Emerging Drug Class May Enhance Red Blood Cell Production In Anemic Patients

FINDINGS: By determining how corticosteroids act to increase production of red blood cell progenitors, Whitehead Institute researchers have identified a class of drugs that may be beneficial in treating some erythropoietin-resistant anemias. One such anemia is Diamond-Blackfan anemia (DBA), which is frequently treated with corticosteroids, despite their severe side-effects. The identified class of drugs may be able to treat other anemias, including those resulting from trauma, sepsis, malaria, kidney dialysis, and chemotherapy.

RELEVANCE: Some common anemias can be treated with the hormone erythropoietin (EPO), which stimulates red blood-cell production. However, certain anemias, including DBA, do not respond to EPO, creating a large unmet medical need.

By determining how corticosteroids act to promote red blood cell progenitor formation, Whitehead Institute researchers have identified a class of drugs that may be beneficial in anemias, including those resulting from trauma, sepsis, malaria, kidney dialysis, and chemotherapy.

Anemia occurs due to a breakdown in erythropoiesis, the multi-step process that creates red blood cells. Some common anemias can be treated with a recombinant form of the hormone erythropoietin (EPO), which normally stimulates red blood-cell production at a fairly early stage of erythropoiesis.

However, certain anemias fail to respond to EPO, creating a large unmet medical need. In the case of Diamond Blackfan anemia (DBA), patients lack a sufficient number of EPO-responsive cells. Instead, corticosteroids such as prednisone or prednisolone are used to treat DBA, although it has been unclear exactly how these agents affect erythropoiesis.

To see how corticosteroids are able to increase red blood cell counts, Johan Flygare, a postdoctoral researcher in the lab of Whitehead Institute Founding Member Harvey Lodish, purified two progenitors of red blood cells, called burst forming unit-erythroids (BFU-Es) and colony forming unit-erythroids (CFU-Es), from mouse fetal liver cells. During erythropoiesis, BFU-Es produce CFU-Es, which are then stimulated by EPO to generate the pro-erythroblasts that eventually become red blood cells. By dividing numerous times before maturing, both BFU-Es and CFU-Es have a limited ability to self-renew. When Flygare exposed BFU-Es and CFU-Es in vitro to a corticosteroid, only the BFU-Es responded–dividing 13 times instead of the usual 9 times before maturing into CFU-Es. These additional cell divisions ultimately led to a 13-fold increase in red blood-cell production.

Flygare identified 83 genes in BFU-Es that are stimulated by the corticosteroid, and he examined the promoters that facilitate those genes’ transcription. The promoters appeared to have binding sites for a transcription factor, called hypoxia-induced factor 1-alpha (HIF1-alpha), that is activated when an organism is deprived of oxygen. To prolong the 83 genes’ promotion by HIF1-alpha, Flygare used a class of drugs known as prolyl hydroxylase inhibitors (PHIs), which extends HIF1-alpha’s effectiveness. PHIs have also been used in early-stage clinical trials to increase EPO production.

When Flygare added both a corticosteroid and a PHI to BFU-Es in culture, the cells produced 300 times more red blood cells than did cells without exposure to the drugs. Flygare repeated the experiment with adult human BFU-Es, and found that a corticosteroid plus a PHI generated 10 times more red blood cells than BFU-Es exposed to a corticosteroid alone.

Flygare hopes this research eventually leads to improved treatment for DBA patients who currently suffer from a host of corticosteroid-induced side effects, including decreased bone density, immunosuppression, stunted growth, and cataracts.

“If you could lower the dose of steroids so DBA patients would get just a little bit, and then add on this kind of drug, like a PHI, that would boost the effect, maybe you could get around the steroids’ side effects,” says Flygare. “That would be good.”

This new approach to increasing erythropoiesis by extending the self-renewal of BFU-Es – resulting in creation of more EPO-responsive cells – could lead to novel therapies for other anemias.

“There are a number of anemias that are much more prevalent than DBA and that cannot be treated with EPO, either, such as anemias from trauma, sepsis, malaria, and anemia in kidney dialysis patients,” says Lodish, who is also a professor of biology and bioengineering at MIT. “Whether these treatments will work in those conditions remains to be seen.”

Notes:

This research was supported by the Diamond Blackfan Anemia Foundation, the Swedish Research Council, Maja och Hjalmar Leanders Stiftelse, The Sweden-America Foundation, and the National Institutes of Health (NIH).

Nicole Giese

Harvey Lodish’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology and a professor of bioengineering at Massachusetts Institute of Technology.

Full Citations:

“HIF-1 Alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal”

Blood, published online the week of December 22, 2010

Johan Flygare (1), Violeta Rayon Estrada (1), Chanseok Shin (1, 2), Sumeet Gupta (1), and Harvey F. Lodish (1, 3, 4).

1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142
2. Department of Agricultural Biotechnology, Seoul National University, Seoul, 151-921, Republic of Korea
3. Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA

Source:
Nicole Giese
Whitehead Institute for Biomedical Research Continue reading

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American Medical Systems Announces FDA Clearance For MiniArc(R) Precise Single Incision Sling

American Medical Systems® (AMS) (Nasdaq: AMMD), a leading provider of world-class devices and therapies for both male and female pelvic health, announced the Food and Drug Administration (FDA) has cleared the MiniArc® Precise Single-Incision Sling System, a product for the treatment of female stress urinary incontinence (SUI). MiniArc Precise is the next generation sling in the MiniArc family sling system, the number one selling single-incision sling in the United States.

“We are excited to receive clearance on this important product. It further demonstrates our commitment to product innovation and is a good example of using physician feedback to improve a surgical procedure and support improved outcomes,” says John Nealon, senior vice president and general manager of women’s health at American Medical Systems.

Over 33 million women worldwide are affected by SUI, a condition in which activities such as coughing, sneezing, or heavy lifting put pressure on the bladder resulting in unintentional loss of urine. SUI is more common in women than men and is caused by weakening of pelvic floor muscles often tied to tissue and nerve damage resulting from pregnancy, childbirth, radiation, hormone changes or a prior surgery.

To treat SUI with the MiniArc Precise system, the physician surgically places a narrow strip of mesh material called a sling under the urethra to give it a point of support. This procedure is minimally invasive with only one small incision. MiniArc Precise is built upon the success of the original MiniArc single-incision sling which since its launch in late 2007, has been implanted in more than 75,000 patients and incorporates proven mesh that has been used in more than 750,000 procedures.

“MiniArc Precise builds upon the existing MiniArc Sling. With the new design and fixed needle to sling connection, MiniArc Precise further simplifies the ease of use while maintaining the integrity of the existing MiniArc clinical evidence,” says John Nealon. “Its slim needle profile minimizes the potential for tissue trauma and allows for precise placement of the sling under the urethra for support. A limited launch is underway with a full commercial launch later in 2010.”

MiniArc Precise’s design incorporates low profile self-fixating tips that provide immediate fixation of the mesh. As an outpatient procedure, the MiniArc Precise generally allows patients to return to normal activities within a few days. The single-incision approach minimizes the potential for tissue trauma, which may provide for enhanced patient recovery.

About American Medical Systems:

American Medical Systems, headquartered in Minnetonka, Minnesota, is a diversified supplier of medical devices and procedures to cure incontinence, erectile dysfunction, benign prostate hyperplasia (BPH), pelvic floor repair and other pelvic disorders in men and women. These disorders can significantly diminish one’s quality of life and profoundly affect social relationships. In recent years, the number of people seeking treatment has increased markedly as a result of longer lives, higher-quality-of-life expectations and greater awareness of new treatment alternatives. American Medical Systems’ products reduce or eliminate the incapacitating effects of these diseases, often through minimally invasive therapies. The Company’s products were used to treat more than 335,000 patients in 2009.

Source: American Medical Systems Continue reading

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“Food Insecure” Appalachians More Likely To Be Obese, Diabetic, Study Finds

Members of rural Appalachian households who lack access to food or experience hunger are more likely to be obese and have diabetes, according to an Ohio University study.

Researcher David Holben found that subjects from households with greater levels of what medical, nutrition and dietetic professionals call “food insecurity” had a greater body mass index (BMI) than those with smaller levels of food insecurity (an average BMI of 30.3 vs. average BMI of 29). Those from food insecure households also were more likely to have diabetes (37.9 percent) and to be overweight (48.1 percent) than subjects from food secure households (25.8 percent and 35.1 percent, respectively). The study was published in the July 2006 issue of Preventing Chronic Disease, a publication of the Centers for Disease Control.

A total of 2,580 people participated in the Ohio University project, with 72.8 percent from food secure households and 27.2 percent from food insecure households that may or may not be experiencing hunger. That’s higher than the national average: In 1999, the year the Ohio University study was conducted, 10.1 percent of U.S. households were food insecure.

Food insecurity is associated health problems such as stress, obesity, diabetes and heart disease, as well as with poor management of chronic disease, said Holben, who recently wrote a major position paper about the problem for the American Dietetic Association.

The survey included residents of Athens, Hocking, Meigs, Perry, Pike and Vinton counties in Ohio. Researchers asked participants about food access of their households, as well as health care access and use. Those who agreed to an additional health exam were checked for weight, blood pressure, hemoglobin levels, total cholesterol and blood glucose control, said Holben, associate professor of human and consumer sciences and the director of the Didactic Program in Dietetics in Ohio University’s College of Health and Human Services.

Volunteers were recruited from community sites, such as fairs and festivals, food distribution programs, churches, senior centers, community centers, grocery stores and shopping malls. While the sample is not representative of the region in which it was collected, the study provides an impression of the problems faced by residents of rural Appalachia.

“This does have implications for policy, and it has implications for patient care,” Holben said about the study findings. “Physicians, nurses – not just dietitians – need to be aware that people may not have money to buy medicine, and that they have a harder time managing a chronic disease if they’re food insecure.”

While it might be surprising that someone can be overweight while experiencing hunger, Holben explained that low-cost foods such as fast food “are lower in cost, usually are high fat and high sugar and taste good,” which makes it easier for families to rely on these foods. He also pointed to preliminary studies conducted elsewhere that show that malnourishment at a young age can result in adults whose metabolism works more slowly, predisposing them for quick weight gain.

An irregular food supply, caused by monthly food allotments that may run out by the end of the month, also can set up periods of bingeing and fasting, which in turn prompt the body to store as much energy as possible for those times when food is in short supply, Holben said.

To address the food insecurity problem, Holben suggests educational programs on better managing food supply, nutrition education (such as recipe ideas for some of the foods provided by the food assistance programs) and proper interpretation of sell-by dates on food labels.

“(Those dates) don’t mean that magically on that date the food rots, but if we have people throwing away foods, and yet they don’t have resources to buy foods, that could be a problem,” said Holben, who is continuing to study issues of food security, obesity and diabetes in a national sample.

###

Co-author on the Preventing Chronic Disease paper is Alfred Pheley, a former Ohio University College of Osteopathic Medicine professor who is now on the faculty of the Virginia College of Osteopathic Medicine in Blacksburg, Va. The study was funded by a grant from the Ohio University College of Osteopathic Medicine.

Christina Dierkes.
Contact: David Holben, holbenohio.edu

Contact: Andrea Gibson
Ohio University Continue reading

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Mice Protected From Avian Flu By Human Antibodies

An international team of scientists, including researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, report using antibodies derived from immune cells from recent human survivors of H5N1 avian influenza to successfully treat H5N1-infected mice as well as protect them from an otherwise lethal dose of the virus.

“The possibility of an influenza pandemic, whether sparked by H5N1 or another influenza virus to which humans have no natural immunity, is of serious concern to the global health community,” says NIAID Director Anthony S. Fauci, M.D. “If the success of this initial study is confirmed through further laboratory and clinical trials, human monoclonal antibodies could prove to be valuable therapeutic and prophylactic public health interventions for pandemic influenza.”

The research published in PLoS Medicine, represents a three-way collaboration among Kanta Subbarao, M.D., and her coworkers at NIAID; Antonio Lanzavecchia, M.D., and colleagues from the Institute for Research in Biomedicine, Bellinzona, Switzerland; and Cameron Simmons, Ph.D., from the Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

Four Vietnamese adults diagnosed with H5N1 influenza infection between January 2004 and February 2005 agreed to donate blood soon after they had recovered from their illness. In Switzerland, Dr. Lanzavecchia extracted antibody-producing white blood cells, called memory B cells, from the Vietnamese samples and treated them with a process he developed so that they rapidly and continuously produced large amounts of antibody. Next, researchers in Dr. Subbarao’s lab screened 11,000 antibody-containing samples provided by the Swiss team and found a handful able to neutralize H5N1 influenza virus. Based on these results, Dr. Lanzavecchia purified the B cells and ultimately created four monoclonal antibodies (mAbs) that secrete H5N1-specific neutralizing antibodies.

Dr. Subbarao and her coworkers first tested whether the human H5N1 mAbs could protect mice from severe H5N1 infection. Groups of five mice received either of two human H5N1 mAbs at one of three dosages or human mAbs against diphtheria or anthrax. One day later, the mice were exposed through their noses to lethal doses of H5N1 influenza virus.

All the control mice – those receiving non-H5N1 mAbs – rapidly developed severe illness and died within a week. In contrast, all the mice that received the first H5N1 mAb tested – regardless of dose – survived, while 80 percent of mice receiving the highest dose of the second H5N1 mAb survived. Additional tests showed that mice receiving either of the two protective H5N1 mAbs had levels of virus in the lungs that were 10 to 100 times lower than those in control mice, and little or no virus moved beyond the lungs.

The investigators also tested the therapeutic potential of the human H5N1 mAbs. Using blood products from influenza survivors is an old idea, the researchers note. During the flu pandemic of 1918-19, for example, physicians took serum from recovered flu patients and gave it to new victims; recent historical research indicates that those blood transfusions, when given early in the illness, sometimes saved recipients’ lives.

In their study, Dr. Subbarao and her colleagues infected groups of mice with a lethal dose of an H5N1 virus that had circulated in Vietnam in 2004. A total of 60 mice were given one of the four H5N1 mAbs at 24, 48 or 72 hours after infection while a control group received non-influenza mAbs. All the mice in the control group died within 10 days of infection, while 58 of the 60 treated mice survived. All four H5N1 mAbs conferred robust protection. Most surprisingly, says Dr. Subbarao, the survival rate was excellent even when treatment was delayed for three days.

Spurred by these results, the NIAID investigators next tested whether the H5N1 mAbs might be used to treat mice infected with a related but distinct H5N1 virus. Although the four mAbs used in the experiment originated after infection with the 2004 H5N1 virus, three of them nevertheless prevented the mice from dying when given 24 hours after they were infected with a 2005 H5N1 virus. This suggests, the researchers say, that human mAbs may provide broad protection against variant H5N1 viruses – a desirable quality in any therapeutic aimed at the constantly evolving flu virus.

Taken together, the findings from this international collaboration are encouraging, says Dr. Subbarao. They show that fully human mAbs with potent H5N1 influenza virus neutralizing ability can be rapidly generated from the blood of convalescent patients and that these mAbs work well to both treat H5N1 infection and prevent death from such infection in a mouse model. The authors plan to take the research forward by scaling up the production of H5N1 mAbs and, if the technique proves safe and effective in additional animal tests, to evaluate these human mAbs in clinical trials in humans.

For more information on influenza see www3.niaid.nih/news/focuson/flu.

Also visit pandemicflu/ for one-stop access to U.S. Government information on avian and pandemic flu.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH) – The Nation’s Medical Research Agency – includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit nih/.

Reference: CP Simmons et al. Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza. PLoS Medicine (2007) DOI:10.1371/journal.pmed.0040178

Contact: Anne A. Oplinger

NIH/National Institute of Allergy and Infectious Diseases Continue reading

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Bad Backs Are Headed Back To School: Overloaded Backpacks To Blame For Back Pain In Children

As children head back to school, they may be expanding their minds but there is a good chance they’re also damaging their bodies. Back pain, historically an adult affliction, is now becoming common among school-aged children and studies show a direct correlation between backpacks and back pain in children.

In a recent study by Children’s Hospital Los Angeles and the Keck School of Medicine at the University of Southern California, 37% of the children studied reported back pain, with 82% of these kids believing their backpack either caused or worsened their pain. Of the children reporting back pain, 34% limited their activity due to the pain. The study also found children with lockers reported less back pain.

Separate studies have also found that girls suffer back pain more often and more intense than boys, and the onset of pain often correlates just prior to the onset of puberty.

“Probably most disturbing about these findings is the fact that back pain in children and adolescents is very likely a precursor to low back pain as an adult,” said Anthony Carey, founder and CEO of Function First, a company that helps people eliminate back pain, joint pain and chronic pain through a form of exercise called corrective exercise. “It also concerns us that back pain is limiting activity in children. Children need structured exercise programs just like adults. We need to look at the relationship of back pain in kids with the increase in childhood obesity and sedentary lifestyles,” added Carey.

The study findings identify two changes to address the problem: 1) increasing the availability of school lockers; and 2) lighter backpacks. Carey also points out that The American Physical Therapy Association, American Academy of Orthopedic Surgeons and the American Chiropractic Association provide backpack weight limit guidelines. Recommendations are based on the child’s weight and are as follows:

– A 60 lb. child can carry a maximum backpack weight of 5 lbs.
– 60-75 lbs. can carry 10 lbs.
– 100 lbs. can carry 15 lbs.
– 125 lbs. can carry 18 lbs.
– 150 lbs. can carry 20 lbs.
– 200 lbs. can carry 25 lbs.

Anthony Carey, M.A., CSCS, CES is the author of “The Pain-Free Program” and the founder and CEO of Function First, Inc. Function First provides a variety of corrective exercise products and services that provide pain relief for those with back pain, neck pain, joint pain and chronic pain. Carey, a continuing education provider for the American Council on Exercise, the National Strength and Conditioning Association, the American College of Sports Medicine, and the National Academy of Sports Medicine also trains health and fitness professionals in his methods of corrective exercise. For more information about Anthony Carey and Function First, please visit FunctionFirst Continue reading

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NSF Funding In Basic Research Yields Great Payoffs In Scientific Contributions Worldwide

The National Science Foundation (NSF) congratulates the 2009 Nobel laureates, particularly those who have received NSF funding over the years: Jack W. Szostak, who shared the prize in physiology or medicine; Thomas A. Steitz, who shared the prize in chemistry; and Elinor Ostrom and Oliver E. Williamson who earned the Sveriges Riksbank Prize in economic sciences in memory of Alfred Nobel 2009.

“Through a highly competitive, merit-based system, NSF is in the business of identifying raw scientific talent early, funding promising research and fueling discovery,” said Arden L. Bement, Jr., NSF director. “This year’s Nobel Prize recipients embody the investment of America and of the NSF in talented and hardworking researchers whose contributions improve the global future for society and mankind.”

Now a total of 187 U.S. and U.S.-based researchers have had their research pursuits funded by NSF earlier in their careers, before their research became widely recognized and they became Nobel laureates.

The NSF-funded 2009 laureates were recognized for the following research:

Jack W. Szostak – Nobel Prize in Physiology or Medicine

Jack W. Stostak shared the Nobel Prize in Physiology or Medicine with Carol W. Greider and Elizabeth H. Blackburn “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.”

Together, they have solved a major problem in biology: how chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. The Nobel Laureates have shown that the solution is to be found in the ends of the chromosomes–the telomeres–and in an enzyme that forms them–telomerase.

The long, thread-like DNA molecules that carry our genes are packed into chromosomes, the telomeres being the caps on their ends. Elizabeth Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects the chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase.

If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life. Certain inherited diseases, in contrast, are characterized by a defective telomerase, resulting in damaged cells. The award of the Nobel Prize recognizes the discovery of a fundamental mechanism in the cell, a discovery that has stimulated the development of new therapeutic strategies.

The discoveries by Blackburn, Greider and Szostak have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies.

To date, NSF has funded 42 researchers who earned Nobel Prizes in Medicine.

Thomas A. Steitz – Nobel Prize in Chemistry

Thomas A. Steitz, shared the Nobel Prize in Chemistry with Venkatraman Ramakrishnan and Ada E. Yonath “for studies of the structure and function of the ribosome,” one of life’s core processes, the ribosome’s translation of DNA information into life. Ribosomes produce proteins, which in turn control the chemistry in all living organisms. As ribosomes are crucial to life, they are also a major target for new antibiotics.

Ramakrishnan, Steitz and Yonath showed what the ribosome looks like and how it functions at the atomic level. All three have used a method called X-ray crystallography to map the position for each and every one of the hundreds of thousands of atoms that make up the ribosome.

Inside every cell in all organisms, there are DNA molecules. They contain the blueprints for how a human being, a plant or a bacterium, looks and functions. But the DNA molecule is passive. If there was nothing else, there would be no life.

The blueprints become transformed into living matter through the work of ribosomes. Based upon the information in DNA, ribosomes make proteins: oxygen-transporting haemoglobin, antibodies of the immune system, hormones such as insulin, the collagen of the skin, or enzymes that break down sugar. There are tens of thousands of proteins in the body and they all have different forms and functions. They build and control life at the chemical level.

An understanding of the ribosome’s innermost workings is important for a scientific understanding of life. This knowledge can be put to a practical and immediate use; many of today’s antibiotics cure various diseases by blocking the function of bacterial ribosomes. Without functional ribosomes, bacteria cannot survive. This is why ribosomes are such an important target for new antibiotics.

This year’s three Laureates have all generated 3D models that show how different antibiotics bind to the ribosome. These models are now used by scientists in order to develop new antibiotics, directly assisting the saving of lives and decreasing humanity’s suffering.

To date, NSF has funded 48 researchers who earned Nobel Prizes in Chemistry.

Elinor Ostrom and Oliver E. Williamson – Nobel Prize in Economics

Elinor Ostrom earned the Nobel Prize in Economics “for her analysis of economic governance, especially the commons,” and Oliver E. Williamson also earned the Nobel Prize in Economics “for his analysis of economic governance, especially the boundaries of the firm.”

Ostrom has demonstrated how common property can be successfully managed by user associations. Oliver Williamson has developed a theory where business firms serve as structures for conflict resolution. Over the last three decades these seminal contributions have advanced economic governance research from the fringe to the forefront of scientific attention.

Economic transactions take place not only in markets, but also within firms, associations, households, and agencies. Whereas economic theory has comprehensively illuminated the virtues and limitations of markets, it has traditionally paid less attention to other institutional arrangements. The research of Ostrom and Williamson demonstrates that economic analysis can shed light on most forms of social organization.

Ostrom has challenged the conventional wisdom that common property is poorly managed and should be either regulated by central authorities or privatized. Based on numerous studies of user-managed fish stocks, pastures, woods, lakes, and groundwater basins, Ostrom concludes that the outcomes are, more often than not, better than predicted by standard theories. She observes that resource users frequently develop sophisticated mechanisms for decision-making and rule enforcement to handle conflicts of interest, and she characterizes the rules that promote successful outcomes.

Williamson has argued that markets and hierarchical organizations, such as firms, represent alternative governance structures which differ in their approaches to resolving conflicts of interest. The drawback of markets is that they often entail haggling and disagreement. The drawback of firms is that authority, which mitigates contention, can be abused. Competitive markets work relatively well because buyers and sellers can turn to other trading partners in case of dissent. But when market competition is limited, firms are better suited for conflict resolution than markets. A key prediction of Williamson’s theory, which has also been supported empirically, is therefore that the propensity of economic agents to conduct their transactions inside the boundaries of a firm increases along with the relationship-specific features of their assets.

To date, NSF has funded 41 researchers who earned Nobel Prizes in Economics.

A complete list of all NSF-funded Nobel Prize winners to date is posted at: nsf/news/news_summ.jsp?cntn_id=100683.

Source:
Lisa-Joy Zgorski

National Science Foundation Continue reading

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New Buffer Resists PH Change, Even As Temperature Drops

Researchers at the University of Illinois have found a simple solution to a problem that has plagued scientists for decades: the tendency of chemical buffers used to maintain the pH of laboratory samples to lose their efficacy as the samples are cooled. The research team, headed by chemistry professor Yi Lu, developed a method to formulate a buffer that maintains a desired pH at a range of low temperatures.

The study appears this month in Chemical Communications.

Scientists have known since the 1930s that the pH of chemical buffers that are used to maintain the pH of lab samples can change as those samples are cooled, with some buffers raising and others lowering pH in the cooling process.

Freezing is a standard method for extending the shelf life of biological specimens and pharmaceuticals, and biological samples are routinely cooled to slow chemical reactions in some experiments. Even tiny changes in the acidity or alkalinity of a sample can influence its properties, Lu said.

“We like to freeze proteins, nucleic acids, pharmaceutical drugs and other biomolecules to keep them a long time and to study them more readily under very low temperatures using different spectroscopic techniques and X-ray crystallography,” Lu said. “But when the pH changes at low temperature, the sample integrity can change.”

Graduate student Nathan Sieracki demonstrated this by repeatedly freezing and thawing oxacillin, a penicillin analog used to treat infections.

“After one freeze-thaw 50 percent of the drug was dead in several of the buffers investigated,” Sieracki said.

Sieracki was able to demonstrate that the loss of activity was due to changes in pH and not a result of the temperature changes.

To find a buffer that would maintain a stable pH at varying temperatures, Sieracki first evaluated the behavior of several commonly used buffers over a range of temperatures. He saw that some buffers became more alkaline at lower temperatures while others grew more acidic.

These observations led to an obvious methodology: “Why don’t we just mix them together”” Sieracki said.

Little by little, he varied the proportions of the combined buffers until he found a formula that exhibited minimal pH changes at a variety of temperatures. Instead of registering changes of 2 or more pH units while cooling, which was typical of some standard buffers, the new formula changed less than 0.2 pH units during cooling, he said.

“We’re canceling out 100-fold changes in proton concentration and bringing them down within an order of magnitude,” Sieracki said.

The creation of a temperature-independent pH (TIP) buffer could have broad implications for new – and previously published – research, Lu said.

“We’re not in the business of looking at the literature and correcting other mistakes,” he said. “But some of the conclusions from previous studies could be on shaky ground if a buffer was used that changed pH dramatically at low temperatures.”

The new buffer is immediately useful for biological research, and Sieracki said he is confident that a similar buffer could be made for use in many fields, such as biochemistry, biophysics, chemical biology and biomedical research.

Lu also is affiliated with the Beckman Institute.

Source: Diana Yates

University of Illinois at Urbana-Champaign Continue reading

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Discovery Of Gatekeepers In The Human Cell ‘Shredder’ Could Lead To A New Target For Cancer Drugs

Insulin, a hormone released in large quantities when food is consumed, is reduced by 50% only three to five minutes later. However, if the cell’s internal waste disposal system malfunctions, illnesses such as Alzheimer’s or Parkinson’s disease may occur. To prevent this from happening, the complex process of protein degradation first needs to be fully understood at an atomic level so that appropriate drugs can be developed. Biochemists at Frankfurt University, collaborating with an international team of scientists have just taken an important step towards unravelling the workings of this mechanism. In the current edition of the scientific journal Nature they report finding the long-awaited receptor for ubiquitin on the proteasome. This receptor may well turn out to have a key role in fighting tumours.

“A discovery of this kind happens only once in a researcher’s lifetime” comments Professor Ivan Dikic, in whose group at the Institute for Biochemistry the significant finding was made. The editors of “Nature” agree and have accepted two manuscripts describing this discovery: an article (leading manuscript in the issue) and a letter (regular publication). The Institute’s director Professor Werner MГјller-Esterl states “We are delighted by his success of a member of our Cluster of Excellence on Macromolecular complexes. This sort of recognition is only achieved by one in a thousand scientists”.

However, things were looking very different only a year ago when it appeared that the research groups involved in this project – in Frankfurt, Munich, Minnesota and Harvard – were treading water. The scientists were hoping to solve structure of the portal protein from yeast using protein crystallography but the protein refused to crystallize. However, Koraljka Husnjak, a postdoctoral researcher found a way to isolate the ubiquitin binding domain in the mammalian protein, that was amenable for rapid crystallization and subsequent determination of its structure.

Already some 30 years ago, the basic mechanism of cellular waste disposal was elucidated by three scientists, Aaron Ciechanover, Avram Hershko, and Irwin Rose, for which they won Nobel Prize in Chemistry in 2004. Since then it has been known that proteins due for disposal are marked with ubiquitin molecules, which are present throughout the cell. They reach the barrel-like proteasome complex via ‘shuttle’ molecules or through diffusion. On the upper side of the proteasome there is a kind of gatekeeper’s lodge with a narrow entrance leading to an inner chamber, where aggressive enzymes cleave the protein. But first the protein is subjected to a strict control procedure to ensure that it is indeed destined for the shredder. If the gatekeeper – a receptor – recognizes that the protein is tagged with ubiquitin, the tagged protein is unfolded and can then pass through the narrow opening. While this takes place the ubiquitin separates from the protein, ready to be re-used. Until now, only one such gatekeeper, a proteasomal receptor called Rpn 10, was known. The scientists then conducted experiments to genetically remove Rpn 10 from the cell and were surprised to discover that the proteasome continued to function normally. This led them to suspect that there must be an additional protein in the cell, which compensates in the absence of Rpn 10 and serves a similar purpose. This has now been discovered: protein Rpn 13.

According to Koraljka Husnjak the first breakthrough occurred about four years ago, when they found out that ubiquitin binds to a subunit in the gatekeeper’s lodge. “So it became clear to us that the proteasome subunit might act as ubiquitin receptor on the proteasome. But first of all we had to clarify this binding site’s function and understand the details of the binding process at an atomic level”. Ivan Dikic then asked other leading international groups for their expertise in helping to solve this complex research problem. The X-ray structural analysis was carried out by Prof. Michael Groll and his group at the Technical University in Munich, and a group led by Prof. Kylie Walters at the University of Minnesota, Minneapolis undertook the NMR structure work. As soon as the binding mechanism had been understood at an atomic level, Professor Finley and his group at Harvard Medical School conducted experiments with various yeast strains in which they were able to prove that in living cells the process was indeed identical to that already suggested by the structural model.

The discovery of this second receptor on the proteasome is of particular significance in cancer research since it has the potential to be blocked by specific drugs. This would then prevent the proteins in the cell from being broken down. Since developing cancer cells depend on the breakdown of specific proteins in signalling cascades, which appear critical for tumour cell survival and proliferation, the cancer cells would no longer be able to multiply. It is likely that both these receptors react selectively to certain groups of proteins. So even if one is blocked, the other continues to ensure that the proteins that are no longer needed nevertheless still gain access to the proteasome.

Source: Professor Dr. Ivan Dikic

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Shape Matters In The Case Of Cobalt Nanoparticles

Shape is turning out to be a particularly important feature of some commercially important nanoparticles – but in subtle ways. New studies* by scientists at the National Institute for Standards and Technology (NIST) show that changing the shape of cobalt nanoparticles from spherical to cubic can fundamentally change their behavior.

Building on a previous paper** that examined the properties of cobalt formed into spheres just a few nanometers in diameter, the new work explores what happens when the cobalt is synthesized instead as nanocubes. Nanoparticles of cobalt possess large magnetic moments – a measure of magnetic strength – and unique catalytic properties, and have potential applications in information storage, energy and medicine.

One striking difference is the behavior of the two different particle types when external magnetic fields are applied and then removed. In the absence of a magnetic field, both the spherical and cubic nanoparticles spontaneously form chains – lining up as a string of microscopic magnets. Then, when placed in an external magnetic field, the individual chains bundle together in parallel lines to form thick columns aligned with the field. These induced columns, says NIST physicist Angela Hight Walker, imply that the external magnetic fields have a strong impact on the magnetic behavior of both nanoparticle shapes.

But their group interactions are somewhat different. As the strength of the external field is gradually reduced to zero, the magnetization of the spherical nanoparticles in the columns also decreases gradually. On the other hand, the magnetization of the cubic particles in the columns decreases in a much slower fashion until the particles rearrange their magnetic moments from linear chains into small circular groups, resulting in a sudden drop in their magnetization.

The team also showed that the cubes can be altered merely by observing with one of nanotechnology’s microscopes of choice. After a few minutes’ exposure to the illuminating beam of a transmission electron microscope, the nanocubes melt together, forming “nanowires” that are no longer separable as individual nanoparticles. The effect, not observed with the spheres, is surprising because the cubes average 50 nm across, much larger than the spheres’ 10 nm diameters. “You might expect the smaller objects to have a lower melting point,” Hight Walker says. “However, the sharp edges and corners in the nanocubes could be the locations to initiate melting.”

While Walker says that the melting effect could be a potential method for fabricating nanostructures, it also demands further attention. “This newfound effect demonstrates the need to characterize the physico-chemical properties of nanoparticles extremely well in order to pursue their applications in biology and medicine,” she says.

Notes:

* G. Cheng, R.D. Shull and A.R. Hight Walker. Dipolar chains formed by chemically synthesized cobalt nanocubes. Journal of Magnetism and Magnetic Materials, May 11, 2009, Vol. 321, issue 10, pp. 1351-1355.

** G. Cheng, D. Romero, G.T. Fraser and A.R. Hight Walker. Magnetic-field-induced assemblies of cobalt nanoparticles. Langmuir, December 2005. See Oct. 20, 2007, Tech Beat article, “Magnetic Nanoparticles Assembled into Long Chains”.

Source:
Chad Boutin
National Institute of Standards and Technology (NIST) Continue reading

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Glivec Helps 90% Of Myeloid Leukaemia Patients Live 5 Years Or More

Clinical trial results show that Glivec helps 90% of patients with myeloid leukaemia survive for five years or more. In the UK the National Institute of Clinical Excellence (NICE) only wanted to approve its use for patients with advanced myeloid leukaemia. Patients with gastrointestinal stromal tumours also seem to benefit from Glivec.

Having a patient on Glivec costs the UK National Health Service (NHS) about Ј14,000 per year ($26,000). In the UK the state pays for medical treatment. There are 600 patients with Chronic Myeloid Leukaemia (CML) in the UK.

In 2002, NICE advised only giving Glivec to some CML patients. After lots of lobbying, NICE increased the number of people who could receive it.

Myeloid leukaemia is a form of blood cancer, there is a defect in the production of white blood cells in the bone marrow. Glivec attacks molecules that cause the cancer while leaving other healthy cells intact. Unlike chemotherapy, which has unpleasant side-effects, Glivec doesn’t.

A recent clinical trial, called IRIS, funded by Glivec makers Novartis, found that 93% of newly diagnosed ML (myeloid leukaemia) patients taking Glivec did not then go on to develop more advanced stages of the cancer. 83% of all patients on the trial survived for five years with no evidence that their disease had progressed. Just 4.6% of the trial participants died as a result of ML progression. In the first year of treatment 69% of patients responded well to treatment, on the fifth year 87% responded well.

Without Glivec, ML advances from within 4 to 6 years. Prognosis is not good.

Patients with advanced GISTs (Gastrointestinal Stromal Tumours) would normally expect to survive about 15 months with chemotherapy treatment. With Glivec treatment they survived an average of 58 months.

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