an ezrin-binding motif, a sequence of amino acids that connects NHREF1 to cellular proteins such as ezrin. Together these structures allow NHERF1 to serve as a signaling adaptor, an important link between different proteins in a pathway. Oddly, researchers have noted that the ezrin-binding motif conveniently fits into a cleft on the surface of the PDZ domains, but assumes a helical structure, which is highly unusual for this class of proteins.

As is typical for human proteins, over one third of the amino acids that make up NHERF1 were predicted to be intrinsically disordered, forming no known structures and matching no known evolutionarily-conserved pattern. According to Roder, it is one of these disordered segments, approximately 100 amino acids long, which enable the protein to work. That is, it allows the PDZ binding module to "bite" its own ezrin-binding tail, effectively shutting the protein down. "The flexibility of the linker and its tendency to be more or less disordered are critical for regulating the balance between internal ("autoinhibitory") forces and external interactions with the protein's signaling partners," Roder says. This idea is reinforced by a recent observation by Zimei Bu, PhD, a Fox Chase researcher a coauthor of this study, who found that enzymatic modification (phosphorylation) of amino acids in the disordered region tips the balance towards the more open, active, form of the protein.

"Evolution has provided researchers with convenient modular structures, areas that are repeated over and over again to make up proteins, and so we tend to dismiss the interspersed disordered sequences that don't seem to have any definable structure," Roder says. "Here we show that the weak molecular interactions in a disorganized protein sequence are essential in giving this protein its unique attributes."

It was also this disorganized domain that made it difficult for researchers to create an accurate model of the entire protein, Roder says. Typically, researchers use a technique called x-ray crystallography, in which they can tell a protein's structure from how crystals made from the protein samples scatter x-rays. The disorganized section of NHREF1 makes it nearly impossible to create the necessary crystals to use this technique. Instead, Roder and colleagues used a technique called nuclear magnetic resonance spectroscopy, which can determine a protein's shape by measuring how the individual atomic nuclei of a protein interact with an intense magnetic field.

Since NMR spectroscopy works best with small proteins - not large flexible molecules like NHREF1 - Roder, his staff scientist Hong Cheng, PhD, and their colleagues came up with an innovative technique that allowed them to look at the protein from numerous angles with the NMR spectrometer, and subtract out the overlapping areas to form a more complete picture of the molecule. This picture enabled them to see what NHREF1 looks like in both its "on" and "off" conformation.

"When it is not working, the protein is in this 'off' conformation until acted upon by outside agents," Roder says. "It is a way for the cell to shut off a signaling pathway when it is not in use."

Although teen depression poses a widespread problem for which proven treatments exist, few depressed teens receive any care.

Why don't they undergo treatment? The answer depends whether you ask parents or the adolescents themselves, according to a study in the June issue of the journal Medical Care.

"With teenagers, treatment decisions greatly involve other parties, especially parents. For instance, teenagers often rely on adults for transportation. Doctors need a sense not just of what the teen thinks or what the parent thinks, but what both think," said Lisa Meredith, Ph.D., lead author of the new study.

The ability of their physicians to address all the perceived barriers "affects the teenager's own ability to acknowledge their depression and do something about it," said Meredith, a researcher at RAND.

Teens with untreated depression more often have social and academic problems, become parents prematurely, abuse drugs and alcohol and suffer adult depression and suicide.

For the study, researchers recruited 368 adolescent patients of diverse backgrounds receiving care in seven public or private primary care practices. Of these, half had a diagnosis of depression. One parent or guardian of each enrolled teenager also participated.

Teens and parents rated the effects of seven possible barriers: 1) cost of care, 2) what others might think, 3) problems finding or making appointments with a doctor or therapist, 4) time constraints and other responsibilities, 5) not wanting family to know about the depression (this was asked of teens only), 6) good care being unavailable and 7) just not wanting care.

Parents were significantly less likely to report barriers than teens.

For teens, concerns about stigma and relatives' reactions were among the significant issues, and those who perceived barriers were less likely to undergo therapy or take medications. Depressed teens were significantly more likely to perceive barriers to care than their non-depressed peers were.

"Adolescents do tend to go undiagnosed and untreated. They don't want to seem abnormal. They want to fit in. Yet when they deny problems, they often act out adaptively, drinking a lot and pursuing other high-risk behaviors," said Deborah Amdur, a psychiatrist with the Advanced Psychiatric Group in Orlando, Fla.

The largest study of its kind to date shows that women may not be able to learn as well shortly before menopause compared to other stages in life. The research is published in the May 26, 2009, print issue of Neurology®, the medical journal of the American Academy of Neurology.

For a four-year period, researchers studied 2,362 women, who were between the ages of 42 and 52 had at least one menstrual period in the three months before the study started.

The women were given three tests: verbal memory, working memory and a test that measured the speed at which they processed information. Scientists tested the women throughout four stages of the menopause transition: premenopausal (no change in menstrual periods), early perimenopausal (menstrual irregularity but no "gaps" of 3 months), late perimenopausal (having no period for three to 11 months) and postmenopausal (no period for 12 months).

The study found that processing speed improved with repeated testing during premenopause, early perimenopause and postmenopause, but that scores during late perimenopause did not show the same degree of improvement. Improvements in processing speed during late perimenopause were only 28 percent as large as improvements observed in premenopause. For verbal memory performance, compared to premenopause, improvement was not as strong during early and late perimenopause. Improvements in verbal memory during early perimenopause were 29 percent as large as improvements observed in premenopause. During late perimenopause, verbal memory improvement was seven percent as large as in premenopause. Combined, these findings suggest that during the early and late perimenopause women do not learn as well as they do during other menopause transition stages.

"These perimenopausal test results concur with prior self-reported memory difficulties--60 percent of women state that they have memory problems during the menopause transition," said Gail Greendale, MD, with the David Geffen School of Medicine at the University of California, Los Angeles. "The good news is that the effect of perimenopause on learning seems to be temporary. Our study found that the amount of learning improved back to premenopausal levels during the postmenopausal stage."

The study also found that taking estrogen or progesterone hormones before menopause helped verbal memory and processing speed. In contrast, taking these hormones after the final menstrual period had a negative effect: postmenopausal women using hormones showed no improvement in either processing speed scores or verbal memory scores, unlike postmenopausal women not taking hormones. "Our results suggest that the 'critical period' for estrogen or progesterone's benefits on the brain may be prior to menopause, but the findings should be interpreted with caution," said Greendale.

The National Institutes of Health (NIH), the National Institute on Aging, the National Institute of Nursing Research and the NIH Office of Research on Women's Health supported the study.

British scientists have found a significant link between later retirement age and later onset of dementia in men.

The research is published in the International Journal of Geriatric Psychiatry.

This result came from an analysis of 382 men with probable Alzheimer's by scientists from the Institute of Psychiatry and Cardiff University. Information based on education and employment was used to determine the effects of early life education, mid life employment and later life retirement on the age of onset of dementia.

A significant affect was found between later retirement age and later onset of dementia. The small sample of men make the other measures difficult to interpret, but they suggest that education or specific job type has a weaker link with dementia risk.

The study was funded by the Medical Research Council and the Alzheimer's Research Trust. 'There could be a number of reasons why later retirement in men is linked with later onset of dementia. Men who retire early often do so because of health conditions, such as hypertension or diabetes, which increase your risk of dementia. It could also be that working helps keep your mind and body active, which may reduce risk of dementia.

The best way to reduce your risk of dementia is to combine keeping physically active, with eating a balanced diet and getting your blood pressure and cholesterol checked regularly. One million people will develop dementia in the next 10 years. Investing in research into how to prevent dementia is vital if we are to defeat this devastating condition.'

Facial fractures from motor vehicle crashes appear to be decreasing, most likely due to design improvements in newer vehicles, according to a report in the May/June issue of Archives of Facial Plastic Surgery, one of the JAMA/Archives journals.

Facial trauma is the most common injury among individuals involved in motor vehicle collisions, according to background information in the article. Fractures to the face often occur simultaneously with other injuries, including damage to the eyes and brain. In 2000, the National Highway Traffic Safety Administration estimated that facial injuries cost between $9,000 and $725,000 per injury in lost productivity, medical costs, emergency services and other expenses.

Brian T. McMullin, M.D., plastic and reconstructive surgery resident at the Medical College of Wisconsin, Milwaukee, and colleagues analyzed records from a national database of individuals (drivers and front seat occupants) with facial fractures following motor vehicle crashes. Between 1993 and 2005, 167,391 individuals involved in collisions had one or more facial fractures, 55,150 had skull base fractures (breaks in the bones of the skull) and 196,855 had nasal fractures.

Each year during that time period, the incidence of facial fractures decreased. In addition, a decline in the probability of injury was associated with newer car models. "As older cars are scrapped and more vehicles with next-generation safety features enter the vehicle fleet, we would expect decreasing injury probabilities and ultimately overall decreased injury incidence for year-to-year trends," the authors write.

Individuals involved in side-impact collisions, in vehicles in which speed increased as a result of collision, who were taller or who collided with a stationary object, light truck, sports utility vehicle or van were significantly more likely to sustain facial fractures. "Occupants who were restrained with seat belts only, as well as those restrained with seat belts and air bags, were significantly less likely to have facial fractures," the authors write. "Air bags alone were not associated with a reduced probability of facial fractures, and there was no difference in injury probability between sexes or based on occupant weight."

"Restraint use continues to be the most significant element for facial and skull base injury prevention, and more research is necessary to elucidate the mechanisms for facial and skull base fractures in side impacts, as well as to determine the effectiveness of side impact supplemental restraint systems," they conclude.