For Mitochondria, Bigger May Not Be Better: Optimal Length of Mitochondria Is Essential to Preventing Alzheimer's

Goldilocks was on to something when she preferred everything "just right." Harvard Medical School researchers have found that when it comes to the length of mitochondria, the power-producing organelles, applying the fairy tale's mantra is crucial to the health of a cell. More specifically, abnormalities in mitochondrial length promote the development of neurodegenerative diseases such as Alzheimer's.

"There had been a fair amount of interest in mitochondria in Alzheimer's and tau-related diseases, but causality was unknown," said Brian DuBoff, first author of the study and a post-doctoral research fellow at Massachusetts General Hospital.

"Ultimately, a deeper understanding of the relationship between mitochondrial function and Alzheimer's may guide us to develop more targeted therapies in the future," said Mel Feany, HMS professor of pathology at Brigham and Women's Hospital and senior author of the paper.

The findings will be published online in the August 23 issue of Neuron.

Tau-related diseases are caused when tau, a protein most commonly found in neurons, malfunctions. Tau binds to microtubules in cells, a process known as stabilization. This binding is necessary so the microtubules can help maintain cell structure and aid in intracellular processes such as transporting molecules. When tau is defective, most often due to changes introduced during protein synthesis, it can accumulate in neurofibrillary tangles, one of the primary markers of Alzheimer's.

In this particular study, conducted in fruit flies with defective tau protein, DuBoff found that the mitochondria in the brain cells of these flies were elongated compared with the mitochondria in flies with normal tau. The elongation, he observed, adversely affected mitochondrial function.

"Normally, one mitochondrion will split into two, two mitochondria will join into one, and that's a critical process for the health and stability of the mitochondria," said DuBoff. "This mitochondrial dynamic happens continuously in almost all cells. Interruption of this process leads to cell death, and loss of nerve cells in the brain results in loss of function -- memory loss and difficulty in comprehension and coordination." The presence of defective tau, then, interrupts the functioning of mitochondria and contributes to neurodegeneration.

To further observe how mitochondrial dynamics were affected by the presence of defective tau, the researchers modified two sets of genes in human-tau-expressing flies, one that controls how mitochondria divide and another that guides how they come together. When the expression of the gene that causes mitochondrial lengthening, or fusion, was increased, the level of neurodegeneration in the flies increased and the flies were sicker. Conversely, when the expression of the gene that causes mitochondrial division, or fission, was increased, the defect reversed and the flies' condition improved.

The study also showed that, in addition to tau, two other key proteins influenced the neurodegenerative process: DRP1, which helps in the fission of mitochondria, and actin, which is essential to maintaining cell structure and movement. A previous study in Feany's lab had shown that the presence of defective tau hampers the activity of actin. With this knowledge, the researchers were able to piece together the relationship among the three proteins. DRP1 and actin are interdependent: the regulatory state of actin is essential for DRP1 and mitochondria to come together, thus preserving mitochondrial dynamics. But the presence of defective tau harms this relationship, rendering DRP1 incapable of maintaining mitochondrial dynamics, which ultimately leads to neurodegeneration.

"We have a good idea now of where the process starts. We know it ends with neurodegeneration, and with this study, we know some milestones along the way," said Feany. "But we still have to fill in the gaps and learn more about DRP1 and its role in this process."

"Many studies begin by looking at a normal biological process and then finding ways it goes wrong," said DuBoff. "We did the opposite. We started with the disease model, identified this phenomenon of DRP1 and mitochondrial dysfunction, and then followed it back to the basic biological regulation of this process."

The study was supported by the National Institute of Aging and the Ellison Medical Foundation.

Journal Reference:

1. Brian DuBoff, Jürgen Götz, Mel B. Feany. Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo. Neuron, 2012; 75 (4): 618 DOI: 10.1016/j.neuron.2012.06.026

Courtesy: ScienceDaily

New Molecular Interactions Behind the Inhibition of TGF Beta-Signaling Described

Researchers headed by Maria Macias an ICREA researcher at the Institute for Research in Biomedicine (IRB Barcelona) and Joan Massagué, a Howard Hughes Medical Institute investigator at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, have identified a new molecular mechanism that plays a crucial role in the control of the activation of certain genes associated with cancer.

Through detailed structural and biochemical studies, the researchers identified a key domain present in a family of proteins called Smads, whose binding determines whether the transcription of genes controlled by the TGF-beta and BMP signaling cascades will be bound by activators or labeled for degradation. These processes are critical to the correct development and maintenance of tissues and organisms.

When looking at inhibitory Smads , the researchers found that the specific domain binds directly and constitutively to their targets. This is in contrast to what happens with receptor-activated Smads, where the proteins must first undergo processing by phosphorylation -- a chemical change whereby the proteins are first activated and then labeled for degradation after completing their transcriptional function. The study appears online August 23 in the journal Structure.

Smads are key proteins in the signaling pathways of the hormones TGF-beta and BMP, which are known to participate in the control of stem cell pluripotency and differentiation and in the development and maintenance of metazoan organisms. In this study, the researchers looked at the interactions of Smad7 -- a protein inhibitor of TGF-beta signaling -- with molecules implicated in the cascade, including three ubiquitin ligases and YAP, a transcription coactivator. They identified the domains in the four proteins that interact with the same region of Smad7 and quantified these interactions in terms of affinity values.

Previous work by the groups on a similar type of protein, called receptor-activated Smads, has shown that in order for transcription to take place, these Smads undergo the process of phosphorylation. In this study, which focuses on inhibitory Smads, the researchers found that this step of molecular processing was not necessary and that the four proteins bind constitutively and directly to the targets.

The TGF-beta pathway is tightly regulated. Its regulation includes a feedback process whereby the two sets of Smads play complementary roles in the same signaling cascade, as they can either inhibit or trigger gene transcription, depending on cell type and the physiological needs of the tissue or organism. As with most biological processes, achieving a fine balance between the two is key, since uncontrolled gene transcription is a hallmark of serious diseases such as cancer. This latest discovery helps to shed light on how organisms achieve this balance.

One of the keys to success of this project was the unique combination of perspectives and methodologies that the partners contributed. Macias' team at IRB Barcelona used a mixture of biophysical and molecular biology techniques to decipher the minute structures of subdomains within the proteins at the atomic level. "The problem," she says, "is that we are looking at small sections of the full proteins in vitro, isolated from their cellular environment. Using techniques such as nuclear magnetic resonance, we are able to see the details down to the atoms in the binding sites. But because we zoom in so closely, we can lose sight of what the interactions we characterize can actually mean for the function of the entire protein in the cell."

Massagué's group at MSKCC was able to take each of Macias' detailed conformational changes and, using mammalian cells and full length proteins, see the effects these changes had in the cells. "Merging the detailed and bigger pictures is a difficult but key step to understanding the nature of biological processes, and to identifying what happens in disease," he says. "Detailed information on the structures of molecules involved in fundamental processes, such as that provided by this study, can tell us where to look to take to control when things go wrong."

Journal Reference:

1. Eric Aragón, Nina Goerner, Qiaoran Xi, Tiago Gomes, Sheng Gao, Joan Massagué, Maria J. Macias. Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-β Pathways. Structure, 2012; DOI: 10.1016/j.str.2012.07.014

Courtesy: ScienceDaily

Type 2 Diabetes: Preliminary Results in Aliskiren Trial Show Drug 'May Even Be Harmful'

Preliminary results from the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) do not support administration of aliskiren on top of standard therapy with renin-angiotensin-aldosterone system (RAAS) blockade in type 2 diabetics at high risk of cardiovascular and renal events, according to Professor Hans-Henrik Parving from Rigshospitalet, University of Copenhagen, Denmark. Presenting results from the study August 26, he said the treatment "may even be harmful.".

The ALTITUDE trial was stopped prematurely in December 2011 on recommendation of the data monitoring committee after it found an increased occurrence of side effects and continuation of the study was deemed "futile." The study had been investigator initiated to determine whether use of the direct renin inhibitor aliskiren would improve prognosis by reducing fatal and non-fatal cardiovascular and renal events in type 2 diabetics at high risk of these complications. Macro- and microvascular complications of type 2 diabetes are augmented in those with concomitant kidney and/or cardiovascular disease.

ALTITUDE was an international double-blind study in 8561 subjects randomised to aliskiren 300 mg once daily or placebo on top of single RAAS blockade. The primary outcome measure was time to first event for the composite endpoint of cardiovascular death, resuscitated death, myocardial infarction, stroke, unplanned hospitalisation for heart failure, onset of end-stage renal disease or doubling of baseline creatinine.

At a median follow-up of 32 months the primary composite endpoint had occurred in 767 patients (17.9%) assigned to aliskiren and 721 (16.8%) assigned to placebo, HR for aliskiren vs. placebo 1.08 (95% CI 0.98-1.20, p=0.14). Stroke occurred in 146 (3.4%) of the aliskiren and 118 (2.7%) in placebo, HR 1.25 (95% CI 0.98-1.60, p=0.070).

Doubling of serum creatinine or end-stage renal disease was similar in the two groups and the mean reduction in albuminuria was 14% (95% CI 11-17) lower in aliskiren treated patients.

Patients in the aliskiren group experienced significantly increased serum potassium ≥6 mmol/L (8.8% vs. 5.6%), and reported hypotension (12.1% vs. 8.0%).

Story Source:

The above story is reprinted from materials provided by European Society of Cardiology (ESC), via AlphaGalileo.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Courtesy: ScienceDaily

Computational Analysis Identifies Drugs to Treat Drug-Resistant Breast Cancer

Researchers have used computational analysis to identify a new Achilles heel for the treatment of drug-resistant breast cancer. The results, which are published in Molecular Systems Biology, reveal that the disruption of glucose metabolism is an effective therapeutic strategy for the treatment of tumours that have acquired resistance to front-line cancer drugs such as Lapatinib.

“The growth and survival of cancer cells can often be impaired by treatment with drugs that interfere with the actions of one or more oncogenes,” said Prahlad Ram, the senior author of the study and Professor at the University of Texas MD Anderson Cancer Center, Houston, Texas. “However, the clinical benefits to patients are often short lived due to acquired drug resistance. Finding alternative intervention points or so-called new addictions for cancer cells is of critical importance for designing novel therapeutic strategies against tumours. Our results reveal specific new targets for drug intervention in the metabolic pathways of cancer cells and identify existing drugs that can be used to treat drug-resistant cancer.”

Lapatinib is used for the treatment of patients with advanced or metastatic breast cancer in cases where tumours overexpress the ErbB2 gene. The ErbB2 gene provides instructions for making a specific growth factor receptor. If too much of this ErbB2 growth factor receptor is made, it can lead to cells that grow and divide continuously, one of the defining characteristics of breast cancer.  

The scientists used microarrays to measure gene expression in breast cancer cells with and without treatment with Lapatinib. Computational analysis of more than 15000 gene interactions revealed four major populations of genes that were regulated in a significant way. Three of these groups were the regular suspects related to drug resistance, such as genes involved in oxidation and reduction reactions or cell cycle processes. A fourth group comprised a network of reactions linked to the deprivation of glucose.

Analysis of the gene expression networks of ErbB2-positive breast cancer patients revealed that the glucose deprivation network is linked to low survival rates of the patients. Computational screening of a library of existing drugs for therapeutics that target the glucose deprivation response identified several drugs that could be effective in treating drug-resistant breast cancer.

“By developing novel gene expression analysis algorithms and integrating diverse data, we have been able to look beyond changes in the immediate molecular signaling pathways of breast cancer cells and to consider the wider system of molecular networks within the cell,” remarked Ram. “Our approach predicts new uses for existing drugs that impact the metabolism of breast cancer cells and may offer an expedient route to improved treatments for breast cancer patients.”

Journal Reference:

1. Kakajan Komurov, Jen-Te Tseng, Melissa Muller, Elena G Seviour, Tyler J Moss, Lifeng Yang, Deepak Nagrath, Prahlad T Ram. The glucose-deprivation network counteracts lapatinib-induced toxicity in resistant ErbB2-positive breast cancer cells. Molecular Systems Biology, 2012; 8 DOI: 10.1038/msb.2012.25

Courtesy: ScienceDaily

Flu Vaccine Research: Overcoming 'Original Sin'

Scientists studying flu vaccines have identified ways to overcome an obstacle called "original antigenic sin," which can impair immune responses to new flu strains.

Original antigenic sin (OAS) is a situation where the immune system is fighting with obsolete weapons and has trouble adapting. After encountering one viral strain, and then a new one that is related to the first, the immune system can respond by making antibodies against the first strain, resulting in a less effective defense.

Researchers at Emory Vaccine Center have demonstrated in experiments with mice that OAS can be overcome by using a vaccine additive called an adjuvant, or by repeated immunization with the second viral strain. The results were published this week in Proceedings of the National Academy of Sciences (PNAS).

The first author of the paper is postdoctoral fellow Jin Hyang Kim, who now works on influenza at the Centers for Disease Control and Prevention. The senior author is Joshy Jacob, associate professor of microbiology and immunology at Emory University School of Medicine.

The findings could be important when vaccinating individuals with weaker immune systems, such as people with chronic infections, small children or the elderly, the authors write.

The influenza virus has become so widespread because it can infect a wide range of hosts such as pigs and birds, and because its genome is flexible, Jacob says.

Influenza strains change their DNA in two ways. Antigenic drift occurs as a strain accumulates small mutations, which can help it escape from the host's immune system. Antigenic shift occurs when two strains, possibly from different host species, swap DNA.

"Original antigenic sin is really a reflection of the agility of the influenza virus," he says. "OAS becomes a factor when the new circulating strain is a 'drifted' version of what came before. The old antibodies can't neutralize the new virus, and that helps the new virus survive."

In a Journal of Immunology paper published in 2009, Jin and Jacob showed that OAS could impair the immune responses of mice exposed to two well-studied H1N1 flu strains: PR8, from 1934, and FM1, from 1947.

If mice are immunized first with inactivated PR8 virus and a month later FM1, and then exposed to live FM1, the lungs of the mice had higher viral levels than those that weren't immunized first with PR8. This effect was even stronger after sublethal infection with live virus, rather than vaccination with inactivated virus.

In the new PNAS paper, Jin and colleagues demonstrated that combining the FM1 immunization with an adjuvant allows the mice to respond better to the live virus. The adjuvant is a squalene oil-in-water emulsion. Squalene is a vaccine additive licensed in European countries since the 1990s, but not approved for use in the United States. Surprisingly, the adjuvant could also improve immune responses when combined with the initial PR8 immunization.

"It appears that the adjuvant is making the immune responses to the first viral strain broader, so that a wider range of antibody-producing cells are able to respond to the second strain," Jacob says.

The handicap of the twice-immunized mice against the second virus could also be overcome by a booster shot against the second virus. The authors write:

"Collectively, our findings imply that OAS could potentially be prevented in the naïve human population, especially children, by administering adjuvants with the first influenza vaccine. Alternatively, in the older population with prior influenza virus exposure or vaccinations, original antigenic sin can be minimized by using adjuvants."

The research was supported by the National Institute of Allergy and Infectious Diseases (HHSN266 200700006C).

Journal Reference:

1. J. H. Kim, W. G. Davis, S. Sambhara, J. Jacob. Strategies to alleviate original antigenic sin responses to influenza viruses. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.0912458109

Courtesy: ScienceDaily

Brain's Mysterious Switchboard Operator Revealed

A mysterious region deep in the human brain could be where we sort through the onslaught of stimuli from the outside world and focus on the information most important to our behavior and survival, Princeton University researchers have found.

The researchers report in the journal Science that an area of our brain called the pulvinar regulates communication between clusters of brain cells as our brain focuses on the people and objects that need our attention. Like a switchboard operator, the pulvinar makes sure that separate areas of the visual cortex -- which processes visual information -- are communicating about the same external information, explained lead author Yuri Saalmann, an associate research scholar in the Princeton Neuroscience Institute (PNI). Without guidance from the pulvinar, an important observation such as an oncoming bus as one is crossing the street could get lost in a jumble of other stimuli.

Saalmann said these findings on how the brain transmits information could lead to new ways of understanding and treating attention-related disorders, such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. Saalmann worked with senior researcher Sabine Kastner, a professor in the Department of Psychology and the Princeton Neuroscience Institute; and PNI researchers Xin Li, a research assistant; Mark Pinsk, a professional specialist; and Liang Wang, a postdoctoral research associate.

The researchers developed a new technique to trace direct communication between clusters of neurons in the visual cortex and the pulvinar. The team produced neural connection maps using magnetic resonance imaging (MRI), then placed electrodes along those identified communication paths to monitor brain signals of macaques. The researchers trained the monkeys to play a video game during which they used visual cues to find a specific shape surrounded by distracting information. As the macaques focused, Saalmann and his colleagues could see that the pulvinar controlled which parts of the visual cortex sent and received signals.

Saalmann explains the Princeton findings as follows:

"A fundamental problem for the brain is that there is too much information in our natural environment for it to be processed in detail at the same time. The brain instead selectively focuses on, or attends to, the people and objects most relevant to our behavior at the time and filters out the rest. For instance, as we cross a busy city street, our brain blocks out the bustle of the crowd behind us to concentrate more on an oncoming bus.

"The transmission of behaviorally relevant information between various parts of the brain is tightly synchronized. As one brain area sends a signal about our environment, such as that a bus is approaching, another brain area is ready to receive it and respond, such as by having us cross the street faster. A persistent question in neuroscience, though, is how exactly do different brain areas synchronize so that important information isn't lost in the other stimuli flooding our brains.

"Our study suggests that a mysterious area in the center of the brain called the pulvinar acts as a switchboard operator between areas on the brain's surface known as the visual cortex, which processes visual information. When we pay attention to important visual information, the pulvinar makes sure that information passing between clusters of neurons is consistent and relevant to our behavior.

"These results could advance the understanding of the neural mechanisms of selective attention and how the brain transmits information. This is a necessary step in developing effective treatment strategies for medical disorders characterized by a failure of attention mechanisms. These conditions include ADHD, schizophrenia and spatial neglect, which is an inability to detect stimuli often observed following stroke.

"For our study, we trained monkeys to play a video game in which they paid attention to visual cues in order to detect different target shapes. We simultaneously recorded brain activity in the pulvinar and two different areas of the visual cortex. We could see a clear connective path from one portion of the cortex to another, as well as connective paths from the pulvinar to the cortex. When the monkeys paid attention to the visual cues, the pulvinar sent electrical pulses to synchronize particular groups of brain cells in the visual cortex to allow them to communicate effectively.

"A challenge in this study was that we needed to record the activity of cells that were 'speaking' directly with each other so we could trace the line of communication. But there are billions of brain cells. Traditionally, finding a cell-to-cell connection is as likely as randomly selecting two people talking on cell phones in different parts of New York City and discovering that they were speaking to each other.

"To 'listen in' on a direct cell conversation, we developed a new approach of using electrodes to record groups of brain cells that were anatomically connected. We first mapped neural connections in the brain via diffusion tensor imaging, which uses an MRI scanner to measure the movement of water along neural connections. We then used these images to implant electrodes at the endpoints of the neural connections shared by the pulvinar and the visual cortex.

"Our mapping of these communication networks and our finding that the pulvinar is vital to attention prompts a new consideration of the mechanisms behind higher cognitive function. We challenge the common notion that these functions depend exclusively on the cerebral cortex, the outermost layer of the brain responsible for decision-making, attention and language, among other abilities. It also suggests that the prevailing view that visual information is transmitted solely through a network of areas in the visual cortex needs to be revised to include the pulvinar as an important regulator of neural transmission."

Journal Reference:

1. Y. B. Saalmann, M. A. Pinsk, L. Wang, X. Li, S. Kastner. The Pulvinar Regulates Information Transmission Between Cortical Areas Based on Attention Demands. Science, 2012; 337 (6095): 753 DOI: 10.1126/science.1223082

Courtesy: ScienceDaily

Reviled Substance Involved in Alzheimer's Can Reverse Paralysis in Mice With Multiple Sclerosis

A molecule widely assailed as the chief culprit in Alzheimer's disease unexpectedly reverses paralysis and inflammation in several distinct animal models of a different disorder -- multiple sclerosis, Stanford University School of Medicine researchers have found.

This surprising discovery, which will be reported in a study to be published online Aug. 1 as the cover feature in Science Translational Medicine, comes on the heels of the recent failure of a large-scale clinical trial aimed at slowing the progression of Alzheimer's disease by attempting to clear the much-maligned molecule, known as A-beta, from Alzheimer's patients' bloodstreams. While the findings are not necessarily applicable to the study of A-beta's role in the pathology of that disease, they may point to promising new avenues of treatment for multiple sclerosis.

The short protein snippet, or peptide, called A-beta (or beta-amyloid) is quite possibly the single most despised substance in all of brain research. It comes mainly in two versions differing slightly in their length and biochemical properties. A-beta is the chief component of the amyloid plaques that accumulate in the brains of Alzheimer's patients and serve as an identifying hallmark of the neurodegenerative disorder.

A-beta deposits also build up during the normal aging process and after brain injury. Concentrations of the peptide, along with those of the precursor protein from which it is carved, are found in multiple-sclerosis lesions as well, said Lawrence Steinman, MD, the new study's senior author. In a lab dish, A-beta is injurious to many types of cells. And when it is administered directly to the brain, A-beta is highly inflammatory.

Yet little is known about the physiological role A-beta actually plays in Alzheimer's -- or in MS, said Steinman, a professor of neurology and neurological sciences and of pediatrics and a noted multiple-sclerosis researcher. He, first author Jacqueline Grant, PhD, and their colleagues set out to determine that role in the latter disease. (Grant was a graduate student in Steinman's group when the work was done.)

Multiple sclerosis, an inflammatory autoimmune disease, occurs when immune cells invade the brain and spinal cord and attack the insulating coatings of nerve cells' long, cable-like extensions called axons. Damage to these coatings, composed largely of a fatty substance called myelin, disrupts the transmission of signals that ordinarily travel long distances down axons to junctions with other nerve cells. This signal disruption can cause blindness, loss of muscle control and difficulties with speech, thought and attention.

Previous research by Steinman, who is also the George A. Zimmerman Professor, and others showed that both A-beta and its precursor protein are found in MS lesions. In fact, the presence of these molecules along an axon's myelinated coating is an excellent marker of damage there.

Given the peptide's nefarious reputation, Steinman and his associates figured that A-beta was probably involved in some foul play with respect to MS. To find out, they relied on a mouse model that mimics several features of multiple sclerosis -- including the autoimmune attack on myelinated sections of the brain that causes MS.

Steinman had, some years ago, employed just such a mouse model in research that ultimately led to the development of natalizumab (marketed as Tysabri), a highly potent MS drug. That early work proved that dialing down the activation and proliferation of immune cells located outside the central nervous system (which is what natalizumab does) could prevent those cells from infiltrating and damaging nerve cells in the CNS.

Knowing that immunological events outside the brain can have such an effect within it, the Stanford scientists were keen on seeing what would happen when they administered A-beta by injecting it into a mouse's belly, rather than directly to the brain.

"We figured it would make it worse," Steinman said.

Surprisingly, the opposite happened. In mice whose immune systems had been "trained" to attack myelin, which typically results in paralysis, A-beta injections delivered before the onset of symptoms prevented or delayed the onset of paralysis. Even when the injections were given after the onset of symptoms, they significantly lessened the severity of, and in some cases reversed, the mice's paralysis.

Steinman asked Grant to repeat the experiment. She did, and got the same results.

His team then conducted similar experiments using a different mouse model: As before, they primed the mice's immune cells to attack myelin. But rather than test the effects of A-beta administration, the researchers harvested the immune cells about 10 days later, transferred them by injection to another group of mice that did not receive A-beta and then analyzed this latter group's response. The results mirrored those of the first set of experiments, proving that A-beta's moderating influence on the debilitating symptoms of the MS-like syndrome has nothing to do with A-beta's action within the brain itself, but instead is due to its effect on immune cells before they penetrate the brain.

Sophisticated laboratory tests showed that A-beta countered not only visible symptoms such as paralysis, but also the increase in certain inflammatory molecules that characterizes multiple-sclerosis flare-ups. "This is the first time A-beta has been shown to have anti-inflammatory properties," said Steinman.

Inspection of the central nervous systems of the mice with the MS-resembling syndrome showed fewer MS-like lesions in the brains and spinal cords of treated mice than in those not given A-beta. There was also no sign of increased Alzheimer's-like plaques in the A-beta-treated animals. "We weren't giving the mice Alzheimer's disease" by injecting A-beta into their bellies, said Grant.

In addition, using an advanced cell-sorting method called flow cytometry, the investigators showed A-beta's strong effects on the immune system composition outside the brain. The numbers of immune cells called B cells were significantly diminished, while those of two other immune-cell subsets -- myeloid cells and memory T-helper cells -- increased.

"At this point we wanted to find out what would happen if we tried pushing A-beta levels down instead of up," Grant said. The researchers conducted a different set of experiments, this time in mice that lacked the gene for A-beta's precursor protein, so that they could produce neither the precursor nor A-beta. These mice, when treated with myelin-sensitized immune cells to induce the MS-like state, developed exacerbated symptoms and died faster and more frequently than normal mice who underwent the same regimen.

Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease in San Francisco and a veteran Alzheimer's researcher, noted that while A-beta's toxicity within the brain has been established beyond reasonable doubt, many substances made in the body can have vastly different functions under different circumstances.

"A-beta is made throughout our bodies all of the time. But even though it's been studied for decades, its normal function remains to be identified," said Mucke, who is familiar with Steinman's study but wasn't involved in it. "Most intriguing, to me, is this peptide's potential role in modulating immune activity outside the brain."

The fact that the protection apparently conferred by A-beta in the mouse model of multiple sclerosis doesn't require its delivery to the brain but, rather, can be attributed to its immune-suppressing effect in the body's peripheral tissues is likewise intriguing, suggested Steinman.

"There probably is a multiple-sclerosis drug in all this somewhere down the line," he said.

Journal Reference:

1. J. L. Grant, E. E. B. Ghosn, R. C. Axtell, K. Herges, H. F. Kuipers, N. S. Woodling, K. Andreasson, L. A. Herzenberg, L. A. Herzenberg, L. Steinman. Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of  -Amyloid in TH1 and TH17 Versions of Experimental Autoimmune Encephalomyelitis. Science Translational Medicine, 2012; 4 (145): 145ra105 DOI: 10.1126/scitranslmed.3004145

Courtesy: ScienceDaily

Weight Training Linked to Reduced Risk of Type 2 Diabetes

Men who do weight training regularly -- for example, for 30 minutes per day, five days per week -- may be able to reduce their risk of type 2 diabetes by up to 34%, according to a new study by Harvard School of Public Health (HSPH) and University of Southern Denmark researchers. And if they combine weight training and aerobic exercise, such as brisk walking or running, they may be able to reduce their risk even further -- up to 59%.

This is the first study to examine the role of weight training in the prevention of type 2 diabetes. The results suggest that, because weight training appears to confer significant benefits independent of aerobic exercise, it can be a valuable alternative for people who have difficulty with the latter.

The study will be published online in Archives of Internal Medicine on August 6, 2012.

"Until now, previous studies have reported that aerobic exercise is of major importance for type 2 diabetes prevention," said lead author Anders Grøntved, visiting researcher in the Department of Nutrition at HSPH and a doctoral student in exercise epidemiology at the University of Southern Denmark. "But many people have difficulty engaging in or adhering to aerobic exercise. These new results suggest that weight training, to a large extent, can serve as an alternative to aerobic exercise for type 2 diabetes prevention."

Type 2 diabetes is a major public health concern and it's on the rise. An estimated 346 million people worldwide have type 2 diabetes, and diabetes-related deaths are expected to double between 2005 and 2030, according to the World Health Organization. More than 80% of these deaths occur in low- and middle-income countries.

The researchers, including senior author Frank Hu, professor of nutrition and epidemiology at HSPH, followed 32,002 men from the Health Professionals Follow-up Study from 1990 to 2008. Information on how much time the men spent each week on weight training and aerobic exercise came from questionnaires they filled out every two years. The researchers adjusted for other types of physical activity, television viewing, alcohol and coffee intake, smoking, ethnicity, family history of diabetes, and a number of dietary factors. During the study period, there were 2,278 new cases of diabetes among the men followed.

The findings showed that even a modest amount of weight training may help reduce type 2 diabetes risk. The researchers categorized the men according to how much weight training they did per week -- between 1 and 59 minutes, between 60 and 149 minutes, and at least 150 minutes -- and found that the training reduced their type 2 diabetes risk by 12%, 25%, and 34%, respectively, compared with no weight training. Aerobic exercise is associated with significant benefits as well, the researchers found -- it reduced the risk of type 2 diabetes by 7%, 31%, and 52%, respectively, for the three categories above.

The researchers also found that the combination of weight training and aerobic exercise confers the greatest benefits: Men who did more than 150 minutes of aerobics as well as at least 150 minutes of weight training per week had a 59% reduced risk of type 2 diabetes.

Grøntved said that further research is needed to confirm the results of the study as well as to analyze whether or not the findings can be generalized to women.

"This study provides clear evidence that weight training has beneficial effects on diabetes risk over and above aerobic exercise, which are likely to be mediated through increased muscle mass and improved insulin sensitivity," said Hu. "To achieve the best results for diabetes prevention, resistance training can be incorporated with aerobic exercise."

Other HSPH authors included Eric Rimm, associate professor in the Departments of Epidemiology and Nutrition, and Walter Willett, Frederick John Stare Professor of Epidemiology and Nutrition and chair of the Department of Nutrition.

Support for the study was provided by the National Institutes of Health (DK58845 and CA55075).

Journal Reference:

1. Eric B. Rimm. A Prospective Study of Weight Training and Risk of Type 2 Diabetes Mellitus in MenWeight Training and Risk of Type 2 Diabetes. Archives of Internal Medicine, 2012; : 1 DOI: 10.1001/archinternmed.2012.3138

Courtesy: ScienceDaily

Daily Aspirin Usage Linked to Lower Cancer Mortality

A large new observational study finds more evidence of an association between daily aspirin use and modestly lower cancer mortality, but suggests any reduction may be smaller than that observed in a recent analysis. The study, appearing early online in the Journal of the National Cancer Institute (JNCI), provides additional support for a potential benefit of daily aspirin use for cancer mortality, but the authors say important questions remain about the size of the potential benefit.

A recent analysis pooling results from existing randomized trials of daily aspirin for prevention of vascular events found an estimated 37% reduction in cancer mortality among those using aspirin for five years or more. But uncertainty remains about how much daily aspirin use may lower cancer mortality, as the size of this pooled analysis was limited and two very large randomized trials of aspirin taken every other day found no effect on overall cancer mortality.

For the current study, American Cancer Society researchers led by Eric J. Jacobs, Ph.D., analyzed information from 100,139 predominantly elderly participants in the Cancer Prevention Study II Nutrition Cohort who reported aspirin use on questionnaires, did not have cancer at the start of the study, and were followed for up to 11 years. They found daily aspirin use was associated with an estimated 16% lower overall risk of cancer mortality, both among people who reported taking aspirin daily for at least five years and among those who reported shorter term daily use. The lower overall cancer mortality was driven by about 40% lower mortality from cancers of the gastrointestinal tract (such as esophageal, stomach, and colorectal cancer) and about 12% lower mortality from cancers outside the gastrointestinal tract.

The reduction in cancer mortality observed in the current study is considerably smaller than the 37% reduction reported in the recent pooled analysis of randomized trials. The authors note that their study was observational, not randomized, and therefore could have underestimated or overestimated potential effects on cancer mortality if participants who took aspirin daily had different underlying risk factors for fatal cancer than those who did not. However, the study's large size is a strength in determining how much daily aspirin use might lower cancer mortality.

"Expert committees that develop clinical guidelines will consider the totality of evidence about aspirin's risks and benefits when guidelines for aspirin use are next updated," said Dr. Jacobs. "Although recent evidence about aspirin use and cancer is encouraging, it is still premature to recommend people start taking aspirin specifically to prevent cancer. Even low-dose aspirin can substantially increase the risk of serious gastrointestinal bleeding. Decisions about aspirin use should be made by balancing the risks against the benefits in the context of each individual's medical history. Any decision about daily aspirin use should be made only in consultation with a health care professional."

Journal Reference:

1. Eric J. Jacobs, Christina C. Newton, Susan M. Gapstur, Michael J. Thun. Daily Aspirin Use and Cancer Mortality in a Large US Cohort. Journal of the National Cancer Institute, August 10, 2012 DOI: 10.1093/jnci/djs318

Courtesy: ScienceDaily

Heat-Shock Factor Reveals Its Unique Role in Supporting Highly Malignant Cancers

Whitehead Institute researchers have found that increased expression of a specific set of genes is strongly associated with metastasis and death in patients with breast, colon, and lung cancers. Not only could this finding help scientists identify a gene profile predictive of patient outcomes and response to treatment, it could also guide the development of therapeutics to target multiple cancer types.

The genes identified are activated by a transcription factor called heat-shock factor 1 (HSF1) as part of a transcriptional program distinct from HSF1's well-known role in mediating the response of normal cells to elevated temperature.

In normal cells, a variety of stressors, including heat, hypoxia, and toxins, activate HSF1 leading to increased expression of so-called heat-shock or chaperone proteins that work to maintain protein homeostasis in stressed cells. Scientists have known for some time that many cancer cells have higher levels of chaperones and that elevation of these proteins is important for survival and proliferation of tumor cells.

Now, however, researchers in the lab of Whitehead Member Susan Lindquist report that HSF1 supports cancers not only by increasing chaperones, but by unexpectedly regulating a broad range of cellular functions that are important for the malignant behavior of tumor cells. This activity allows for the development of the most aggressive forms of three of the most prevalent cancers -- breast, lung, and colon. The findings, published this week in the journal Cell, build on earlier research from the Lindquist lab showing that elevated levels of HSF1 are associated with poorer prognosis in some forms of breast cancer.

"This work shows that HSF1 is fundamentally important across a broad range of human cancers, cancers of various types from all over the body turn on this response," says Sandro Santagata, a postdoctoral researcher in the Lindquist lab. "That's very interesting. It suggests how important HSF1 must be for helping tumors become their very worst."

In addition to confirming that this gene activation program differs from that associated with heat shock, the researchers found that in many tumors, it becomes active in virtually all of the tumor's cells.

"This demonstrates it isn't simply regions of microenvironmental stress within a tumor that drive HSF1 activity, but rather that HSF1 activation is wired into the core circuitry of cancer cells, orchestrating a distinct gene regulatory program that enables particularly aggressive phenotypes," says Marc Mendillo, a postdoctoral researcher in the Lindquist lab. "This suggests HSF1 itself could be a great therapeutic target."

Luke Whitesell, an oncologist and senior research scientist in the Lindquist lab, concurs that HSF1 is a conceptually appealing target for therapeutic intervention, noting that suppressing HSF1 for short periods of time should have minimal consequences on normal cells. However, he adds, actually developing such a drug could be problematic.

"Coming up with a drug that disrupts HSF1's interaction with DNA, which is how it activates all of these genes, that is going to be really tough," says Whitesell. "No one has come up with a clinically useful drug that directly interrupts a transcription factor's interaction with DNA yet. But there are ways to disrupt a transcription factor's function indirectly, as opposed to directly targeting the protein itself. What we have now from this research is a new view of the landscape and the possibilities for drug discovery and development that are out there."

This research was supported by the Johnson & Johnson Focused Funding Program, the Marble Fund, the American Cancer Society New England Division-SpinOdyssey, the National Institutes of Health (NIH), the Brain Science Foundation, the V Foundation, GlaxoSmithKline, the National Cancer Institute (NCI), Department of Health and Human Services (HHS), the Breast Cancer Research Foundation, and the Department of Defense (DoD).

Journal Reference:

1. Marc L. Mendillo, Sandro Santagata, Martina Koeva, George W. Bell, Rong Hu, Rulla M. Tamimi, Ernest Fraenkel, Tan A. Ince, Luke Whitesell, Susan Lindquist. HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers. Cell, 2012; 150 (3): 549 DOI: 10.1016/j.cell.2012.06.031

Courtesy: ScienceDaily

Researchers Invent New Tool to Study Single Biological Molecules

By blending optical and atomic force microscope technologies, Iowa State University and Ames Laboratory researchers have found a way to complete 3-D measurements of single biological molecules with unprecedented accuracy and precision.

Existing technologies allow researchers to measure single molecules on the x and y axes of a 2-D plane. The new technology allows researchers to make height measurements (the z axis) down to the nanometer -- just a billionth of a meter -- without custom optics or special surfaces for the samples.

"This is a completely new type of measurement that can be used to determine the z position of molecules," said Sanjeevi Sivasankar, an Iowa State assistant professor of physics and astronomy and an associate of the U.S. Department of Energy's Ames Laboratory.

Details of the technology were recently published by the journal Nano Letters. Co-authors of the study are Sivasankar; Hui Li, an Iowa State post-doctoral research associate in physics and astronomy and an associate of the Ames Laboratory; and Chi-Fu Yen, an Iowa State doctoral student in electrical and computer engineering and a student associate of the Ames Laboratory.

The project was supported by lab startup funds from Iowa State University and a $120,075 grant from the Grow Iowa Values Fund, a state economic development program.

Sivasankar's research program has two objectives: to learn how biological cells adhere to each other and to develop new tools to study those cells.

That's why the new microscope technology -- called standing wave axial nanometry (SWAN) -- was developed in Sivasankar's lab.

Here's how the technology works: Researchers attach a commercial atomic force microscope to a single molecule fluorescence microscope. The tip of the atomic force microscope is positioned over a focused laser beam, creating a standing wave pattern. A molecule that has been treated to emit light is placed within the standing wave. As the tip of the atomic force microscope moves up and down, the fluorescence emitted by the molecule fluctuates in a way that corresponds to its distance from the surface. That distance can be compared to a marker on the surface and measured.

"We can detect the height of the molecule with nanometer accuracy and precision," Sivasankar said.

The paper reports that measurements of a molecule's height are accurate to less than a nanometer. It also reports that measurements can be taken again and again to a precision of 3.7 nanometers.

Sivasankar's research team used fluorescent nanospheres and single strands of DNA to calibrate, test and prove their new instrument.

Users who could benefit from the technology include medical researchers who need high-resolution data from microscopes. Sivasankar thinks the technology has commercial potential and is confident it will advance his own work in single molecule biophysics.

"We hope to use this technology to move that research forward," he said. "And in doing that, we'll continue to invent new technologies."

Journal Reference:

1. Hui Li, Chi-Fu Yen, Sanjeevi Sivasankar. Fluorescence Axial Localization with Nanometer Accuracy and Precision. Nano Letters, 2012; 12 (7): 3731 DOI: 10.1021/nl301542c

Courtesy: ScienceDaily

 

New Target for Treating Diabetes and Obesity

Researchers at Washington University School of Medicine in St. Louis have identified a potential target for treating diabetes and obesity.

 Studying mice, they found that when the target protein was disabled, the animals became more sensitive to insulin and were less likely to get fat even when they ate a high-fat diet that caused their littermates to become obese.

The findings are published online in the journal Cell Metabolism.

The researchers studied how the body manufactures fat from dietary sources such as carbohydrates. That process requires an enzyme called fatty acid synthase (FAS). Mice engineered so that they don't make FAS in their fat cells can eat a high-fat diet without becoming obese.

"Mice without FAS were significantly more resistant to obesity than their wild-type littermates," says first author Irfan J. Lodhi, PhD. "And it wasn't because they ate less. The mice ate just as much fatty food, but they metabolized more of the fat and released it as heat."

To understand why that happened, Lodhi, a research instructor in medicine, analyzed their fat cells. Mice have two types of fat: white fat and brown fat. White fat stores excess calories and contributes to obesity. Brown fat helps burn calories and protects against obesity.

In mice genetically blocked from making fatty acid synthase in fat cells, Lodhi and his colleagues noticed that the animals' white fat was transformed into tissue that resembled brown fat.

"These cells are 'brite' cells, brown fat found where white fat cells should be," Lodhi says. "They had the genetic signature of brown fat cells and acted like brown fat cells. Because the mice were resistant to obesity, it appears that fatty acid synthase may control a switch between white fat and brown fat. When we removed FAS from the equation, white fat transformed into brite cells that burned more energy."

Determining whether humans also have brown fat has been somewhat controversial throughout the years, but recent studies elsewhere have confirmed that people have it.

"It definitely exists, and perhaps the next strategy we'll use for treating people with diabetes and obesity will be to try to reverse their problems by activating these brown fat cells," says senior investigator Clay F. Semenkovich, MD.

Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, says the new work is exciting because FAS provides a target that may be able to activate brown fat cells to treat obesity and diabetes. But even better, he says it may be possible to target a protein downstream from FAS to lower the risk for potential side effects from the therapy.

That is possible because the scientists learned that the FAS pathway involves a family of proteins known as the PPARs (peroxisome proliferator-activated receptors). PPARs are important in lipid metabolism. One of them, PPAR-alpha, helps burn fat, but the related protein, PPAR-gamma manufactures fat and helps store it.

Lodhi and Semenkovich noticed that in mice without FAS in their fat cells, activity of PPAR-alpha (the fat burner) was increased, while PPAR-gamma (the fat builder) activity decreased.

A protein called PexRAP (Peroxisomal Reductase Activating PPAR-gamma) turned out to be a downstream mediator of the effects of FAS and a key regulator of the PPAR-gamma, fat-storing pathway. When the researchers blocked PexRAP in fat cells in mice, they also interfered with the manufacture and buildup of fat.

"There was decreased fat when we blocked PexRAP," Lodhi says. "Those mice also had improved glucose metabolism, so we think that inhibiting either fatty acid synthase or PexRAP might be good strategies for treating obesity and diabetes."

Several pharmaceutical companies are working on FAS inhibitors. Meanwhile, the discovery that inhibiting PexRAP also makes the animals less obese and less diabetic has convinced the Washington University researchers to continue those studies.

"Because PexRAP is downstream, it theoretically might cause fewer side effects, but nobody knows what role the protein might play in different tissues in the body," Semenkovich says. "We need to conduct more experiments with the goal that we may be able to move into some sort of clinical trials relatively soon. It's very important to find new treatments for obesity and diabetes because these disorders aren't just an inconvenience, both can be lethal."

Journal Reference:

1. Irfan J. Lodhi, Li Yin, Anne P.L. Jensen-Urstad, Katsuhiko Funai, Trey Coleman, John H. Baird, Meral K. El Ramahi, Babak Razani, Haowei Song, Fong Fu-Hsu, John Turk, Clay F. Semenkovich. Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARγ Activation to Decrease Diet-Induced Obesity. Cell Metabolism, 2012; DOI: 10.1016/j.cmet.2012.06.013

Courtesy: ScienceDaily

Protein Discovery Links to Cancer Research

A Simon Fraser University graduate student's collaboration with her thesis supervisor on how a particular type of protein controls the growth of another protein could advance cancer research.

Their findings have just been published in the online July 26 issue of Current Biology, a Cell Press journal.

Esther Verheyen, an SFU professor of molecular biology and biochemistry, has helped her Master's of Science student Joanna Chen uncover how Hipk can be manipulated to stop Yorkie from causing tissue overgrowth in flies.

Hipk is a protein kinase -- a type of enzyme that controls the activity of other proteins by depositing a phosphate residue on them.

Yorkie, known as Yap in humans, is another type of protein that induces the overgrowth of cell tissue in the eyes, legs and wings of flies. High levels of Yap are often found in human tumours.

In experiments on the fruit fly Drosophila, Verheyen and Chen first found that Hipk could cause overgrowths similar to those found on tissue with too much Yorkie.

The researchers then genetically generated flies in which there was a higher concentration of Yorkie but a lower concentration of Hipk present than normal in their organ and limb tissues.

"When we did that," says Chen, "Yorkie could not cause overgrowths anymore. We were able to show this need for Hipk to be present in a number of different fly tissues, such as the eyes, legs and wings."

"We found that Hipk could add a phosphate residue on Yorkie and we thought this might explain how Hipk could disrupt Yorkie's ability to cause an overgrowth," adds Verheyen. "This is a very common and reversible method of regulating protein activity, and, as a result, many essential developmental processes."

"Next we tested a mutant form of Hipk that had lost its ability to add phosphates to Yorkie," says Verheyen. "This form of Hipk could no longer prompt Yorkie to trigger cell proliferation or do anything to regulate cell growth.

"Hipk is the first discovery of a protein kinase that regulates Yorkie by stimulating its cell proliferation ability. All other known protein kinases either directly inhibit or block Yorkie from working."

Chen and Verheyen say their discovery is generating a lot of excitement in the molecular biology science community. "We have identified a factor that in flies is required for even overly active Yorkie to trigger overgrowth," explains Chen, who graduated in June. She begins working as a research assistant at the Vancouver Prostate Centre in August.

"By analogy, perhaps the human form of Hipk is needed in cells for overly active Yap (human form of Yorkie) to induce tumours. So if we can inhibit or reduce Hipk activity, it would allow us to prevent overgrowths and possibly cancer caused by excessive Yap in humans."

The two are now checking to see if this new cell growth regulation mechanism they've discovered is conserved across different species, including mice, which have similar Hipk proteins to humans. Note: The title of the duo's paper in Current Biology is the same as the name of Chen's master's thesis: Homeodomain-Interacting Protein Kinase Regulates Yorkie Activity to Promote Tissue Growth.

Journal Reference:

1. Joanna Chen, Esther M. Verheyen. Homeodomain-Interacting Protein Kinase Regulates Yorkie Activity to Promote Tissue Growth. Current Biology, 2012; DOI: 10.1016/j.cub.2012.06.074

Courtesy: ScienceDaily

Protective Role of Skin Microbiota Described

A research team at the National Institutes of Health has found that bacteria that normally live in the skin may help protect the body from infection. As the largest organ of the body, the skin represents a major site of interaction with microbes in the environment. Although immune cells in the skin protect against harmful organisms, until now, it has not been known if the millions of naturally occurring commensal bacteria in the skin -- collectively known as the skin microbiota -- also have a beneficial role.

Using mouse models, the NIH team observed that commensals contribute to protective immunity by interacting with the immune cells in the skin.

Their findings appear online on July 26 in Science.

The investigators colonized germ-free mice (mice bred with no naturally occurring microbes in the gut or skin) with the human skin commensal Staphylococcus epidermidis. The team observed that colonizing the mice with this one species of good bacteria enabled an immune cell in the mouse skin to produce a cell-signaling molecule needed to protect against harmful microbes. The researchers subsequently infected both colonized and non-colonized germ-free mice with a parasite. Mice that were not colonized with the bacteria did not mount an effective immune response to the parasite; mice that were colonized did.

In separate experiments, the team sought to determine if the presence or absence of commensals in the gut played a role in skin immunity. They observed that adding or eliminating beneficial bacteria in the gut did not affect the immune response at the skin. These findings indicate that microbiota found in different tissues -- skin, gut, lung -- have unique roles at each site and that maintaining good health requires the presence of several different sets of commensal communities.

This study provides new insights into the protective role of skin commensals and demonstrates that skin health relies on the interaction of commensals and immune cells. Further research is needed, say the authors, to determine whether skin disorders such as eczema and psoriasis may be caused or exacerbated by an imbalance of skin commensals and potentially harmful microbes that influence the skin and its immune cells.

The study was led by investigators in the laboratories of Yasmine Belkaid, Ph.D., at the National Institute of Allergy and Infectious Diseases, in collaboration with Julie Segre, Ph.D., at the National Human Genome Research Institute, and Giorgio Trinchieri, M.D., and Heidi Kong, M.D., at the National Cancer Institute. All three Institutes are NIH components.

Journal Reference:

1. S Naik et al. Compartmentalized control of skin immunity by resident commensals. Science, 2012 DOI: 10.1126/science.1225152

Courtesy: ScienceDaily