Breakdown Of Barriers In Old Cells May Hold Clues To Aging Process

Like guards controlling access to a gated community, nuclear pore complexes are communication channels that regulate the passage of proteins and RNA to and from a cell's nucleus. Recent studies by researchers at the Salk Institute for Biological Studies offer new insights about the pores' lifespan and how their longevity affects their function.

Their findings, reported in the Jan. 23 issue of Cell, may provide clues to one of the most enduring questions of biology: how and why cells age. They also offer a new, promising avenue of investigation for scientists pursuing intervention strategies for neurodegenerative diseases.

"We still have a very poor understanding of the mechanisms behind cell aging. It has been known for some time that the gene expression profile of an aging cell changes and somehow is linked to age-related diseases, but no one really knows why. Our work could provide an explanation for why we observe age-dependent defects in cells," says Martin Hetzer, Ph.D., an assistant professor in the Salk's Molecular and Cell Biology Laboratory.

Made up of 30 different proteins, nuclear pore complexes assemble during cell division and penetrate the membrane separating the nucleus from the cytoplasm. Their job is traffic control on the world's busiest thoroughfare: Each one mediates approximately 1,000 transport events a second. Since nuclear pore complexes are as essential to nondividing cells as they are to dividing ones, the Salk team wanted to determine what happens to them over time. Do they turn over in nondividing cells, or do they remain in place for the life of the cell?

Because most of the cells in our body are not actively dividing, the answer would have implications for aging and age-related diseases. "Many of the neurons in the cortex area of the brain are as old as we are; they are nondividing for a very long time," explains Hetzer.

Approximately half the proteins in the nuclear pore complex make up the central scaffold, or core, while the other, peripheral proteins attach to the scaffold. Using C. elegans, a tiny roundworm that as an adult consists entirely of nondividing cells, Hetzer and his group found that while the peripheral proteins are continually exchanged, the proteins comprising the scaffold remain in place for the life of the cell.

Although the scaffold proteins are detectable, their genes are no longer active. The same held true in nondividing rat neurons. "If proteins are there, but transcripts of the information making the protein are no longer there, they have to be very stable," says Hetzer, noting that whereas most proteins turn over in minutes or hours, the ones comprising the scaffold in the nuclear pore complex remained intact for the entire lifespan of an organism. "We discovered one of the most stable structures in our cells."

"It's a novel concept," adds first author Maximiliano A. D'Angelo, Ph.D., a research associate in the Hetzer lab. "No one really saw a structure that would last for the entire life of the cell."

Hetzer and his group then set out to ascertain how these stable proteins hold up over time. Since one of the functions of the nuclear pore complex is to set a permeability barrier between the nucleus and cytoplasm, the researchers developed a reporting system that would scrutinize the barriers to see how efficient they were at excluding inappropriate molecules, much as security auditors keep tabs on airport baggage screeners' ability to detect and block contraband.

What they found was that in aging cells, one of the proteins composing the scaffold structure becomes damaged, and the permeability barrier deteriorates; molecules that should be restricted to the cytoplasm invade the nucleus.

"Because some cells live for a long time, the accumulation of damage in the long-lived nuclear pore complexes can impair their function and have important consequences for cell homeostasis and survival," says D'Angelo. "It may also play a significant role in the aging process."

In particular, a protein called tubulin, which is strictly a cytoplasmic protein, shows up as long filaments that co-opt a large part of the nucleus. For more than 100 years, pathologists had been aware of these filaments, but their origins were unknown. Associated with several neurodegenerative diseases, including Parkinson's, the filaments are found particularly in the substantia nigra of many Parkinson's patients, the part of the brain that is involved in dopamine production and that is affected by the condition.

Hetzer's team hypothesizes that it is the age-dependent defects in the scaffold proteins that undermine the nuclear permeability barrier. "We predict that when the permeability barrier is impaired, molecules are either lost from the nucleus or can leak into the nucleus and thereby change gene expression profiles," says Hetzer. "This could be a general aging mechanism, and it provides an explanation for the origin of these filaments, which have been known by pathologists for a long time."

By finding ways to prevent or reverse the leakage, the Salk researchers may be on course to identify novel approaches to treating these perplexing, devastating, and costly conditions.

In addition to Hetzer and D'Angelo, postdoctoral researcher Marcela Raices, Ph.D., and doctoral candidate Siler H. Panowski of Dr. Andrew Dillin's laboratory at the Salk Institute contributed to this study. The research was carried out with funding from the NIH.

Getting Diabetes Before 65 More Than Doubles Risk For Alzheimer's Disease

Diabetics have a significantly greater risk of dementia, both Alzheimer's disease — the most common form of dementia — and other dementia, reveals important new data from an ongoing study of twins. The risk of dementia is especially strong if the onset of diabetes occurs in middle age, according to the study.
"Our results . . . highlighted the need to maintain a healthy lifestyle during adulthood in order to reduce the risk of dementia late in life," explained Dr. Margaret Gatz, who directs the Study of Dementia in Swedish Twins.

In a study published in the journal Diabetes, Gatz and researchers from Sweden show that getting diabetes before the age of 65 corresponds to a 125 percent increased risk for Alzheimer's disease. Nearly 21 million people in the United States have diabetes, according to the American Diabetes Association, which publishes the journal.

This risk of Alzheimer's disease or other dementia was significant for mid-life diabetics — as opposed to those who develop diabetes after 65 — even when controlling for family factors. In other studies, genetic factors and childhood poverty have been shown to independently contribute to the risk of both diabetes and dementia.

"Twins provide naturally matched pairs, in which confounding factors such as genetics and childhood environment may be removed when comparisons are made between twins," explained Gatz, professor of psychology, gerontology and preventive medicine at the University of Southern California and foreign adjunct professor of medical epidemiology and biostatistics at the Karolinska Institute in Sweden.

Indeed, the chances of a diabetic developing Alzheimer's disease may be even greater in real life than in the study, the researchers write. They identify several factors that might have led them to underestimate the risk of dementia and Alzheimer's among those who develop diabetes before the age of 65.

Diabetes usually appears at a younger age than dementia does, the researchers note. Diabetes is also associated with a higher mortality rate, which may reduce the size of the sample of older adults. In addition, approximately 30 percent of older adults with diabetes have not been diagnosed.

The results of the study implicate adult choices such as exercise, diet and smoking, as well as glycemic control in patients with diabetes, in affecting risk for Alzheimer's disease and diabetes, according to the researchers.

The sample for the study was 13,693 Swedish twins aged 65 or older in 1998, the year tracking for dementia began. Information about diabetes came from prior surveys of twins and linkage to hospital discharge registry data beginning in the 1960s.

Weili Xu of the Karolinska Institute was the lead author of the study, which was a part of her dissertation research.

The research was supported by grants from the National Institute on Aging, the Alzheimer's Association (U.S.A.), the Swedish Research Council in Medicine, and Swedish Brain Power.

Safely Fixed Hip Prostheses

Artificial hip joints are firmly anchored to the patient’s damaged bone by screws. But which parts of the bone will safely hold the screws in place? A simulation model is to calculate the strength of the bone from computer tomography images.Hip prostheses do not hold forever. If an implant comes loose, the doctors have to replace it. Most patients need this second operation after about 15 years. By then, the first prosthesis has often worn down the pelvic bone in several places. Moreover, the bone density, and thus also its strength, changes with increasing age. Medics therefore have to work out where best to place the screws that connect the artificial joint to the bone, and what shape the hip prosthesis needs to be in order to fit the surrounding bones as well as possible.

At present, doctors examine patients using computer tomography (CT), and determine the rough density of the bones from the images. On the basis of various assumptions, they then calculate how strong the bones are in different places. The problem is that, although there are various theories on which the simulations can be based, the results often deviate significantly from reality. The consistency of the damaged bones is usually different from what the simulation leads to believe.

This is set to be changed by researchers at the Fraunhofer Institute for Machine Tools and Forming Technology IWU in Dresden and their colleagues at the biomechanics laboratory of the University of Leipzig. They are developing a model with which doctors can reliably and realistically calculate the density and elasticity of the bone from the CT scanner images. To this end, the researchers are transferring methods usually used for component testing to human hip bones, which involve inducing oscillations in the bone. This type of examination cannot be carried out on the patient. The bone has to be clamped into an apparatus.

“The nature of the oscillations enables us to deduce local properties of the bone – such as its density and elasticity,” explains IWU group manager Martin Quickert. The researchers compare these results with scanned images of the bone and describe the correlations on the basis of a mathematical model. This should make it possible in future to determine the strength of a bone directly from the CT scanner images. The scientists have already performed the first examinations on prepared and thus preserved bones, and plan to induce oscillations in unprepared bones left in their natural state over the coming months. The researchers hope that in about two years’ time, doctors will be able to obtain a realistic simulation model of unprecedented quality from computer tomography data. The prostheses can then be perfectly anchored, and will be held safely in place for longer.

Structure Of TIGAR, A Possible Cancer Flag, Discovered

Two Brown University researchers have determined the three-dimensional structure of an enzyme whose presence in the body could help doctors detect cancer earlier or develop more targeted treatments
Hua Li and Gerwald Jogl detail their progress with the enzyme known as TIGAR in a paper to be published Jan. 16, 2009, in The Journal of Biological Chemistry.

“It will help us to understand where else we should be looking for good [anti-cancer] targets,” said Jogl, assistant professor of biology in the Department of Molecular Biology, Cell Biology and Biochemistry at Brown. Jogl is the study’s principal investigator and corresponding author. Li is a fifth-year Ph.D. student based in Jogl’s lab and is the lead author.

Jogl and Li wanted to determine the structure of TIGAR. After more than a year of research, they discovered that it is has a more substantive active site than they had expected. To map the structure, the pair used a method called X-ray crystallography.

The process involved using intensive X-ray light produced at the National Synchroton Light Source in Brookhaven, N.Y., to analyze crystals grown from samples of the TIGAR enzyme.

A separate study by researchers from St. Jude’s Children’s Research Hospital first identified the existence of TIGAR. Those results were published in CELL in 2006.

TIGAR, which helps regulate energy production in the cell, is activated after cell damage. Because of this, the presence of the enzyme can indicate potential problems that may lead to cancer. But TIGAR itself is positive. Once activated, TIGAR slows all processes in the cell, allowing time to repair cell damage. This process is also intended to prevent further damage that could lead to cancer.

Jogl and Li believe their finding may suggest that TIGAR has additional functions in the cell.

Understanding TIGAR is important, Jogl said, because the enzyme is “one of the good guys” in the battle against cancer. Because its presence can come in tandem with cellular damage, TIGAR is an important clue for scientists that could indicate cancer may follow. Knowing more about TIGAR could lead to earlier cancer detection or even preventative treatments.

“We are looking at the good guys,” Jogl said. “Studying the good guys will lead us to the bad guys and where the places are to interfere.”

A National Institutes of Health grant helped support the study.

MRSA’s 'Weak Point' Visualized By Scientists

An enzyme that lives in MRSA and helps the dangerous bacterium to grow and spread infection through the human body has been visualised for the first time, according to a new study.Now, armed with detailed information about the structure of this enzyme, researchers hope to design new drugs that will seek it out and disable it, providing a new way of combating MRSA and other bacterial infections.

The enzyme, a ‘worker-protein’ called LtaS, produces an important component of the protective outer-layer that surrounds all Staphylococcus aureus cells as well as many other bacteria that cause disease.

Staphylococcus aureus is a type of bacterium that causes a variety of infections in the human body, including skin infections and abscesses, sometimes leading to blood poisoning and life-threatening lung or brain infections. MRSA is a particular strain of Staphylococcus aureus, which has evolved to be resistant to the antibiotic methicillin and a large number of other antibiotics, and can be life threatening.

To counter this drug resistance and ensure that it is possible to treat MRSA infection in the future, new antibiotics are needed that work differently, for example by attacking parts of the pathogen that are not targeted by current drugs.

The team from Imperial College London behind today’s study, funded by the Medical Research Council, thinks that LtaS might be a good candidate target for a new antibiotic to which MRSA will not be resistant. This is because its job is to build a polymer called lipoteichoic acid (LTA), which is an important structure found on the surface of Staphylococcus aureus cells.

Although the role of the cell surface polymer LTA is not fully understood, lab tests carried out by the same researchers have shown that if the LtaS enzyme is depleted, production of LTA on the cell surface draws to a halt. As a result growth of the Staphylococcus aureus cell is blocked. So in a patient infected with MRSA, inhibiting this enzyme could clear up the infection because the bacterial cells would be unable to grow properly. Many existing antibiotics work in a similar way by inhibiting the production of other such important structures on the surface of bacterial cells.

The trick, according to one of the paper’s lead authors, Dr Angelika Grundling from Imperial College London’s Division of Investigative Science, is to now find a way of using the new knowledge to develop a drug for use in real world scenarios:

“We’re not quite sure how it works, but we know that this surface structure called LTA is involved in cell growth and cell division – we have shown that without it the cell cannot grow properly, and eventually dies. Because LtaS is the ‘machine’, which builds LTA, developing a drug that knocks out the machine will provide us with a new way to disable the growth of these cells, which would represent a novel new treatment for MRSA and other Staphylococcus aureus infections.”

Dr Grundling and her colleagues have produced a detailed image of the molecular structure of the LtaS enzyme using X-ray crystallography techniques. The image includes a map of LtaS’s active binding site: the part of the enzyme which plays a key role in building LTA. This is the very part that researchers now need to home in on with a drug, in order to prevent the LtaS enzyme from doing its job.

Professor Paul Freemont from Imperial’s Division of Molecular Biosciences, co-lead-author of the paper, explains the importance of the information they have gained about this particular part of the enzyme:

“If we’re to develop a drug which disables LtaS from doing its job, then we need to make sure the drug molecule is as perfectly matched as possible to the enzyme’s binding site, so it can trick the enzyme into taking it up. Once the drug is bound to the enzyme it will be able start its job of sabotage.

“So the more detailed information about the binding site we have, the better we’ll be able to develop an effective drug to match it,” he said.

The two Imperial teams led by Professor Freemont and Dr Grundling now hope to work with the College’s Drug Discovery Centre to search for a biological agent that interacts with the LtaS binding site, as the basis for a new antibiotic drug.

They hope that in the future such a drug could be used to treat not just MRSA, but a whole host of infections caused by bacterial pathogens.

Additional funding for the research was obtained through the US National Institute of Health.

New Sperm Shaker Set To Improve IVF Success Rates

Scientists have developed a ground-breaking method for testing the quality of a sperm before it is used in IVF and increase the chances of conception.Researchers at the University of Edinburgh have created a way of chemically ‘fingerprinting’ individual sperm to give an indication of quality. Scientists can then consider whether the sperm is healthy enough to be used to fertilise an egg as part of an IVF treatment.

The sperm are captured in two highly focussed beams of laser light. Trapped in what are essentially ‘optical tweezers’, an individual sperm’s DNA properties are identified by the pattern of the vibrations they emit in a process known as Raman spectroscopy. This is the first time this process has been used to evaluate DNA damage in sperm.

Dr Alistair Elfick, lead scientist on the project, said: “In natural conception the fittest and healthiest sperm are positively selected by the arduous journey they make to the egg. What our technology does is to replace natural selection with a DNA based ‘quality score’. But this is not about designer babies. We can only tell if the sperm is strong and healthy not if it will produce a baby with blue eyes.”

In the past quality tests of sperm have mostly been carried out on the basis of shape and activity. While these do give some indication of health of the sperm they do not give its DNA status.

There are established tests for sperm DNA quality but they work by cutting the cells in half and tagging them with fluorescent dye – a process that kills the sperm and renders it useless. This new process does not destroy the sperm,

so if it is found to have good DNA quality, it can still be used in IVF treatment.

Conception rates in both IVF treatment and intercourse are at around one in four. By selecting the best quality sperm it is hoped this new process could both increase a couple’s chances of conception and give the child the best potential start in life.

The research is currently in a pre-clinical phase, and if successful could be available to patients in the next five to ten years.

This research was funded by the EPSRC (Engineering and Physical Sciences Research Council).

Researchers Identify Potential Cancer Target

Dartmouth Medical School researchers have found two proteins that work in concert to ensure proper chromosome segregation during cell division. Their study is in the January 2009 issue of the journal Nature Cell Biology.

This finding is relevant for treating solid cancerous tumors that lose the ability to accurately segregate their chromosomes. Tumors that shuffle chromosomes, a process called chromosomal instability, are known to have a poor prognosis.

"We show that the function of two proteins, called Kif2b and MCAK, is to correct improper attachments during cell division to prevent the mis-segregation of chromosomes" said Duane Compton, the senior author on the paper and a professor of biochemistry at Dartmouth Medical School. "The two proteins share the workload as Kif2b acts early in cell division and MCAK acts later. This cooperation underlines the importance of proper chromosome segregation for the healthy life of all cells." Compton is also director of the Cancer Mechanisms Research Program at Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center.

Compton explained this finding follows a study his team published in the February 2008 issue of The Journal of Cell Biology that showed that the main cause of chromosomal instability is that chromosomes make improper attachments to the spindle apparatus during cell division. "These improper attachments occur normally during cell division in all cells, but in the tumor cells, the improper attachments fail to get corrected and cells attempt to divide with persistent improper attachments," said Compton.

The current study shows the two proteins complete their job by regulating the attachment between the chromosomes and the spindle apparatus. Based on these results, the team also determined that increasing quantities of either Kif2b or MCAK in tumor cells restored nearly normal accuracy of chromosome segregation.

"We discovered how to make the tumor cells faithfully segregate their chromosomes every time the cell divides," said Compton. "Chromosomal instability has been studied for over a decade in tumor cells; this is the first time anyone has suppressed it in tumor cells indicating a strong causal relationship between correction of improper attachments of chromosomes to the spindle apparatus and chromosomal instability. These results give us insight into the overall mechanisms of cell division in tumor cells compared to normal cells, and we may be able to exploit that, leading to new therapeutic strategies or treatments that might prevent tumor progression."

Compton and his team will now work to directly test the contribution of CIN to tumor development.

Co-authors on the paper include: Samuel Bakhoum, Sarah Thompson, and Amity Manning, all with the Department of Biochemistry at Dartmouth Medical School and the Norris Cotton Cancer Center.

This research is supported by funding from the National Institutes of Health.

New Hope For Diabetes Patients?

Researchers have identified a signal pathway that could be involved in the occurrence of Type 2 diabetes. If it is deactivated, it may be possible to delay the illness by many years.

Diabetes, a metabolic disease, affects about 246 million people throughout the world, about a quarter of a million of them in Switzerland. Obesity and lack of exercise often play a decisive role in the illness. During his thesis work in collaboration with researchers from Oxford and the University of Lausanne, Jens Zehetner, a doctoral student with Wilhelm Krek, Professor at the Institute of Cell Biology of ETH Zurich, has identified one of the mechanisms that may play a part in diabetes. The study reveals that the signal pathway for the secretion of insulin is controlled by the pVHL and HIF1a genes, which are familiar from cancer research and are known to play an important role in growth and in the cell’s energy supply. Not only do the results help understand the origin of diabetes, the knowledge could also be used to combat the illness.

Signal pathway for insulin production

Wilhelm Krek explains that, “Cells need energy in the form of adenosine triphosphate (ATP), the cell’s energy currency, to enable them to maintain their functions. In a healthy person, the b-cells of the pancreas, which are responsible for insulin production, recognise when food is ingested. Sugar is burnt in the mitochondria of the b-cells by what is known as oxidative phosphorylation, producing ATP which, in turn, initiates insulin secretion in the b-cells. This stimulates the muscle cells, among others, to absorb sugar, thus regulating and normalising the level of sugar in the blood. Krek says that some diabetics may have an abnormality in this signal pathway. The plan now is to investigate this in a follow-up study.

Changeover to glycolysis

In their study of the pVHL and HIF1a genes, the scientists began by modifying mice genetically to end up with four kinds of mice with different gene combinations: those in which both genes were intact and those in which one, or the other, or both had been deactivated.

Under normal conditions with an adequate oxygen supply, HIF1a is constantly suppressed and destroyed by pVHL. However, if there is a shortage of oxygen, ATP cannot be formed in the mitochondria, which in turn activates HIF1a to enable the cells to produce the necessary ATP via glycolysis – independently of the mitochondria. The researchers now studied what happens in the b-cells if HIF1a is activated in mice.

Zehetner says, “Even when the amount of ATP produced was equal to that in “normal” mice, the insulin secretion profile in the animals without pVHL changed dramatically.” The secretion of insulin is increased at basal glucose levels but is less efficiently upon glucose stimulation. He says that this shows that the ATP production taking place in the mitochondria activates yet more factors – at present unknown – that are important in regulating the secretion of insulin. ATP production on its own is not enough.

Oxygen deficiency as the cause

In obese mice, the mass of the b-cells increases. This causes newly formed b-cells to have a worse blood supply at first, due to a lack of oxygen. Krek explains that, “Our hypothesis states that this oxygen deficiency is exactly what leads to activation of the suppressed HIF1a gene to keep the oxygen-starved cells alive.” The result is a changeover from a regulated, effective secretion of insulin to a physically increased but less efficient glucose-stimulated insulin secretion – the possible start of Type 2 diabetes. The illness becomes apparent when all the b-cells gradually die off through permanent overloading.

Gene deactivation as a therapy

Krek explains that “The study enabled us to show that pVHL and HIF1a play an important part in insulin secretion and that they are decisive in the strategy of ATP production.” One of the next steps will now be to utilise this knowledge in the form of a treatment for diabetes, although this has yet to be developed. If one were to be able to inactivate the HIF1a signal pathway in the b-cells of diabetes patients, it might be possible to delay the outbreak of the illness perhaps for many years. This is because experiments in mice whose HIF1a was inactivated showed that their insulin secretion was stimulated by the ATP formed in the mitochondria and functioned with no problems.

New Family Of Antibacterial Agents Uncovered

As bacteria resistant to commonly used antibiotics continue to increase in number, scientists keep searching for new sources of drugs. One potential new bactericide has now been found in the tiny freshwater animal Hydra.

The protein identified by Joachim Grötzinger, Thomas Bosch and colleagues at the University of Kiel, hydramacin-1, is unusual (and also clinically valuable) as it shares virtually no similarity with any other known antibacterial proteins except for two antimicrobials found in another ancient animal, the leech.

Hydramacin proved to be extremely effective though; in a series of laboratory experiments, this protein could kill a wide range of both Gram-positive and Gram-negative bacteria, including clinically-isolated drug-resistant strains like Klebsiella oxytoca (a common cause of nosocomial infections). Hydramacin works by sticking to the bacterial surface, promoting the clumping of nearby bacteria, then disrupting the bacterial membrane.

Grötzinger and his team also determined the 3-D shape of hydramacin-1, which revealed that it most closely resembled a superfamily of proteins found in scorpion venom; within this large group, they propose that hydramacin and the two leech proteins are members of a newly designated family called the macins.

New Research Lights Up Chronic Bacterial Infection Inside Bone

A new report demonstrates how a sensitive imaging technique gives scientists the upper hand in seeking out bacteria in chronic infections.Listeria monocytogenes is a type of pathogenic bacteria that can cause severe illness and death. Listeria outbreaks recently claimed twenty lives in Canada. Additionally, Listeria infection is the third most common cause of bacterial meningitis in newborns, and can cause abortion and stillbirth. When the infection is caught in time, treatment can be difficult and take weeks to clear with intravenous administration of antibiotics.

Therefore, in order to understand how this pathogen can be so elusive and difficult to treat, a research team from Stanford University School of Medicine studied mice infected with Listeria. Their report describes how they use a technique called in vivo bioluminescence to light up bacteria and allow them to see extremely tiny amounts of bacterial cells in living animals. Using this method, they found that small persistent patches of Listeria took up residence inside bone marrow in the mice. This is significant because it is thought that the bone marrow can act as a reservoir to the brain and spinal cord, potentially causing life-threatening infections, such as in bacterial meningitis in newborns.

Another interesting aspect of this study is due to the use of specially designed Listeria stains in treating cancer. Clinical trials are currently underway in which non-disease-causing strains of Listeria are administered to cancer patients to generate immune responses against tumors. The researchers thus also looked at these attenuated strains, and found that they too could be harbored in bone marrow. It is still unclear, however, if such bacterial persistence will increase or decrease therapeutic effects.

The report was written by Jonathan Hardy, Pauline Chu, and Christopher H. Contag of the Stanford University School of Medicine in California. The report is published in the January/February issue of a new research journal, Disease Models & Mechanisms (DMM), published by The Company of Biologists, a non-profit based in Cambridge, UK.

Women's Brains Recognize, Encode Smell Of Male Sexual Sweat

A new Rice University study published in the Journal of Neuroscience found that socioemotional meanings, including sexual ones, are conveyed in human sweat.

Denise Chen, assistant professor of psychology at Rice, looked at how the brains of female volunteers processed and encoded the smell of sexual sweat from men. The results of the experiment indicated the brain recognizes chemosensory communication, including human sexual sweat.

Scientists have long known that animals use scent to communicate.

Chen's study represents an effort to expand knowledge of how humans’ sense of smell complement their more powerful senses of sight and hearing.

The experiment directly studied natural human sexual sweat using functional magnetic resonance imaging (fMRI). Nineteen healthy female subjects inhaled olfactory stimuli from four sources, one of which was sweat gathered from sexually aroused males.

The research showed that several parts of the brain are involved in processing the emotional value of the olfactory information. These include the right fusiform region, the right orbitofrontal cortex and the right hypothalamus.

"With the exception of the hypothalamus, neither the orbitofrontal cortex nor the fusiform region is considered to be associated with sexual motivation and behavior," Chen said. "Our results imply that the chemosensory information from natural human sexual sweat is encoded more holistically in the brain rather than specifically for its sexual quality."

Humans are evolved to respond to salient socioemotional information.

Distinctive neural mechanisms underlie the processing of emotions in facial and vocal expressions. The findings help explain the neural mechanism for human social chemosignals.

The understanding of human smell at the neural level is still at the beginning stage. The present work is the first fMRI study of human social chemosignals.

The research, co-authored by Chen and Wen Zhou, graduate student in the Psychology Department, appeared in the December 31 issue of Journal of Neuroscience.

The research was supported in part by the National Institutes of Health.

Antipsychotic Drugs Double Risk Of Death Among Alzheimer's Patients

New research into the effects of antipsychotic drugs commonly prescribed to Alzheimer’s patients concludes that the medication nearly doubles risk of death over three years.

The study, funded by the Alzheimer’s Research Trust, was led by Prof Clive Ballard’s King’s College London team and is published in Lancet Neurology on 9 January.

The study involved 165 Alzheimer’s patients in care homes who were being prescribed antipsychotics. 83 continued treatment and the remaining 82 had it withdrawn and were instead given oral placebos.

Findings showed a significant increase in risk of death for patients who continued taking antipsychotic medication. The difference between the two groups became more pronounced over time, with 24-month survival rates for antipsychotic-treated patients falling to 46% versus 71% on the placebo and at 36 months it was 30% versus 59%. It means that after three years, less than a third of people on antipsychotics were alive compared to nearly two thirds using the dummy drug.

Antipsychotics are used to treat symptoms of agitation, delusions and aggressive behaviour. NICE guidelines recommend that the drugs should only be used for short periods of time and where symptoms are severe, and should be very carefully monitored, although in clinical practice the average length of prescription is 1-2 years. While there is evidence of modest short-term (6-12 weeks) benefits of antipsychotic treatment for the serious behavioural symptoms of Alzheimer’s, a previous Alzheimer’s Research Trust study showed that these benefits were not evident over longer periods of treatment.

As many as 100,000 people with dementia are routinely prescribed antipsychotics in UK care homes. It could mean 23,500 people dying prematurely, according to a 2008 report by Paul Burstow MP.

Prof Clive Ballard of King’s College London said: “The results further highlight the need to seek less harmful alternatives for the long-term treatment of behavioural symptoms in Alzheimer’s patients. At the moment, there is still a limited place for antipsychotics in the treatment of Alzheimer’s, particularly severe aggression, but the serious concerns of the drugs shown by our research emphasise the urgent need to put an end to unnecessary and prolonged prescribing”.

Rebecca Wood, Chief Executive of the Alzheimer’s Research Trust, said: “The findings of this research are a real wake-up call and underline the danger of prescribing antipsychotics long-term for anything other than exceptional circumstances. We must avoid the use of these drugs as a potentially dangerous ‘chemical cosh’ to patients who would be better off without it. The study also highlights the urgent need to develop better treatments as Alzheimer’s patients have few options available to them.

"700,000 people in the UK have dementia; we urgently need to fund more research to develop the new treatments we so desperately need”.

Dr Mark Baxter of the University of Oxford added: "Antipsychotic drugs can be effective in controlling unpleasant and disturbing behavioural symptoms of Alzheimer's disease, including severe aggression, delusions, and agitation. But this study shows, conclusively, that these drugs have a severe and serious cost in terms of increased mortality. The study follows the gold-standard double-blind, placebo-controlled method for clinical trials, and is unique in examining long-term effects of antipsychotic treatment on mortality in patients with Alzheimer's disease.

"Antipsychotics do not have any effects on the underlying disease processes of Alzheimer's disease. What is needed is not only an increased application of non-drug methods to improve behavioural health in patients with dementia -- including cognitive-behavioural therapy and environmental design -- as well as a better understanding of how Alzheimer's neuropathology causes behavioural disturbances in addition to its effects on memory, so that rational drug therapies can be developed that do not have the liabilities of currently-available antipsychotics."

Olive Skins Provide Natural Defense Against Colon Cancer, Study Suggests

Researchers from the University of Granada and the University of Barcelona have shown that treatment with maslinic acid, a triterpenoid compound isolated from olive-skin pomace, results in a significant inhibition of cell proliferation and causes apoptotic death in colon-cancer cells. Maslinic acid is a novel natural compound and it is able to induce apoptosis or programmed death in human HT29 colon-cancer cells via the intrinsic mitochondrial pathway.

New research suggest this could be a useful new therapeutic strategy for the treatment of colon carcinoma.

This study is the first to investigate the precise molecular mechanisms of the anti-tumoral and pro-apoptotic effects of maslinic acid against colon-cancer. Chemopreventive agents of a natural origin, often a part of our daily diet, may provide a cheap, effective way of controlling such diseases as cancer of the colon. A wide range of studies in recent years has shown that triterpenoids hinder carcinogenesis by intervening in pathways such as carcinogen activation, DNA repair, cell cycle arrest, cell differentiation and the induction of apoptosis in cancer cells.

Triterpenoids are compounds present in a wide range of plants used in traditional medicine and known to have antitumoral properties. Low concentrations of maslinic acid are to be found in plants with medicinal properties, but its concentration in the waxy skin of olives may be as high as 80%.

The results of the study could contribute to the development of maslinic acid for use as cancer chemotherapeutic or chemopreventive agents.

Scientists See Brain Aging Before Symptoms Appear

UCLA scientists have used innovative brain-scan technology developed at UCLA, along with patient-specific information on Alzheimer's disease risk, to help diagnose brain aging, often before symptoms appear. Published in the January issue of Archives of General Psychiatry, their study may offer a more accurate method for tracking brain aging.

Researchers used positron emission tomography (PET), which allows "a window into the brain" of living people and specifically reveals plaques and tangles, the hallmarks of neurodegeneration. The PET scans were complemented by information on patients' age and congnitive status and a genetic profile.

"Combining key patient information with a brain scan may give us better predictive power in targeting those who may benefit from early interventions, as well as help test how well treatments are working," said study author Dr. Gary Small, who holds UCLA's Parlow-Solomon Chair on Aging and is a professor at the Semel Institute for Neuroscience and Human Behavior at UCLA.

Scientists took PET brain scans of 76 non-demented volunteers after they had been intravenously injected with a new chemical marker called FDDNP, which binds to plaque and tangle deposits in the brain. Researchers were then able to pinpoint where these abnormal protein deposits were accumulating.

They reported that older age correlated with higher concentrations of FDDNP in the medial and lateral temporal regions of the brain, areas involved with memory, where plaques and tangles usually collect. The average age of study volunteers was 67.

Thirty-four of the 76 volunteers carried the APOE-4 gene allele, which heightens the risk for developing Alzheimer's disease. This group demonstrated higher FDDNP levels in the frontal region of the brain, also involved in memory, than study participants without allele.

"We found that for many volunteers, the imaging scans reflected subtle brain changes, which take place before symptoms manifest," said Small, who is also director of the UCLA Center on Aging.

Small noted that the brain will try to compensate for any problems, which is why cognitive symptoms may not become apparent until much later.

"This type of scan offers an opportunity to see what is really going on in the brain," he said.

Another subset of the volunteers had mild cognitive impairment (MCI), a condition that increases the risk of developing Alzheimer's disease. These 36 volunteers had higher measures of FDDNP in the medial temporal brain regions than normal volunteers. Those who had both MCI and the APOE-4 gene had higher concentrations of FDDNP in the medial temporal brain regions than volunteers who had MCI but not APOE-4.

"We could see more advancing disease in those with mild cognitive impairment, who are already demonstrating some minimal symptoms," Small said. "Eventually, this imaging method, together with patient information like age, cognitive status and genetics, may help us better manage brain aging."

According to Small, in the future, brain aging may be controlled similarly to high cholesterol or high blood pressure. Patients would receive a brain scan and perhaps a genetic test to predict their risk. Medications and other interventions could be prescribed, if necessary, to prevent or delay future neurodegeneration, allowing doctors to protect a healthy brain before extensive damage occurs. The brain scans may also prove helpful in tracking the effectiveness of treatments.

PET, combined with the FDDNP probe, is the only imaging technology that offers a full profile of neurodegeneration that includes measures of both plaques and tangles — the physical evidence of Alzheimer's disease in the brain.

"The fact that we can see tau tangles as well as amyloid plaques is critically important in early detection of brain aging, since the tangles are the first abnormal proteins that appear in the brain, long before dementia is clinically obvious to the physician," said Dr. Jorge R. Barrio, a study author and professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

Such subtleties allow more insight into how the plaques and tangles spread and ultimately how Alzheimer's disease may develop.

Currently, the new FDDNP-PET scans are used in a research setting, but clinical trials are in development to bring the technology to wider patient use.

The study was funded by both government and nonprofit agencies, including the National Institutes of Health, the U.S. Department of Energy, the Ahmanson Foundation, the Larry L. Hillblom Foundation and the Tamkin Foundation.

Additional UCLA authors include Prabha Siddarth, Ph.D.; Alison C. Burggren, Ph.D.; Linda M. Ercoli, Ph.D.; Karen J. Miller, Ph.D.; Dr. Helen Lavretsky; and Susan Y. Bookheimer, Ph.D, all from the UCLA Department of Psychiatry and Biobehavioral Sciences and the Semel Institute for Neuroscience and Human Behavior at UCLA; Vladimir Kepe, Ph.D.; S.C. Huang, Ph.D.; and Michael E. Phelps, Ph.D. from the UCLA Department of Molecular and Medical Pharmacology; and Paul M. Thompson, Ph.D., and Greg M. Cole, Ph.D., from the UCLA Department of Neurology.