Biochemistry and Bioinformatics

New Detection Technology Identifies Bacteria, Viruses, Other Organisms Within 24 Hours

2010-05-06T02:55:00.000-07:00

Law enforcement authorities seeking to detect bioterrorism attacks, doctors diagnosing diseases and regulatory agencies checking product safety may find a new ally in a Lawrence Livermore National Laboratory (LLNL) detection technology.

The advance, known as the Lawrence Livermore Microbial Detection Array (LLMDA), could enable law enforcement, medical professionals and others to detect within 24 hours any virus or bacteria that has been sequenced and included among the array's probes.

Developed between October 2007 and February 2008, the LLMDA detects viruses and bacteria with the use of 388,000 probes that fit in a checkerboard pattern in the middle of a one-inch wide, three-inch long glass slide.

The current operational version of the LLMDA contains probes that can detect more than 2,000 viruses and about 900 bacteria.

"The ability to detect the major bacterial and viral components of any sample can be used in countless different ways," said Tom Slezak, LLNL's associate program leader for Informatics. "This is important because it fills a cost-performance gap that is relevant to many missions: biodefense, public health and product safety."

In the area of biodefense, current systems are centered upon the detection of smaller prioritized sets of high-risk pathogens, rather than testing for a much broader spectrum of organisms.

"The LLMDA allows us to not only identify the biological pathogens on a priority screening list, but also any other already-sequenced bacteria or virus in a sample that you might not have been expecting to find, including possible novel or emerging pathogens," Slezak said.

Current plans call for the detection array to be evaluated for operational bioforensic use at the Frederick, Md.-based National Biodefense Analysis and Countermeasures Center of the U.S. Department of Homeland Security.

As the cost of the array is reduced, the LLMDA technology could be used to improve public health diagnostics, Slezak said, adding that dozens of bacteria and viruses can be detected in a single test from the entire spectrum of sequenced organisms.

One advantage of the Livermore array is that it provides researchers with the capability of detecting pathogens over the entire range of known viruses and bacteria. Current multiplex polymerase chain reaction (PCR) techniques can at most offer detection from among 50 organisms in one test.

In April, in a Journal of Virology article, Livermore researchers working with a scientist from the San Francisco-based Blood Systems Research Institute said they used the LLMDA technology to confirm the presence of an apparently benign pig virus in a vaccine.

The pig virus, porcine circovirus-1 (PCV-1), was unexpectedly found in GlaxSmithKline's Rotarix vaccine, which is used to prevent diarrhea in babies.

"One result of this research is that it demonstrates how modern technologies could change and drastically improve product safety," Slezak said.

While product safety rules require demonstrating that a list of known contaminants is not present, Slezak said the use of modern advances in DNA sequencing and arrays would allow manufacturers to identify the potential presence of contaminating biological material present in quantities large enough to be of potential concern.

"For each bacteria or virus that has been sequenced anywhere in the world, we have several dozen squares on the checkerboard that will identify sequences from that organism," Slezak explained.

Currently, Slezak's team is testing a next-generation LLMDA that boasts 2.1 million probes. This version contains probes representing about 178,000 viral sequences from some 5,700 viruses, and about 785,000 bacterial sequences from thousands of bacteria.

The latest LLMDA version also encompasses fungi and protozoa -- with probes representing about 237,000 fungal sequences from thousands of fungi and about 202,000 protozoa sequences from 75 protozoa.

As a screening tool, Slezak sees the LLMDA as occupying niche roles between PCR machines and sequencing.

The LLMDA process starts with the purification of DNA or RNA from a sample, such as sputum or blood. The sample is next labeled with a fluorescent dye and hybridized on the microarray at 42 degrees C or about 107.6 degrees Fahrenheit. In turn, a fluorescent scanner and analysis software are used to detect the probes that have lit up, identifying the presence of viral or bacterial sequences.

The Livermore team plans to update probes on the array with new sequences of bacteria, viruses and other microorganisms from GenBank and other public databases about once per year, in addition to using sequences obtained from collaborators for their probes.

LLNL's current collaborators include the University of California, San Francisco; the Blood Systems Research Institute; the University of Texas Medical Branch (Galveston); the National Institute for Public Health and the Environment of Bilthoven, the Netherlands; the Statens Serum Institut of Copenhagen, Denmark; the University of California, Davis; Imigene; the U.S. Food & Drug Administration; and the Marine Mammal Center of Sausalito, Calif.

A computer scientist and the team's leader, Slezak came up with the idea for the LLMDA in 2003. His team includes biologist Crystal Jaing, who leads the microarray lab work and manages the collaborations; bioinformaticist Shea Gardner, who designed the array; biostatistician Kevin McLoughlin, who designed the analysis software; and James B. Thissen, who performs the microarray experiments.

Story Source:

Adapted from materials provided by DOE/Lawrence Livermore National Laboratory, via EurekAlert!, a service of AAAS.

Journal Reference:

J. G. Victoria, C. Wang, M. S. Jones, C. Jaing, K. McLoughlin, S. Gardner, E. L. Delwart. Viral nucleic acids in live-attenuated vaccines: detection of minority variants and an adventitious virus.. Journal of Virology, 2010; DOI: 10.1128/JVI.02690-09

Courtesy: ScienceDaily

osteoarthritis (OA)

2010-01-03T11:28:00.000-08:00

People whose index finger is shorter than their ring finger are at higher risk of osteoarthritis, a new University of Nottingham study has found.

A study of more than 2,000 people suggests that people whose index finger is shorter than their ring finger are up to twice as likely to suffer from the condition, which is the most common form of arthritis.

Index to ring finger length ratio (referred to as 2D:4D) is a trait known for its differences between the sexes. Men typically have shorter second than fourth digits; in women, these fingers tend to be about equal in length. Smaller 2D:4D ratios have intriguing hormonal connections, including higher prenatal testosterone levels, lower oestrogen concentrations, and higher sperm counts. Reduction in this ratio has also been linked to athletic and sexual prowess.

Whether this trait affects the risk of osteoarthritis (OA), the most common form of arthritis that may associate with both physical activity and oestrogen deficiency, has not been examined — until now.

Researchers at The University of Nottingham conducted a case-control study to assess the relationship between the 2D: 4D ratio and the risk of knee and hip OA. Their findings suggest that having a relatively long ring finger to index finger ratio raises the risk for developing OA of the knee, independent of other risk factors and particularly among women.

For the study, 2,049 case subjects were recruited from hospital orthopaedic surgery lists and a rheumatology clinic in Nottingham. All had clinically significant symptomatic OA of the knees or hips, requiring consideration of joint replacement surgery. Recruited from hospital lists of patients who had undergone intravenous urography (IVU) within the past five years, 1,123 individuals with no radiographic evidence of hip or knee OA, no present hip or knee symptoms, and no history of joint disease or joint surgery served as a control group.

The study population was comprised of both men and women, with an average age of approximately 67 years for cases and 63 years for controls.

Radiographs of both knees and the pelvis were obtained for all participants. Every participant also underwent separate radiographs of the right and left hands. Researchers then assessed the 2D:4D length ratio from radiographs using three methods: a direct visual comparison of the two finger ends, the measured ratio from the base to the tip of the upper finger joints, and the measured ratio of the metacarpal bone lengths.

Hands radiographs were classified visually as either type 1, index finger longer than the ring finger; type 2, index finger equal to the ring finger; or type 3, index finger shorter than the ring finger. Not surprisingly, men were 2.5 times more likely than women to have the type 3 pattern.

Using blind comparisons of hand radiographs with both knee and hip radiographs from random case and control samples combined with statistical analysis and odds ratios, researchers assessed the relationship between 2D:4D length ratio and OA. Compared with the other finger types, the type 3 finger was associated with an increased risk of OA involving any part of the knee or the hip, and including the presence of arthritic finger nodes. Of particular note, the risk of knee OA in participants with the type 3 finger pattern was nearly double that of the risk for participants without this pattern. Women with this finger pattern had a greater risk of knee OA than men.

Among participants of both sexes, researchers also found an interesting trend: the smaller the 2D:4D upper finger joint ratio, the greater the risk of OA of the tibiofemoral knee joint. Finally, after adjusting for established OA risk factors — age, sex, body mass index, joint injury, and lack of physical activity — the strong association of smaller 2D:4D length ratio with the risk for knee OA was deemed independent.

Professor Michael Doherty, lead researcher, said: “The 2D:4D length ratio appears to be a new risk factor for the development of OA. Specifically, women with the 'male' pattern of 2D:4D length ratio — that is, ring finger relatively longer than the index finger — are more likely to develop knee OA.”

As the first study to examine the relationship between 2D:4D length ratio and OA, it also raises questions.

“The underlying mechanism of the risk is unclear,” Professor Doherty stressed, “and merits further exploration.”

Journal article: "Index to Ring Finger Length Ratio and the Risk of Osteoarthritis," W. Zhang, J. Robertson, S. Doherty, J.J. Liu, R.A. Maciewicz, K.R. Muir, and M. Doherty, Arthritis & Rheumatism, January 2008; 58:1.

Courtesy: ScienceDaily

The ten most exciting tools to hit the life sciences this year.

2010-01-01T10:42:00.000-08:00

It’s been a tough year for every industry, and the life sciences are no exception. Yet companies and academic laboratories across the globe have developed innumerable new products designed to take your research to the next level. But with many lab budgets tighter than last year, which technologies are worth the investment?

That’s why, for the second year in a row, we have gathered a panel of expert judges to pick the year’s best innovations to hit the life sciences market in the past year. This year’s winners run the gamut from imaging, genomics, and other tools that stunningly capture both intracellular and extracellular processes. Our judges—Steven Wiley, Jean Wang, Shawn Levy, and David Piston—are all known for pushing the technical boundaries, and have collectively published more than 600 academic papers.

It may have been a tough year for industry in general, but it was a great one for life science innovation.

1. Pluripotency from proteins

This year’s most exciting innovation, announced in April, circumvents the complications that come with the most common technique for reprogramming cells to an embryonic-like state. For the first time, Sheng Ding of Scripps Research Institute in La Jolla, Calif., and his colleagues induced pluripotency in mouse embryonic fibroblast cells using only proteins, avoiding genetic modification altogether.

“The iPS cell technology was really a breakthrough discovery, but genetic modification [poses] tremendous hurdles for practical applications,” including the potential to cause diseases such as cancer, says Ding.

The team struggled with the idea for nearly 2 years before finding the right conditions and the perfect combination of ingredients, which included the protein form of Shinya Yamanaka’s four transcription factors, as well as a histone deacetylase inhibitor known to enhance reprogramming efficiency (Cell Stem Cell, 4(5):381–84, 2009).

San Diego–based Fate Therapeutics, of which Ding is a founder, holds the exclusive license for the protein-induced stem cell technology and the specialized cells derived from it. The technology—which could consist of the solution of proteins with validated protocols or the pluripotent cells themselves—is not commercially available yet, but is being developed “in association with partners,” says Fate CFO Scott Wolchko.

Wolchko declined to comment on the cost other than to say that it will depend on “the ultimate application of the technology,” with the most basic applications such as toxicology testing and the development of reagents at the low end of the price scale, and more advanced drug development and cell therapy applications costing a bit more.

2. Quick pathogen ID

When facing an outbreak of an unknown, deadly pathogen, any delay costs lives. So in the 1990s, during a government-run meeting on biodefense, David Ecker was disappointed by the best ideas being offered for pathogen detection. “They were talking about the Gram stain,” Ecker recalls.

At the time Ecker, at Ibis Biosciences, had been using mass spectrometry to test drug candidates for their ability to bind to RNA, by comparing the atomic weight of a bound RNA to an unbound (lighter) molecule. He figured, why not use the tool to identify genomes based on their different weights? “If we could measure a small molecule sticking to a nucleic acid, I could just measure a nucleic acid.”

The trick was to design PCR primers for conserved areas in a viral or bacterial genome, making them universal for an entire class of pathogens. The part of the genome sandwiched by the primers and amplified by PCR would be variable enough to distinguish a particular strain and subtype within each class of pathogen.

While it hasn’t been approved for clinical trials or diagnostics yet, the machine is being used for testing basic mutation rates in viruses, forensics, and other applications, including being used by the U.S. Navy and Centers for Disease Control and Prevention to identify the new H1N1 virus.

After their acquisition by Abbott Laboratories late last year, Ibis and Abbott engineers designed a sleeker version of the machine called the PLEX-ID, which the Wall Street Journal dubbed the Innovation of the Year. The tool costs more than $100,000, and $30–$40 per sample.

3.Manipulate cells using light

There’s an ever-growing armament of tools for tagging proteins to watch cellular events unfold, but until recently, researchers lacked ways to experimentally manipulate those events with the same molecular-level precision. A handful of genetically encoded light-sensitive systems have now been reported that do just that, but most require a heavy dose of protein engineering.

Wendell Lim and his colleagues at the University of California, San Francisco, may have found a solution. Normally, the light-sensitive plant protein phytochrome and its binding partner, phytochrome interaction factor (PIF), link up and translocate to the nucleus in response to red light; infrared light breaks the bond. The researchers modified the genes so that the pair, when activated, instead moved to the cell membrane. They then linked PIF to a cytoskeletal protein. Spatially targeted pulses of red light flipped on PIF, which in turn activated the cytoskeletal protein, reshaping the cell (Nature, 461:997–1001, 2009).

Phytochrome “converts light into a protein-protein interaction,” says Lim. Researchers can link PIF to any number of proteins, potentially making the system applicable to a broader array of cell processes than other light-controlled systems, he adds.

The group submitted the mutant phytochrome and PIF plasmids to Addgene, a nonprofit plasmid repository that facilitates distribution of plasmids among the scientific community. Researchers can request the plasmids for about $65 each.

4. A camera that quantifies

Measuring and comparing the level of fluorescence emanating from proteins, capturing co-localization events at membranes, and depicting viral entry are the bread and butter of cell biologists, who often measure these phenomena using electron-multiplying charge-coupled device (EMCCD) cameras. But these devices spit out figures in units of measurement that are essentially arbitrary, dependent on gain settings that can vary from camera to camera or over time. This means that imaging data is basically irreproducible within and across labs.

The Evolve camera, however, makes imaging data quantifiable and reproducible by measuring images in units of photoelectrons, which result when photons from fluorescent proteins or reflected light hit the camera’s sensors. This overlays detailed images with quantitative, standardized data on how many photoelectrons were captured per pixel.

“What we want is for scientists to realize the value of this and start using that unit of measure,” says Deepak Sharma, senior product manager at Photometrics, which released the camera at the end of February.

Sharma won’t say exactly how many Evolves Photometrics has sold so far, but says that the number sold this year is “not in the thousands yet.” Sharma says that the cost of a new Evolve varies according to geography, but that it is “comparable” to EM cameras with a similar CCD, which can go for upwards of $30,000. “We feel that in 4 or 5 years this is going to have changed the direction of imaging science—standardized it.”

5. Zinc fingers create knockout rat

Sigma-Aldrich took the bronze in last year’s competition for their CompoZr zinc finger nuclease (ZFN) service, which initiates double-strand DNA breaks at specific sites to knock out even a single base pair. This year the company follows up with the first fruit of that platform—the knockout rat.

“We all knew how well CompoZr worked in cell lines, and the natural extension was to use that in vivo,” says Edward Weinstein, director of the company’s Sigma Advanced Genetic Engineering (SAGE) Labs.

This year, Medical College of Wisconsin researchers used custom zinc-finger nucleases from Sigma to create the first targeted knockout rats, some of which glowed green with the expression of a fluorescent protein, such as GFP. Now rodents beyond mice can be developed into models of specific human diseases.

Dave Smoller, president of Sigma’s research biotech business unit, says that Sigma can make custom zinc finger nucleases for $25,000–$35,000, but that as different proteins are validated and “put on the shelf,” the price could come down for some commonly targeted genes. Weinstein said that SAGE Labs aims to sell rat models of human diseases for “a reasonable price,” but declined to be more specific, and will take orders for custom knockout rats. SAGE has already inked a deal with the Michael J. Fox Foundation to create a panel of five different knockout rats that lack genes implicated in Parkinson’s disease.

6. All-in-one microscopes

This year saw the introduction of two new all-in-one microscope systems from Olympus: the FluoView FV10i, the world’s first self-contained confocal microscope, which can be used for creating 3D views of a specimen, and the FSX100, a self-contained fluorescence and brightfield microscope, the first of its kind commercially available in the United States. Both systems combine the illumination systems, microscopes, movable stages, and cameras all into a simple little box.

“They don’t look like anything that is typical for scientists,” says Mark Clymer, a product manager for Olympus. The fact that they are self-contained means they “can be installed just about anywhere.” Furthermore, he adds, these systems hold a particular advantage “for fluorescence imaging, which is typically done in dark rooms, [as] it can be done in the laboratories [with] the lights on.”

The FSX100 costs $55,000, and the FluoView FV10i runs $147,000 for the oil-based model and $167,000 for the water immersion version, optimal for live cell imaging.

In addition, both microscopes are completely “software driven,” meaning they are extremely logical and can be easily navigated, even by first-time users. “Someone could sit down and really without any guidance can generate publication-quality images in minutes,” Clymer says, making these microscopes particularly useful in multiuser facilities.

7. New sequence capture tool

Scientists have a plethora of invaluable genomic data—3 billion base pairs’ worth—but no way to use it. The genome has been too large and cluttered for researchers to fully analyze the information. Now HybSelect, launched by the Germany-based company febit in March, uses DNA microarrays to narrow in on regions of the genome that play an important role in a particular disease. The technology has already been used to study cancer, multiple sclerosis, Alzheimer’s, and diabetes.

“It lets us dissect a large genome and isolate the juicy bits that can be used to research diseases,” says Peer Stähler, febit’s chief scientific officer and a former microbiologist at the Max Planck Institute for Brain Research.

Researchers interested in isolating specific DNA sequences have two options: they can either send their samples to febit or buy the HybSelect technology themselves. Samples isolated at febit are sent back to researchers with tips on how to best sequence the genes. In case researchers don’t have access to sequencing equipment, the company also offers next-generation sequencing, the whole process taking just 2 weeks and costing as little as $10,000 (for a pilot study), says Stähler. Labs interested in cutting down shipping time can also purchase a Geniom RT Analyzer, the company’s all-in-one microarray processing and analysis instrument, and Geniom Biochip, which contains the HybSelect application, for $150,000. The machine is relatively small (55.7 x 90.7 x 66.5 cm; 110 kg) and can process up to 16 samples a day.

8. New measure of metabolism

Invented by Seahorse Bioscience in Massachusetts, the XF96 Analyzer is the first instrument that can measure the two major energy pathways in cells—mitochondrial respiration and glycolysis—providing a comprehensive picture of cellular metabolism and how that process goes awry in disease. “Before this instrument, we could never do the magnitude or complexity of experiments,” says Steve Chomicz, vice president of sales & marketing at Seahorse Bioscience.

Prior to the XF96 Extracellular Analyzer, scientists relied on the Clark electrode technology for measuring cellular oxygen consumption, a time-consuming technique that provided minimal information. Now in just 35 to 90 minutes, the XF Analyzer can measure oxygen consumption—an indicator of mitochondrial respiration—as well as extracellular acidification, which is a byproduct of glycolysis. After isolating a small volume of cells in a microplate, the instrument can measure the change in dissolved oxygen and pH levels using optical biosensors. With the instrument’s 96 wells, researchers can test the effects of up to four drugs on cellular metabolism, elucidating the bioenergetics of the cell. Currently selling for $100,000 to $200,000, the machine was first released to users in January 2009, and now boasts more than 400 clients worldwide.

9. New recipe for protein expression

Synthetic genes are considered the most cost-efficient, timely, and flexible tool for achieving high levels of protein expression, a fundamental component of modern biotechnology research. But since different codons can produce the same amino acid, scientists have innumerable combinations to choose from when encoding a protein. And some combinations produce better results than others. Typically, researchers use anecdotal evidence to pick which set of codons will optimize protein expression, with hit-or-miss results. Now, scientists from the California-based company DNA2.0 have developed new design algorithms to predict the best set of codons to use based on actual gene characteristics. The system, described in the September issue of PLoS ONE, (4(9): e7002), produces protein expression up to 10 times better than previous approaches, says Mark Welch, the director of gene design for DNA2.0.

The team designed, synthesized, and expressed varied sets of genes encoding two different proteins (a DNA polymerase and a single-chain antibody) and, based on which codons produced the most protein, developed a design principle to predict the gene combinations that optimize protein expression.

The company made their E. coli algorithm free when they published it in PLoS ONE, but their yeast algorithm will cost up to $25,000 per year for use on an infinite number of genes, says Claes Gustafsson, the company’s vice president of sales and marketing. The price of already-made algorithms for other species varies depending on the size of the requesting institution and number of genes that need to be synthesized. The company can also develop algorithms for new hosts from scratch, but the process can take up to a year and cost between $100,000 and $250,000. The technology is still so new, Gustafsson says, that “the exact business plan is still up in the air.”

1o.Cell culture in 3D

The Benchtop BioLevitator, which combines an incubator and a centrifuge into a single unit, is one of the first 3D cell culture systems.

“This is a completely new kind of technology,” says Amy Schneck, assistant product manager of the Hamilton Company, which developed the instrument. Besides creating a 3D culture, which is closer to an in vivo environment, the BioLevitator also allows researchers to grow more cells in less time relative to 2D culture, Schneck adds. Global Cell Solutions, a partner company, developed a unique microcarrier—a matrix lined with proteins—that facilitates cell growth on the 3D surface.

The BioLevitator can grow four cell culture tubes at once and also contains internal magnets that keep cells suspended and homogenous. Multiple protein coatings support different cell lines. During the culture, each tube is monitored for carbon dioxide, temperature, cell density, and pH. When cultures are complete, all data can be transferred to a computer for analysis using the BioLevitator’s USB port.

At $35,000, this compact, multipurposed instrument is also environmentally friendly because it works more efficiently than 2D systems, reducing the use of harsh chemicals and labware required for other instruments. As a result, Hamilton estimates that the 3D system can cut annual costs by 60 percent when culturing 40 million Chinese hamster ovary cells per week. The BioLevitator will be available in December 2009.

Women Tend to Have Better Sense of Touch Due to Smaller Finger Size

2009-12-30T10:38:00.000-08:00

People who have smaller fingers have a finer sense of touch, according to new research in the Dec. 16 issue of The Journal of Neuroscience. This finding explains why women tend to have better tactile acuity than men, because women on average have smaller fingers.

"Neuroscientists have long known that some people have a better sense of touch than others, but the reasons for this difference have been mysterious," said Daniel Goldreich, PhD, of McMaster University in Ontario, one of the study's authors. "Our discovery reveals that one important factor in the sense of touch is finger size."

To learn why the sexes have different finger sensitivity, the authors first measured index fingertip size in 100 university students. Each student's tactile acuity was then tested by pressing progressively narrower parallel grooves against a stationary fingertip -- the tactile equivalent of the optometrist's eye chart. The authors found that people with smaller fingers could discern tighter grooves.

"The difference between the sexes appears to be entirely due to the relative size of the person's fingertips," said Ethan Lerner, MD, PhD, of Massachusetts General Hospital, who is unaffiliated with the study. "So, a man with fingertips that are smaller than a woman's will be more sensitive to touch than the woman."

The authors also explored why more petite fingers are more acute. Tinier digits likely have more closely spaced sensory receptors, the authors concluded. Several types of sensory receptors line the skin's interior and each detect a specific kind of outside stimulation. Some receptors, named Merkel cells, respond to static indentations (like pressing parallel grooves), while others capture vibrations or movement.

When the skin is stimulated, activated receptors signal the central nervous system, where the brain processes the information and generates a picture of what a surface "feels" like. Much like pixels in a photograph, each skin receptor sends an aspect of the tactile image to the brain -- more receptors per inch supply a clearer image.

To find out whether receptors are more densely packed in smaller fingers, the authors measured the distance between sweat pores in some of the students, because Merkel cells cluster around the bases of sweat pores. People with smaller fingers had greater sweat pore density, which means their receptors are probably more closely spaced.

"Previous studies from other laboratories suggested that individuals of the same age have about the same number of vibration receptors in their fingertips. Smaller fingers would then have more closely spaced vibration receptors," Goldreich said. "Our results suggest that this same relationship between finger size and receptor spacing occurs for the Merkel cells."

Whether the total number of Merkel cell clusters remains fixed in adults and how the sense of touch fluctuates in children as they age is still unknown. Goldreich and his colleagues plan to determine how tactile acuity changes as a finger grows and receptors grow farther apart.

The research was supported by the National Eye Institute and the Natural Sciences and Engineering Research Council in Canada.

Courtesy: Science Daily

Microcephaly Genes Associated With Human Brain Size

2009-12-28T05:51:00.000-08:00

A group of Norwegian and American researchers have shown that common variations in genes associated with microcephaly -- a neuro-developmental disorder in which brain size is dramatically reduced -- may explain differences in brain size in healthy individuals as well as in patients with neurological and psychiatric disorders.

The study, which involved collaboration between researchers from the University of Oslo, the University of California, San Diego and Scripps Translational Science Institute in La Jolla, California, will be published online the week of December 21 in the Proceedings of the National Academy of Science.

In relation to body size, brain size has expanded dramatically throughout primate and human evolution. In fact, in proportion to body size, the brain of modern humans is three times larger than that of non-human primates. The cerebral cortex in particular has undergone a dramatic increase in surface area during the course of primate evolution.

The microcephaly genes have been hot candidates for a role in the evolutionary expansion of the human brain because mutations in these genes can reduce brain size by about two-thirds, to a size roughly comparable to our early hominid ancestors. There is also evidence that four of the genes -- MCPH1, ASPM, CDK5RAP2 and CENPJ -- have evolved rapidly and have been subject to strong selective pressure in recent human evolution.

"It is obvious that such anatomical changes must have a basis in genetic alterations, said Lars M. Rimol, a research fellow at the University of Oslo. "Until now, little has been known about the molecular processes involved in this evolution and their genetic underpinnings. Now we have a piece of that genetic puzzle."

Several previous MRI studies have attempted to demonstrate a link between single polymorphisms (an inherited genetic variation that is found in more than one percent of the population) in these genes and brain size in healthy human adults, all of them unsuccessful. According to the research team, the success of the current study is likely due to two unique characteristics: first, by using a whole genome scan, the scientists could access an unprecedented number of polymorphisms, including non-coding regions outside of the gene itself; second, they were able to estimate cortical surface area, using software that reconstructs the cortical surface, based on volumetric MR scans, allowing for highly precise measurements of cortical thickness and areal expansion.

The software was developed by Anders Dale, PhD, professor of Radiology and Neurosciences at the UC San Diego School of Medicine, who headed the American branch of the research team. "The most statistically significant associations were consistently found with the areal expansion measure, which has implications also for future studies," said Dale.

The initial discovery was made in a sample of 289 psychiatric patients and controls from the Norwegian Thematically Organized Psychosis research project (TOP), led by Ole Andreassen from the University of Oslo, principal investigator of the Norwegian branch of the international research team. The most significant findings were then replicated in a sample of 655 healthy and demented patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the largest Alzheimer's disease study ever funded by the National Institutes of Health. The Norwegian sample was ethnically homogenous; the ADNI sample was ethnically diverse. According to the researchers, the fact that reported associations were found across two independent studies, including healthy controls and various patient groups, shows that these effects are likely to be independent of population or disease.

Highly significant associations were found between cortical surface area and polymorphisms in possible regulatory regions near the gene CDK5RAP2. This gene codes for a protein involved in cell-cycle regulation in neuronal progenitor cells -- cells that migrate to the cerebral cortex during the second trimester of gestation and eventually become fully functioning neurons. The cerebral cortex is the outer layer of the brain, often referred to as "gray matter." The most highly developed part of the human brain, the cerebral cortex is responsible for higher cognitive functions, such as thinking, perceiving, producing and understanding language, some of which is considered uniquely human.

Similar but less significant findings were made for polymorphisms in two other microcephaly genes, known as MCPH1 and ASPM. All findings were exclusive to either males or females but the functional significance of this sex-segregated effect is unclear.

"One particularly interesting feature of this new discovery is that the strongest links with cortical area were found in regulatory regions, rather than coding regions of the genes," said Andreassen. "One upshot of this may be that in order to further understand the molecular and evolutionary processes that have determined human brain size, we need to focus on regulatory processes rather than further functional characterization of the proteins of these genes. This has huge implications for future research on the link between genetics and brain morphology."

Additional contributors include Ingrid Agartz, Srdjan Djurovic, Andrew A. Brown, Anna K. Khäler,Morten Mattingsdal, Lavinia Athanasiu, Kjetil Sundet and Ingrid Melle of the University of Oslo, Norway; J. Cooper Roddey and Eric Halgren of UC San Diego; Alexander H. Joyner, of UC San Diego and Scripps Translational Science Institute;,and Nicholas J. Schork of Scripps Translational Science Institute.

Funding for this study was provided in part by the National Institutes of Health, Eastern Norway Health Authority and Research Council of Norway, and by the National Institute of Aging of the National Institutes of Health.

Exposure to Young Triggers New Neuron Creation in Females Exhibiting Maternal Behavior

2009-12-27T22:31:00.000-08:00

Maternal behavior itself can trigger the development of new neurons in the maternal brain independent of whether the female was pregnant or has nursed, according to a study released by researchers at Tufts University's Cummings School of Veterinary Medicine. These findings performed in adult, virgin rats were published in Brain Research Bulletin.

In the study, virgin, or nulliparous, rats were exposed to foster pups each day until they began to exhibit maternal behavior, including crouching over the young, grouping them, or retrieving them back to the nest. Data from the study showed that the nulliparous rats exposed to pups have increased numbers of new neurons.

The research was undertaken by Cummings School Department of Biomedical Sciences researchers Miyako Furuta and Robert Bridges, who is the head of the Cummings School's reproduction and neurobiology section.

Previous research has found that exposure to young can stimulate maternal behavior not only in rats, but also mice, hamsters, monkeys, and even humans. Increased creation of new neurons, or neurogenesis, has also been shown during pregnancy and lactation in rodents and associated with maternal behavior, but studies analyzing neurogenesis in nulliparous animals exhibiting maternal behavior had not been done. The area of the brain that was the focus of the present study was the subventricular region -- a region involved in the production of cells that affect odor recognition and possibly recognition of young. Bridges and Furuta found increased numbers of new neurons in the subventricular zone in adult, nulliparous rats that behaved maternally compared with numbers in subjects that either were not exposed to young or exposed to young, but did not behave maternally.

What stimulates increased new neuron production in the nulliparous mothers is not known. One possibility is that the hormone prolactin, which stimulates both the onset of maternal behavior as well as production of neurons during pregnancy, may play a role in the production of new neurons in nulliparous females exhibiting maternal behavior. However, this possibility remains to be investigated. A second possibility is that stimulation received from the young themselves may, in fact, play a crucial role in stimulating maternal neuron production.

"As with all scientific studies, these findings trigger more questions than answers," said Dr. Robert Bridges, section head of reproduction and neurobiology at Tufts University's Cummings School of Veterinary Medicine. "Next, we hope to determine what role this neurogenesis plays in terms of the female's behavior and physiological processes. Where do these new cells migrate to within the brain and what do they do? For example, do they affect how a female subsequently perceives her young through recognition of baby odors? These are the questions we hope to answer."

The study was funded by a National Institutes of Health grant.

Journal Reference:

Furuta et al. Effects of maternal behavior induction and pup exposure on neurogenesis in adult, virgin female rats. Brain Research Bulletin, 2009; 80 (6): 408 DOI: 10.1016/j.brainresbull.2009.08.011

Crystallographer faked data

2009-12-26T07:49:00.000-08:00

A protein researcher at the University of Alabama at Birmingham (UAB) has been found guilty of falsifying data that he used to construct 12 fraudulent protein structures that made it into the scientific literature and an international archive of protein structures.

After investigating the misconduct -- with the help of a committee of independent protein scientists -- the university has asked that the structures be removed from the database and that ten research papers, authored by former UAB researcher H.M. Krishna Murthy over the past decade, be retracted from the literature.

"What we know is that when Dr. Murthy was asked to provide the data behind the structures, there was not sufficient material presented to allow the expert panel to determine the source of the error," Richard Marchase, UAB's vice president for research and economic development, told The Scientist.

The UAB investigation concluded that the structures Murthy proposed violated basic physical and chemical laws, making their existence virtually impossible. "There were just many aspects of the proposed structures that didn't appear to be at all plausible given the physical laws of how proteins come together," added Marchase, who is also UAB's scientific integrity officer.

"I think [Murthy] deserves tarring and feathering," Gert Vriend, a bioinformatician at Radboud University Nijmegen Medical Centre in The Netherlands, told The Scientist.

Murthy, whose UAB contract at the school's Center for Biophysical Sciences and Engineering expired in February of this year with the university opting not to renew it, "has always denied any misconduct," according to Marchase. Murthy could not be reached for comment by email, and UAB is unaware of his current whereabouts.

According to Marchase, the university informed the Office of Research Integrity (ORI) of the U.S. Department of Health & Human Services that UAB was investigating Murthy's suspect structures, and presumably the ORI will now initiate their own investigation of Murthy. But the agency is not talking about the Murthy case yet. "We can neither confirm nor deny that we have such a case," wrote an ORI spokesperson in an email to The Scientist.

Murthy's fraud was uncovered when European crystallographers who were working on some of the same structures that Murthy was claiming to solve raised red flags. Piet Gros, a crystallographer at Utrecht University in The Netherlands, was alerted to potential problems with Murthy's structures by one of his grad students. Gros's lab published a structure for the immune protein C3b in a 2006 issue of Nature. Along with the Gros group's paper, two other papers on the structure of C3b were published in the issue. One was from Murthy's group at UAB and the other from researchers at the biotech company Genentech.

"We noticed quite quickly that there was a problem with the crystal lattice in the Murthy structure," Gros told The Scientist. "There were huge gaps between layers of molecules. That was a huge red flag."

Gros said that he contacted Murthy about the abnormalities, but the UAB researcher brushed aside his concerns. "Basically we were not satisfied with his answers to the questions," Gros said. "He could not give an explanation to us."

Gros and his colleagues began looking into more of Murthy's structures and noticing other "abnormal features." After unsuccessfully trying to get answers from Murthy, they had independent colleagues, including Vriend, analyze the structures and wrote a letter to Nature and to UAB detailing their findings.

Using sophisticated validation software, Gros and his colleagues uncovered several problems with more of Murthy structures. There were unexplained gaps in the packing pattern of amino acids in the structures and contacts between atoms that were unrealistic, and "there was no solvent in the data," according to Gros. "There are things which are physically impossible," he said.

Though the problems with Murthy's data seem glaring, uncovering the fraud required intricate analysis by protein experts. "The structure [of C3b] was strange, but it did require an expert to read from the numbers that something was worrisome," said Vriend.

Murthy was able to publish fraudulent data on 12 protein structure over the span of 10 years in several different journals, such as Nature, Proceedings of the National Academy of Science, Biochemistry, and Cell. At the beginning of this month, the Journal of Biological Chemistry (JBC) retracted one paper that Murthy published in 1999 on the structure of a domain in the dengue virus. According to Marchase, "Another journal is likely to retract but has not yet," but he declined to say which one.

Officials at the Protein Data Bank (PDB), which archives thousands of protein crystal structures from the literature, have removed the structure (dengue virus NS3 serine protease) reported in the JBC paper from its database, and "will make the remaining 11 entries obsolete if and when the corresponding papers are retracted," according to a PDB statement.

Vriend and Gros said that one good thing to come out of the Murthy fraud case is that journals and the protein structure archives are rethinking the process whereby they validate submitted crystal structures. "This appears to be an extremely rare case," Gros said. "But the [validation] process has to be improved. People are discussing processes of doing this better, and I think that will happen, and it's a good thing."

Vriend agreed, adding that the analysis of Murthy's fraud demonstrated the importance of carefully validating proposed crystal structures for proteins. "Protein structures are so important for so many fields in science that they must be right."

Correction (18th December): In the original version of this story, Murthy was said to have been the recipient of five NIH grants this year. The NIH's Research Portfolio Online Reporting Tool, inaccurately lists the UAB email and name of H.M. Krishna Murthy under grants won by Krishna K. Murthy of the Southwest Foundation for Biomedical Research in Texas. Krishna K. Murthy was not involved in any way with the fraud perpetrated by H.M Krishna Murthy, and the subject of this story was not awarded any NIH grants in 2009. The Scientist regrets the error.

The five hottest biology papers of 2009

2009-12-24T05:39:00.000-08:00

Which papers made the biggest splash this year? ScienceWatch, a website that tracks and analyzes trends in basic science research, compiles bimonthly lists of the 10 most cited papers. From those lists, The Scientist pulled the five papers in biology published in the last two years which were some of the most cited papers in 2009. The two topics that dominate the top five papers this year: genomics and stem cells.

5. A M. Wernig, et al., "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state," Nature 448: 318-24, 2007.
Citations this year: 237
Total citations to date: 512
Findings: Scientists successfully performed somatic-cell nuclear transfer (SCNT), producing stem cell lines and cloned animals for the first time using fertilized mouse eggs. This paper consistently ranked in the top 10 most cited papers in 2009, according to ScienceWatch.

4. E. Birney, et al., "Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project, "Nature, 447: 799-816, 2007.
Citations this year: 267
Total citations to date: 618
Findings: The ENCODE project -- ENCODE stands for the ENCyclopedia Of DNA Elements -- set out to identify all functional elements in the human genome. After examining one percent of the genome, the paper revealed several new insights about how information encoded in the DNA comes to life in a cell.

3. A. Barski, et al., "High-resolution profiling of histone methylations in the human genome," Cell, 129: 823-37, 2007.
Citations this year: 299
Total citations to date:: 560
Findings: This study looked at how histone modifications influence gene expression in more detail than previous attempts. Using a powerful sequencing tool called Solexa 1G, the researchers mapped more than 20 million DNA sequences associated with specific forms of histones, finding there were differences in methylation patterns between stem cells and differentiated T cells.

2. K.A. Frazer, et al., "A second generation human haplotype map of over 3.1 million SNPs," Nature, 449: 854-61, 2007.
Citations this year: 389
Total citations to date: 588
Findings: Since the sequencing of the human genome in 2003, the International HapMap Project has explored single nucleotide polymorphisms (SNPs) -- differences in a single letter of the DNA -- to study how these small variations affect the development of diseases and the body's response to pathogens and drugs. HapMap I, the original report, placed one SNP at roughly every 5,000 DNA letters. The newest map, featured in this paper, sequenced an additional 2 million SNPs, increasing the map's resolution to one SNP per kilobase. The additional detail allows scientists to more closely investigate patterns in SNP differences, especially in hotspot regions, or concentrated stretches of DNA.

1. K. Takahashi, et al., "Induction of pluripotent stem cells from adult human fibroblasts by defined factors," Cell, 131: 861-72, 2007.
Citations this year: 520
Total citations to date: 886
Findings: This work from Shinya Yamanaka's lab in Japan was the first to demonstrate that induced pluripotent stem (iPS) cells can be generated from adult human dermal fibroblasts. Previous efforts by the team showed that iPS cells could be derived from mouse somatic cells. This paper was an easy top pick, receiving the most citations this year, according to ScienceWatch.

The top 5 people of 2009

2009-12-22T19:37:00.000-08:00

From budgets padded with stimulus funding to advancements in stem cell legislation, 2009 has been an all around big year for research. But in The Scientist's mind, a few individuals have stuck out in terms of their contributions, support, and leadership in the life sciences.

Here are our picks for the top five most influential people of the year, presented in alphabetical order:
Francis Collins

Unless you have been living under a rock this year, you know that Collins was appointed director of the National Institutes of Health in August. The geneticist accepted the position after 15 years at the helm of the National Human Genome Research Institute, during which time he helped finish the Human Genome Project ahead of schedule and under budget. Since taking control of the NIH, Collins has been pushing an agenda focused on personalized medicine and stem cell research, backing the efforts by approving 40 new human embryonic stem cell lines as eligible for federal funding. Collins has also found time to be a much more public figure than previous NIH directors, taking time out to rock with Aerosmith's Joe Perry and joke around with Stephen Colbert.

Sheng Ding

For the first time, Ding and colleagues at the Scripps Research Institute induced pluripotency in mouse embryonic cells using only recombinant proteins, avoiding gene manipulation altogether, publishing the research in Cell Stem Cell. The technology, which was named The Scientist's top life science tool of 2009, is being used by Fate Therapeutics, a company cofounded by Ding in 2007, to interrogate stem cell biology in an effort to enable new drug discovery. Ding was also featured in our pages as Scientist to Watch in November.

Bart Gordon

As Chairman of the House Committee on Science and Technology, the 13th term Democrat from Tennessee played a key role in ensuring science got a major boost from stimulus funding. Gordon also authored bills to further nanotechnology research and commercialization (H.R. 554, passed February 11), require that the President create a national water strategy (H.R. 1145, passed April 23), and improve science, technology, engineering, and math (STEM) education programs (H.R. 1709, passed June 8). Gordon also helped allocate $400 million in stimulus funding to start the Department of Energy's Advanced Research Projects Agency -- Energy, which funds high risk, high reward energy research. Although the Congressman announced he won't be running for re-election next year, science sure was lucky to have him around in 2009.

Henry Gustav Molaison

Known to scientists for most of his life only as H.M., Molaison is recognized as one of the most important patients in the history of brain science. After undergoing experimental surgery in 1953 to correct a seizure disorder, which included removing two slivers of brain tissue and cutting into the hippocampus, Molaison lost the ability to form new memories. For the next 55 years, he helped transform scientists' understanding of memory, including the identification of two different systems of remembrance -- declarative (names and faces, for example) and motor learning. Molaison died in December 2008 at the age of 82, but not before agreeing to donate his brain to research. This year, scientists at the University of California, San Diego, began slicing the organ into approximately 2,600 fragments in an effort to correlate individual brain structures with specific functions.

Erika Sasaki

Sasaki, from the Central Institute for Experimental Animals in Kawasaki, Japan, led the team of researchers that successfully generated the world's first transgenic primates capable of passing on a foreign gene to their offspring. The research, published in Nature, brings scientists one step closer to being able to use primates as models for studying human neurological and behavioral conditions, such as Parkinson's, Huntington's and amyotrophic lateral sclerosis. The team injected viral vectors with a green fluorescence protein transgene into embryos of marmosets. Out of 80 transgenic embryos planted into 50 surrogate mothers, five offspring survived, all of which expressed the glowing transgene.

Parasite Evades Death By Promoting Host Cell Survival

2009-12-20T06:41:00.000-08:00

The parasite Trypanosoma cruzi (or T. cruzi), which causes Chagas' disease, will go to great lengths to evade death once it has infected human host cells, researchers have discovered. In a study published in the November 17 online issue of Science Signaling, the researchers describe how a protein called parasite-derived neurotrophic factor (PDNF) prolongs the life of the T. cruzi parasite by activating anti-apoptotic (or anti-cell-death) molecules in the host cell. These protective mechanisms help to explain how host cells continue to survive despite being exploited by T. cruzi parasites.

"We asked ourselves, 'How is it possible that the host cells stay alive for so long with thousands of T. cruzi parasites consuming the host cell's vital resources?' We discovered that PDNF on the surface of the T. cruzi parasite essentially inhibits cell death signals and activates cell-protective mechanisms, ensuring T. cruzi sufficient time to develop and reproduce in the host cell," says senior author Mercio Perrin, MD, PhD, professor in the pathology department at Tufts University School of Medicine (TUSM) and member of the immunology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Taking a multi-faceted approach, the researchers used bioinformatics, immunochemistry, intracellular colocalization microscopy, and in vitro enzymatic techniques to study T. cruzi's survival in the host. Perrin and co-author Marina Chuenkova, PhD, a research instructor in the pathology department at TUSM and the Sackler School, demonstrated that PDNF is a substrate and activator of Akt kinase, an enzyme that promotes cell survival by inhibiting "cell death" proteins.

"Further investigation showed that within T. cruzi-infected cells, PDNF also activates increased production of Akt, prolonging its protective effects," says Chuenkova. "Akt is a key regulator of diverse cellular processes, and supports cell survival not only by inhibiting apoptotic molecules, but additionally by increasing nutrient uptake and metabolism," she continued.

"In short, the T. cruzi parasite has a means of establishing life insurance once it has invaded the host. If we can fully understand the mechanisms behind this protection, we can begin to explore ways to undermine it with treatment," said Perrin.

Chagas' disease, typically transmitted to humans by blood-feeding insects, infects an estimated 8 to 11 million people throughout Mexico, and Central and South America. Although it is still rare in the United States, according to the Centers for Disease Control and Prevention (CDC), there are 300,000 people with Chagas' disease living in the United States, most of whom acquired the disease while living in other countries.

The acute phase of Chagas' disease can result in fever or swelling at the site of the insect bite, but many people do not experience symptoms at all. If left untreated, the disease enters an indeterminate phase in which no symptoms are present. During this phase, many people are not aware that they are infected, but approximately 30 percent will eventually develop life-threatening complications of the disease, including enlargement of the digestive tract and/or heart.

This study was funded by grants from the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health.

Chuenkova MV and PereiraPerrin M. Science Signaling. 2009. (November 17); 2(97), ra74. "Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy." Published online November 17, 2009, doi: 10.1126/scisignal.2000374

About Tufts University School of Medicine

Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. The Sackler School undertakes research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.

Source: Tufts University

Tiny RNA Has Big Impact On Lung Cancer Tumors

2009-12-19T06:34:00.000-08:00

Researchers from Yale University and Mirna Therapeutics, Inc., reversed the growth of lung tumors in mice using a naturally occurring tumor suppressor microRNA. The study reveals that a tiny bit of RNA may one day play a big role in cancer treatment, and provides hope for future patients battling one of the most prevalent and difficult to treat cancers.

"This is the first time anybody has shown a positive effect of microRNAs in shrinking lung cancer," said Frank Slack, Ph.D., co-senior author of the paper, researcher at the Yale Cancer Center and professor of molecular, cellular & developmental biology.

The tumors in mice with non-small cell lung cancer shrank after the Yale team delivered an intranasal dose containing a type of micro-RNA called let-7, the authors reported in the Dec. 7 issue of the journal Oncogene. MicroRNAs are small bits of genetic material most often associated with transmission of information encoded in DNA. However in the past decade microRNAs have been shown to play crucial roles in gene regulation and/or gene silencing

The Yale team also found that mice without let-7 developed cancer, supporting their hypothesis that the microRNA acts as a tumor suppressor. The tumors in mice that received let-7 were not eliminated, but reduced by 66 percent, the study showed. The team is currently studying whether let-7 therapy in combination with chemotherapy and radiation can induce full remission.

Slack noted let-7 is absent in many cancers and acts upon a gene known to play a role in about a quarter of all human cancers.

"We hope it will be valuable in the treatment of many other forms of cancer," he said.

The research was conducted as part of collaboration between Yale and Mirna Therapeutics Inc, a biotechnology company in Austin, Texas. Joanne B. Weidhaas, MD/Ph.D. of Yale and Andreas G. Bader, Ph.D. of Mirna were co-senior authors of the paper. Other Yale authors on the paper are first author Phong Trang, Pedro P. Medina and Robert Homer; other Mirna authors are Jason F. Wiggins, Lynnsie Ruffino, Kevin Kelnar, Michael Omotola and David Brown, Ph.D.

Funding for the work came from the National Institutes of Health, Connecticut Department of Health, The Hope Funds for Cancer Research and Mirna Therapeutics, Inc.

Source:
Bill Hathaway
Yale University

Scientists Hear Cell Conversation For First Time

2009-12-17T06:32:00.000-08:00

A cutting edge technique that allows scientists to monitor communication between cells could transform the way laboratory medical experiments are conducted. The method is likely to make laboratory studies of cancers and other human diseases, and assessment of new drugs to target them, more accurate.

The study was completed by Dr Rune Linding, head of the Cellular and Molecular Logic Team at The Institute of Cancer Research (ICR) in the UK, along with UK and Canadian-based colleagues. The research is published in the latest edition of the journal Science.

Dr Linding says that understanding communication between cells is crucial, as many cancers and other diseases are caused by a breakdown in communications systems.

"Organs and tissues are composed of many different cell types with distinct roles to play," Dr Linding says. "To function properly, the cells must communicate with each other, which they do through a network of specialised proteins known as signalling molecules. When cells are unable to send or receive the correct signals, they can behave abnormally and this can lead to disease."

Until now, scientists have generally studied cell communication by taking a single population of cells, adding a molecule to stimulate the cells and measuring the level of signalling molecules produced. But this technique does not take into account that cells respond to the signals they receive and feedback to each other, like a conversation between people.

"In our latest study, we have developed a way to more accurately replicate what's happening in the body - before scientists could only hear a monologue, but now for the first time we can assess the outcome of a conversation," Dr Linding says.

The new method involves growing cells in media containing labelled amino acids (the fundamental building blocks of proteins) that are incorporated into the cells' proteins. Two cell types, grown with different labels, are then combined for a short time to allow them to talk to each other, and then the cells are broken open so the proteins produced can be examined. A technique called mass spectrometry is then used to measure the level of each label, showing from which cell type the proteins originated.

The team then looked for genes that were involved in the conversation. They tested about 10 per cent of all human genes by blocking them within the cells one by one, using small interfering RNA molecules, and measured whether the cells behaved differently. Information about the proteins and genes was used to make a computer model of the signalling networks involved - effectively highlighting the important points in the conversation.

The research team first used this technique to study a key communications system known as EphB2, which is used to position cells precisely within the body and is important for maintaining boundaries between tissues. Cancer cells need to cross tissue boundaries to spread throughout the body, so a mutation in this system can promote metastasis.

Co-author Dr Claus Jørgensen from The Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Canada says: "Many types of cancers - including colorectal cancer, lung, prostate and breast cancer and glioma - have an abnormality in the Eph communications system, and it may also play a role in other diseases. However, until now it has not been possible to study this network during cell-to-cell contact, the most crucial time".

"Our study identified several new molecules involved in this system, knowledge that may play a role in future network biology-based drug development at the ICR. Perhaps most importantly, we found that the two cell types we studied responded differently to the conversation, which shows that previous experiments on just one cell type could well be inaccurate. This means that if you want to measure how cells will respond to signals - including signals that trigger cancer, or signals from drugs - you need to look at how they will respond when they are with other cell populations, not just one cell type alone."

Co-author Dr Tony Pawson, also from The Samuel Lunenfeld Research Institute, says: "This technique, which lets us consider two cell populations at once, is a major step towards more accurate laboratory research. We will adopt this approach to study how distinct cell populations talk to one another in diseases like cancer; the next stage is to find a way to take even more cell types and molecules into account. We can't mimic what goes on in the body yet, but we are getting closer."

Funding for this project came from the ICR, the Medical Research Council, Genome Canada through the Ontario Genomics Institute, a Terry Fox Programme grant from the Canadian Cancer Society, the Canadian Institutes for Health Research, the Canada Foundation for Innovation, the Human Frontiers Science Program and The Lundbeck Foundation.

Source
The Institute of Cancer Research

EMBL Scientists Uncover The Gene Responsible For Keeping Females Female

2009-12-15T06:31:00.000-08:00

Is it a boy or a girl? Expecting parents may be accustomed to this question, but contrary to what they may think, the answer doesn't depend solely on their child's sex chromosomes. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany and the Medical Research Council's National Institute for Medical Research (NIMR) at Mill Hill, UK discovered that if a specific gene located on a non-sex chromosome is turned off, cells in the ovaries of adult female mice turn into cells typically found in testes. Their study, published in Cell, challenges the long-held assumption that the development of female traits is a default pathway. At the same time, it grants a valuable insight into how sex determination evolved.

In humans and most other mammals, an individual's sex is determined by its sex chromosomes: females have two X chromosomes, males have one X and one Y. Scientists had long assumed that the female pathway - the development of ovaries and all the other traits that make a female - was a kind of default: if it had a gene called Sry, which is located on the Y chromosome, an embryo would develop into a male, if not, then the result would be a female. But in adult animals it is the male pathway that needs to be actively suppressed, as Mathias Treier and his team at EMBL discovered.

A gene called Foxl2, which is located on an autosome - a chromosome other than the sex chromosomes - and therefore present in both sexes, was known to play an important role in the female pathway, but its precise function remained elusive. To elucidate the matter, Treier and colleagues ablated, or 'turned off', this gene in the ovaries of adult female mice.

"We were surprised by the results," says Treier, "We expected the mice to stop producing oocytes, but what happened was much more dramatic: somatic cells which support the developing egg took on the characteristics of the cells which usually support developing sperm, and the gender-specific hormone-producing cells also switched from a female to a male cell type."

Thus, the scientists discovered that Foxl2 plays a crucial role in keeping female mice female.

Teaming up with the group of Robin Lovell-Badge at the NIMR, they were able to decipher together the underlying molecular mechanism. They showed that FOXL2 and estrogen receptor act together by repressing a DNA element called TESCO that Lovell-Badge's group had previously identified to regulate expression of the testes-promoting gene Sox9. Sox9 was known to function in the embryo to make the early gonads become testes rather than ovaries, but the new studies suggest that it can perform the same task in the adult. FOXL2 is therefore critical to keep Sox9 turned off in ovaries throughout life.

"As most vertebrates have Foxl2, estrogen receptors and Sox9," Lovell-Badge explains, "this mechanism for maintaining female traits probably appeared early on in the evolution of vertebrates, while Sry and the mammalian Y chromosome are relatively new inventions."

These findings will have wide-ranging implications for reproductive medicine and may, for instance, help to treat sex differentiation disorders in children, for example where XY individuals develop as females or XX as males, and understand the masculinising effects of menopause on some women.

The study is discussed by author Mathias Treier in an online video in Cell's 'PaperFlicks' series, which is also available on YouTube.

Source: Sonia Furtado
European Molecular Biology Laboratory

Novel Detection Method Unmasks Circulating Breast Cancer Cells

2009-12-13T18:29:00.001-08:00

Circulating metastatic breast cancer cells can lose their epithelial receptors, a process that enables them to travel through the bloodstream undetected, according to research from The University of Texas M. D. Anderson Cancer Center.

The findings were presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

Levels of these circulating tumor cells (CTCs) - which are shed from a primary tumor or its metastases - have been used to monitor and tailor cancer therapy and to predict a patient's prognosis. CTCs that have undergone epithelial-mesenchymal transition (EMT), however, evade current detection methods and lose their traditional prognostic and therapeutic value. Those cancer cells also become more resistant to chemotherapy and radiation therapy. Finding a reliable method to detect these stealth breast cancer cells may reveal additional therapeutic targets that could help eradicate micrometastatic disease in patients with breast cancer or other epithelial tumors.

EMT and the Invasion-Metastasis Cascade

EMT is a process in which cancer cells undergo transdifferentiation (transformation into a different type of cell). "The carcinoma cells activate a transdifferentiation program in order to acquire the ability to execute the multiple steps necessary for the invasion-metastasis cascade," said the study's first author Michal Mego, M.D., Ph.D., formerly a fellow at M. D. Anderson. "During EMT, epithelial cells acquire a mesenchymal appearance with increased motility and invasiveness."

The researchers hypothesized that these changes render the EMT-CTCs undetectable by current detection assays, such as CellSearch (Veridex). The cells' acquired resistance to chemotherapy and radiotherapy also suggested that EMT-CTCs are tumor-initiating cells and are responsible for tumor dissemination. Moreover, the researchers had found subgroups of high-risk patients with brain metastases, triple receptor-negative disease, or inflammatory breast cancer whose blood tests did not reveal elevated levels of CTCs, further supporting their hypothesis.

Detecting CTCs Through EMT Gene Expression

The researchers then set out to develop a detection method that could identify EMT-CTCs in the peripheral blood of breast cancer patients. They took approximately 5 mL of peripheral blood from 27 patients ranging in age from 34 - 72 years, with a median age of 54. Sixteen of the women had metastatic disease, 19 had inflammatory breast cancer, and 12 had primary, non-inflammatory breast cancer.

"Using magnetic beads coated with monoclonal antibodies capable of capturing the majority of hematopoietic cells in peripheral blood, we obtained a fraction of cells enriched for CTCs," said Mego, who is now a scientist at the National Cancer Institute in the Slovak Republic. "Next we isolated RNA from these cells to detect genes that are involved in epithelial-mesenchymal transition, using molecular biology technology, such as the polymerase chain reaction."

Five EMT genes were identified: TWIST1, SNAIL1, SLUG, ZEB1, and FOXC2. At least one of these genes was over-expressed in 21 percent of the patients. Over-expression of EMT genes was more common among women with triple receptor-negative breast cancer than among those without this high-risk signature. The researchers found no correlation between EMT gene expression and CTC count as measured by CellSearch or the carcinoma-associated antigen known as Ep-CAM (epithelial cell adhesion molecule).

"We found that current CTC detection methods underestimate the most important subpopulation of CTCs involved in tumor dissemination-those with tumor-initiating properties," said James Reuben, Ph.D., professor in M. D. Anderson's Department of Hematopathology, the study's senior author. "A novel detection method such as ours that is capable of detecting CTCs after EMT could add important new prognostic information and could be useful for monitoring treatment efficacy in real time."

The M. D. Anderson and the Slovak National Cancer Institute teams have initiated a confirmatory study among patients with metastatic breast cancer, prostate cancer, or colon cancer. They also have initiated studies designed to identify therapeutic targets on EMT-CTCs. In addition to Mego and Reuben, other authors on the M. D. Anderson study include: Massimo Cristofanilli, M.D., Eleni Andreopoulou, M.D., and Summer Jackson, all of the Department of Breast Medical Oncology; Hui Gao, Ph.D. Changping Li, M.D., Sanda Tin, M.D. and Evan Cohen, all of the Department of Hematopathology; and Sendurai Mani, Ph.D., Department of Molecular Pathology.

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2009, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

Source: University of Texas M. D. Anderson Cancer Center

2009-12-07T18:29:00.000-08:00

Those extra helpings of gravy and dessert at the holiday table are even less of a help to your waistline than previously thought. According to a new research report recently appearing online in The FASEB Journal, a diet that is high in fat and in sugar actually switches on genes that ultimately cause our bodies to store too much fat.

This means these foods hit you with a double-whammy as the already difficult task of converting high-fat and high-sugar foods to energy is made even harder because these foods also turn our bodies into "supersized fat-storing" machines.

In the research report, scientists show that foods high in fat and sugar stimulate a known opioid receptor, called the kappa opioid receptor, which plays a role in fat metabolism. When this receptor is stimulated, it causes our bodies to hold on to far more fat than our bodies would do otherwise.

According to Traci Ann Czyzyk-Morgan, one of the researchers involved in the work, "the data presented here support the hypothesis that overactivation of kappa opioid receptors contribute to the development of obesity specifically during prolonged consumption of high-fat, calorically dense diets."

To make this discovery, Czyzyk-Morgan and her colleagues conducted tests in two groups of mice. One group had the kappa opioid receptor genetically deactivated ("knocked out") and the other group was normal. Both groups were given a high fat, high sucrose, energy dense diet for 16 weeks. While the control group of mice gained significant weight and fat mass on this diet, the mice with the deactivated receptor remained lean. In addition to having reduced fat stores, the mice with the deactivated receptor also showed a reduced ability to store incoming nutrients.

Although more work is necessary to examine what the exact effects would be in humans, this research may help address the growing obesity problem worldwide in both the short-term and long-term. Most immediately, this research provides more proof that high-fat and high-sugar diets should be avoided. In the long-term, however, this research is even more significant, as it provides a new drug target for developing therapies for preventing obesity and helping obese people slim down.

"In times when food was scarce and starvation an ever-present threat, an adaptation that allows our bodies to store as much energy as possible during plentiful times was probably a lifesaver," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "By taking that opioid receptor off the table, researchers may have found a way to keep us from eating ourselves to death."

Journal Reference:

Traci A. Czyzyk, Ruben Nogueiras, John F. Lockwood, Jamie H. McKinzie, Tamer Coskun, John E. Pintar, Craig Hammond, Matthias H. Tschöp, and Michael A. Statnick. κ-Opioid receptors control the metabolic response to a high-energy diet in mice. The FASEB Journal, 2009; DOI: 10.1096/fj.09-143610

New Mechanism of Blocking HIV-1 from Entering Cells Identified

2009-12-05T18:27:00.000-08:00

Publishing in PLoS Pathogens, researchers at from the Kimmel Cancer Center at Jefferson have found a novel mechanism by which drugs block HIV-1 from entering host cells.

Cellular invasion by HIV-1 requires the concerted action of two proteins on the viral surface: gp120 and gp41. The function of gp41 is to get the viral contents into the interior of the host cells. This requires the association of two distinct regions of gp41 called N-HR and C-HR. Anti-HIV-1 agents known as fusion inhibitors target the N-HR or C-HR and disrupt their association, which prevents the virus from entering into the host cell. One drug that works like this is Fuzeon (Roche), and there are other agents in the pipeline.

But blocking the N-HR/C-HR association is not only mechanism by which fusion inhibitors prevent HIV-1 entry, according to Michael Root, M.D., Ph.D., assistant professor of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University. The inhibitors also induce irreversible deactivation of gp41.

"After these drugs bind, they seem to shuttle gp41 into a dead conformation from which the protein cannot recover," Dr. Root said. "Importantly, the speed of this drug-induced deactivation greatly influences how potent a drug is at preventing HIV-1 infection."

When the inhibitors bind to the gp41 C-HR, the protein rapidly deactivates before inhibitors have time to dissociate. But when the inhibitors bind to the gp41 N-HR, deactivation takes a very long time, and many inhibitors can readily unbind. To potently inhibit HIV-1 entry, a C-HR targeting fusion inhibitor can have a relatively low affinity, but an N-HR targeting fusion inhibitor must bind extremely tightly.

A major drawback to using Fuzeon and related drugs that target N-HR is the rapid emergence of HIV-1 strains resistant to the drugs. Dr. Root's study suggests that the resistance phenomenon is related to the slow speed of gp41 deactivation induced by these fusion inhibitors. HIV-1 appears to have more difficulty developing resistance to drugs that can remain bound to gp41 for much longer than gp41 takes to deactivate, even if the drugs are no more potent than Fuzeon against the original HIV-1 strain. Armed with this knowledge, Dr. Root and his team have developed a new strategy to improve the antiviral activities of N-HR-targeting fusion inhibitors.

These unexpected properties of HIV-1 fusion inhibitors are a consequence of the short time interval these drugs have to work. The N-HR and C-HR are only accessible to drug binding in a short-lived "intermediate state" that occurs right before N-HR/C-HR association. Most pharmaceutical agents bind targets that exist for long times, but a growing class of drugs target similar, short-lived intermediate states. These drugs include local anesthetics, antibiotics and immunosuppressive agents used in clinical practice. The results of this study might also be extended to understand the activities and limitations of these drugs.

How Did Flowering Plants Evolve to Dominate Earth?

2009-12-03T06:22:00.001-08:00

To Charles Darwin it was an 'abominable mystery' and it is a question which has continued to vex evolutionists to this day: when did flowering plants evolve and how did they come to dominate plant life on earth? A new study in Ecology Letters reveals the evolutionary trigger which led to early flowering plants gaining a major competitive advantage over rival species, leading to their subsequent boom and abundance.

The study, by Dr Tim Brodribb and Dr Taylor Field of the University of Tasmania and University of Tennessee, used plant physiology to reveal how flowering plants, including crops, were able to dominate land by evolving more efficient hydraulics, or 'leaf plumbing', to increase rates of photosynthesis.

"Flowering plants are the most abundant and ecologically successful group of plants on earth," said Brodribb. "One reason for this dominance is the relatively high photosynthetic capacity of their leaves, but when and how this increased photosynthetic capacity evolved has been a mystery."

Using measurements of leaf vein density and a linked hydraulic-photosynthesis model, Brodribb and Field reconstructed the evolution of leaf hydraulic capacity in seed plants. Their results revealed that an evolutionary transformation in the plumbing of angiosperm leaves pushed photosynthetic capacity to new heights.

The reason for the success of this evolutionary step is that under relatively low atmospheric C0₂ conditions, like those existing at present, water transport efficiency and photosynthetic performance are tightly linked. Therefore adaptations that increase water transport will enhance maximum photosynthesis, exerting substantial evolutionary leverage over competing species.

The evolution of dense leaf venation in flowering plants, around 140-100 million years ago, was an event with profound significance for the continued evolution of flowering plants. This step provided a 'cretaceous productivity stimulus package' which reverberated across the biosphere and led to these plants playing the fundamental role in the biological and atmospheric functions of the earth.

"Without this hydraulic system we predict leaf photosynthesis would be two-fold lower then present," concludes Brodribb. "So it is significant to note that without this evolutionary step land plants would not have the physical capacity to drive the high productivity that underpins modern terrestrial biology and human civilisation."

Courtesy: ScienceDaily

Naked Mole Rats May Hold Clues to Surviving Stroke

2009-12-01T18:20:00.000-08:00

Blind, nearly hairless, and looking something like toothy, plump, pink fingers, naked mole rats may rank among nature's most maligned creatures, but their unusual physiology endears them to scientists.

Two University of Illinois at Chicago researchers report in the Dec. 9 issue of NeuroReport (now online) that adult naked mole rat brain tissue can withstand extreme hypoxia, or oxygen deprivation, for periods exceeding a half-hour -- much longer than brain tissue from other mammals.

The findings may yield clues for better treatment of brain injuries associated with heart attack, stroke and accidents where the brain is starved of vital oxygen.

John Larson, associate professor of physiology in psychiatry, and Thomas Park, professor of biological sciences, studied African naked mole rats -- small rodents that live about six feet underground in big colonies of up to 300 members. The living is tight and the breathing even worse, with the limited air supply high in carbon dioxide and low in oxygen.

The air they breathe is so foul it would be fatal or lead to irreversible brain damage in any other mammal, Larson and Park said.

But naked mole rats studied were found to show systemic hypoxia adaptations, such as in the lungs and blood, as well as neuron adaptations that allow brain cells to function at oxygen and carbon dioxide levels that other mammals cannot tolerate.

"In the most extreme cases, naked mole rat neurons maintain function more than six times longer than mouse neurons after the onset of oxygen deprivation," said Larson.

"We also find it very intriguing that naked mole rat neurons exhibit some electrophysiological properties that suggest that neurons in these animals retain immature characteristics."

All mammal fetuses live in a low-oxygen environment in the womb, and human infants continue to show brain resistance to oxygen deprivation for a brief time into early childhood. But naked mole rats, unlike other mammals, retain this ability into adulthood.

"We believe that the extreme resistance to oxygen deprivation is a result of evolutionary adaptations for surviving in a chronically low-oxygen environment," said Park.

"The trick now will be to learn how naked mole rats have been able to retain infant-like brain protection from low oxygen, so we can use this information to help people who experience temporary loss of oxygen to the brain in situations like heart attacks, stroke or drowning," he said.

Larson said study of the naked mole rat's brain may yield clues for learning the mechanisms that allow longer neuronal survival after such accidents or medical emergencies, which may suggest ways to avoid permanent human brain damage.

Courtesy: ScienceDaily

Some Germs Are Good for You: Surface Bacteria Maintain Skin's Healthy Balance

2009-11-29T06:18:00.000-08:00

On the skin's surface, bacteria are abundant, diverse and constant, but inflammation is undesirable. Research at the University of California, San Diego School of Medicine now shows that the normal bacteria living on the skin surface trigger a pathway that prevents excessive inflammation after injury.

"These germs are actually good for us," said Richard L. Gallo, MD, PhD, professor of medicine and pediatrics, chief of UCSD's Division of Dermatology and the Dermatology section of the Veterans Affairs San Diego Healthcare System.

The study, to be published in the advance on-line edition of Nature Medicine on November 22, was done in mice and in human cell cultures, primarily performed by post-doctoral fellow Yu Ping Lai .

"The exciting implications of Dr. Lai's work is that it provides a molecular basis to understand the 'hygiene hypothesis' and has uncovered elements of the wound repair response that were previously unknown. This may help us devise new therapeutic approaches for inflammatory skin diseases," said Gallo.

The so-called "hygiene hypothesis," first introduced in the late 1980s, suggests that a lack of early childhood exposure to infectious agents and microorganisms increases an individuals susceptibility to disease by changing how the immune system reacts to such "bacterial invaders." The hypothesis was first developed to explain why allergies like hay fever and eczema were less common in children from large families, who were presumably exposed to more infectious agents than others. It is also used to explain the higher incidence of allergic diseases in industrialized countries.

The skin's normal microflora -- the microscopic and usually harmless bacteria that live on the skin -- includes certain staphylococcal bacterial species that will induce an inflammatory response when they are introduced below the skin's surface, but do not initiate inflammation when present on the epidermis, or outer layer of skin.

In this study, Lai, Gallo and colleagues reveal a previously unknown mechanism by which a product of staphylococci inhibits skin inflammation. Such inhibition is mediated by a molecule called staphylococcal lipoteichoic acid (LTA) which acts on keratinocytes -- the primary cell types found on the epidermis.

The researchers also found that Toll-like receptor 3 (TLR3) activation is required for normal inflammation after skin injury.

"Keratinocytes require TLR3 to mount a normal inflammatory response to injury, and this response is kept from becoming too aggressive by staphylococcal LTA," said Gallo. "To our knowledge, these findings show for the first time that the skin epithelium requires TLR3 for normal inflammation after wounding and that the microflora helps to modulate this response."

Additional contributors to the paper include Yuping Lai, Anna Di Nardo, Teruaki Nakatsuji, Anna L Cogen, Chun-Ming Huang and Katherine A. Radek, UCSD Division of Dermatology and the VA San Diego Healthcare System; Anke Leichtle and Allen F. Ryan, UCSD Department of Surgery/Otolaryngology and the VA San Diego Healthcare System; Yan Yang and Zi-Rong Wu, School of Life Science, East China Normal University, Shanghai; Lora V Hooper, Howard Hughes Medical Institute and University of Texas Southwestern Medical Center, Dallas; and Richard R Schmidt and Sonja von Aulock, University of Konstanz, Germany.

The study was funded by grants from the National Institutes of Health, and a US Veterans Administration Merit Award.

Courtesy: ScienceDaily

Can Meditation Curb Heart Attacks?

2009-11-27T06:17:00.000-08:00

When Julia Banks was almost 70, she took up transcendental meditation. She had clogged arteries, high blood pressure and too much weight around the middle, and she enrolled in a clinical trial testing the benefits of meditation.

Now Mrs. Banks, 79, of Milwaukee, meditates twice a day, every day, for 20 minutes each time, setting aside what she calls “a little time for myself.”

“You never think you’ve got that time to spare, but you take that time for yourself and you get the relaxation you need,” said Mrs. Banks, who survived a major heart attack and a lengthy hospitalization after coronary artery bypass surgery six years ago.

“You have things on your mind, but you just blot it out and do the meditation, and you find yourself being more graceful in your own life,” she said. “You find out problems you thought you had don’t exist — they were just things you focused on.”

Could the mental relaxation have real physiological benefits? For Mrs. Banks, the study suggests, it may have. She has gotten her blood pressure under control, though she still takes medication for it, and has lost about 75 pounds.

Findings from the study were presented this week at an American Heart Association meeting in Orlando, Fla. They suggest that transcendental meditation may have real therapeutic value for high-risk people, like Mrs. Banks, with established coronary artery disease.

After following about 200 patients for an average of five years, researchers said, the high-risk patients who meditated cut their risk of heart attacks, strokes and deaths from all causes roughly in half compared with a group of similar patients who were given more conventional education about healthy diet and lifestyle.

Among the roughly 100 patients who meditated, there were 20 heart attacks, strokes and deaths; in the comparison group, there were 32. The meditators tended to remain disease-free longer and also reduced their systolic blood pressure by five millimeters of mercury, on average.

“We found reduced blood pressure that was significant – that was probably one important mediator,” said Dr. Robert Schneider, director of the Institute for Natural Medicine and Prevention, a research institute based at the Maharishi University of Management in Fairfield, Iowa, who presented the findings. The study was conducted at the Medical College of Wisconsin in Milwaukee, in collaboration with the institute.

An earlier study of high-risk Milwaukee residents, many of them overweight or obese, also found transcendental meditation, along with conventional medications, could help reduce blood pressure. Most of those in the study had only high-school educations or less, about 40 percent smoked and roughly half had incomes of less than $10,000 a year.

The participants found transcendental meditation easy to learn and practice, Dr. Schneider said.

“Fortunately, it does not require any particular education and doesn’t conflict with lifestyle philosophy or beliefs; it’s a straightforward technique for getting deep rest to the mind and body,” he said, adding that he believes the technique “helps to reset the body’s own self-repair and homeostatic mechanism.”

Dr. Schneider said other benefits of meditation might follow from stress reduction, which could cause changes in the brain that cut stress hormones like cortisol and dampen the inflammatory processes associated with atherosclerosis.

“What is it about stress that causes cardiovascular disease?” said Dr. Theodore Kotchen, associate dean for clinical research at the Medical College of Wisconsin. “Hormones, neural hormones, cortisol, catecholamines — all tend to be elevated in stress. Could they in some way be contributing to cardiovascular disease? Could a reduction in these hormones with meditation be contributing to reduction in disease? We can only speculate.”

Another recent study focusing on transcendental meditation, published in The American Journal of Hypertension, focused on a young healthy population. It found that stressed-out college students improved their mood through T.M., and those at risk for hypertension were able to reduce their blood pressure. Dr. Schneider was also involved in that study, which was carried out at American University in Washington and included 298 students randomly assigned to either a meditation group or a waiting list.

Students who were at risk of hypertension and practiced meditation reduced systolic blood pressure by 6.3 millimeters of mercury and their diastolic pressure by 4 millimeters of mercury on average.

Courtesy:Newyork times

Termites Create Sustainable Monoculture Fungus Farming

2009-11-25T06:13:00.000-08:00

Food production of modern human societies is mostly based on large-scale monoculture crops, but it now appears that advanced insect societies have the same practice. Our societies took just ten thousand years of (mainly cultural) evolution to adopt this habit and we are far from convinced that it is sustainable. Farming ants and termites had tens of millions of years to evolve their fungus farming systems and here monocultures are apparently evolutionary stable.

In a study published in the journal Science, researchers from the Laboratory of Genetics of Wageningen University and the Centre for Social Evolution at the University of Copenhagen take significant steps to resolve this puzzle.

The fungus-growing termites of the old-world tropics build impressive mounds consisting of thousands of workers and soldiers. These societies domesticated African Termitomyces mushrooms more than 30 million years ago and became obligatorily dependent on farming their own fungal food in their often gigantic nest mounds. The termite fungus-farming symbiosis had a single African rain-forest origin and now comprises ca 330 species. It is of major ecological importance for decomposition and mineralcycling.

A colony-founding termite queen and king normally do not acquire their first garden until they have raised the first workers. These helpers collect Termitomyces spores while foraging, together with the plant material that they defecate in the nest to establish a garden substrate. These spores are amply available because the fungus gardens produce large mushrooms once a year on top of the termite mounds.

However, this farming practice offers a paradox: Evolutionary theory predicts that symbioses with multiple lineages per colony should be unstable, because these genotypes can be expected to compete for making mushrooms rather than collaborate to serve the termite farmers.

The new study shows that a very special mechanism is in place to prevent this from happening. All colonies from which multiple fungal samples were genetically analyzed contained only a single fungal genotype in spite of gardens having been initiated from at least two and probably many more genetically different spores.

Duur Aanen, Koos Boomsma and their respective colleagues in Wageningen and Copenhagen show that genotypes that happen to be common in a garden, become even more common at the expense of rarer genotypes. This happens not because common genotypes are better direct competitors, but because they have a higher chance of having an identical genotype as neighbor. Every time this happens, such genetically identical mycelia merge, which enhances the efficiency by which they produce asexual spores that the termites eat and deposit in new garden material of the colony. This process of positive reinforcement makes every colony end up with a life-time commitment to a single fungal symbiont in spite of the population at large having many fungal genotypes.

Shifting Vaccine for Flu to Elderly

2009-11-23T18:11:00.000-08:00

Federal health officials are trying to shift supplies of the seasonal flu vaccine away from chain pharmacies and supermarkets to nursing homes, hoping to counter a shortage that threatens to cause a wave of deaths this winter among the nation’s most vulnerable population.

The extent of the shortage is still unclear, but Janice Zalen, director of special programs for the American Health Care Association, which represents 11,000 nursing homes and assisted-living facilities, called it “a very big problem.”

Ms. Zalen said that of 1,000 nursing home managers who responded to a survey of the association’s 11,000 members, 800 reported they could not get enough vaccine.

Dr. Carol Friedman, head of adult immunization at the Centers for Disease Control and Prevention, said she did not have a figure for the size of the shortage, but added, “It’s a problem, and it’s all over the country.”

Mary Hahn, who manages six Ohio nursing homes with 800 beds, said she could not get vaccine for any of her patients.

“It’s just so disheartening, because we’re having to leave people unprotected,” she said. “You see people get flus and get sent to the hospital because they really can’t fight it off.”

A nationwide shortage of the seasonal flu vaccine has been reported for several weeks, but nursing homes and their suppliers have grown more alarmed in recent days. Of the 36,000 Americans who die of seasonal flu in the average year, more than 90 percent are 65 or older, and nursing home outbreaks are particularly deadly. By contrast, the swine flu epidemic has been most deadly among younger people.

The nursing homes’ predicament has been caused by a confluence of factors. Because of the swine flu pandemic, far more people than usual are seeking vaccination, Dr. Friedman said — even though the seasonal vaccine does not protect against swine flu.

The five companies licensed to make flu shots for the United States originally planned to make only slightly more than the 118 million they made in 2008. Then, production problems caused GlaxoSmithKline to cut its run by half; Novartis’s shrank by 10 percent. Then all five companies had to switch over early to making swine flu vaccine.

So the total supply of vaccine is about 114 million doses, of which about 95 million have been shipped.

At the same time, reports of price gouging have grown more frequent. That also happened in 2004, when sterility problems at a British plant cut the American flu vaccine supply in half; prices shot up as high as $90 a dose, from the normal level of $8 to $9.

Gouging is illegal in about half the states, but each state varies in how big a price increase constitutes gouging and as to whether an emergency must have been declared for the law to kick in.

“To pursue a case, we need to show it’s not just a couple of dollars but is very significant,” said Attorney General Richard Blumenthal of Connecticut, who has opened an investigation.

Criminal charges are less likely than a civil suit, Mr. Blumenthal said. But he added that if distributors were “masquerading or fraudulently claiming to have vaccine,” that could end in a criminal charge. While he had suspicions, he said, “we don’t have hard evidence yet.”

Dr. Friedman said that once the agency became aware of the shortage at nursing homes, “we began working with the manufacturers to see if they could redirect some of their vaccine.”

“Several big-box retailers and pharmacies volunteered to go into the long-term-care facilities and set up flu clinics,” she said.

Dr. Friedman said she knew of one major supplier to nursing homes that received 100,000 fewer doses from the vaccine makers than it had ordered. Her agency began acting as a broker among the homes, vaccine distributors and other customers. Since then, she said, that supplier has found about 50,000 more doses.

“That’s definitely not going to close the gap,” she said, “but it will help.”

Also, both she and Ms. Zalen said, pharmacy and supermarket chains like Walgreen’s and Safeway that bought millions of doses to sell for $25 to $30 have offered to give shots in nursing homes. They do not charge but get Medicare reimbursements, which vary by state but run up to $25.

By contrast, Bob McKay, chief of sales for PharMerica, one of the two largest wholesale pharmacies supplying nursing homes, said he had received 95 percent of the 300,000 doses he ordered and “the voids are getting filled in” at the nursing homes he supplies.

“We’re not hearing rage and craziness out there,” Mr. McKay said. “If a lot of homes were still short, they’d be beating our doors down.”

But he said he had asked some not to buy shots for their staffs. Flu experts say that in nursing homes, vaccination of staff members is just as important as patient vaccination.

Prices offered to PharMerica for the extra doses they needed were “in the $15-$16 range,” Mr. McKay said. “That’s more than we’d normally pay, but not price-gouging.”

Jim Mathews, an executive at Hometown Pharmacy, a smaller wholesale pharmaceutical company supplying Michigan nursing homes, said that late last month he found himself 3,000 doses short; his usual supplier, which charges $6.75 per dose, was out of stock. He called the C.D.C. for advice, was directed to a Web page listing other suppliers and contacted all 10. Only one had vaccine, and it sent him a fax in broken English asking for $57 to $59 per dose.

Mr. Mathews said he reported that to local law enforcement officials, but he is more worried about the patients who will not get shots.

“When I first recognized the potential death toll from this shortage, there was time to prioritize the remaining supply for the most vulnerable elderly,” he said. “Now I’m afraid it’s too late. From what I see, the seasonal flu vaccine shortage is going to cost more lives than the H1N1 shortage is.”

Dr. Friedman, of the C.D.C., said she had heard of “about 15” price-gouging complaints.

Dr. Lillian Overman, an internist in East Hartford, Conn., was one of the first to alert Mr. Blumenthal, the state’s attorney general, about gouging accusations. On Oct. 26, her office manager began looking for vaccine, for which she normally pays $8.50 a dose. A saleswoman at ABO Pharmaceuticals in San Diego wanted $60 per dose, she said.

“That’s just prohibitive,” a frustrated Dr. Overman said. “If I’d known there would be a shortage, I would have called in my most vulnerable patients first.”

Mark Nemeth, an ABO sales manager, denied that anyone there had asked for $60.

“I can guarantee you without a shadow of a doubt, we would never have offered it at that price,” he said; the company is asking “in the ballpark of $12 to $14” for its remaining supplies.

Courtesy: Newyorktimes

New Synthetic Molecules Trigger Immune Response To HIV And Prostate Cancer

2009-11-17T07:27:00.000-08:00

Researchers at Yale University have developed synthetic molecules capable of enhancing the body's immune response to HIV and HIV-infected cells, as well as to prostate cancer cells. Their findings, published online in theJournal of the American Chemical Society, could lead to novel therapeutic approaches for these diseases.

The molecules -- called "antibody-recruiting molecule targeting HIV" (ARM-H) and "antibody-recruiting molecule targeting prostate cancer" (ARM-P) -- work by binding simultaneously to an antibody already present in the bloodstream and to proteins on HIV, HIV-infected cells or cancer cells. By coating these pathogens in antibodies, the molecules flag them as a threat and trigger the body's own immune response. In the case of ARM-H, by binding to proteins on the outside of the virus, they also prevent healthy human cells from being infected.

"Instead of trying to kill the pathogens directly, these molecules manipulate our immune system to do something it wouldn't ordinarily do," said David Spiegel, Ph.D., M.D., assistant professor of chemistry and the corresponding author of both papers.

Because both HIV and cancer have methods for evading the body's immune system, treatments and vaccinations for the two diseases have proven difficult. Current treatment options for HIV and prostate cancer -- including antiviral drugs, radiation and chemotherapy -- involve severe side effects and are often ineffective against advanced cases. While there are some antibody drugs available, they are difficult to produce in large quantities and are costly. They also must be injected and are accompanied by severe side effects of their own.

By contrast, the ARM-H and ARM-P molecules, which the team has begun testing in mice, are structurally simple, inexpensive to produce, and could in theory be taken in pill form, Spiegel said. And because they are unlikely to target essential biological processes in the body, the side effects could be smaller, he noted.

"This is an entirely new approach to treating these two diseases, which are extraordinarily important in terms of their impact on human health," Spiegel said.

HIV is a global pandemic that affects 33 million people worldwide, while prostate cancer is the second leading cause of cancer-related death among American men, with one out of every six American men expected to develop the disease.

Funding for this research was provided by the National Institutes of Health.

Courtesy: ScienceDaily

Seafloor Fossils Provide Clues To Climate Change

2009-11-15T05:25:00.000-08:00

Deep under the sea, a fossil the size of a sand grain is nestled among a billion of its closest dead relatives. Known as foraminifera, these complex little shells of calcium carbonate can tell you the sea level, temperature, and ocean conditions of Earth millions of years ago. That is, if you know what to look for.

Assistant Professor of Earth and Environmental Sciences at Rensselaer Polytechnic Institute Miriam Katz has spent the past two decades studying these ancient, deep-sea fossils to reconstruct the climates of Earth up to 250 million years ago. Through ice ages and greenhouse climates, Katz has been able to piece together oxygen, carbon, and faunal data to paint a portrait of how, when, and why our climate has changed so drastically over geologic history. In addition, her investigations into the deep past of Earth have important implications for understanding and tracking the potential drastic repercussions of modern, human-induced climate change.

"There is a saying among scientists in my field that 'the past is a window on the future,' " Katz said. "By reconstructing the climates of the past, particularly those where we see massive and rapid changes in the climate, we can provide a science-based means to explore or predict possible system responses to the current climate change."

While her work requires a lot of time in the laboratory, Katz has spent nearly two years at sea on seven different ocean voyages around the world to drill for foraminifera as part of the Integrated Ocean Drilling Program (IODP), an international marine research effort that explores the Earth's history and structure by looking at seafloor sediments and rocks. During each two-month IODP excursion, Katz and the other scientists on board never set foot on land and spend hours poking through the millions of layers of sediment, trapped gases, fossils, and trace elements found in huge cores drilled from deep under the seafloor.

Just a few inches in diameter, each core is painstakingly drilled and removed from the seafloor. From top to bottom, the core provides a reverse chronology of the various organisms, sediments, and elements that were found on Earth throughout history. Unlike cores from sedimentary layers from the continents that are quickly destroyed by the forces of plate tectonics, wind, and water, these rarely disturbed ocean sediment cores can provide records up to 180 million years ago as new layers of sediment bury and preserve those of the past.

Katz is most interested in the foraminifera found in the cores. The foraminifera she studies live on or just below the seafloor. When they die, their hard shells are incorporated in the surrounding sediments and buried over time in a nearly uniform layer.

The assemblages of foraminifera in each layer can provide valuable information on the climate of that time. "Some species are only found in certain environments, such as in warm water or in shallow, tidal areas," Katz said. "By piecing together the species assemblages that are found in a given area during the given time period, we can reconstruct the sea level and ocean and climate conditions of that period based on our knowledge of each foraminiferal species."

In addition to the specific type of foraminifera seen in each layer, valuable information can also be gathered by looking at variations in the chemical structure of the fossilized calcium carbonate (CaCO3) shell seen in the various layers. During their life, the foraminiferal shells are formed from the elements found in the seas that they lived in. The ratios of various isotopes of the elements carbon and oxygen found in foraminiferal shells at different times in Earth's history provide important information needed to reconstruct the climate and ocean waters that surrounded them during their short lives millions of years ago.

In the case of oxygen (O), the ratio between isotopes 18O and 16O tells scientists how much water is trapped in glacial ice, providing important clues about temperature and the size of the ancient continental ice sheets. Carbon (C) in the shells can be analyzed for either 12C or 13C isotopes. Plants prefer to incorporate lighter 12C during photosynthesis, increasing the ratio of 13C to 12C in foraminifera when plant and algae production is high. This carbon data provides clues on the types and amounts of vegetation at various times as well as ocean circulation, according to Katz.

Gathering this information from cores has allowed Katz to develop important theories on one of the most recent and dramatic climate change events that has occurred in recent geologic history -- the transition from the greenhouse climate of the Eocene epoch to the "icehouse" or glacial conditions of the Oligocene epoch approximately 33.5 million years ago.

"The boundary between the late Eocene to the early Oligocene is a striking example of rapid climate change that we can look to in Earth's past," Katz said. "Information from this period can provide us with important information on how rapid changes in temperature can significantly impact ice volume, sea level, and the evolution of life on Earth."

Katz has used oxygen and carbon isotopes as well as the ratio of magnesium to calcium within foraminifera from this period to reconstruct the changes that occurred as the climate rapidly cooled. Along with her research colleagues, she has shown that ice sheets at the end of the transition were approximately 25 percent larger than today, causing a decrease in sea level of approximately 105 meters.

Her research also reaches even further back to reconstruct conditions earlier in Earth's history. In particular, she took part in a study of atmospheric oxygen and carbon dioxide concentrations since the Jurassic period 205 million years ago. The group has found that oxygen levels doubled in the short period of time from the Jurassic period to the Eocene epoch (~150 million years ago), providing a climate with just enough oxygen for placental mammals to develop.

Scientists make cells that form eggs and sperm in lab

2009-11-13T06:29:00.000-08:00

U.S. researchers have found a way to coax human embryonic stem cells to turn into the types of cells that make eggs and sperm, shedding light on a stage of early human development that has not been fully understood.

The findings could lead to new understanding of inherited diseases and transform treatments for infertility, they said.

"We are really trying to look at the origins of normal and abnormal human development by going to the source," said Dr. Renee Riejo Pera of Stanford University in California, whose study appears in the journal Nature.

"For years and years, we haven't had the ability to look at how germ cells -- the cells that give rise to eggs and sperm -- how they are made -- what genes are required, what pathways are active," Pera said in a telephone interview.

This part of the human reproductive cycle cannot be studied in animals because the genes involved are unique to humans.

"Germ cells in humans normally develop between day 12 after fertilization through the first trimester. That is a place we can't look. We can't see because obviously it is in utero," Pera said.

She said the findings will finally allow researchers to begin to study the earliest stages of human development, and gather new clues about inherited diseases and infertility.

"The potential is enormous," Darren Griffin, a professor of Genetics at the Britain's University of Kent, said in a statement.

He said the work could make it possible to study a range of genetic and environmental effects on fertility, including pollution.

GREEN LIGHT

Dr. Kehkooi Kee, a researcher in Pera's lab, devised a way to isolate the germ cells from embryonic stem cells by adding a gene that makes green glowing proteins when germ cells are active.

"A green light comes on when a germ cell has been formed. It raises its hand," Pera said.

Once they were convinced they had germ cells, they began turning on and off several genes -- called DAZ, DAZL and BOULE -- they believed were important in converting stem cells to immature germ cells.

One of these genes, DAZL, was key to transforming embryonic stem cells into germ cells. When turned off, half as many germ cells formed.

The other two genes, DAZ and BOULE, played a role in getting cells to cut the number of chromosomes in half, a process called meiosis that must take place before fertilization.

Some of the sperm cells went all the way through meiosis. "It means we really did hit the nail on the head. We got where we wanted to go if we see meiosis in the dish," Pera said.

She said these cells formed a round spermatid, an immature sperm cell that contains just one copy of the chromosomes that would be suitable for use in an in vitro fertilization clinic.

Producing too few germ cells or poor quality germ cells is a major cause of infertility in humans.

"We think if there's immature germ cells that are available in a person, we might be able to use this system to mature them and push them forward into development," she said.

Pera hopes to try the same approach with so-called induced pluripotent stem cells, which are adult cells that have been reprogrammed to behave like embryonic stem cells.

The idea is to take cells from people with infertility problems, produce germ cells and study them to see what caused the infertility.

The study was funded in part by the National Institutes of Health.

Courtesy: ScienceDaily

Pig DNA mapped: may help with vaccines

2009-11-11T06:27:00.000-08:00

An international team of researchers said Monday it had mapped the DNA of a domestic pig, work they say could help lead to better breeding techniques as well as improve vaccines against diseases such as swine flu.

They plan to look for genes useful in pork production and immunity in pigs, which are similar in size to humans. And, like humans, they catch influenza very easily.

"Understanding the swine genome will lead to health advancements in the swine population and accelerate the development of vaccinations for pigs," said Roger Beachy, Director of the U.S. Department of Agriculture's National Institute of Food and Agriculture.

"This new insight into the genetic makeup of the swine population can help reduce disease and enable medical advancements in both pigs and humans," Beachy said in a statement.

"The pig is a unique animal that is important for food and that is used as an animal model for human disease," added Larry Schook of the University of Illinois in Champaign, who helped direct the project.

"And because the native wild animals are still in existence, it is a really exciting animal to look at to learn about the genomic effects of domestication."

The pandemic H1N1 swine flu virus originated in pigs and evidence suggests it can be passed from humans to pigs and back again. Pigs are also susceptible to many other strains of influenza.

Courtesy: ScienceDaily

Common Pain Relievers May Dilute Power Of Flu Shots

2009-11-09T06:22:00.000-08:00

With flu vaccination season in full swing, research from the University of Rochester Medical Center cautions that use of many common pain killers -- Advil, Tylenol, aspirin -- at the time of injection may blunt the effect of the shot and have a negative effect on the immune system.

Richard P. Phipps, Ph.D., professor of Environmental Medicine, Microbiology and Immunology, and of Pediatrics, has been studying this issue for years and recently presented his latest findings to an international conference on inflammatory diseases.

"What we've been saying all along, and continue to stress, is that it's probably not a good idea to take common, over-the-counter pain relievers for minor discomfort associated with vaccination," Phipps said. "We have studied this question using virus particles, live virus, and different kinds of pain relievers, in human blood samples and in mice -- and all of our research shows that pain relievers interfere with the effect of the vaccine."

A study by researchers in the Czech Republic reported similar findings in the Oct. 17, 2009, edition of The Lancet. They found that giving acetaminophen, the active ingredient in Tylenol, to infants weakens the immune response to vaccines.

Phipps' research has tested whether production of antibodies using a cell culture system was blunted by over-the-counter pain relievers. He found that a variety of pain relievers -- even though Tylenol and Advil have different ingredients -- seemed to dilute the production of necessary antibodies to protect against illness.

Many of the pain relievers in question are classified as NSAIDs or nonsteroidal anti-inflammatory drugs, which act in part by blocking the cyclooxygenase-2 (cox-2) enzyme. Blocking the cox-2 enzyme is not a good idea in the context of vaccination, however, because the cox-2 enzyme is necessary for the optimal production of B-lymphocytes.

Therefore, when a person takes a medication to reduce pain and fever, he or she might also inadvertently reduce the ability of B cells to make antibodies.

Phipps and colleagues also demonstrated that timing of the administration of pain relievers is important as well, according to the study published earlier this year in the journal Cellular Immunology

They exposed human cells and mice to ibuprofen, Tylenol, aspirin and naproxen (Aleve) in amounts comparable to doses commonly used by millions of Americans every day to prevent or treat pain and fever, or arthritis, or to prevent heart attack and stroke.

Treatment during the earliest stages of inflammation -- or when the first signs of pain, swelling, redness or fever would occur -- had the most detrimental effects on the immune system, the study noted.

The connection between NSAIDs and antibody production is still being actively pursued. Phipps said researchers believe ibuprofen, in particular, affects lymphocytes' ability to produce antibodies.

Meanwhile, until a full clinical trial provides a clearer picture, Phipps urges regular users of NSAIDs to be aware of the risks.

"NSAIDs are one of the most commonly used drugs; they are recommended for all age categories, are prescribed for relieving transient pain or in cases of serious inflammatory diseases," Phipps said. "By decreasing antibody synthesis, NSAIDs also have the ability to weaken the immune system which can have serious consequences for children, the elderly and the immune-compromised patients."

The U.S. Public Health Service has funded Phipps' studies.

URMC co-investigators on the study in Cellular Immunology include: David Topham, Ph.D., an expert in the immune response to influenza and a principal investigator in the David H. Smith Center for Vaccine Biology and Immunology, and Simona Bancos and Matthew P. Bernard, of the Department of Environmental Medicine, Lung Biology and Disease Program.

Courtesy: ScienceDaily

Stem Cell 'Daughters' Lead To Breast Cancer

2009-11-07T06:24:00.000-08:00

Walter and Eliza Hall Institute scientists have found that a population of breast cells called luminal progenitor cells are likely to be responsible for breast cancers that develop in women carrying mutations in the gene BRCA1.

BRCA1 gene mutations are found in 10-20 per cent of women with hereditary breast cancer. Women with BRCA1 mutations often develop 'basal-like' breast cancer, which is a particularly aggressive form of the disease.

A team led by Associate Professors Jane Visvader and Geoff Lindeman from the institute's Victorian Breast Cancer Research Consortium Laboratory have discovered that luminal progenitor cells – the 'daughters' of breast stem cells – are the likely source of basal-like breast tumours. Their finding, published in today's issue of the international journal Nature Medicine, represents a major shift in the way scientists think breast cancer develops.

Dr Visvader said it had been thought in recent years that breast stem cells gave rise to BRCA1 tumours. "However, research carried out at the institute by Drs Elgene Lim and François Vaillant has shown that breast tissue from women with BRCA1 mutations has unexpectedly high numbers of luminal progenitor cells," she said.

"Further, our gene expression studies have revealed that BRCA1 breast tissue and basal breast tumors are more similar to normal luminal progenitor cells than any other cell type in the breast. This places the spotlight on errant luminal progenitors, rather than breast stem cells."

Dr Lindeman, who also heads the Familial Cancer Centre at the Royal Melbourne Hospital, said that now the importance of luminal progenitor cells in breast cancer was known it opened the way for the development of new drugs or therapies to treat breast cancer, one of the biggest causes of premature death in women.

"BRCA1 women have approximately a 65 per cent lifetime chance of developing breast cancer. Following surgery, treatment options available to these women are often limited to chemotherapy and radiotherapy, so identifying new treatment and prevention strategies is a priority for us," he said.

Luminal progenitor cells in women with BRCA1 mutations have 'forgotten' how to behave, Dr Lindeman said. "Usually, luminal progenitor cells multiply rapidly in the presence of certain growth factors. In BRCA1 women these cells don't even require growth factors to proliferate – they misbehave from the outset.

"We also know that the BRCA1 gene is required for normal DNA repair. There may therefore be a triple whammy effect – faulty growth control, faulty DNA repair and expanded luminal progenitor cell numbers –ultimately resulting in breast cancer in some BRCA1 mutation carriers."

Dr Visvader said in the long-term, breast biopsies might be able to reveal misbehaving luminal progenitor cells. What's more, certain 'markers' might one day help guide diagnosis and treatment. "For example, c-KIT is a key marker of the luminal progenitor cell and I expect we will see an increase in pathologists routinely using this as a diagnostic marker for basal-like tumours," she said. "It may even be possible to develop new drugs that target c-KIT, since drugs are already available that target different forms of this marker."

Dr Lindeman said the identification of stem cells, luminal progenitor cells and other cell types in the breast was now beginning to reveal a breast cancer roadmap - highlighting cancer-prone cell types and key genetic pathways. "Hopefully this will lead to new, tailored therapies for the next generation of women."

Dr Visvader said the research had only been possible through the generous donation of breast tissue by women undergoing breast surgery, together with the support of their surgeons and pathologists. The study was facilitated by the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer.

The research was supported by the Victorian Breast Cancer Research Consortium, the Susan G. Komen Foundation, the National Breast Cancer Foundation, the National Health and Medical Research Council, the Australian Stem Cell Centre, the US Department of Defense and the Australian Cancer Research Foundation.

Courtesy: ScienceDaily

Medical Imaging May Help Researchers Understand Pathogenesis Of H1N1 Virus

2009-11-05T06:19:00.000-08:00

Researchers at the National Institutes of Health (NIH) have found that imaging can now be used as a tool for identifying severe cases of H1N1 and may play a key role in understanding the pathogenesis of the virus, possibly leading to earlier diagnoses of severe cases in the future, according to a study published online today in the American Journal of Roentgenology.

The study will be published in the December issue of AJR.

Imaging revealed a severe case of H1N1 after a patient had tested negative using a nasal swab rapid antigen test. Radiography (standard X-ray) showed peripheral lung opacities, and computed tomography (CT) revealed peripheral ground-glass opacities. Both findings raised suspicion of H1N1 and reports revealed that the patient later died from a severe case of H1N1.

"The role of radiologic imaging in epidemic detection and response is evolving, with imaging being used as a tool for identifying severe cases," said Daniel J. Mollura, M.D., lead author of the study. "At the Center for Infectious Disease Imaging (CIDI) at the NIH, the study of influenza is a priority with a focus on achieving early diagnosis and understanding its pathogenesis," he said.

"Early CT may help clinicians recognize cases of severe influenza and monitor response to treatment. More cases will certainly need to be analyzed and compared in the future, but this is a promising early result," said Dr. Mollura.

Reference:

Mollura et al. Imaging Findings in a Fatal Case of Pandemic Swine-Origin Influenza A (H1N1). American Journal of Roentgenology, December 2009 (in press)

TV Exposure May Be Associated With Aggressive Behavior In Young Children

2009-11-03T18:17:00.000-08:00

Three-year-old children who are exposed to more TV appear to be at an increased risk for exhibiting aggressive behavior, according to a report in the November issue of Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives journals.

"Early childhood aggression can be problematic for parents, teachers and childhood peers and sometimes is predictive of more serious behavior problems to come, such as juvenile delinquency, adulthood violence and criminal behavior," according to background information in the article. Various predictive factors for childhood aggression have been studied. These include parents' discipline style, neighborhood safety and media exposure. "After music, television is the medium children aged 0 to 3 years are exposed to the most." Although the American Academy of Pediatrics recommends no screen media for children younger than age 2, studies have found consistent use of television in that age group.

Jennifer A. Manganello, Ph.D., M.P.H., of University at Albany, State University of New York, Rensselaer, and Catherine A. Taylor, Ph.D., M.S.W., M.P.H., of Tulane University School of Public Health and Tropical Medicine, New Orleans, analyzed data from 3,128 mothers of children born from 1998 to 2000 in 20 large U.S. cities to examine associations of child television exposure and household television use with aggressive behavior in children. Parents were interviewed at the time of the child's birth and at one and three years. At three years, they were asked to report time the child spent watching TV directly as well as household TV use on a typical day. Aggression also was assessed at 3 years of age using a 15-item aggressive subscale for 2- and 3-year-old children. Demographic information and other risk factors for aggression were also noted.

About two-thirds (65 percent) of mothers reported that their 3-year-old child watched more than two hours of television per day. On average, children were exposed to an additional 5.2 hours of household TV use per day.

Direct child TV exposure and household TV use were both significantly associated with childhood aggression, after accounting for other factors such as parent, family, neighborhood and demographic characteristics. "One explanation that could link both child and household TV measures with aggression involves the parenting environment," the authors write. Households with higher rates of TV use may have fewer restrictions on children's viewing habits such as exposure to unregulated television content. Increased household television use may also affect daily routines such as eating and communication patterns and may decrease time spent on other activities.

"Current American Academy of Pediatrics recommendations mainly suggest limitations for direct child exposure to TV and other media; however, our findings suggest that additional household TV use may also be an important predictor of negative childhood outcomes, such as early childhood aggression," the authors conclude. "Future research in this area should consider inclusion of both of these TV variables along with additional parent-child interaction assessments, observational assessments when possible, quality and/or content of TV programs and longitudinal analyses."

Reference:

Jennifer A. Manganello; Catherine A. Taylor. Television Exposure as a Risk Factor for Aggressive Behavior Among 3-Year-Old Children. Archives of Pediatrics and Adolescent Medicine, 2009; 163 (11): 1037 DOI: 10.1001/archpediatrics.2009.193

Messenger RNA With FLASH

2009-10-30T05:46:00.000-07:00

A study from the University of North Carolina at Chapel Hill has identified a key player in a molecular process essential for DNA replication within cells.

The new findings highlight a protein called FLASH, already shown to play a role in initiating apoptosis, or programmed cell death. Apoptosis is a normal biochemical response that occurs when a cell is damaged beyond repair after viral infection or accumulation of mutations that could lead to uncontrolled cellular proliferation, or cancer. Apoptosis is also crucial to the developing embryo through selective cell death, which allows proper differentiation of physical structures, such as fingers and toes.

According to senior study author Zbigniew Dominski, Ph.D., associate professor of biochemistry and biophysics at UNC, the new study demonstrates that FLASH is also required for the proper synthesis of histone messenger RNA, which gives rise to histone proteins.

Histones are the chief protein components of chromatin and act as a scaffold allowing packaging of DNA into a condensed form that fits inside the nucleus of a cell. As the DNA interacts with histones and with metabolic signals from within the cell, these proteins help regulate gene expression.

"Our study suggests for the first time that a potential link exists between the processes of histone messenger RNA formation and apoptosis," Dominski said. "FLASH is crucial for the production of histone messenger RNA, without which the cell can't make the histone proteins around which DNA is packaged."

The research is described in the Oct. 23, 2009 issue of the journal Molecular Cell.

For the study, Dominski adapted a laboratory system that reproduces in the test tube what normally occurs in the cell when FLASH participates in the biochemical cleavage event that results in mature histone messenger RNA. This enabled his team to explore what might occur when FLASH was added or removed.

"We could then figure out exactly what portion of FLASH would restore the protein's function in generating histone mRNAs and remarkably, only the first 100 or so amino acids are required. The remaining 2,000 amino acids of this large protein likely control other processes in the cell, including apoptosis and DNA replication," he explained.

Co-author William F. Marzluff, Ph.D., is distinguished professor of biochemistry and biophysics and executive associate dean for basic research in the UNC School of Medicine. He noted that FLASH is the first component found in this protein complex "that integrates or initiates many cellular functions DNA replication, apoptosis, histone production. Having this small piece of the puzzle makes it a lot easier to identify others."

Other UNC coauthors include Xiao-cui Yang, laboratory technician, and Yan Yan, undergraduate student, both from the Department of Biochemistry and Biophysics and the UNC Program in Molecular Biology and Biotechnology and Brandon D. Burch, graduate student in in genetics and molecular biology.

Funding for the study came from the National Institute of General and Medical Sciences, a component of the National Institutes of Health.

Source: University of North Carolina

New Molecules Created By University Of California Riverside Chemists Have Wide Applications

2009-10-29T06:45:00.000-07:00

Researchers at the University of California, Riverside have successfully created in the laboratory a class of carbenes, highly reactive molecules, used to make catalysts - substances that facilitate chemical reactions. Until now, chemists believed these carbenes, called "abnormal N-heterocyclic carbenes" or aNHCs, were impossible to make.

Carbenes are made up of unusual carbon atoms and are usually unstable in nature. They attach themselves to metals to form metal-carbene complexes that serve as efficient catalysts used widely in the pharmaceutical industry.

The metal-carbene complexes are formed in two ways: (a) the complex is created in one step, without first preparing carbene independently, and (b) a metal and an independent carbene are brought together to make the complex.

Most often the metal used in a metal-carbene complex is rhodium, gold, platinum or palladium - all of which are very expensive and, in some cases, even toxic. To bring down the cost of catalysts, when possible, carbenes are used independently (without metals) in many chemical reactions.

Until now, aNHCs have been used as only metal-carbene complexes, never independently. Chemists had assumed that aNHCs cannot exist freely, which made them impossible to make.

Now UC Riverside's Guy Bertrand, a distinguished professor of chemistry, and colleagues have challenged that assumption by successfully creating aNHCs that are metal-free and can be used to make any desired complex.

"Many chemical species are believed to be unstable because they do not obey the rules we learned at school, and consequently nobody tries to make them," said Bertrand, who led the research project. "The role of scientists, however, is to challenge former hypotheses. That is just what we did in the case of the aNHCs, and we were successful.

"The aNHCs are stable at room temperature both in the solid state and in solution, which means their application as metal-free catalysts is extremely wide, greatly benefiting industry by making possible scores of new chemical reactions."

Results of the study appear in the Oct. 23 issue of Science.

"This study, reporting the synthesis and characterization of an entirely different class of metal-free NHCs, could open new horizons and have a huge impact on the field of catalysis," said John Schwab, who oversees organic synthesis grants at the National Institutes of Health's National Institute of General Medical Sciences. "The potential applications to drug discovery and manufacture are exciting, since catalytic processes can help keep costs in check and be environmentally friendly, to boot."

Bertrand is interested in making aNHCs commercially available. "We hope many chemists in the world will use these carbenes and find some new applications," he said.

The UCR Office of Technology Commercialization has filed a patent application on the technology and is currently seeking partners in industry interested in developing the technology commercially.

An internationally renowned scientist, Bertrand came to UCR in 2001 from France's national research agency, the Centre National de la Recherche Scientifique (CNRS). He is the director of the UCR-CNRS Joint Research Chemistry Laboratory.

A recipient of numerous awards and honors, most recently he won the 2009-2010 Sir Ronald Nyholm Prize for his seminal research on the chemistry of phosphorus-phosphorus bonds and the chemistry of stable carbenes and their complexes.

He is a recipient of the Japanese Society for Promotion of Science Award, the French-German Humboldt Award, and the International Council on Main Group Chemistry Award. He is a fellow of the American Association for the Advancement of Sciences, and a member of the French Academy of Sciences, the European Academy of Sciences, Academia Europea, and Academies des Technologies.

He has authored more than 300 scholarly papers and holds 35 patents.

Bertrand was joined in the research by Eugenia Aldeco-Perez, Amos J. Rosenthal, and Bruno Donnadieu of UCR; and Gernot Frenking and Pattiyil Parameswaran of Phillips-Universitat Marburg, Germany.

The research project was funded by the National Institutes of Health. The National Council for Science and Technology (CONACYT), Mexico, provided Aldeco-Perez, the first author of the research paper, with financial support.

Source:
Iqbal Pittalwala
University of California - Riverside

Stacks Of Filter Paper Provide A Realistic, Easy-to-use Medium For Growing Cells

2009-10-27T06:42:00.000-07:00

An insight from the labs of Harvard chemist George Whitesides and cell biologist Don Ingber is likely to make a fundamental shift in how biologists grow and study cells – and it's as cheap and simple as reaching for a paper towel.

Ratmir Derda, a postdoctoral student co-mentored by Whitesides and Ingber at Harvard's new Wyss Institute for Biologically Inspired Engineering, has realized that by growing cells on several sheets of uncoated paper, he can solve a problem that has bedeviled biologists for years: how to easily grow and study cells that mimic the three-dimensionality of real tissue.

This work will simplify creation of realistic, three-dimensional models of normal or cancerous tissue -- potentially making it faster and easier to find drugs that fight cancer and other diseases.

"This research has the potential to become a standard laboratory tool, alongside the Petri dish, in laboratories that work with cells," said George M. Whitesides, the Woodford L. and Ann A. Flowers University Professor at Harvard University and a founding faculty member of the Wyss Institute. "Filter paper and other kinds of paper are readily available, and the technique is both very flexible in what it can do, and very convenient to use."

Now, researchers grow cells in a Petri dish, creating a thin, two-dimensional layer of cells. If they want to do a better job of mimicking real tissue, they culture the cells in a gel. But because cells in different locations get vastly different amounts of oxygen and food, these cultures fail to mimic real tissues. And studying the cells from different parts of these gels without destroying the 3D culture is tricky.

By growing the cells in a thin layer of gel supported by paper, and then stacking those pieces of paper, the scientists showed they could recreate the benefits of two-dimensional research – where cells receive a uniform amount of oxygen and food -- while also closely mimicking real tissue. In this case, they engineered a 3D tumor on paper that exhibited behaviors similar to a cancer in the body.

Stacking multiple cell-containing sheets also allows researchers to examine the interior of a large cell cluster, either cultured on a dish or grown in vivo, simply by peeling the layers apart, without disturbing the properties of the cells. Isolating cells grown with other 3D culture techniques requires either performing complex laser-assisted surgery on the tumor sections or destroying the architecture of the tissue and then sorting the cells.

Derda said he had the initial insight that led to this study when he heard a colleague complain that he couldn't use paper to filter blood, because the erythrocytes, which give blood their red color, are sometimes trapped in the paper and sometimes go through it. Derda, who developed and used peptide arrays for stem cell research in his Ph.D. work, thought he might be able to use this trapping property for high-throughput screening. When he discussed that insight with Whitesides, the older chemist suggested Derda try stacking the pages instead.

Fellow postdoctoral student Anna Laromaine helped Derda figure out how to clip multiple layers of paper together while submerged in the gel, allowing the first multi-layer cell culture to grow. When he gingerly pulled the sheets of paper apart and analyzed the distribution of cells in different layers, he realized the versatility of paper as a growing medium and its potential to mimic any three-dimensional tissue.

"The best thing about this approach is that it can be used by everyone," Derda said. "Paper is nearly free, it's all over the place and you don't have to know anything other than how to dip."

The work was supported by funds from the Wyss Institute, National Institutes of Health, Vertex Inc., DoD Breast Cancer Innovator Award, the Fulbright-Generalitat de Catalunya, and the American Heart Association.

In addition to Derda, Whitesides and Ingber, the founding director of the Wyss Institute, a faculty member at Harvard's Medical School and its School of Engineering and Applied Sciences, and a researcher at Children's Hospital Boston, the paper's other authors are: Akiko Mammoto and Tadanori Mammoto of Ingber's lab, and Laromaine and Sindy K. Y. Tang of Whitesides' lab.

Reference:

Akiko Mammoto et al. Paper-Supported Three-Dimensional Cell Culture for Tissue-Based Bioassays. Proceedings of the National Academy of Sciences, October 19, 2009

Scientists Identify Specific Markers That Trigger Aggressiveness Of Liver Cancer

2009-10-25T05:41:00.000-07:00

Hepatocellular carcinoma (HCC) or primary liver cancer forms in the epithelial tissue of the liver and is most commonly caused by the hepatitis B virus (HBV) or hepatitis C virus (HCV). In the U.S., the National Cancer Institute (NCI) estimates that 15,000 men and 6,000 women are diagnosed with HCC each year. Worldwide, HCC accounts for 632,000 cases with the highest regions being Western Pacific and Africa according to a 2004 World Health Organization (WHO) report.

Researchers from Taipei Veterans General Hospital investigated the molecular mechanisms of HCC, one of the most common tumors found in Taiwan and largely caused by the high prevalence (15%-20%) of HBV in the country. The study, funded in part by a grant from the National Science Council, is the first to provide a comprehensive profile of multiple Epithelial-Mesenchymal Transition (EMT) markers and to demonstrate that Snail and Twist, but not Slug, are the major inducers of EMT in HCC. Results of the study are published in the November issue of Hepatology, a journal of the American Association for the Study of Liver Diseases.

EMT is critical in the development of invasiveness and metastatic potential of human cancers, and described as process where epithelial cells no longer adhere to one another, taking on fibroblastic properties. The EMT process is initiated by suppression of E-cadherin function through the major EMT regulators (Snail, Slug, and Twist). E-cadherin (calcium dependent adhesion molecules) is a type of protein found in the epithelial cells that ensure tissue cells bind together. When E-cadherin function is lost, cancer is able to progress and metastasize.

Professor Jaw-Ching Wu and colleagues obtained samples of primary HCC with adjacent non-tumorous liver tissues from 123 patients who had hepatic resection surgery between 1990 and 2002 at Taipei Veterans General Hospital. Reduced E-cadherin function was observed in 60.2% of patients. "We found a significant decrease in cancer-free intervals and overall survival for those patients who had a reduction in E-cadherin function," explained Dr. Wu. A downregulated expression of E-cadherin was also associated with large tumor size and multi-nodular tumors.

Results show that co-expression Snail and Twist (transcription factors or proteins that control when genes are switched on or off) indicates the worst prognosis for HCC patients. "Our research is the first to prove that the two proteins (Snail and Twist) work independently, but together promote EMT," noted Dr. Wu.

According to the study, overexpression of Twist is correlated with HCV-related HCC, partially explaining the highly invasive behavior and poor prognosis for patients with this form of liver cancer. Dr Wu added, "Our results provide essential information for determining HCC prognosis in patients and identifies possible new treatments for future HCC management."

Reference

Yang et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology, 2009; DOI: 10.1002/hep.23221
Gianluigi Giannelli. The Epithelial Mesenchymal Transition: fact or fiction in cancer? Hepatology;, Published Online: October 29, 2009 DOI: 10.1002/hep.23329

High-Speed Test To Improve Pathogen Decontamination Developed

2009-10-23T08:39:00.000-07:00

A chemist at NASA's Jet Propulsion Laboratory in Pasadena, Calif., has developed a technology intended to rapidly assess any presence of microbial life on spacecraft. This new method may also help the military test for disease-causing bacteria, such as a causative agent for anthrax, and may also be useful in the medical, pharmaceutical and other fields.

Adrian Ponce, the deputy manager for JPL's planetary science section, devised the new microscope-based method, which has the potential to quickly validate -- from days to minutes -- a spacecraft's cleanliness.

NASA adheres to international protocols by striving to ensure that spacecraft don't harbor life from Earth that could contaminate other planets or moons and skew science research. Microbes known as bacterial endospores can withstand extreme temperatures, ultraviolet rays and chemical treatments, and have been known to survive in space for six years. This resilience makes them important indicators for cleanliness and biodefense, Ponce said.

"Bacterial endospores are the toughest form of life on Earth," Ponce explained. "Therefore, if one can show that all spores are killed, then less-resistant, disease-causing organisms will also be dead."

The new technology works by looking for dipicolinic acid -- a major component of endospores and evidence of endospore growth -- by first applying terbium to a dime-sized area. Terbium is a chemical element used to generate the color green on television screens. That area is then illuminated under an ultraviolet lamp. Within minutes, one can see through a microscope aided by a digital camera whether live endospores are present. That's because they will literally glow: The terbium will show the endospores as bright green spots.

Ponce co-authored a paper on the new technology, called Germinable Endospore Biodosimetry, along with Pun To Young, a post-doctoral student at the California Institute of Technology in Pasadena, in the journal Applied and Environmental Microbiology. The research was also highlighted in Microbe, a magazine of the American Society for Microbiology.

The technology has piqued the interest of the U.S. Department of Homeland Security. The federal agency is funding development of a portable instrument based on Ponce's research that could quickly check for decontamination of pathogens after a biological attack. Ponce is working with the Department of Homeland Security and Advance Space Monitor, a company based in Falls River, Mass., to develop the instrument, which they plan to have ready for use by 2011. JPL and Caltech licensed the technology to Advance Space Monitor.

"As part of the Department of Homeland Security Science and Technology Directorate's near-term bioassays effort, the technology could enable the rapid assessment of facility sterilization. This could significantly reduce the time and cost of building restoration following a bio-contamination event," said James Anthony, chemical and biological research and development program manager at the Dept. of Homeland Security. A bioassay is an assessment of whether certain biological material is present on a surface being tested.

Anthony added that the technology could also be used in bio-containment facilities that have regularly scheduled decontamination requirements and rapidly reactivate important bio-defense research facilities.

Besides outer space and defense purposes, this new technology might also be applied in hospitals, child-care centers, dentists' offices and nursing homes.

"Given all the problems with hospital-acquired infections, assessing the sterility and hygiene of medical equipment and surfaces is becoming increasingly important," said Ponce.

Funding for Ponce's project was provided by NASA's Astrobiology Science and Instrument Development Program and Mars Technology Program, and the U.S. Department of Homeland Security's Chemical and Biological Research and Development division.

Courtesy: ScienceDaily

Chromosomal Test By Molecular Biologists Determines Cancer Spread

2009-10-14T19:52:00.000-07:00

A new biopsy test, created by molecular biologists, can tell ocular melanoma patients if theirs is the kind that will spread. Using very thin needles, surgeons collect cells from tumors and analyze them. If tumors are missing a copy of chromosome three, patients are at high risk of having their cancer spread. While there's no cure for ocular melanoma, patients who are at higher risk can be followed more closely and put on experimental treatments.

Ocular melanoma, or eye cancer, is a serious disease that affects about 2,000 Americans each year. Roughly half of patients will die from the cancer because their tumor spreads to other areas of the body. Now, a new test can tell patients if they're looking at life ... or death.

Just like everyone, Susan Izanstark-Rosenthal relies on her eyes every second of every day. "I'm an attorney, and I read and write all day long," she says.

But about a year ago, she didn't know if she'd be able to see out of her left eye ever again. Rosenthal was diagnosed with ocular melanoma. Surgery followed.

"It was very scary, and I didn't know when I woke up if I'd be able to see in the other eye," she says. Even scarier -- she found out she could die if her cancer spread. Ocular oncologist Tara Young, says a new biopsy test can tell patients if their tumor is the kind that will spread.

"It represents the first step that we've been able to make in a long time with this cancer," Young, of the Jules Stein Eye Institute at UCLA, tells DBIS.

Using very thin needles, surgeons collect cells from tumors and analyze them. If tumors are missing a copy of chromosome three, patients are at high risk of having their cancer spread. If tumors are normal, they have a very low risk.

"If someone could tell you that you were gonna go and die of your cancer, I think that most people want that information and that knowledge, so that they can just take a little bit more control over their lives," Young says.

Only a handful of medical centers across the country are performing the eye biopsy technique. While there's no cure for ocular melanoma, patients who are at higher risk can be followed more closely and put on experimental treatments. She says so far, all of her patients have wanted to know the results of their biopsy.

Rosenthal wasn't missing a copy. It's a great relief for her -- and her daughter. "It's given me, once again, a reminder that you need to appreciate every day and be very grateful for what you have," Rosenthal says.

BACKGROUND: The Jules Stein Eye Institute at the University of California, Los Angeles, is the first center in the country to practice analyzing rare eye cancers at a level as small as a molecule. The new biopsy technique looks for a certain chromosome within the tumor that can predict which tumors have a high risk of spreading. Physicians can determine this earlier, and thereby recommend much more aggressive treatment, resulting in longer survival rates for their patients. Since 2005, JSEI has performed more than 70 procedures.

ABOUT THE DISEASE: Ocular melanoma -- eye cancer -- is a particularly rare and aggressive form of cancer that attacks the pigment cells in the retina. There are essentially two types of intraocular melanoma: low-grade tumors, which grow slowly and rarely metastasize, and high-grade tumors, which grow more quickly and metastasize at a very early stage. Once a tumor metastasizes, the cancer spreads quickly to the liver and other organs, and a patient has only 6 to 12 months to live in most cases, although some can survive for as long as 5 years. The National Eye Institute reports some 2000 newly diagnosed cases of ocular melanoma per year in the US and Canada's roughly seven in one million people. It affects people of all ages and races, and is not hereditary. Ocular melanoma kills nearly half of those who develop it

IT'S ALL IN THE GENES: Doctors understand very little about the molecular changes that result in this aggressive behavior, but they now know that patients who are missing one copy of chromosome 3 in their tumor tissue are more likely to have highly aggressive cancers. For the first time, UCLA surgeons have demonstrated that it is feasible and safe to perform a biopsy on a living eye. They use an ultra-fine needle to collect cells from the cancer before surgery and send the sample to the lab for culture. After growing the tumor cells, a geneticist analyzes them to determine which are missing a copy of chromosome 3. This genetic marker tells them which patients require more aggressive treatment for their cancer.

WHAT ARE CHROMOSOMES? A chromosome is a single large macromolecule of DNA, and constitutes a physically organized form of DNA in a cell. It is a very long, continuous piece of DNA (a single DNA molecule), which contains many genes, regulatory elements and other intervening nucleotide sequences. A broader definition of "chromosome" also includes the DNA-bound proteins which serve to package and manage the DNA. The word chromosome comes from the Greek chroma ('color') and soma ('body') due to its capacity to be stained very strongly with dyes.

Courtesy:ScienceDaily

Chemical Engineers Call On Nanoparticles To Combat Polluted Groundwater

2009-10-12T05:49:00.000-07:00

Chemical engineers created nanoparticles out of gold and palladium to break down pollutants in groundwater. Adding the particles to groundwater converts dangerous contaminants like trichloroethylene into non-toxic compounds.

He's just 37 years old, but he's already making a difference in the world! A young engineer is creating small solutions to big problems.

We've seen it in the movies -- polluted drinking water is a health and environmental concern. In fact, right now, 30 states need to clean up their groundwater. "They've been designated by the EPA as being highly contaminated, and they've got to do something about the contaminated water," Michael Wong, Ph.D., a chemical engineer at Rice University in Houston, told Ivanhoe.

Dr. Wong is one of Smithsonian Magazine's America's Young Innovators … and for good reason. He's trying to come up with a way to use nanoparticles to clean up our water. "Water is not just H2O. Water has all sorts of stuff in it and the stuff we don't want, those are the things that can really hurt you," Dr. Wong explains.

He's using nanoparticles made out of gold and palladium -- a metal related to platinum -- to get rid of chemicals. One of the most common pollutants in United States groundwater is trichloroethylene, or TCE, a solvent used to degrease metals. And it can cause cancer.

"Our idea was, let's go ahead and break it down -- break it down into something that's safer," Dr. Wong says. "Safer chemicals that won't hurt your body and hurt the animals and the fish and what not."

Wong uses nanoparticles -- ten thousand times smaller than a human hair -- and hydrogen to break TCE into something non-toxic. "We are going to pump water through this guy here and the water is being pumped from the bottom up," Dr. Wong explains.

Glass beads will help to hold the nanoparticles in place. "Then clean water comes out," Dr. Wong says. Dr. Wong plans to test it at military sites first -- then move onto industrial sites and dry cleaning businesses. "I'd like to see our reactor do a really good job of getting rid of some of the contaminants," Dr. Wong says. Possibly, making our water and environment cleaner in the future. Dr. Wong says his reactor will be more efficient and cost less than the carbon reactors being used now.

WHAT IS HAZARDOUS WASTE? In the U.S., hazardous waste is defined as any discarded solid or liquid that is highly corrosive, toxic, reactive enough to release toxic fumes, or easily ignited. It can include solvents, pesticides, and spilled chemicals -- including acids, ammonia, chlorine bleach and other industrial cleaning agents -- as well as most heavy metals. Long-term exposure to hazardous waste can lead to chronic respiratory diseases such as asthma, damaged liver and kidneys, or cancer. Poisoning and chemical burns can result from contact with even small amounts of toxic chemical waste. Even brief exposure can cause headaches, dizziness, and nausea.

WHERE THAT GLASS OF WATER COMES FROM: Drinking water can come from either ground water sources, via wells, or surface water sources, such as rivers, lakes and streams. Most U.S. water systems in small and rural areas use a ground water source, while large metropolitan areas tend to rely on surface water. Causes of contamination can range from agricultural runoff to improper use of household chemicals.

SECONDARY STANDARDS: Even if your tap water meets the EPA's basic requirement for safe drinking water, some people still object to the taste, smell or appearance of their water. These are aesthetic concerns, however, and therefore fall under the EPA's voluntary secondary standards. Some tap water is drinkable, but may be temporarily clouded because of air bubbles, or have a chlorine taste. A bleachy taste can be improved by letting the water stand exposed to the air for a while.

Courtesy:ScienceDaily

A Biochemist Explains The Chemistry Of Cooking

2009-10-10T05:47:00.000-07:00

A biochemist and cook explains that cooking is all about chemistry and knowing some facts can help chefs understand why recipes go wrong. Because cooking is essentially a series of chemical reactions, it is helpful to know some basics. For example, plunging asparagus into boiling water causes the cells to pop and result in a brighter green. Longer cooking, however, causes the plant's cell walls to shrink and releases an acid. This turns the asparagus an unappetizing shade of grey.

You love to cook, but have you whipped up some disasters? Even the best recipes can sometimes go terribly wrong. A nationally recognized scientist and chef says knowing a little chemistry could help.

Long before she was a cook, Shirley Corriher was a biochemist. She says science is the key to understanding what goes right and wrong in the kitchen.

"Cooking is chemistry," said Corriher. "It's essentially chemical reactions."

This kind of chemistry happens when you put chopped red cabbage into a hot pan. Heat breaks down the red anthocyanine pigment, changing it from an acid to alkaline and causing the color change. Add some vinegar to increase the acidity, and the cabbage is red again. Baking soda will change it back to blue.

Cooking vegetables like asparagus causes a different kind of reaction when tiny air cells on the surface hit boiling water.

"If we plunge them into boiling water, we pop these cells, and they suddenly become much brighter green," Corriher said.

Longer cooking is not so good. It causes the plant's cell walls to shrink and release acid.

"So as it starts gushing out of the cells, and with acid in the water, it turns cooked green vegetables into [a] yucky army drab," Corriher said.

And that pretty fruit bowl on your counter? "Literally, overnight you can go from [a] nice green banana to an overripe banana," Corriher said.

The culprit here is ethylene gas. Given off by apples and even the bananas themselves, it can ruin your perfect fruit bowl -- but put an apple in a paper bag with an unripe avocado, and ethylene gas will work for you overnight.

"We use this as a quick way to ripen," Corriher said. Corriher says understanding a little chemistry can help any cook.

"You may still mess up, but you know why," she said. When it works, this kind of chemistry can be downright delicious.

WHAT ARE ACIDS AND BASES? An acid is defined as a solution with more positive hydrogen ions than negative hydroxyl ions, which are made of one atom of oxygen and one of hydrogen. Acidity and basicity are measured on a scale called the pH scale. The value of freshly distilled water is seven, which indicates a neutral solution. A value of less than seven indicates an acid, and a value of more than seven indicates a base. Common acids include lemon juice and coffee, while common bases include ammonia and bleach.

WHY DOES FOOD SPOIL? Processing and improper storage practices can expose food items to heat or oxygen, which causes deterioration. In ancient times, salt was used to cure meats and fish to preserve them longer, while sugar was added to fruits to prevent spoilage. Certain herbs, spices and vinegar can also be used as preservatives, along with anti-oxidants, most notably Vitamins C and E. In processed foods, certain FDA-approved chemical additives also help extend shelf life.

DNA Test Could Be Key To Targeting Treatments For Head And Neck Cancer

2009-10-09T05:54:00.000-07:00

It is estimated that more than 7,000 people are diagnosed with head and neck cancer each year in the UK and approximately 3,500 cases result in death. These cancers include tumours of the mouth, lips, throat and voice-box, and some have been linked to the sexually transmitted infection, HPV-16. Scientists at Liverpool analysed the DNA of more than 90 cancerous tissue samples to look for genes that indicated infection.

The team found that nearly two thirds of tonsil tumour samples showed evidence of the HPV-16 gene. It is thought that chemical alterations in the virus's DNA trigger the production of proteins that can alter the rate at which cells grow and repair. This strongly increases the possibility of subsequent cancer development. Recent studies have found, however, that patients who have the HPV infection when they are diagnosed with cancer, respond better to chemotherapy or radiation therapy than those that do not have the infection. The work will be presented at the National Cancer Research Institute's (NCRI) Cancer Conference in Birmingham.

Mr Richard Shaw, from the School of Cancer Studies, explains: "Recent evidence demonstrates the possible involvement of HPV in the development of tonsil cancer, particularly in non-smokers. Interestingly, the treatment efficiency of chemotherapy and radiation, seems to differ between HPV positive and negative cases. We also need to find out why only a small percentage of people with this common infection develop this cancer. Our study, however, gives us a new lead towards a risk marker.

"It is thought that HPV interacts in the cell with genes controlling the chemical modification of DNA, which affects gene expression and tumour behaviour. Our study shows that HPV may be a trigger of tonsil cancer, independent of the known common causes, such as smoking or drinking. The work also suggests that a DNA test to determine the activity of HPV, could be used to identify the most effective treatment for each individual patient.

"Liverpool has the largest centralised head and neck oncology practice in the UK and our data show a doubling in the rate of non-drinkers and non-smokers presenting with tonsil cancer. As head and neck cancer is one of the cornerstones of the new CR-UK Cancer Centre in Liverpool, we are pleased to be making real progress in this area of research."

Researchers are now working to develop a clinical trial for a therapeutic HPV vaccine in head and neck cancer.

The study, supported by the Royal College of Surgeons, is presented at the NCRI Cancer Conference on Monday, 5 October.

Nobel Prize In Chemistry: What Ribosomes Look Like And How They Functions At Atomic Level

2009-10-07T19:43:00.000-07:00

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry for 2009 jointly to Venkatraman Ramakrishnan, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom; Thomas A. Steitz, Yale University, New Haven, CT, USA; and Ada E. Yonath, Weizmann Institute of Science, Rehovot, Israel, "for studies of the structure and function of the ribosome".

The ribosome translates the DNA code into life

The Nobel Prize in Chemistry for 2009 awards studies of 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.

This year's Nobel Prize in Chemistry awards Venkatraman Ramakrishnan, Thomas A. Steitz and Ada E. Yonath for having 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.

Courtesy: Sciencedaily

How MicroRNAs Drive Tumor Progression

2009-09-29T05:15:00.000-07:00

UCSF researchers have identified collections of tiny molecules known as microRNAs that affect distinct processes critical for the progression of cancer. The findings, they say, expand researchers' understanding of the important regulatory function of microRNAs in tumor biology and point to new directions for future study and potential treatments.

The researchers refer to these microRNA collections as signatures, and their study results are reported in the September 15 issue of Genes & Development. The study, available online at http://genesdev.cshlp.org/, was led by the laboratory of Douglas Hanahan, PhD, an American Cancer Society Research Professor in the Department of Biochemistry and Biophysics at UCSF.

Approximately five percent of all known human genes encode, or produce, microRNAs, yet scientists are only now - nearly a decade after their discovery - beginning to unlock the mystery of their functions.

MicroRNAs are snippets of single-stranded RNAs that prevent a gene's code from being translated from messenger RNA into proteins, which are essential for cell growth and development. Produced in the nucleus and released into the cytoplasm, they home in on messenger RNAs that possess a stretch that is complementary to their genetic sequence. When they locate them, they latch on, preventing the messenger RNA from being processed by the protein-making machines known as ribosomes. As such, microRNAs are able to ratchet down a cell's production of a given protein.

Over the last several years, several groups have identified hundreds of microRNAs that are deregulated between normal tissue and tumors, however researchers only understand what a handful of these powerful regulators are doing to drive tumor formation.

"Virtually all cancers acquire approximately six distinct capabilities en route to tumor formation," said lead author Peter Olson, PhD, a postdoctoral fellow in the Diabetes Center and Helen Diller Family Comprehensive Cancer Center at UCSF. "When a cancer researcher observes a gene or microRNA go awry, it can be challenging to understand how that microRNA impacts tumorigenesis."

To home in on the question, the authors turned to a mouse model of pancreatic neuroendocrine tumors in which lesions go through discrete stages before culminating in invasive and metastatic carcinomas. In the three-year microRNA study, they found that cells in the mouse model developed and functioned normally but started to replicate uncontrollably at five weeks. Several weeks later, some pancreatic islets had become angiogenic (forming new blood vessels) - a step in the journey from a dormant state to a malignant state - though had not yet formed a tumor. By 10 weeks, a subset of angiogenic lesions had progressed to the tumor stage, and by week 16, a small percentage of mice had developed liver metastasis.

"This represents the spectrum of stages that we think are important for all tumors, including human disease," said Olson.

By measuring the expression level of all known microRNA in pre-tumor stages, tumors and metastases, the authors were able to associate deregulated microRNAs with processes such as hyperproliferation, angiogenesis and metastasis.

Focusing on the metastatic signature, researchers found - in one of the most striking observations of the project - that tumors bore a startlingly divergent microRNA expression pattern compared to primary tumors. Moreover, a subset of primary tumors showed more similarity to metastases than to other primary tumors.

"If you can identify tumors that have an increased propensity to metastasize, then it would have a very important clinical application," said Olson. "A lively debate in metastatic research has centered around whether primary tumor cells must suffer an additional mutation that endows that cell with a metastatic capability, or whether certain mutational combinations that are responsible for primary tumor formation also significantly increase the propensity of that cell to metastasize. These data provide evidence for the latter.''

Olson conducted the research in the Hanahan laboratory. Hanahan is a member of the UCSF Helen Diller Family Comprehensive Cancer Center. He also is a professor at the UCSF Diabetes Center.

Also collaborating on the project were Anny Shai and Matthew G. Chun of the UCSF Diabetes Center and the UCSF Helen Diller Family Comprehensive Cancer Center, and Yucheng Wang and Eric K. Nakakura of the UCSF Helen Diller Family Comprehensive Cancer Center. Other co-authors include Jun Lu, Hao Zhang, and Todd R. Golub of the Broad Institute of MIT and Harvard, and Steven K. Libutti who is with the Tumor Angiogenesis Section, Surgery Branch, of the National Cancer Institute.

The research was supported in part by the National Cancer Institute, the American Cancer Society and the National Science Foundation.

Source:
Elizabeth Fernandez
University of California - San Francisco

New Way Deadly Food-borne Bacteria Spread Discovered By University Of Central Florida Professor

2009-09-27T05:12:00.000-07:00

University of Central Florida Microbiology Professor Keith Ireton has uncovered a previously unknown mechanism that plays an important role in the spread of a deadly food-borne bacterium.

Listeria monocytogenes is a bacterium that can cause pregnant women to lose their fetuses and trigger fatal cases of meningitis in the elderly or people with compromised immune systems. The bacterium has been linked to outbreaks traced to food processing plants in the U.S. and Canada.

In 2002, a multi-state outbreak of listeriosis - the serious disease caused by Listeria - resulted in 46 confirmed cases, seven deaths and three stillbirths or miscarriages. Those cases in eight states were linked to people eating contaminated sliced turkey deli meat. From January to August 1985, there was another outbreak with 142 cases of listeriosis.

Scientists have long known that Listeria spreads from one human cell to another. Bacteria growing in one cell move fast enough to create a finger-like structure that protrudes from the cell and pushes into an adjacent cell. The bacteria then infect the adjacent cell.

Ireton and his team have discovered a previously unknown second process that aids in the spread of bacteria to healthy cells. The process, which gradually overwhelms the second cell's ability to defend itself from infection, is featured in this week's edition of the science journal Nature Cell Biology.

The plasma membrane, or outer layer, of healthy human cells normally exhibits tension. Such tension might be expected to prevent Listeria from spreading to adjacent uninfected cells. However, Ireton's lab found that a Listeria protein called InlC appears to relieve tension at the plasma membrane in infected cells, making it easier for moving bacteria to deform the membrane and then spread into adjacent, healthy cells.

Ireton's laboratory also reports that the way InlC relieves tension is by blocking the function of a human protein called Tuba. The normal role of Tuba in uninfected human cells appears to be to help generate tension at the plasma membrane. The Listeria protein InlC inactivates Tuba, reducing that tension and enabling bacteria to spread to nearby cells.

"The idea that a pathogenic bacterium can spread by controlling membrane tension in the human cell has not been previously described in the scientific literature," Ireton said. "Our discovery could have relevance for bacterial pathogens that cause Shigellosis or Rocky Mountain spotted fever, as these bacteria resemble Listeria in their ability to move inside the host cell and spread."

More research is needed, but Ireton says that discovering this mechanism could aid in future therapies and perhaps open a window into understanding how certain bacterial pathogens cause disease.

Others who worked on Ireton's team include Tina Rajabian and Scott D. Gray-Owen at the University of Toronto, Balramakrishna Gavicherla at UCF and Martin Heisig, Stefanie Müller-Altrock and Werner Goebel at the University of Würzburg in Germany.

Ireton joined UCF's Burnett School of Biomedical Sciences, housed in the College of Medicine, in 2006. He earned his Ph.D. at the Massachusetts Institute of Technology and completed post-doctoral work at the Pasteur Institute in France, a private institute dedicated to the treatment of diseases through biomedical research, education and public health. He conducted research and taught at the University of Toronto for several years before arriving at UCF.

Source:
Zenaida Gonzalez Kotala
University of Central Florida

Scientists Make First Step Towards Growing Human Lungs For Transplant

2009-09-25T05:09:00.000-07:00

Scientists have successfully converted human embryonic stem cells into lung cells, taking a first step towards building human lungs for transplantation.

According to research to be published in the journal Tissue Engineering, the team from Imperial College London, took human embryonic stem cells and 'directed' them to convert into the type of cells needed for gas exchange in the lung, known as mature small airway epithelium.

Dame Professor Julia Polak, from Imperial College London, who led the research team, says: "This is a very exciting development, and could be a huge step towards being able to build human lungs for transplantation or to repair lungs severely damaged by incurable diseases such as cancer."

The research involved taking human embryonic stem cells and growing them in Petri dishes in the laboratory in a specialized system that encouraged them to change into the cells that line the part of the lung where oxygen is absorbed and carbon dioxide excreted. Although this was done in the first instance on embryonic stem cells, the system will be tested further on stem cells from other sources, including umbilical cord blood and bone marrow.

Dr Anne Bishop, from Imperial College London and based at Chelsea and Westminster Hospital, and senior author of the paper, adds: "Although it will be some years before we are able to build actual human lungs for transplantation, this is a major step towards deriving cells that could be used to repair damaged lungs."

Following further laboratory tests, the researchers plan to use their findings to treat problems such as acute respiratory distress syndrome (ARDS), a condition which causes the lining of the cells to fall off, and which currently kills many intensive care patients. By injecting stem cells that will become lung cells, they hope to be able to repopulate the lung lining.

Two-way Communication Between Common Biological Pathways And Body's Daily Clock

2009-09-23T05:07:00.000-07:00

While scientists have known for several years that our body's internal clock helps regulate many biological processes, researchers have found that the reverse is also true: Many common biological processes – including insulin metabolism – regulate the clock, according to a new study by investigators at the University of Pennsylvania School of Medicine, the Genomics Institute of the Novartis Research Foundation, and the University of California at San Diego.

The new data, published online in Cell this week, suggest that someday physicians may be able to use small molecules that inhibit or stimulate these biological processes in order to influence a person's clock when it gets out of sync due to jetlag or shift work, and to devise new ways to treat metabolic disorders that are intimately tied to the body's daily cycles.

Using a genome-wide screen, the investigators found that reducing expression of any one of hundreds of genes could substantially alter the length of the circadian cycle, which controls the 24-hour sleep/wake cycle. The clock-influencing genes are involved in a large number of biological processes, but the researchers found that components of insulin metabolism, folate metabolism, and the cell cycle were overrepresented in the gene screen, suggesting that these pathways are closely linked to the clock.

"Clock biologists all appreciated that the communication went one direction – from the clock to biological processes – but I don't think anyone anticipated that there would be this level of integration with cell metabolism and the cell cycle, or all these other pathways impinging on clock function," says John Hogenesch, PhD, Associate Professor of Pharmacology in the Institute for Translational Medicine and Therapeutics at Penn. Hogenesch is a co-senior author on the paper with Steve Kay, Dean of the Division of Biological Sciences at UCSD. "There were some hints this might occur for some genes, but not to this extent."

The idea that biological processes might have feedback systems with the circadian clock makes some sense to Hogenesch. For example, he points to the influence of insulin metabolism, saying "If your energy requirements aren't being met, instead of spending a lot of energy on a cell division, a cell might necessarily delay it. It is the same strategy we use when we are not ready to do something, we delay. Maybe procrastination is an evolutionary cellular strategy enabled by the clock to confront situations where resources are limited."

While biologists regularly draw molecular pathways as if they are distinct from one another, they know the reality is much different. "This is a good example showing how dozens of pathways are functionally interconnected with clock function and vice versa," Hogenesch says. "It is important to remember that when you start to change function with a drug, for example, that the perturbation can have unanticipated consequence. Sometimes these consequences are good, but sometimes not."

Hogenesch stresses that while the new experiments show a feedback loop between biological processes and the clock in individual cells in culture, it is not yet clear how feedback systems work in the whole organism. Currently the team is working on biochemical and genetic experiments to answer that question.

In addition to publishing the data in the journal, the investigators have displayed the data on the BioGPS open-access searchable database (http://biogps.gnf.org). The circadian genome-wide screen data can be found at http://biogps.gnf.org/circadian/ and are linked to expression data from Penn, gene function data at Wikipedia and the National Center for Biotechnology Information (NCBI), as well as gene structure information from the University of California at Santa Cruz.

Hogenesch, who helped develop the website when he worked at the Genomics Institute of the Novartis Research Foundation in San Diego, said the site relies on web 2.0 technology and is very simple to use and customize. He and his colleagues built the site because many researchers want to do large database searches but are not computer scientists or informatics specialists. "Andy Su [of Novartis] and I decided to develop a site that even my mom could use, and pitched at the 90% of biologists who want to use something but don't have the skill sets. We decided to build something that would allow them to take advantage of large datasets such as this one."

Co-first authors on the paper are Eric E. Zhang and Tsuyoshi Hirota of the Genomics Institute of the Novartis Research Foundation, and UCSD, and Andrew C. Liu, of the Genomics Institute of the Novartis Research Foundation and the University of Memphis, Tenn. Other authors on the paper include Loren J. Miraglia, Genevieve Welch, Xianzhong Liu, Jon W. Huss III, Jeff Janes, and Andrew I. Su of the Genomics Institute of the Novartis Research Foundation, and Pagkapol Y. Pongsawakul, Ann Atwood, and Steve A. Kay of UCSD.

This research was funded by Silvio O. Conte Center and the National Institute of Mental Health.

Courtesy: ScienceDaily

Star-shaped Cells In Brain Help With Learning

2009-09-21T05:04:00.000-07:00

Every movement and every thought requires the passing of specific information between networks of nerve cells. To improve a skill or to learn something new entails more efficient or a greater number of cell contacts. Scientists at the Max Planck Institute of Neurobiology in Martinsried can now show, together with an international team of researchers, that certain cells in the brain, the astrocytes, actively influence this information exchange.

Until now, astrocytes were thought to have their main role in the development and nutrition of the brain's nerve cells. The new findings improve our comprehension of how the brain learns and remembers. They could also aid in the basic research of diseases such as epilepsy and the amyotrophic lateral sclerosis (ALS).

To live is to learn: Even fruit flies can learn to avoid detrimental odors and also in humans, most abilities are based on what we learn through practice and experience. Thus we are able to perform both fundamental processes such as walking and speaking and also master complex tasks such as logical reasoning and social interactions.

Learning at the cellular level

In order to learn something, i.e. to process new information, nerve cells grow new connections or strengthen existing contact points. At such contact points, the synapses, information is passed from one cell to the next. Once a synapse is created, new information has a means to be passed on and the information is learned. Enhancing an acquired skill through practice is then accomplished by strengthening the synapses involved. Incoming information elicits a much stronger response in the downstream nerve cell when passing through a strengthened synapse, as compared to a "normal" synapse.

At the cellular level, this can be envisioned as follows: At a synapse, the two communicating nerve cells do not come in direct contact but are separated by a small gap. When incoming information reaches the synapse, glutamate is released into the gap. These transmitter molecules cross the gap and bind to special receptors in the downstream nerve cell. This in turn prompts the downstream cell to pass on the information. In a strengthened synapse, the informing cell releases more glutamate into the synaptic gap and/or the informed cell is more efficient at binding the glutamate. As a result, information transmission is significantly enhanced.

Not just passive aid

In the brain, parts of nerve cells and single synapses are often enclosed by star-shaped cells, the astrocytes. So far, astrocytes were mainly thought to aid nerve cells - for example by supporting them or by promoting the maturation of synapses. Scientists of the Max Planck Institute of Neurobiology and an international team of researchers have now shown that astrocytes also have another, much more active role in the brain: They affect the synapses' ability to strengthen, and thus help to facilitate the learning process.

By removing the glutamate transmitter from the synaptic gap via so-called transporters, astrocytes regulate the availability of glutamate. "These transporters are somewhat like small vacuum cleaners", says Ruediger Klein, the supervisor of the study. "They suck surplus glutamate from the gap, which prevents, for example, glutamate spilling over from one synapse to the next." The existence of this "glutamate vacuum cleaner" was already known to science. So far unheard of, and now shown by the scientists, was that the astrocyte and downstream nerve cell communicate with each other and thus regulate the number of glutamate-eliminating transporters.

Signaling pathway with extensive consequences

This communication was found while the neurobiologists were examining the signaling molecule ephrinA3 and its binding partner EphA4 in mice. Ephrins and Eph-receptors are regularly involved when cells recognize or influence each other. Astrocytes, for example, promote synapse maturation via ephrinA3/EphA4 interaction. "Yet it came as a surprise to find an effect working also in the other direction", Ruediger Klein remembers. The scientists found that if a nerve cell is lacking the EphA4-receptor, the neighboring astrocyte increases its transporter numbers. The resulting superabundant transporters eliminate so much glutamate from the synapse that its strengthening becomes impossible, a sure disadvantage for the ability to learn.

The importance of the ephrinA3/EphA4 signaling pathway was further emphasized by the control studies. If the signaling molecule ephrinA3 was absent in an astrocyte, a synaptic strengthening was impaired due to the lack of glutamate - just what happened when EphA4 was missing. In contrast, if ephrinA3 was experimentally increased, the number of astrocyte-transporters decreased. As a result glutamate accumulated in the synaptic gap which in turn quickly led to cell damages and malfunctions of the affected synapses.

Next steps

"We are currently investigating the mechanisms through which ephrinA3/EphA4 affect the transporter production", explains Ruediger Klein. The scientists' aim is to better understand the transporters' function. An important task, as malfunctioning of the astrocyte transporters is known to play a role in neurological and neurodegenerative diseases such as epilepsy and the amyotrophic lateral sclerosis (ALS).

Journal reference:

Alessandro Filosa, Sónia Paixão, Silke D. Honsek, Maria A. Carmona, Lore Becker, Berend Feddersen, Louise Gaitanos, York Rudhard, Ralf Schoepfer, Thomas Klopstock, Klas Kullander, Christine R. Rose, Elena B. Pasquale, Rüdiger Klein. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature Neuroscience, 2009; DOI: 10.1038/nn.2394

Second-hand Smoking Results In Liver Disease, Study Finds

2009-09-19T05:03:00.000-07:00

A team of scientists at the University of California, Riverside has found that even second-hand tobacco smoke exposure can result in nonalcoholic fatty liver disease (NAFLD), a common disease and rising cause of chronic liver injury in which fat accumulates in the liver of people who drink little or no alcohol.

The researchers found fat accumulated in liver cells of mice exposed to second-hand cigarette smoke for a year in the lab. Such fat buildup is a sign of NAFLD, leading eventually to liver dysfunction.

In their study, the researchers focused on two key regulators of lipid (fat) metabolism that are found in many human cells as well: SREBP (sterol regulatory element-binding protein) that stimulates synthesis of fatty acids in the liver, and AMPK (adenosine monophosphate kinase) that turns SREBP on and off.

They found that second-hand smoke exposure inhibits AMPK activity, which, in turn, causes an increase in activity of SREBP. When SREBP is more active, more fatty acids get synthesized. The result is NAFLD induced by second-hand smoke.

"Our study provides compelling experimental evidence in support of tobacco smoke exposure playing a major role in NAFLD development," said Manuela Martins-Green, a professor of cell biology, who led the study. "Our work points to SREBP and AMPK as new molecular targets for drug therapy that can reverse NAFLD development resulting from second-hand smoke. Drugs could now be developed that stimulate AMPK activity, and thereby inhibit SREBP, leading to reduced fatty acid production in the liver."

Results of the study appear in the September issue of the Journal of Hepatology.

The study emphasizes that discouraging cigarette smoking helps prevent not only cardiovascular disease, pulmonary disease and cancer, but now also liver disease.

Second-hand smoke is the combination of smoke exhaled by a smoker and smoke given off by the burning end of a tobacco product. Lingering in the air long after tobacco products have been extinguished, it is involuntarily inhaled by nonsmokers in the vicinity.

Second-hand smoke is a major toxicant that affects children, the elderly and nonsmokers living in the household of adults who smoke. Many state and local governments have passed laws prohibiting smoking in public facilities. Diseases associated with second-hand smoking include cancer, heart disease, atherosclerosis, pneumonia, bronchitis and severe asthma.

Despite the large body of scientific evidence documenting the effects of passive or active smoking on the heart and lungs, reports investigating how smoking causes liver injury are scant.

"Until our study, second-hand smoking had not been linked to NAFLD development," Martins-Green said.

She was joined in the study by her graduate student Hongwei Yuan (first author of the research paper and now a postdoctoral researcher in her lab) and UC Riverside's John Shyy, a professor of biomedical sciences. Next, the team plans to investigate the clinical relevance of their findings. A grant to Martins-Green from Philip Morris USA, Inc., supported the research.

Courtesy: science daily

Cancer Drug May Improve Memory In Alzheimer's Patients

2009-09-17T05:59:00.000-07:00

A drug now used to treat cancer may also be able to restore memory deficits in patients with Alzheimer's disease, according to a new study conducted by scientists at Columbia University Medical Center, which appeared in the September issue of The Journal of Alzheimer's Disease.

The loss of short, day-to-day memories is often the first sign of Alzheimer's -- a disease that is expected, by the year 2050, to afflict 120 million people worldwide.

"People often joke that they must have Alzheimer's because they can't remember where they put their keys, but for a person with the disease, this type of short-term memory loss is extremely debilitating," says the study's lead author, Ottavio Arancio, Ph.D., associate professor of pathology and cell biology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center.

Dr. Arancio says that the cancer drug targets a previously unknown defect in the brains of mice with Alzheimer's.

The reason why the drug improves memory lies in the way the brain records new memories. To create new memories, the neurons in the brain must manufacture new proteins. The first step is to open up and read the DNA, which contains instructions for making the proteins.

To read the DNA, the neuron attaches a chemical reactive group to the spool around which DNA is tightly wound. "These groups, called acetyls, unwind the DNA to make it more accessible," says co-author Yitshak Francis, Ph.D., a postdoctoral research scientist at Columbia. "It's like unwinding knitting wool from its spool."

This unwrapping step, the researchers found, is impaired in mice with a form of Alzheimer's disease. The mice with Alzheimer's attached about half as many acetyls to DNA as normal mice and had poorer memory.

The researchers then discovered that they could improve memory in the Alzheimer's-afflicted mice with a cancer drug from a family of compounds, called HDAC inhibitors, which increase the DNA's spool acetylation and gene transcription. The drug improved memory performance to the level found in normal mice.

"Because this type of drug has already been approved for some cancer patients," says co-author Mauro Fà, Ph.D., associate research scientist in Columbia's Taub Institute, "we hope that clinical trials for Alzheimer's disease can start in about three to four years."

"For making memories, you need transcription and protein synthesis at the cellular level. If you don't have that, you don't have memory," said Dr. Francis.

This work was supported in part by Alzheimer Disease Research Zenith Award ZEN-07-58977, National Institutes of Health Grant R01 NS049442 (to O.A.) and by United Kingdom Alzheimer's Research Trust Pilot Grant, The International Sephardic Educational Foundation (ISEF) Scholarship, The Lewis Family Trust Scholarship, The Sidney & Elizabeth Corob Charitable Trust Scholarship, the Charlotte and Yule Bogue Research Fellowships (to Y.I.F).

Journal reference:

Yitshak I Francis, Mauro Fà, Haider Ashraf, Hong Zhang, Agnieszka Staniszewski, David S. Latchman, Ottavio Arancio. Dysregulation of Histone Acetylation in the APP/PS1 Mouse Model of Alzheimer%u2019s Disease. Journal of Alzheimer's Disease, 18:1 (September 2009)

Human Brain Could Be Replicated In 10 Years, Researcher Predicts

2009-09-15T04:43:00.000-07:00

A model that replicates the functions of the human brain is feasible in 10 years according to neuroscientist Professor Henry Markram of the Brain Mind Institute in Switzerland. "I absolutely believe it is technically and biologically possible. The only uncertainty is financial. It is an extremely expensive project and not all is yet secured."

The apparent complexity of the human mind is not a barrier to building a 'replica' brain claims Professor Markram. "The brain is of course extremely complex because it has trillions of synapses, billions of neurons, millions of proteins, and thousands of genes. But they are still finite in number. Today's technology is already highly sophisticated and it allows us to reverse engineer the brain rapidly." An example of the capability already in place is that today's robots can do screenings and mappings tens of thousands of times faster than human scientists and technicians.

Another hurdle on the path to a model human brain is that 100 years of neuroscience discovery has led to millions of fragments of data and knowledge that have never been brought together and exploited fully. "Actually no one even knows what we already understand about the brain," says Professor Markram. "A model would serve to bring this all together and then allow anyone to test whatever theory you want about the brain. The biggest challenge is to understand how electrical-magnetic-chemical patterns in the brain convert into our perception of reality. We think we see with our eyes, but in fact most of what we 'see' is generated as a projection by your brain. So what are we actually looking at when we look at something 'outside' of us?"

For Professor Markram, the most exciting part of his research is putting together the hundreds of thousands of small pieces of data that his lab has collected over the past 15 years, and seeing what a microcircuit of the brain looks like. "When we first switched it on it already started to display some interesting emergent properties. But this is just the beginning because we know now that it is possible to build it. As we progress we are learning about design secrets of our brains which were unimaginable before. In fact the brain uses some simple rules to solve highly complex problems and extracting each of these rules one by one is very exciting. For example we have been surprised at finding simple design principles that allow billions of neurons to connect to each other. I think we will understand how the brain is designed and works before we have finished building it."

The opportunities for this neuroscience research challenge are immense explains Professor Markram: "A brain model will sit on a massive supercomputer and serve as a kind of educational and diagnostic service to society. As the industrial revolution in science progresses we will generate more data than anyone can track or any computer can store, so models that can absorb it are simply unavoidable. It is also essential to build models when it comes to treating brain diseases affecting around two billion people. At present, there is no brain disease for which we really understand what has gone wrong in the processing, in the circuits, neurons or synapses. It is also important if we are to replace the need for the millions of animal experiments each year for brain research."

Courtesy: ScienceDaily

Discovery Leads To Rapid Mouse 'Personalized Trials' In Breast Cancer

2009-09-13T05:42:00.000-07:00

One person's breast cancer is not the same as another person's, because the gene mutations differ in each tumor. That makes it difficult to match the best therapy with the individual patient.

Using a finding that the genetic complexity of tumors in mice parallels that in humans, researchers at the Duke University Institute for Genome Sciences and Policy and Duke University Medical Center are starting trial studies in mice, just like human clinical trials, to evaluate whether understanding tumor diversity can improve cancer treatment.

"Giving everyone the same few current treatments doesn't take the very different types of tumors into account," said Joseph Nevins, Ph.D., Barbara Levine University Professor of Breast Cancer Genomics at Duke, who directs the Center for Applied Genomics & Technology at Duke. "It's like trying to treat a virus infection without recognizing that it may be HIV, influenza or cold virus."

For a study appearing recently in the Proceedings of the National Academy of Sciences, Nevins and colleagues painstakingly examined a large number of mouse breast tumors and performed genomic analyses to differentiate the tumors.

"The genetic pathways in the tumors determine the sensitivity to drugs," Nevins said. "We still have so much to learn about this."

All of the mice were bred to have a Myc gene variant that gave them tumors; however, additional gene mutations are acquired that contribute to the development of the tumor, including mutations in the Ras gene and others. The spectrum of tumor variation at the genetic level mimicked the complexity of human cancers.

"If we are going to successfully treat a tumor, we must recognize the extensive heterogeneity of what we call breast cancer and match drugs carefully to the characteristics of that particular tumor," Nevins said. "Today breast tumors may be sorted by whether they are estrogen-sensitive or HER-2 sensitive, but that is about the extent of it. We are performing human trials to look at the underlying biological pathways and examine how best to match therapies with the individual patient. But, these are lengthy studies. Now we can develop new strategies to match a therapy with a mouse tumor subtype and have results in a much shorter period of time."

Nevins and colleagues plan to conduct trials in the mice just as they would in humans: find the tumor, perform a needle biopsy, learn all they can about the tumor, and match it to a drug based on scientific data. The mouse studies don't replace human trials, but they can be an important component of advancing a strategy, Nevins said.

"This work highlights the importance of both biological and computational model systems to unravel the complexities and heterogeneity of human cancer," said Daniel Gallahan, Ph.D., program director for the Integrative Cancer Biology Program at the National Cancer Institute. "This type of analysis can be exploited to better align a therapeutic strategy with an individual's specific cancer."

Running parallel to human trials, the mouse trials will show what works well and what doesn't in the trial methods, data collection, analysis and other aspects of the trials. Researchers can then translate these findings immediately to keep the human clinical trials advancing as effectively as possible.

With so much mouse model research happening around the globe, why weren't these mouse tumor differences noted before? The gene expression analyses performed on mouse tumors simply haven't been large enough, Nevins said.

"We examined a large number, up to 80 samples of mouse tumors. And in the same way that a picture gets clearer when you add more pixels, the information about the tumors became clearer as we examined more samples," he said. "In effect, we went to a higher resolution and could begin to see patterns more clearly."

The study was funded by the National Institutes of Health and the V Foundation for Cancer Research, named in honor of the late North Carolina State basketball coach Jim Valvano.

Other authors include Eran R. Andrechek, Jeffrey T. Chang, Michael L. Gatza, Chaitanya R. Acharya, and Anil Potti of the Duke Institute for Genome Sciences and Policy, and Robert D. Cardiff of the Center for Comparative Medicine at the University of California at Davis.

Courtesy: ScienceDaily

Hormone important in recognizing familiar faces

2009-09-11T04:38:00.000-07:00

Oxytocin, a hormone involved in child-birth and breast-feeding, helps people recognize familiar faces, according to new research in the January 7 issue of The Journal of Neuroscience. Study participants who had one dose of an oxytocin nasal spray showed improved recognition memory for faces, but not for inanimate objects.

“This is the first paper showing that a single dose of oxytocin specifically improves recognition memory for social, but not for nonsocial, stimuli,” said Ernst Fehr, PhD, an economist at the University of Zurich who has studied oxytocin’s effect on trust and is unaffiliated with the new study. “The results suggest an immediate, selective effect of the hormone: strengthening neuronal systems of social memory,” Fehr said.

In mice, oxytocin has been shown to be important in social recognition — remembering that another mouse is familiar. Unlike humans, who use visual cues, mice use smell to recognize and distinguish other mice.

In humans, oxytocin increases social behaviors like trust, but its role in social memory has been unclear. “Recognizing a familiar face is a crucial feature of successful social interaction in humans,” said Peter Klaver, PhD, at the University of Zurich, the senior author of the new study, which was led by Ulrike Rimmele, PhD, at New York University. “In this study, we investigated for the first time the systematic effect of oxytocin on social memory in humans,” Klaver said.

Klaver and colleagues had study participants use a nasal spray containing either oxytocin or a placebo and then showed them images of faces and inanimate objects, including houses, sculptures, and landscapes. Participants were given a surprise test when they returned the next day — they were shown some of the images they had seen the day before as well as some new ones and were asked to distinguish between images that were “new,” images that they specifically “remembered” being presented, and images they recognized (”knew”) as familiar but could not recall the presentation context.

Volunteers who used the oxytocin spray more accurately recognized the faces they had seen before than did those in the placebo group. However, the two groups did not differ in recognizing the other, nonsocial images, suggesting that oxytocin specifically improved social memory and that different mechanisms exist for social and nonsocial memory. Further analysis showed that oxytocin selectively improved the discrimination of new and familiar faces — participants with oxytocin were less likely to mistakenly characterize unfamiliar faces as familiar. “Together, our data indicate that oxytocin in humans immediately strengthens the capability to correctly recognize and discriminate faces,” Klaver said.

“The study highlights the parallels in social information processing in mice and man, and adds further support to the notion that oxytocin plays a critical role,” said Larry Young, PhD, at Emory University, an expert on oxytocin who is unaffiliated with the current study. “This has important implications for disorders such as autism, where social information processing is clearly impaired,” Young said.

Source : http://www.sfn.org/

Scientists discover an ancient odor-detecting mechanism in insects

2009-09-09T04:37:00.000-07:00

In 1913 Theodore Roosevelt added cartographer to his resume when he and his crew ventured up an unspeakably dangerous and uncharted tributary named the River of Doubt. Now, on a charting expedition of their own, Rockefeller University scientists have completed a journey that has also defied expectation. In work to be published in the January 9 issue of Cell, the team reports the discovery of a new family of receptors in the fly nose, a finding that not only fills in a missing piece in the organizational logic of the insect olfactory system but also unearths one of the most ancient mechanisms that organisms have evolved to smell.

Vosshall, head of the Laboratory of Neurogenetics and Behavior, revamps traditional ideas regarding the roles of ionotropic glutamate receptors, proteins that reside deep in the brain at the synapses. There, they grab glutamate molecules and quickly relay messages from one nerve cell to the next, helping animals learn, move and remember. But Vosshall’s group now shows that insects do not relegate these receptors to the depths of the brain. They also put them to use elsewhere: in the nose.

“On the surface it’s a completely absurd idea,” says Vosshall, who is also a Howard Hughes Medical Institute investigator. “We know what these proteins do; they sit at the synapse and mediate fast neuronal communication. So the idea that the fly has massively expanded the number of these receptors and positioned them to interact with small molecules in the air seems very strange. But if you think about it, it makes sense. The process is the same, but rather than grabbing small molecules at the synapse, they’re grabbing small molecules from the air.”

The project began two years ago, when Vosshall and Richard Benton, then a postdoc in her lab, noticed a group of six ionotropic glutamate receptor genes while sifting through the fly genome. Although this group was recognized 10 years ago, ever since the genome was sequenced, the genes did not have a known function, in part because it was assumed they must be similar to any other ionotropic glutamate receptor deep in the fly brain. But to Vosshall and Benton, who is now at the Center for Integrative Genomics in Lausanne, Switzerland, that didn’t matter.

Vosshall and her team wondered whether these receptors could in fact represent the “missing” receptors thought to exist in the fly’s “nose” — its two antennae. Each antenna is divided into three types of smell neurons. Scientists have characterized the receptors that detect odors in two of these types but those receptors were mysteriously absent in the third, a swath of territory known as the coeloconic sensilla. “It has been shown that cells in the coeloconic sensilla detect odors,” Vosshall says. “It’s just that we didn’t know how they did it.”

The team showed that these receptors, which the Vosshall lab named ionotropic receptors, do in fact explain how cells in coeloconic sensilla detect odors. First, they showed that they are expressed in complex combinatorial patterns at the sensory end of olfactory neurons where they have access to and can scan the outside world for odors. They then showed that when these receptors are expressed in the cells in the coeloconic sensilla, the cells respond to odors. Finally, the researchers showed that when they plucked a receptor — say one that detects an odor that resembles a mix of grass and honey — out of its native cell and genetically embedded it in a different cell, the new cell would now detect that odor.

Although it is still unclear why insects have developed two sets of chemosensory receptors — olfactory receptors and ionotropic receptors — the work raises questions regarding their evolutionary origin. Ten years ago, researchers at New York University revealed that plants, which detect soil nutrients and chemicals in the air, also express glutamate receptors, suggesting that the ancestral origin of glutamate receptors may have been to detect small molecules in the air, rather than small molecules in the brain.

“In a way, these receptors were very well hidden because everyone assumed that they were extra glutamate receptors that were unlikely to be of interest,” explains Vosshall. “All we did to find them was searched for a gene family of unknown function — and left our preconceived notions aside.”

Source : http://www.rockefeller.edu/

Chemist Shows How RNA Can Be the Starting Point for Life

2009-09-07T05:35:00.000-07:00

By NICHOLAS WADE

An English chemist has found the hidden gateway to the RNA world, the chemical milieu from which the first forms of life are thought to have emerged on earth some 3.8 billion years ago.

He has solved a problem that for 20 years has thwarted researchers trying to understand the origin of life — how the building blocks of RNA, called nucleotides, could have spontaneously assembled themselves in the conditions of the primitive earth. The discovery, if correct, should set researchers on the right track to solving many other mysteries about the origin of life. It will also mean that for the first time a plausible explanation exists for how an information-carrying biological molecule could have emerged through natural processes from chemicals on the primitive earth.

The author, John D. Sutherland, a chemist at the University of Manchester, likened his work to a crossword puzzle in which doing the first clues makes the others easier. “Whether we’ve done one across is an open question,” he said. “Our worry is that it may not be right.”

Other researchers say they believe he has made a major advance in prebiotic chemistry, the study of the natural chemical reactions that preceded the first living cells. “It is precisely because this work opens up so many new directions for research that it will stand for years as one of the great advances in prebiotic chemistry,” Jack Szostak of the Massachusetts General Hospital wrote in a commentary in Nature, where the work is being published on Thursday.

Scientists have long suspected that the first forms of life carried their biological information not in DNA but in RNA, its close chemical cousin. Though DNA is better known because of its storage of genetic information, RNA performs many of the trickiest operations in living cells. RNA seems to have delegated the chore of data storage to the chemically more stable DNA eons ago. If the first forms of life were based on RNA, then the issue is to explain how the first RNA molecules were formed.

For more than 20 years researchers have been working on this problem. The building blocks of RNA, known as nucleotides, each consist of a chemical base, a sugar molecule called ribose and a phosphate group. Chemists quickly found plausible natural ways for each of these constituents to form from natural chemicals. But there was no natural way for them all to join together.

The spontaneous appearance of such nucleotides on the primitive earth “would have been a near miracle,” two leading researchers, Gerald Joyce and Leslie Orgel, wrote in 1999. Others were so despairing that they believed some other molecule must have preceded RNA and started looking for a pre-RNA world.

The miracle seems now to have been explained. In the article in Nature, Dr. Sutherland and his colleagues Matthew W. Powner and Béatrice Gerland report that they have taken the same starting chemicals used by others but have caused them to react in a different order and in different combinations than in previous experiments. they discovered their recipe, which is far from intuitive, after 10 years of working through every possible combination of starting chemicals.

Instead of making the starting chemicals form a sugar and a base, they mixed them in a different order, in which the chemicals naturally formed a compound that is half-sugar and half-base. When another half-sugar and half-base are added, the RNA nucleotide called ribocytidine phosphate emerges.

A second nucleotide is created if ultraviolet light is shined on the mixture. Dr. Sutherland said he had not yet found natural ways to generate the other two types of nucleotides found in RNA molecules, but synthesis of the first two was thought to be harder to achieve.

If all four nucleotides formed naturally, they would zip together easily to form an RNA molecule with a backbone of alternating sugar and phosphate groups. The bases attached to the sugar constitute a four-letter alphabet in which biological information can be represented.

“My assumption is that we are here on this planet as a fundamental consequence of organic chemistry,” Dr. Sutherland said. “So it must be chemistry that wants to work.”

The reactions he has described look convincing to most other chemists. “The chemistry is very robust — all the yields are good and the chemistry is simple,” said Dr. Joyce, an expert on the chemical origin of life at the Scripps Research Institute in La Jolla, Calif.

New Find in the Pacific: Worms With Glow Sticks

2009-09-05T05:30:00.000-07:00

By HENRY FOUNTAIN

Scientists have discovered seven new species of deep-sea worms in the Pacific. The worms, members of a new genus, Swima, are up to about four inches long, eyeless and have paddlelike bristles that move rapidly, allowing them to swim forward or backward.

That’s all very interesting, but what makes the worms truly spectacular are the little green glow sticks that are found on five of the species. Attached to segments near the head, these tiny organs — more blobs than sticks, actually — can be released from the body, instantly producing a bright green bioluminescence that lasts for many seconds as the worms swim away. The researchers refer to the worms colloquially as green bombers and say the phenomenon may help them distract potential predators.

Using remotely operated submersibles, Karen J. Osborn of the Scripps Institution of Oceanography and colleagues from the Monterey Bay Aquarium Research Institute and other organizations found the worms at depths of about 6,000 to 12,500 feet off Mexico, California and Oregon and near the Philippines. Their report is published in the journal Science.

The researchers say the new species are more closely related to worms that live in seafloor sediments than to other swimming worms, so they represent an evolutionary adaptation as bottom-dwellers moved into the water column.

The worms seem to be fairly common at those great depths; a video camera on a submersible recorded five of one species, S. bombiviridis, swimming together at about 7,000 feet. The submersibles did not record a bomb release in the wild, but the researchers were able to stimulate the release of bombs in the laboratory by touching the worms. They suggest that predators, presumably fish, that similarly try to disturb the worms would be left with the small glowing blobs instead of the tasty meal they were hoping for.

Researchers Identify New, Cancer-causing Role For Protein

2009-09-03T05:21:00.000-07:00

The mainstay immune system protein TRAF6 plays an unexpected, key role activating a cell signaling molecule that in mutant form is associated with cancer growth, researchers at The University of Texas M. D. Anderson Cancer Center report in the Aug. 28 edition of Science.

"The mechanism that we discovered activates Akt and also contributes to hyperactivation of a mutant form of Akt found in breast, colon and other cancers," said senior author Hui-Kuan Lin, Ph.D., assistant professor in M. D. Anderson's Department of Molecular and Cellular Oncology.

Akt is a signaling protein that plays a central role in numerous biological functions, including cell growth and programmed cell death, or apoptosis, Lin said. Deregulated Akt expression has been found to contribute to cancer development.

"Our novel findings are that Akt undergoes ubiquitination to be activated, and that TRAF6 regulates that process. We've found that TRAF6 is not just involved in the innate immune response, but plays a role in cell growth and carcinogenesis," Lin said.

Ubiquitins are regulatory proteins that work by binding to other proteins. While ubiquitins are best known for marking a defective protein for death by the cell's proteasome complex, Lin said, ubiquitination of Akt is not tied to the proteasome. Ubiquitins are transferred to target proteins by another set of proteins called ligases.

Akt resides in the cell's cytoplasm and must be recruited to the cell membrane in order to be activated by attachment of phosphate groups to specific locations on the protein, Lin explained. The mechanism that gets Akt to the membrane had not been understood.

Because one type of ubiquitination involves protein movement, Lin's team launched a series of cell line experiments that showed Akt is ubiquitinated, and in a way not involving the proteasome.

Screening a different class of ubiquitin ligases showed that overexpression of TRAF6 E3 ligase promotes Akt ubiquitination. Subsequent experiments showed that Akt ubiquitination is required to move Akt to the cell membrane, and leads to Akt's phosphorylation and activation.

Next, the researchers analyzed a mutant form of Akt implicated in human breast cancer, finding that increased Akt ubiquitination contributes to the hyperactivation of Akt in the mutant cells. "We discovered this oncogenic Akt mutant is hyperubiquitinated," Lin said. "If you disrupt its ubiquitination, you deactivate the mutant."

The team found depleting TRAF6 in prostate cancer cells reduced Akt activation. And mice with TRAF6 knocked down developed smaller prostate cancer tumors than those with active TRAF6. "We believe that TRAF6 is a previously unrecognized oncogene and is a new potential target for treating human cancers," Lin said.

Having discovered this Akt activation pathway, Lin and colleagues are now trying to identify the enzyme that normally turns it off.

Research for this paper was funded by an M. D. Anderson Trust Scholar Fund award to Lin.

Co-authors are first author Wei-Lei Yang, Jing Wang, Ph.D., Chia-Hsin Chan, Ph.D., Szu-Wei Lee, Brian C. Grabiner, and Xin Lin, Ph.D., all of the department of Molecular and Cellular Oncology; Yang, Lee, and Grabiner are all students in The University of Texas Graduate School of Biomedical Sciences at Houston, a joint operation of M. D. Anderson and The University of Texas Health Science Center at Houston, and Xin Lin is on the GSBS faculty; and Alejandro Campos, Betty Lamothe, Ph.D., Lana Hur, and Bryant Darnay, Ph.D., all of M. D. Anderson's Department of Experimental Therapeutics.

Discovery Of Natural Odors Could Help Develop Mosquito Repellents

2009-09-01T05:18:00.000-07:00

The image depicts scanning electron micrographs of the heads of a Culex quinquefasciatus mosquito (foreground) and Drosophila melanogaster (fruit fly; background). Representative traces of a CO2-sensitive neuron activated by CO2 (top trace) and inhibited by addition of odor 2,3-butanedione (bottom trace). The structures of CO2 and 2,3-butanedione are also shown. (Credit: S. Turner, UC Riverside)

Entomologists at the University of California, Riverside working on fruit flies in the lab have discovered a novel class of compounds that could pave the way for developing inexpensive and safe mosquito repellents for combating West Nile virus and other deadly tropical diseases.

When fruit flies undergo stress, they emit carbon dioxide (CO₂) that serves as a warning to other fruit flies that danger or predators could be nearby. The fruit flies are able to detect the CO₂ and escape because their antennae are equipped with specialized neurons that are sensitive to the gas.

But fruits and other important food sources for fruit flies also emit CO₂ as a by-product of respiration and ripening. If the innate response of the fruit fly is to avoid CO₂, how then does it find its way to these foods?

Anandasankar Ray, an assistant professor in the Department of Entomology, and Stephanie Turner, his graduate student, now provide an answer to the paradox.

They have identified a new class of odorants – chemical compounds with smells – present in ripening fruit that prevent the CO₂-sensitive neurons in the antennae from functioning. In particular two odors, hexanol and 2,3- butanedione, are strong inhibitors of the CO₂-sensitive neurons in the fruit fly.

The research has strong implications for control of deadly diseases transmitted by Culex mosquitoes such as West Nile virus disease and filariasis, an infectious tropical disease affecting the lymphatic system. Since 1999, nearly 29,000 people in the United States have been reported with West Nile virus disease. Lymphatic filariasis has affected more than 120 million people in the world.

"CO₂ emitted in human breath is the main attractant for the Culex mosquito to find people, aiding the transmission of these deadly diseases," Ray said. "In our experiments we identified hexanol, and a related odor, butanal, as strong inhibitors of CO₂-sensitive neurons in Culex mosquitoes. These compounds can now be used to guide research in developing novel repellents and masking agents that are economical and environmentally safe methods to block mosquitoes' ability to detect CO₂ in our breath, thereby dramatically reducing mosquito-human contact."

Study results appear Aug. 26 in the advance online publication of Nature.

"This is a beautiful study that breaks new ground in the field of olfaction," said John Carlson, the Eugene Higgins Professor of Molecular, Cellular and Developmental Biology at Yale University, who was not involved in the research. "It shows that certain odorants can strongly inhibit the response of receptors that detect CO₂. The results suggest some very interesting new strategies for the control of certain insect pests."

Besides showing that inhibitory odors can play an important role in modifying insect behavior, the research paper also illustrates how some of these odors have a long-term effect. Ray and Turner found, for example, that some odors silenced the CO₂ neuron in the fruit fly well beyond the period of application.

"To our surprise, we found that exposure to a long-term CO₂ response inhibitor can exert a profound and specific effect on the behavior of the insect, even after the inhibitor is no longer in the environment," Ray said. "This means this odorant could potentially be used to keep mosquitoes at bay for longer periods of time, benefiting people in areas where mosquito-transmitted diseases are prevalent."

Ray received his doctoral degree in molecular, cellular and developmental biology from Yale University in 2005. He joined UC Riverside in 2007.

Originally from India, Ray contracted malaria during childhood. When his wife caught dengue fever on a trip to India a few years ago, he decided to intensify his research on mosquito-borne diseases.

Stephanie Turner, the first author of the research paper, received her bachelor's degree in biochemistry from UC Santa Cruz, where she performed research as an undergraduate. She worked for two years in biotechnology before joining the Cell, Molecular and Developmental Biology Graduate Program at UCR.

The research related to this project was conceived, initiated and carried out at UCR over the past one year, and was supported by UCR startup funds. Ray has plans to launch a startup company in the near future to take his basic science research on the odorants from the lab to applications that directly benefit people.

Ray and Turner already have begun work in the lab on mosquitoes that cause malaria and dengue fever. They also are setting up collaborations with a number of scientists from around the globe to do research on various mosquito species and tsetse flies.

The UCR Office of Technology Commercialization has filed a patent application on the discovery.

Courtesy: Science Daily

Artificial Life One Step Closer: Scientists Clone And Engineer Bacterial Genomes In Yeast And Transplant Genomes Back Into Bacterial Cells

2009-08-30T05:17:00.000-07:00

Yeast. The entire bacterial genome from Mycoplasma mycoides was cloned in a yeast cell by adding yeast centromeric plasmid sequence to the bacterial chromosome and modifying it in yeast using yeast genetic systems. This modified bacterial chromosome was then isolated from yeast and transplanted into a related species of bacteria, Mycoplasma capricolum, to create a new type of M. mycoides cell. (Credit: Wikimedia Commons. Public Domain Image)

Researchers at the J. Craig Venter Institute (JCVI), a not-for-profit genomic research organization, have just published results describing new methods in which the entire bacterial genome from Mycoplasma mycoides was cloned in a yeast cell by adding yeast centromeric plasmid sequence to the bacterial chromosome. Researchers modified it in yeast using yeast genetic systems. This modified bacterial chromosome was then isolated from yeast and transplanted into a related species of bacteria, Mycoplasma capricolum, to create a new type of M. mycoides cell.

This is the first time that genomes have been transferred between branches of life—from a prokaryote to eukaryote and back to a prokaryote. The research was published by Carole Lartigue et al in the journal Science on August 21.

Hamilton Smith, M.D., one of the leaders of the JCVI team said, “I believe this work has important implications in better understanding the fundamentals of biology to enable the final stages of our work in creating and booting up a synthetic genome. This is possibly one of the most important new findings in the field of synthetic genomics.”

The research published today was made possible by previous breakthroughs at JCVI. In 2007 the team published results from the transplantation of the native M. mycoides genome into the M. capricolum cell which resulted in the M. capricolum cell being transformed into M. mycoides. This work established the notion that DNA is the software of life and that it is the DNA that dictates the cell phenotype.

In 2008 the same team reported on the construction of the first synthetic bacterial genome by assembling DNA fragments made from the four chemicals of life—ACGT. The final assembly of DNA fragments into the whole genome was performed in yeast by making use of the yeast genetic systems. However, when the team attempted to transplant the synthetic bacterial genome out of yeast into a recipient bacterial cell, all the experiments failed.

The researchers had previously established that no proteins were required for chromosome transplantations, however they reasoned that DNA methylation (a chemical modification of DNA that bacterial cells use to protect their genome from degradation by restriction enzymes, which are the proteins that cut DNA at specific sites) might be required for transplantation. When the chromosome was isolated direct from the bacterial cells it was likely already methylated and therefore transplantable due to it being protected from the cells restriction enzymes.

In this study, the team began by cloning the native M. mycoides genome into yeast by adding a yeast centromere to the bacterial genome. This is the first time a native bacterial genome has been grown successfully in yeast. Specific methylase enzymes were isolated from M. mycoides and used to methylate the M. mycoides genome isolated from yeast. When the DNA was methylated the chromosome was able to be successfully transplanted into a wild type species of M. capricolum. However, if the DNA was not first methylated the transplant experiments were not successful. To prove that the restriction enzymes in the M. capricolum cell were responsible for the destruction of the transplanted genome the team removed the restriction enzyme genes from the M. capricolum genome. When genome transplantations were performed using the restriction enzyme minus recipient cells, all the genome transplantations worked regardless of if the DNA was methylated or not.

“The ability to modify bacterial genomes in yeast is an important advance that extends yeast genetic tools to bacteria. If this is extendable to other bacteria we believe that these methods may be used in general laboratory practice to modify organisms,” said Sanjay Vashee, Ph.D., JCVI researcher and corresponding author on the paper.

The team now has a complete cycle of cloning a bacterial genome in yeast, modifying the bacterial genome as though it were a yeast chromosome and transplanting the genome back into a recipient bacterial cell to create a new bacterial strain. These new methods and knowledge should allow the team to now transplant and boot up the synthetic bacterial genome successfully.

The research published August 21 by JCVI researchers was funded by the company Synthetic Genomics Inc., a company co-founded by Drs. Smith and Venter.

Journal reference:

Lartigue et al. Creating Bacterial Strains from Genomes That Have Been Cloned and Engineered in Yeast. Science, August 20, 2009; DOI: 10.1126/science.1173759

Vaxine trials show 1st swine flu vaccine works well

2009-08-28T05:53:00.000-07:00

Vaxine trials show 1st swine flu vaccine works well
Narayanan Suresh

Singapore, Aug 26, 2009: The initial results from the clinical trials of the world’s first recombinant vaccine against swine flu, developed by a small South Australian biotech company, Vaxine Pty Ltd, indicates that the vaccine is working well in humans. Vaxine started the human clinical trials of the world’s first swine flu vaccine, on July 20, 2009. Three days ahead of Australia’s pharma giant CSL’s vaccine trials. “The safety data so far is excellent and the vaccine is better tolerated than even the standard flu vaccine,” Vaxine Pty’s research director, Prof Nikolai Petrovsky, told BioSpectrum. Prof Petrovsky said Vaxine’s swin flu vaccine has been tested in three different doses of antigen ranging from 3 to 45 micrograms of haemagglutinin with and without adjuvant. The company is using its own proprietary Advax adjuvant. The vaccine’s antigen is a recombinant protein supplied by Protein Sciences Corporation, based in Meridien, USA. The vaccine is designed to provide powerful protection against influenza through anti-influenza antibodies, and T-cells which are some of the key components of the body’s natural defense against the influenza virus. Seven other trials of swine flu vaccine developed by vaccine companies in five countries are currently going on. Being the world’s first swine flu vaccine, this Australian company’s efforts are watched avidly around the world. The efficacy data of the vaccine is expected to release in a few weeks. For the clinical trials, the Vaxine’s vaccine has been administered to 275 male and female patients in the age group of 18 to 70 at Flinders Medical Center in Adelaide. Vaxine is a spinout of Flinders University. The clinical trials are being conducted by Prof David Gordon at Flinders University. China’s Sinovac has announced that the results of its swine flu vaccine trials which started a week after Vaxine, has also been good. Sinovac is using a single dose of 15 mg. Prof Petrovsky said his company’s genetically-engineered vaccine has several advantages over other products such as CSL’s egg based vaccine. “Our vaccine is free of egg protein contaminants and so is safe for people with serious egg allergy. The vaccine also does not have viral RNA contaminants that cause occasional severe reactogenecity and being in single dose vials does not contain thiomersal,” Vaxine’s research head says. Set up in 2002, Vaxine has started clinical trials of its other vaccines for seasonal flu, Japanese encephalitis, Hepatitis B and bee sting allergy. Vaxine was quickly off the block in the global race to develop a vaccine against swine flu. “Never before has a new influenza vaccine been delivered to the clinic so far. It is extraordinary what has been achieved in less than three months since the seed virus was first identified,” says Dr Dimitar Sajkov, one of Vaxine’s clinical investigators. He indicated that the success of Vaxine’s vaccine could signal the beginning of the end for old-fashioned egg-based vaccines. Most of the seasonal flu vaccines are grown using the chicken-egg method as the virus is known to grow very well in this medium. Vaxine has already received many enquiries for the supply of the vaccine from countries like Malaysia, South Korea, Indonesia and Saudi Arabia. In mid-August, Vaxine was honored with the National Innovation Award at the Telstra Business Awards in Sydney, recognizing the company’s breakthrough efforts in the development of swine flu vaccine.
© BioSpectrum Bureau

New DNA Test Uses Nanotechnology To Find Early Signs Of Cancer

2009-08-26T05:14:00.000-07:00

In this illustration by Yi Zhang, quantum dots are depicted as gold spheres that attract DNA strands linked to cancer risks. When the quantum dots are exposed to certain types of light, they transfer the energy to fluorescent molecules, shown as pink globes, that emit a glow. This enables researchers to detect and count the DNA strands linked to cancer. (Credit: Image courtesy of Johns Hopkins University)

Using tiny crystals called quantum dots, Johns Hopkins researchers have developed a highly sensitive test to look for DNA attachments that often are early warning signs of cancer. This test, which detects both the presence and the quantity of certain DNA changes, could alert people who are at risk of developing the disease and could tell doctors how well a particular cancer treatment is working.

The new test was reported in a paper called “MS-qFRET: a quantum dot-based method for analysis of DNA methylation,” published in the August issue of the journal Genome Research. The work also was presented at a conference of the American Association of Cancer Research.

“If it leads to early detection of cancer, this test could have huge clinical implications,” said Jeff Tza-Huei Wang, an associate professor of mechanical engineering whose lab team played a leading role in developing the technique. “Doctors usually have the greatest success in fighting cancer if they can treat it in its early stage.”

Wang and his students developed the test over the past three years with colleagues at the Johns Hopkins Kimmel Cancer Center. Stephen B. Baylin, deputy director of the center and a co-author of the Genome Research study, said the test represents “a very promising platform” to help doctors detect cancer at an early stage and to predict which patients are most likely to benefit from a particular therapy.

The recent study, which included the detection of DNA markers in the sputum from lung cancer patients, was designed to show that the technology was sound. Compared to current methods, the test appeared to be more sensitive and delivered results more quickly, the researchers said. “The technique looks terrific, but it still needs to be tested in many real-world scenarios,” Baylin said. “Some of these studies are already under way here. If we continue to see exciting progress, this testing method could easily be in wide use within the next five years.”

The target of this test is a biochemical change called DNA methylation, which occurs when a chemical group called methyl attaches itself to cytosine, one of the four nucleotides or base building blocks of DNA. When methylation occurs at critical gene locations, it can halt the release of proteins that suppress tumors. When this occurs, it is easier for cancer cells to form and

multiply. As a result, a person whose DNA has this abnormal gene DNA methylation may have a higher risk of developing cancer. Furthermore, these methylation changes appear to be an early event that precedes the appearance of genetic mutations, another precursor to cancer.

To detect this DNA methylation, the Johns Hopkins team found a way to single out the troublesome DNA strands that have a methyl group attached to them. Through a chemical process called bisulfite conversion, all segments that lack a methyl group are transformed into another nucleotide.

Then, another lab process is used to make additional copies of the remaining target DNA strands that are linked to cancer. During this process, two molecules are attached to opposite ends of each DNA strand. One of these molecules is a protein called biotin. The other is a fluorescent dye. These partner molecules are attached to help researchers detect and count the DNA strands that are associated with cancer.

To do this, these customized DNA strands are mixed with quantum dots, which are crystals of semiconductor material whose sizes are in the range of only few nanometers across. (A nanometer is one-billionth of a meter, far too small to see with the naked eye.).These dots are usually employed in electronic circuitry, but they have recently proved to be helpful in biological applications as well. Quantum dots are useful because they possess an important property: They easily transfer energy. When light shines on a quantum dot, the dot quickly passes this energy along to a nearby molecule, which can use the energy to emit a fluorescent glow. This behavior makes the cancer-related DNA strands light up and identify themselves.

In the Johns Hopkins cancer test, the quantum dots have been coated with a chemical that is attracted to biotin–one of the two molecules that were attached to the DNA strands. As a result, up to 60 of the targeted DNA strands can stick themselves to a single quantum dot, like arms extending from an octopus. Then, an ultraviolet light or a blue laser is aimed at the sample. The quantum dots grab this energy and immediately transfer it to the fluorescent dyes that were attached earlier to the targeted DNA strands. These dye molecules use the energy to light up.

These signals, also called fluorescence, can be detected by a machine called a spectrophotometer. By analyzing these signals, the researchers can discover not only whether the sample contains the cancer-linked DNA but how much of the DNA methylation is present. Larger amounts can be associated with a higher cancer risk.

“This kind of information could allow a patient with positive methylation to undergo more frequent cancer screening tests. This method could replace the traditionally more invasive ways for obtaining patient samples with a simple blood test,” said Vasudev J. Bailey, a biomedical engineering doctoral student from Bangalore, India, who was one of the two lead authors on the Genome Research paper. “It’s also important because these test results could possibly help a doctor determine whether a particular cancer treatment is working. It could pave the way for personalized chemotherapy.”

In addition, because different types of cancer exhibit distinctive genetic markers, the researchers say the test should be able to identify which specific cancer a patient may be at risk of developing. Markers for lung cancer, for example, are different from markers for leukemia.

The other lead author of the Genome Research paper was Hariharan Easwaran, a cancer biology research fellow in the Johns Hopkins School of Medicine. Along with Wang and Baylin, the other co-authors were Yi Zhang, a biomedical engineering doctoral student at Johns Hopkins; Elizabeth Griffiths, an oncology clinical fellow in the School of Medicine; Steven A. Belinsky, of the Lovelace Respiratory Research Institute in Albuquerque, N.M.; James G. Herman, a professor of cancer biology in the School of Medicine; and Hetty E. Carraway, an assistant professor of oncology in the School of Medicine.

Johns Hopkins Technology Transfer staff members have applied for international patent protection covering the testing technique and are in talks with a biotechnology company that has expressed interest in licensing the application.

The research was supported by grants from the National Cancer Institute, the National Science Foundation, the Hodson Foundation and the Flight Attendant Medical Research Institute.

Courtesy: ScienceDaily

Bio-Nanomachines: Proteins As Resistance Fighters

2009-08-24T05:09:00.000-07:00

Fluorescent image of single motor proteins (left): Motion of two diffusing kinesin molecules (green) on a microtubule (red) shown as a time series kymograph. Schematic (right): By dragging diffusing kinesin molecules with laser tweezers over a microtubule, the friction force between the motor and its microtubule track can be measured very precisely. (Credit: MPI-CBG, BIOTEC)

Friction limits the speed and efficiency of macroscopic engines. Is this also true for nanomachines? A Dresden research team used laser tweezers to measure the friction between a single motor protein molecule and its track. The team found that also within our cells, motors work against the resistance of friction and are restrained in its operation—usually by far not as much though as their macroscopic counterparts.

These first experimental measurements of protein friction could help researchers to better understand key cellular processes such as cell division which is driven by such molecular machines. (Science, August 14, 2009)

Friction is the force that resists the relative motion of two bodies in contact. The same is true on the nanoscale: Molecular motors have to fight the friction created between them and their tracks. However, since the frictional forces acting on such motors had not been measured before, it was not known how they depend on the speed and the direction of motion.

Friction Slows Down Proteins

Scientists in Dresden at the Biotechnology Center (BIO-TEC) of the Technical University of Dresden and at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) immobilized the molecular motor kinesin on a microsphere which was held by laser tweezers and dragged over its track, a so-called microtubule. In this manner, the friction force between the motor and its microtubule track was measured very precisely. "Just like for macroscopic machines, protein friction limits the speed and efficiency of the small bio-motors", says Erik Schäffer, group leader at the BIOTEC and Jonathon Howard, director and group leader at the MPI-CBG.

The researchers explain that the protein, in the absence of an energy source, takes eight nanometer (a millionth of a millimeter) wide "diffusive hops", corresponding to the length of the tubulin subunits that make up a microtubule. The motors step from one tubulin subunit to the adjacent one by forming a new bond with the microtubule filament as another bond is broken. When pulled by the tweezers, the energy released from these breaking bonds is lost as friction.

Efficient nanomachines

Protein friction also gives insight into the efficiency of kinesin. "About half of the energy from the motor’s fuel ATP is dissipated as friction between the motor and its substrate" Howard comments. Schäffer adds: "What remains after further dissipation inside the motor is used for mechanical work—the efficiency is usually much better than for man-made machines". The dissipated energy is eventually converted to heat, that contributes to the heating of our body. Thus, for example our muscles are partly heated by protein friction as the muscle motor proteins do their work.

Courtesy: ScienceDaily

Journal reference:

Volker Bormuth, Vladimir Varga, Jonathon Howard, Erik Schäffer. Protein Friction Limits Diffusive and Directed Movements of Kinesin Motors on Microtubules. Science, 2009; 325 (5942): 870 DOI: 10.1126/science.1174923

FluBlok - Swine flu vaccine

2009-08-23T05:04:00.000-07:00

FluBlok®

FluBlok® is Protein Sciences' seasonal influenza vaccine candidate.

The company has conducted Phase III clinical studies for FluBlok. At this time a Biologics License Application (BLA) for commercialization of FluBlok is under review at the FDA.

FluBlok is comprised of purified recombinant hemagglutinin antigens (active ingredient) and is formulated to contain 3X the active component as compared to TIV.

Over 90% of influenza-related deaths occur in people over the age of 65. Currently available vaccines have a limited ability to protect the elderly, the age group most at risk for influenza. In clinical trials to date, FluBlok has demonstrated that a significantly higher percentage of elderly subjects developed antibody titers that are considered to be protective compared to licensed vaccine.

FluBlok Advantages:

Higher antigen content
Better immunogenicity for the elderly
No preservatives and no adjuvants (i.e. no thimerisol)
No egg proteins present
No live influenza viruses used in productio

Home page: http://www.proteinsciences.com/flublock-vaccine.htm

Bad News For Coffee Drinkers Who Get Headaches

2009-08-22T04:14:00.000-07:00

People who consume high amounts of caffeine each day are more likely to suffer occasional headaches than those with low caffeine consumption, a team of researchers at the Norwegian University of Science and Technology (NTNU) reports in a study recently published in the Journal of Headache Pain.

But in findings that had “no obvious reason”, the researchers, led by Knut Hagen from NTNU’s Faculty of Medicine, also reported that low caffeine consumption was associated with a greater likelihood of chronic headaches, defined as headaches for 14 or more days each month.

The results are drawn from a large cross-sectional study of 50,483 people who answered a questionnaire about caffeine consumption and headache prevalence as a part of the Nord-Trøndelag Health Survey (HUNT 2), a county-wide health survey conducted in 1995-1997 on a wide range of health topics.

Caffeine is the world’s most commonly consumed stimulant, and has long been known to have both positive and negative effects on headaches. For example, caffeine is a common ingredient in headache analgesics because it can help relieve headaches.

But research worldwide into the relationship between caffeine consumption and headache provides no relief to headache sufferers wondering whether they should drink more coffee or less. Some studies have shown that high caffeine consumption increases the prevalence of headaches and migraines, while other studies have shown no such relationship.

At the same time, headaches are costly to society, in work hours lost, and to individuals themselves. The World Health Organisation ranks migraine 19th in all causes of disability based on a measure called “years lived with disability”, as one example.

The issue is of particular interest in Scandinavia, because Scandinavians are heavy coffee drinkers, consuming on average about 400 mg of caffeine per day. That is roughly twice the average caffeine consumption in other European countries and in the US, and equates to roughly 4 cups of brewed coffee per day, although caffeine levels in coffee vary quite widely.

The HUNT study is powerful because it is large-scale, population-based and cross-sectional, but when it comes to headaches, these characteristics make it difficult to establish cause-and-effect. For example, the frequency of non-migraine headache was found by researchers to be 18 per cent more likely in individuals with high caffeine consumption (500 mg per day or more) than among those with the lowest consumption (with mean levels at 125 mg per day).

But does that mean that all that caffeine causes headaches – or that people who are more likely to suffer from headaches drink caffeinated beverages in search of relief? “Since the study is cross-sectional, it cannot be concluded that high caffeine consumption causes infrequent headache,” the researchers write.

Even more difficult is explaining why chronic headache was less likely among individuals with moderate or high caffeine consumption, the researchers said. One possibility is that caffeine consumption helps change chronic headache into infrequent headache.

But it is equally possible that chronic headache sufferers had reduced their intake of caffeine because they had experienced its headache precipitating properties – and that individuals with infrequent headaches were unaware that high caffeine might be the cause.

In an interview, Hagen said that people should consider cutting back on their coffee consumption if headaches were a problem. “People who suffer from headaches should be focused on their caffeine use, because it can be a cause of their headaches,” he said.

Journal reference:

1. Knut Hagen, Kari Thoresen, Lars Jacob Stovner, John-Anker Zwart. High dietary caffeine consumption is associated with a modest increase in headache prevalence: results from the Head-HUNT Study. Journal of Headache Pain, 2009; 10: 153-159 DOI: 10.1007/s10194-009-0114-6

First Human Gene Implicated In Regulating Length Of Human Sleep

2009-08-20T04:11:00.000-07:00

Scientists have discovered the first gene involved in regulating the optimal length of human sleep, offering a window into a key aspect of slumber, an enigmatic phenomenon that is critical to human physical and mental health.

The team, reporting in the Aug. 14, 2009 issue of Science, identified a mutated gene that allows two members of an extended family to thrive on six hours of sleep a day rather than the eight to eight-and-a-half hours that studies have shown humans need over time to maintain optimal health. Working from this discovery, the scientists genetically engineered mice and fruit flies to express the mutated gene and study its impact.

While most Americans obtain less than eight hours of sleep a night (the average on non-work days is 7.4 hours), and some may feel they succeed with less when engaged in exhilarating work, domestic life or recreation, scientific evidence indicates that, over time, the body suffers from this regimen, the researchers say.

"Short term and chronic disruptions in the length of optimal sleep can have serious consequences on cognition, mood and physical health, including cancer and endocrine function," says the senior author of the study, Ying-Hui Fu, PhD, UCSF professor of neurology. However, teasing out this impact can be challenging, she says, given access to such stimuli as coffee and chocolate.

The finding, she says, offers an opportunity to unravel the regulatory mechanism of sleep. While the mutation may be rare, it could offer a probe more generally into the regulatory mechanisms of sleep quality and quantity. Understanding these mechanisms could lead to interventions to alleviate pathologies associated with sleep disturbance.

Sleep remains a relatively inscrutable biological phenomenon. Scientists know that it is regulated in large part by two processes: 1) circadian rhythms -- genetic, biochemical and physiological mechanisms that wax and wane during a 24 hour period to regulate the timing of sleep, 2) and homeostasis – unknown mechanisms that ensure that the body acquires over time the necessary amount of sleep, nudging it toward sleep when it has been deprived, prompting it out of sleep when it has received enough. This regulation of sleep intensity is measured in non rapid eye movement sleep and REM sleep. Interactions between the circadian rhythms and homeostatic mechanisms influence the timing, duration and quality of sleep and wakefulness.

But "the details in the process are really completely unknown," says Fu.

In 2001, the team discovered a mutated gene that caused some members of several families to be "morning larks," awaking around 3:30 a.m. and going to bed around 7:30 p.m. The condition, which the researchers named "familial advanced sleep phase syndrome," is believed to be primarily a variant, or mutated, form of a gene involved in regulating circadian rhythms. The total daily sleep time in people with this condition is normal.

In the current study, the team identified a small extended family in which a mother and her adult daughter had life-long shorter daily sleep requirements than most individuals. Fu's lab then studied blood samples from these women and their extended family. They identified a mutation in a gene known as hDEC2, which is a transcription factor that represses expression of certain other genes and is implicated in the regulation of circadian rhythms.

Next, the team genetically engineered mice and fruit flies to express the mutated human gene, and Ying He, PhD, a postdoctoral fellow in the Fu lab, studied its impact on their behavior and sleep patterns. Mice slept less, as seen in the extent of their scampering about in the dark (mouse preference) over the course of 24 hours and in electroencephalography (EEG) and electromyography (EMG) measurements indicating reduced nonREM and REM sleep. While lacking a Lilliputian size EEG to monitor the fruit flies, He studied the miniscule creatures' activity and sleep patterns by tracking the frequency of their movements through infrared light.

Next, the team compared the response of the genetically engineered mice and normal mice to the consequence of six hours of sleep deprivation. The engineered mice needed to compensate for their lost sleep to a much lesser extent – as seen in nonREM and REM measures – than their normal counterparts.

"These changes in sleep homeostasis in the mutant mice could provide an explanation for why human subjects with the mutation are able to live unaffected by shorter amounts of sleep throughout their lives," says Fu.

The next step, she says, is determining the DEC2's precise role. "We know the gene encodes a protein that is a transcriptional repressor and we know it makes the repressor's activity weaker. But we don't know if the weaker repressor is directly related to the shorter amount of sleep, because proteins can have many functions. It could be the protein functions as part of a larger transcriptional machinery, not necessarily as a repressor."

DEC2 could be involved in modulating "sleep quantity" alone, or it could be mediating both "sleep quantity" and "wakefulness-behavioral drive," according to Fu. The latter drive, she says, is critical for the procurement of food, shelter, and mates and could be more potent in individuals with this mutation.

"The mouse model also provides an opportunity to investigate whether there are other behaviors or physiological conditions associated with a short sleep syndrome," says Fu. She suspects there will be.

Co-authors of the study are Christopher R. Jones, MD, at the University of Utah; Nobuhiro Fujiki, PhD, and Seiji Nishino, PhD, both of Stanford University; Ying Xu, PhD, and Jimmy Holder, MD, PhD, both at the time of the study in the Fu lab; Bin Guo, PhD, of the University of California, Berkeley; and Moritz J. Rossner, PhD, of the Max-Planck-Institute of Experimental Medicine.

The study was funded by the National Institutes of Health, a Conte Center grant, and by the Sandler Neurogenetics fund.

E. Coli and You

2009-08-18T04:08:00.000-07:00

From Victorian England to contemporary America, creationists have often denied that we are related to other primates. But the hard truth of our genealogy does even greater damage to human pride. We are cousins of every living thing, including the billions of E. coli bacteria in our intestines. This kinship may not be flattering, but it is useful. By studying these tiny creatures, we learn about other organisms, including ourselves. As the French biologist Jacques Monod once said, “What is true for E. coli is true for the elephant.”

Carl Zimmer effectively applies this principle in his engrossing new book, “Microcosm,” relating the study of these microbes to larger developments in biology and thoughtfully discussing the social implications of science. If you must limit yourself to only one title on bacteria this year, “Microcosm” is a good pick.

As Zimmer explains, a number of landmark discoveries have involved E. coli, including experiments confirming the universality of biochemistry and revealing how genes function. Studying the many strains of E. coli (most are innocuous) suggests something further: the divergent behavior of genetically identical bacteria, Zimmer writes, is “a warning to those who would put human nature down to any sort of simple genetic determinism.”

Along with some more familiar material, Zimmer vividly describes the unfamiliar microscopic world of E. coli and their tightly packed, rod-shaped bodies: “If you prick us, we bleed, but if you prick E. coli, it blasts.” And unlike mammals, bacteria often swap genetic material, placing limits on Monod’s dictum. However, species large and small absorb DNA from viruses. For E. coli and humans alike, Zimmer emphasizes, “there are no fixed essences in life.”

“Microcosm” also examines E. coli’s contentious public life. Creationists claim its tail-like, propulsive flagellum is proof of someone’s intentional design. But at the 2005 trial over the teaching of “intelligent design” in Dover, Pa., scientists showed that the flagellum is not inexplicably complex. The resistance some E. coli have developed to antibiotics (whose limits are given their own slightly disquieting chapter) provides yet more evidence for evolution.

In the 1970s, tinkering with E. coli helped scientists learn to manipulate genes, making the bacterium, Zimmer says, “the monster and the mule” of bioscience — a symbol of fears about genetic experimentation, as well as a workhorse used to make drugs. Here, he calmly finds a middle ground. While these initial concerns have remained largely unrealized, “genetic engineering has fallen far short of the more extravagant promises” about the eradication of major diseases that were offered 30 years ago.

Broadly, Zimmer sees public tolerance for genetic engineering increasing as science further reveals our patchwork genomic cloth. “New research on human evolution,” he writes, “makes it impossible to believe that a thing either is or is not a whole human being,” as some conservative opponents of biomedical inventions have argued. If our attempts to define a uniquely human core are arbitrary, however, they help us decide how to live. Zimmer thus hopes a debate over genetic engineering will produce a “deeper understanding of what it means to be human: not as an inviolable essence but as a complex cloud of genes, traits, environmental influences and cultural forces.”

Desirable as this discussion sounds, is it likely? As Zimmer notes, a bit too briefly, the emergence of biotechnology as an economic force dampened this debate three decades ago. Still, some public advocacy groups remain wary of bioscience, and coming innovations could revive opposition from cultural conservatives, rights-based interest groups and liberals upset at the uneven distribution of these goods. Genetic engineering and new forms of biomedicine could therefore engender a worthy civic dialogue or aggravate old political fractures. Or biotechnology may simply roll on. In any case, Zimmer adroitly links the common heritage we share with E. coli and the emerging horizons of science: “Through E. coli we can see the history of life, and we can see its future as well.”

Courtesy: Newyork times

Tulsi Fights Swine Flu - Among A Host Of Health Benefits

2009-08-16T05:02:00.000-07:00

Tulsi is a medicinal plant of Indian origins that has medicinal benefits abound in it. Tulsi has much of a cultural significance in India as well, where it is considered divine and its presence in households, auspicious.

The latest revelation about the medicinal properties of Tulsi comes in the wake of pandemic alerts world over – Tulsi helps in countering the deadly H1Ni virus! Tulsi is found to improve the body’s defence mechanisms against viruses in general and its effectiveness has been vouched for in its ability to act against the virus causing flu. It has been revealed that Tulsi could ward off the Swine Flu virus as well as could cure people who have been infected with Swine Flu.

The treatment for Swine Flu involves consumption of 20 – 25 leaves of Tulsi in its fresh form or as liquid and to be taken in empty stomach twice a day. The revelation assumes significance as traditional medicines are found lacking in their ability to tackle H1N1 virus, with Swine Flu sweeping across the world, spreading panic among people and offices and schools being shut down to control the spread of the epidemic.

Other Benefits of Tulsi: Tulsi’s effectiveness against Swine Flu may have come as news to people who are unaware of the wealth of benefits that the humble herb has to offer. Traditionally, Hindu temples provide water that has Tulsi leaves soaked in it to devotees. Tulsi leaves are boiled in water and the essence is given to children and adults who suffer from flu and common cold.

Tulsi plant is a repellent against mosquitoes and other insects and Tulsi leaves and juice extracted from the leaves are found to be cures against malaria. Tulsi is also a remedy against constipation, indigestion, poor appetite and acidity. Tulsi is known to help solve health problems in women that are associated with menstruation and pregnancy. Tulsi strengthens the body’s immune system in children and protects them from common infections

The effectiveness of the medicinal plant in preventing and curing swine flu only vouches for the host of other health benefits that the plant is traditionally known to offer.

Television Viewing Linked to Blood Pressure Increases in Children

2009-08-15T05:36:00.000-07:00

By RONI CARYN RABIN

Children who spend a lot of time watching television have higher blood pressure than those who watch less, even if the children are thin and get enough exercise, according to new research.

Earlier studies have found associations between television viewing and obesity, which is linked to higher blood pressure. But the new report suggests a more direct relationship between extensive TV watching and increases in blood pressure, the authors said.

Researchers at Michigan State University have been following a group of 111 children, ages 3 to 8, for about four years. The team asked the children to wear accelerometers — devices that record physical motion — for a week in order to objectively measure the amount of time that they were sedentary. The researchers also gathered information from parents about how many hours their children spent watching television, playing video games and using the computer. They also measured the children’s body fat.

Children who watched the most television (from 1.5 to 5.5 hours a day) had significantly higher diastolic and systolic blood pressure readings than those who watched the least television (less than half an hour a day), the researchers found. Data from the accelerometers showed that the increased blood pressure wasn’t associated with the sedentary behavior overall, but specifically linked to increased TV viewing.

Although this study did not report on the prevalence of hypertension and pre-hypertension, earlier research with a similar group of children found that one in five had high blood pressure, the authors said. Children generally have lower blood pressure than adults, and their blood pressure rises as they grow.

Extensive TV viewing may have harmful physiological effects because children often snack while watching TV, or perhaps because the programs are distressing to them, suggested Joey Eisenmann, an assistant professor of kinesiology at Michigan State University and the paper’s senior author. Watching TV late at night may cut into sleep time or disrupt sleep, he added; it’s also possible that watching television reduces the body’s metabolic rate more than other sedentary activities.

The American Academy of Pediatrics recommends that children watch no more than two hours of high quality television each day.

The study was published in this month’s issue of Archives of Pediatrics and Adolescent Medicine.

Cortesy: Newyork times

People With Lots Of Working Memory Are Not Easily Distracted

2009-08-13T05:32:00.000-07:00

"That blasted siren. I can't focus." That reaction to undesired distraction may signal a person's low working-memory capacity, according to a new study.

Based on a study of 84 students divided into four separate experiments, University of Oregon researchers found that students with high memory storage capacity were clearly better able to ignore distractions and stay focused on their assigned tasks.

Principal investigator Edward K. Vogel, a UO professor of psychology, compares working memory to a computer's random-access memory (RAM) rather than the hard drive's size -- the higher the RAM, the better processing abilities. With more RAM, he said, students were better able to ignore distractions. This notion surfaced in a 2005 paper in Nature by Vogel and colleagues in the Oregon Visual Working Memory & Attention Lab.

In experiments with some variations in approaches -- detailed in the July 8 issue of the Journal of Neuroscience -- students' brain activity was monitored using electroencephalography (EEG) while they studied images on a computer screen, recognizing a shape with a missing component, and then identifying the object after it moved simply to another location or amid distractions. Using a "task irrelevant probe" -- a 50 millisecond-long flash of light -- Vogel and Keisuke Fukuda, a doctoral student of Vogel's and lead author, were able to determine where exactly a subject's attention was focused.

All of the subjects were able to quickly and accurately identify the targets when the objects moved around the screen, but as distracting components were added some maintained accuracy while others diverted their attention and slipped in performing the assigned tasks.

Vogel is quick to say that the findings don't necessarily signify problems for an easily distracted person, although people who hold their focus more intensely tend to have higher fluid intelligence; they score higher on achievement tests, do better in math and learn second languages easier than peers who are captured by interruptions. Vogel currently is working with other UO researchers to explore if the easily distracted indeed have a positive side, such as in artistic creativity and imagination.

The new research, funded by the National Science Foundation, zeroed in on the brain's prefrontal cortex -- a region linked to executive function and under scrutiny for its association with many neurological disorders -- and the intraparietal sulcus (IPS), which is involved in perceptual-motor coordination, including eye movements.

The IPS, Vogel said, acts as a pointer system that seeks out goal-related cues, and it possibly is the gateway for memory circuitry in the brain.

"Our attention is the continual interplay between what our goals are and what the environment is trying to dictate to us," Vogel said. "Often, to be able to complete complex and important goal-directed behavior, we need to be able to ignore salient but irrelevant things, such as advertisements flashing around an article you are trying to read on a computer screen. We found that some people are really good at overriding attention capture, and other people have a difficult time unhooking from it and are really susceptible to irrelevant stimuli."

Vogel theorizes that people who are good at staying on focus have a good gatekeeper, much like a bouncer or ticket-taker hired to allow only approved people into a nightclub or concert. Understanding how to improve the gatekeeper component, he said, could lead to therapies that help easily distracted people better process what information is allowed in initially, rather than attempting to teach people how to force more information into their memory banks.

Cortesy: ScienceDaily

Itch-specific Neurons Identified In Mice Offers Hope For Better Treatments

2009-08-11T05:28:00.000-07:00

Historically, many scientists have regarded itching as just a less intense version of pain. They have spent decades searching for itch-specific nerve cells to explain how the brain perceives itch differently from pain, but none have been found.

Now researchers at Washington University School of Medicine in St. Louis have discovered that those itch-specific neurons do exist in mice, and their studies suggest that itch and pain signals are transmitted along different pathways in the spinal cord. Reporting in the Aug. 6 issue of Science Express, the advance online publication of the journal Science, the researchers say they can knock out an animal's itch response without affecting its ability to sense and attempt to avoid pain.

"This finding has very important therapeutic implications," says Zhou-Feng Chen, Ph.D., the study's principal investigator. "We've shown that particular neurons are critical for the itching sensation but not for pain, which means those cells may contain several itch-specific receptors or signaling molecules that can be explored or identified as targets for future treatment or management of chronic itching."

The new finding follows research by Chen and his team in 2007 that identified the first itch gene — gastrin-releasing peptide receptor (GRPR) — in the spinal cord. They also showed that when mice were exposed to things that make them itchy, those without a GRPR gene scratched less than their normal littermates. Chen's team also found GRPR in a group of spinal-cord cells called lamina 1 neurons that relay both itch and pain sensations to the brain.

"But the identification of an itch receptor in spinal-cord neurons didn't mean those neurons were itch-specific because it was possible that they also could have pain-related genes," says Chen, associate professor of anesthesiology, of psychiatry and of developmental biology. "A key question was whether those GRPR neurons also were transmitting pain signals. We approached that question by injecting a toxic substance that binds to GRPR and then exposing mice to both itchy and painful stimuli."

Chen's team injected the spinal cords of mice with a neurotoxin called bombesin-saporin. It bound to GRPR and killed the neurons where the gene was expressed. When these mice then were exposed to things that caused itching, they didn't scratch. With an appropriate dose of the neurotoxin, their scratching could be reduced by more than 80 percent or completely eliminated in some instances. That finding proved that the neurons with GRPR were required for normal itch sensation.

There are two major types of itching that are classified according to the presence or absence of the chemical histamine. Histamine-dependent itching can be caused by bug bites or allergic reactions. It is treated with antihistamine drugs, such as Benadryl®. Most chronic, severe itching, however, is resistant to antihistamine treatment. But in this study, it made no difference whether mice were exposed to histamines or to other itch-inducing substances. Those mice whose GRPR-expressing neurons had been destroyed by the neurotoxin didn't scratch, regardless of what type of itchy agent they encountered.

"However, the same mice continued to respond normally to pain," Chen says. "This is a very striking and unexpected result because it suggests there is an itch-specific neuronal pathway in the spinal cord."

Further tests showed that other neurologic functions, such as motor control were not affected by the destruction of the GRPR-expressing neurons.

Whereas Chen's earlier work found that pain and itch are regulated through different molecular pathways, this study suggests they also are regulated through different cellular pathways. That, he says, could have important implications for treating itch because the neurons with GRPR may contain more itch-specific genes.

"We've shown that these GRPR neurons are important for itching sensation and not for pain, but we really don't know much more about them," Chen says. "We still have a lot of questions, and we are very interested to find more answers."

Funding for this research comes from a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.

Journal references:

1. Sun YG, Zhao ZQ, MengXL, Yin J, Liu XY, Chen ZF. Cellular basis of itch sensation. Science, Aug. 7, 2009
2. Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature, Online July 25, 2007; (448), pp. 700-703. Aug. 9, 2007 DOI: 10.1038/nature06029

Warmer Environment Means Shorter Lives For Cold-blooded Animals

2009-08-09T05:25:00.000-07:00

A Bearded Dragon (Pogona vitticeps) on the forest floor, Daintree National Park (Australia). Temperature explains much of why cold-blooded organisms such as fish, amphibians, crustaceans, and lizards live longer at higher latitudes than at lower latitudes. (Credit: iStockphoto/Donall O Cleirigh)

Temperature explains much of why cold-blooded organisms such as fish, amphibians, crustaceans, and lizards live longer at higher latitudes than at lower latitudes, according to research recently published in the Proceedings of the National Academy of Sciences (PNAS) online. Assistant Professor Dr. Stephan Munch and Ph.D. candidate Santiago Salinas, both of Stony Brook University's School of Marine and Atmospheric Sciences (SoMAS), found that for a diverse range of species whose body temperatures vary with the temperature of their surroundings, ambient temperature is the dominant factor controlling geographic variation of lifespan within species.

"We were intrigued by the fact that that pearl mussels in Spain have a maximum lifespan of 29 years, while in Russia, individuals of the same species live nearly 200 years," said Dr. Munch. "We wondered how a relatively small difference in latitude (Spain 43ºN and Russia 66ºN) could have such a drastic impact on lifespan. While one might expect that local adaptations or geographic variations in predator and food abundance would account for this disparity, we wanted to see whether the geographical variation in lifespan that we see in all sorts of species has a common physiological basis in temperature."

Munch and Salinas looked at lifespan data from laboratory and field observations for over 90 species from terrestrial, freshwater, and marine environments. They studied organisms with different average longevities--from the copepod Arcartia tonsa, which has an average lifespan of 11.6 days, to the pearl mussel Margaritifera margaritifera, which has an average lifespan of 74 years. They found that across this wide range of species, temperature was consistently exponentially related to lifespan.

The relationship between temperature and lifespan that Munch and Salinas found through data analysis was strikingly similar to the relationship that the metabolic theory of ecology (MTE) predicts. The MTE is a modeling framework that has been used to explain the way in which life history, population dynamics, geographic patterns, and other ecological processes scale with an animal's body size and temperature.

"You can think of an animal as a beaker in which chemical reactions are taking place," said Salinas. "The same rules that apply to a liquid inside a beaker should apply to animals. Chemists have a relationship for how an increase in temperature will speed up reaction rates, so the MTE borrows that relationship and applies it--with some obvious caveats--to living things."

The lifespan in 87% of the free-living species Munch and Salinas studied varied as predicted by the MTE. Yet after removing the effect of temperature, there was still considerable variation in lifespan within species, indicating that other, local factors still play a role in determining lifespan.

"It is interesting to consider how cold-blooded species are likely to react in the face of global warming," said Salinas. "Because of the exponential relationship between temperature and lifespan, small changes in temperature could result in relatively large changes in lifespan. We could see changes to ecosystem structure and stability if cold-blooded species change their life histories to accommodate warmer temperatures but warm-blooded species do not."

Courtesy: Science Daily

Ovarian Tumor Growth Slowed By Nanoparticle-Delivered 'Suicide' Genes

2009-08-07T05:17:00.000-07:00

Nanoparticle delivery of diphtheria toxin-encoding DNA selectively expressed in ovarian cancer cells reduced the burden of ovarian tumors in mice, and researchers expect this therapy could be tested in humans within 18 to 24 months, according to a report in Cancer Research, a journal of the American Association for Cancer Research.

Although early stage ovarian cancer can be treated with a combination of surgery followed by chemotherapy, there are currently no effective treatments for advanced ovarian cancer that has recurred after surgery and primary chemotherapy. Therefore, the majority of treated early stage cancers will relapse.

"This report is definitely a reason to hope. We now have a potential new therapy for the treatment of advanced ovarian cancer that has promise for targeting tumor cells and leaving healthy cells healthy," said lead researcher Janet Sawicki, Ph.D., a professor at the Lankenau Institute for Medical Research.

Sawicki and colleagues at the Massachusetts Institute of Technology evaluated the therapeutic efficacy of a cationic biodegradable beta-amino ester polymer as a vector for the nanoparticle delivery of a DNA encoding diphtheria toxin suicide gene. These nanoparticles were injected into mice with primary or metastatic ovarian tumors.

To test the efficacy of this technique, the researchers measured tumor volume before and after treatment. They found that while treated tumors increased 2-fold, this was significantly less than the between 4.1-fold and 6-fold increase in control mice.

Furthermore, four of the treated tumors failed to grow at all, while all control tumors increased in size. Administration of nanoparticles to three different ovarian cancer mouse models prolonged lifespan by nearly four weeks and suppressed tumor growth more effectively, and with minimal non-specific cytotoxicity, than in mice treated with clinically relevant doses of cisplatin and paclitaxel.

Edward Sausville, M.D., Ph.D., an associate editor of Cancer Research and associate director for clinical research at the Greenebaum Cancer Center at the University of Maryland, said this report illustrates significant progress in targeted therapy.

"In oncology we have been studying ways to kill tumors for a long time, but much of this has run up against the real estate principle of location, location, location," he said. "In other words, an effective therapy is not effective if it cannot get to the target."

Sausville said a major accomplishment of this research is the multiple ways it can target ovarian cancer cells, as scientists were able to deliver diphtheria toxin genes, using a nanoparticle, to the actual tumor site (peritoneum) with a basis for selective activity in the cancer cells (how the toxin genes were regulated once inside the cells).

"A real plus of a cancer therapy like this is not just the functionality of the nanoparticle construct molecule, but the ability to deliver the toxin to the tumor cells," said Sausville, who agrees that inception of clinical trials could be just 18 months away.

Source:
Jeremy Moore
American Association for Cancer Research

New Glimpses of Life’s Puzzling Origins

2009-08-05T05:11:00.000-07:00

By NICHOLAS WADE

Some 3.9 billion years ago, a shift in the orbit of the Sun’s outer planets sent a surge of large comets and asteroids careening into the inner solar system. Their violent impacts gouged out the large craters still visible on the Moon’s face, heated Earth’s surface into molten rock and boiled off its oceans into an incandescent mist.

Yet rocks that formed on Earth 3.8 billion years ago, almost as soon as the bombardment had stopped, contain possible evidence of biological processes. If life can arise from inorganic matter so quickly and easily, why is it not abundant in the solar system and beyond? If biology is an inherent property of matter, why have chemists so far been unable to reconstruct life, or anything close to it, in the laboratory?

The origins of life on Earth bristle with puzzle and paradox. Which came first, the proteins of living cells or the genetic information that makes them? How could the metabolism of living things get started without an enclosing membrane to keep all the necessary chemicals together? But if life started inside a cell membrane, how did the necessary nutrients get in?

The questions may seem moot, since life did start somehow. But for the small group of researchers who insist on learning exactly how it started, frustration has abounded. Many once-promising leads have led only to years of wasted effort. Scientists as eminent as Francis Crick, the chief theorist of molecular biology, have quietly suggested that life may have formed elsewhere before seeding the planet, so hard does it seem to find a plausible explanation for its emergence on Earth.

In the last few years, however, four surprising advances have renewed confidence that a terrestrial explanation for life’s origins will eventually emerge.

One is a series of discoveries about the cell-like structures that could have formed naturally from fatty chemicals likely to have been present on the primitive Earth. This lead emerged from a long argument between three colleagues as to whether a genetic system or a cell membrane came first in the development of life. They eventually agreed that genetics and membranes had to have evolved together.

The three researchers, Jack W. Szostak, David P. Bartel and P. Luigi Luisi, published a somewhat adventurous manifesto in Nature in 2001, declaring that the way to make a synthetic cell was to get a protocell and a genetic molecule to grow and divide in parallel, with the molecules being encapsulated in the cell. If the molecules gave the cell a survival advantage over other cells, the outcome would be “a sustainable, autonomously replicating system, capable of Darwinian evolution,” they wrote.

“It would be truly alive,” they added.

One of the authors, Dr. Szostak, of the Massachusetts General Hospital, has since managed to achieve a surprising amount of this program.

Simple fatty acids, of the sort likely to have been around on the primitive Earth, will spontaneously form double-layered spheres, much like the double-layered membrane of today’s living cells. These protocells will incorporate new fatty acids fed into the water, and eventually divide.

Living cells are generally impermeable and have elaborate mechanisms for admitting only the nutrients they need. But Dr. Szostak and his colleagues have shown that small molecules can easily enter the protocells. If they combine into larger molecules, however, they cannot get out, just the arrangement a primitive cell would need. If a protocell is made to encapsulate a short piece of DNA and is then fed with nucleotides, the building blocks of DNA, the nucleotides will spontaneously enter the cell and link into another DNA molecule.

At a symposium on evolution at the Cold Spring Harbor Laboratory on Long Island last month, Dr. Szostak said he was “optimistic about getting a chemical replication system going” inside a protocell. He then hopes to integrate a replicating nucleic acid system with dividing protocells.

Dr. Szostak’s experiments have come close to creating a spontaneously dividing cell from chemicals assumed to have existed on the primitive Earth. But some of his ingredients, like the nucleotide building blocks of nucleic acids, are quite complex. Prebiotic chemists, who study the prelife chemistry of the primitive Earth, have long been close to despair over how nucleotides could ever have arisen spontaneously.

Nucleotides consist of a sugar molecule, like ribose or deoxyribose, joined to a base at one end and a phosphate group at the other. Prebiotic chemists discovered with delight that bases like adenine will easily form from simple chemicals like hydrogen cyanide. But years of disappointment followed when the adenine proved incapable of linking naturally to the ribose.

Last month, John Sutherland, a chemist at the University of Manchester in England, reported in Nature his discovery of a quite unexpected route for synthesizing nucleotides from prebiotic chemicals. Instead of making the base and sugar separately from chemicals likely to have existed on the primitive Earth, Dr. Sutherland showed how under the right conditions the base and sugar could be built up as a single unit, and so did not need to be linked.

“I think the Sutherland paper has been the biggest advance in the last five years in terms of prebiotic chemistry,” said Gerald F. Joyce, an expert on the origins of life at the Scripps Research Institute in La Jolla, Calif.

Once a self-replicating system develops from chemicals, this is the beginning of genetic history, since each molecule carries the imprint of its ancestor. Dr. Crick, who was interested in the chemistry that preceded replication, once observed, “After this point, the rest is just history.”

Dr. Joyce has been studying the possible beginning of history by developing RNA molecules with the capacity for replication. RNA, a close cousin of DNA, almost certainly preceded it as the genetic molecule of living cells. Besides carrying information, RNA can also act as an enzyme to promote chemical reactions. Dr. Joyce reported in Science earlier this year that he had developed two RNA molecules that can promote each other’s synthesis from the four kinds of RNA nucleotides.

“We finally have a molecule that’s immortal,” he said, meaning one whose information can be passed on indefinitely. The system is not alive, he says, but performs central functions of life like replication and adapting to new conditions.

“Gerry Joyce is getting ever closer to showing you can have self-replication of RNA species,” Dr. Sutherland said. “So only a pessimist wouldn’t allow him success in a few years.”

Another striking advance has come from new studies of the handedness of molecules. Some chemicals, like the amino acids of which proteins are made, exist in two mirror-image forms, much like the left and right hand. In most naturally occurring conditions they are found in roughly equal mixtures of the two forms. But in a living cell all amino acids are left-handed, and all sugars and nucleotides are right-handed.

Prebiotic chemists have long been at a loss to explain how the first living systems could have extracted just one kind of the handed chemicals from the mixtures on the early Earth. Left-handed nucleotides are a poison because they prevent right-handed nucleotides linking up in a chain to form nucleic acids like RNA or DNA. Dr. Joyce refers to the problem as “original syn,” referring to the chemist’s terms syn and anti for the structures in the handed forms.

The chemists have now been granted an unexpected absolution from their original syn problem. Researchers like Donna Blackmond of Imperial College London have discovered that a mixture of left-handed and right-handed molecules can be converted to just one form by cycles of freezing and melting.

With these four recent advances — Dr. Szostak’s protocells, self-replicating RNA, the natural synthesis of nucleotides, and an explanation for handedness — those who study the origin of life have much to be pleased about, despite the distance yet to go. “At some point some of these threads will start joining together,” Dr. Sutherland said. “I think all of us are far more optimistic now than we were five or 10 years ago.”

One measure of the difficulties ahead, however, is that so far there is little agreement on the kind of environment in which life originated. Some chemists, like Günther Wächtershäuser, argue that life began in volcanic conditions, like those of the deep sea vents. These have the gases and metallic catalysts in which, he argues, the first metabolic processes were likely to have arisen.

But many biologists believe that in the oceans, the necessary constituents of life would always be too diluted. They favor a warm freshwater pond for the origin of life, as did Darwin, where cycles of wetting and evaporation around the edges could produce useful concentrations and chemical processes.

No one knows for sure when life began. The oldest generally accepted evidence for living cells are fossil bacteria 1.9 billion years old from the Gunflint Formation of Ontario. But rocks from two sites in Greenland, containing an unusual mix of carbon isotopes that could be evidence of biological processes, are 3.830 billion years old.

How could life have gotten off to such a quick start, given that the surface of the Earth was probably sterilized by the Late Heavy Bombardment, the rain of gigantic comets and asteroids that pelted the Earth and Moon around 3.9 billion years ago? Stephen Mojzsis, a geologist at the University of Colorado who analyzed one of the Greenland sites, argued in Nature last month that the Late Heavy Bombardment would not have killed everything, as is generally believed. In his view, life could have started much earlier and survived the bombardment in deep sea environments.

Recent evidence from very ancient rocks known as zircons suggests that stable oceans and continental crust had emerged as long as 4.404 billion years ago, a mere 150 million years after the Earth’s formation. So life might have had half a billion years to get started before the cataclysmic bombardment.

But geologists dispute whether the Greenland rocks really offer signs of biological processes, and geochemists have often revised their estimates of the composition of the primitive atmosphere. Leslie Orgel, a pioneer of prebiotic chemistry, used to say, “Just wait a few years, and conditions on the primitive Earth will change again,” said Dr. Joyce, a former student of his.

Chemists and biologists are thus pretty much on their own in figuring out how life started. For lack of fossil evidence, they have no guide as to when, where or how the first forms of life emerged. So they will figure life out only by reinventing it in the laboratory.

Birds born to fear red

2009-08-03T05:03:00.000-07:00

Colour intimidation in finches is innate, not learned.

Matt Kaplan

Finches instinctively avoid competitors coloured red, rather than learning to fear the colour during their upbringing, Australian research concludes.¹

The results are tempting researchers to suspect that in other animals, including ourselves, red's aggressive and intimidating character might also be hard-wired into brains from birth.

Dozens of experiments have shown that red intimidates competitors. In humans, wearing red improves chances of winning at sports.² Studies have also revealed that red is associated with aggression and dominance in fish, reptiles and birds.³,⁴ But whether fear of red is innate or learned is an "unresolved mystery", says Robert Barton, an anthropologist at the University of Durham, UK.

Sarah Pryke of Macquarie University in Sydney tested this question in Australian Gouldian finches (Erythrura gouldiae). As adults, the finches develop either red or black heads, a genetically determined trait. The red-headed birds are aggressive, dominant and avoided by others.

To find out whether these traits were learned or inborn, Pryke examined competition between young Gouldian finches — whose heads, yet to blossom into coloured adulthood, are all dull grey.

Red destiny

She first raised finches that were genetically destined to be red-headed with black-headed parents, raised others that were genetically destined to be black-headed with red-headed parents, and left still other finches to be raised by parents of the same colour group. In contests staged between these young birds over food, it was body size rather than genetic destiny or rearing environment that decided the winner.

The still-uncoloured juveniles were then either allowed to mingle with adult red- and black-headed birds, or placed in isolation. They finally had their heads randomly painted red, black or a blue control colour.

Pryke again set pairs of hungry birds to fights over food. After the conflict, she inferred stress in individual birds by measuring blood levels of the hormone corticosterone.

Red-painted juveniles won contests with non-red juveniles 81.5% of the time, Pryke reports, regardless of what coloured head they would ultimately grow up to have. And juveniles facing red-painted opponents showed corticosterone levels 57.6% higher than those of birds that faced blue or black-headed opponents.

Don't mess with a redhead

"How the experimentally reddened finches won contests was interesting: their opponents simply moved out the way. It was not that the birds with fake red heads were suddenly more aggressive," recalls Pryke.

The results suggest that birds don't just avoid red because they have learned from experience to fear it. Rearing conditions and prolonged experience with aggressive red adults made no difference to an individual's aggressive response or stress levels.

"This suggests that Gouldian finches hatch 'knowing', as it were, that birds with red should be avoided," says Pryke.

"There are numerous examples in the literature suggesting an evolutionary bias towards red as an innate signal of aggression, [but] Pryke is the first to show explicitly and experimentally that this is indeed true … regardless of genetic and environmental background," says Mats Olsson, who works on evolutionary ecology at the University of Wollongong in New South Wales, Australia.

Red for a reason?

What remains unclear is why red is the colour of intimidation. White and blue are as commonly used as warning colours in plants and animals as red, says Pryke — so it's surprising that an innate fear of red should emerge from natural selection.

"There could be something about red that is particularly costly to produce or maintain, therefore making it very likely to be an 'honest' signal that other animals have to respect," thinks Barton. Many primates, including humans, show anger or dominance by bringing oxygenated blood to the surface of the skin. This creates a red colouration but at the cost of shunting blood away from core tissues.

Barton also suggests that the high visibility of becoming red, which increases the risk of being picked out by predators or rivals, may suggest to others of the same species that an animal is tough enough to cope with being more noticeable.

"Considering this study and all of those associated with red uniforms in games², it is tempting to suspect that in humans, as in birds, it is also innate for red to signal aggression and intimidation," adds neuroscientist Mihai Moldovan, at the University of Copenhagen.

References

Pryke, S. R. Anim. Behav. published online. doi: 10.1016/j.anbehav.2009.05.013 (2009).
Hill, R. and Barton, R. Nature, 435, 293 (2005)
Healey, M. et al Animal Behaviour, 74, 337-341 (2007)
Pryke, S. et al , Behavioural Ecology, 13, 622-631 (2002)