Thursday, May 27, 2010

RESPONSE TO VACCINES COULD DEPEND ON YOUR SEX

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Biological differences between the sexes could be a significant predictor of responses to vaccines, according to researchers at the Johns Hopkins Bloomberg School of Public Health. They examined published data from numerous adult and child vaccine trials and found that sex is a fundamental, but often overlooked predictor of vaccine response that could help predict the efficacy of combating infectious disease. The review is featured in the May 2010 issue of The Lancet Infectious Diseases.

"Sex can affect the frequency and severity of adverse effects of vaccination, including fever, pain and inflammation," said Sabra Klein, PhD, lead author of the review and an assistant professor at the Bloomberg School's W. Harry Feinstone Department of Molecular Microbiology and Immunology. "This is likely due to the fact that women typically mount stronger immune responses to vaccinations compared to men. In some cases, women need substantially less of a vaccine to mount the same response as men. Pregnancy is also a factor that can alter immune responses to vaccines."

Researchers conducted a review of existing literature on several vaccines including yellow fever, influenza, measles, mumps and rubella, hepatitis and herpes simplex to obtain evidence of the difference in responses between women and men. They also examined the effect hormonal changes that occur during pregnancy have on vaccine efficacy. Researchers found that despite data supporting a role for sex in the response to vaccines, most studies did not document sex-specific effects in vaccine efficacy or induced immune responses.

"Understanding the biological differences between men and women to vaccines could have led to better distribution of the 2010 H1N1 vaccine during the early months. Our review of the literature found that healthy women often generated a more robust protective immune response to vaccination when compared to men," said Andrew Pekosz, PhD, associate professor at the Bloomberg School's W. Harry Feinstone Department of Molecular Microbiology and Immunology. "An understanding and appreciation of the effect of sex and pregnancy on immune responses might change the strategies used by public health officials to start efficient vaccination programs, optimizing the timing and dose of vaccines so that the maximum number of people are immunized." added Klein.

Johns Hopkins University

SPIDERS AT THE NANOSCALE: MOLECULES THAT BEHAVE LIKE ROBOTS

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A team of scientists from Columbia University, Arizona State University, the University of Michigan, and the California Institute of Technology (Caltech) have programmed an autonomous molecular "robot" made out of DNA to start, move, turn, and stop while following a DNA track.

The development could ultimately lead to molecular systems that might one day be used for medical therapeutic devices and molecular-scale reconfigurable robots—robots made of many simple units that can reposition or even rebuild themselves to accomplish different tasks.

A paper describing the work appears in the current issue of the journal Nature.

The traditional view of a robot is that it is "a machine that senses its environment, makes a decision, and then does something—it acts," says Erik Winfree, associate professor of computer science, computation and neural systems, and bioengineering at Caltech.

Milan N. Stojanovic, a faculty member in the Division of Experimental Therapeutics at Columbia University, led the project and teamed up with Winfree and Hao Yan, professor of chemistry and biochemistry at Arizona State University and an expert in DNA nanotechnology, and with Nils G. Walter, professor of chemistry and director of the Single Molecule Analysis in Real-Time (SMART) Center at the University of Michigan in Ann Arbor, for what became a modern-day self-assembly of like-minded scientists with the complementary areas of expertise needed to tackle a tough problem.

Shrinking robots down to the molecular scale would provide, for molecular processes, the same kinds of benefits that classical robotics and automation provide at the macroscopic scale. Molecular robots, in theory, could be programmed to sense their environment (say, the presence of disease markers on a cell), make a decision (that the cell is cancerous and needs to be neutralized), and act on that decision (deliver a cargo of cancer-killing drugs).

Or, like the robots in a modern-day factory, they could be programmed to assemble complex molecular products. The power of robotics lies in the fact that once programmed, the robots can carry out their tasks autonomously, without further human intervention.

With that promise, however, comes a practical problem: how do you program a molecule to perform complex behaviors?

"In normal robotics, the robot itself contains the knowledge about the commands, but with individual molecules, you can't store that amount of information, so the idea instead is to store information on the commands on the outside," says Walter. And you do that, says Stojanovic, "by imbuing the molecule's environment with informational cues."

"We were able to create such a programmed or 'prescribed' environment using DNA origami," explains Yan. DNA origami, an invention by Caltech Senior Research Associate Paul W. K. Rothemund, is a type of self-assembled structure made from DNA that can be programmed to form nearly limitless shapes and patterns (such as smiley faces or maps of the Western Hemisphere or even electrical diagrams). Exploiting the sequence-recognition properties of DNA base pairing, DNA origami are created from a long single strand of DNA and a mixture of different short synthetic DNA strands that bind to and "staple" the long DNA into the desired shape. The origami used in the Nature study was a rectangle that was 2 nanometers (nm) thick and roughly 100 nm on each side.

The researchers constructed a trail of molecular "bread crumbs" on the DNA origami track by stringing additional single-stranded DNA molecules, or oligonucleotides, off the ends of the staples. These represent the cues that tell the molecular robots what to do—start, walk, turn left, turn right, or stop, for example—akin to the commands given to traditional robots.

The molecular robot the researchers chose to use—dubbed a "spider"—was invented by Stojanovic several years ago, at which time it was shown to be capable of extended, but undirected, random walks on two-dimensional surfaces, eating through a field of bread crumbs.

To build the 4-nm-diameter molecular robot, the researchers started with a common protein called streptavidin, which has four symmetrically placed binding pockets for a chemical moiety called biotin. Each robot leg is a short biotin-labeled strand of DNA, "so this way we can bind up to four legs to the body of our robot," Walter says. "It's a four-legged spider," quips Stojanovic. Three of the legs are made of enzymatic DNA, which is DNA that binds to and cuts a particular sequence of DNA. The spider also is outfitted with a "start strand"—the fourth leg—that tethers the spider to the start site (one particular oligonucleotide on the DNA origami track). "After the robot is released from its start site by a trigger strand, it follows the track by binding to and then cutting the DNA strands extending off of the staple strands on the molecular track," Stojanovic explains.

"Once it cleaves," adds Yan, "the product will dissociate, and the leg will start searching for the next substrate." In this way, the spider is guided down the path laid out by the researchers. Finally, explains Yan, "the robot stops when it encounters a patch of DNA that it can bind to but that it cannot cut," which acts as a sort of flypaper.

Although other DNA walkers have been developed before, they've never ventured farther than about three steps. "This one," says Yan, "can walk up to about 100 nanometers. That's roughly 50 steps."

"This in itself wasn't a surprise," adds Winfree, "since Milan's original work suggested that spiders can take hundreds if not thousands of processive steps. What's exciting here is that not only can we directly confirm the spiders' multistep movement, but we can direct the spiders to follow a specific path, and they do it all by themselves—autonomously."

In fact, using atomic force microscopy and single-molecule fluorescence microscopy, the researchers were able to watch directly spiders crawling over the origami, showing that they were able to guide their molecular robots to follow four different paths.

"Monitoring this at a single molecule level is very challenging," says Walter. "This is why we have an interdisciplinary, multi-institute operation. We have people constructing the spider, characterizing the basic spider. We have the capability to assemble the track, and analyze the system with single-molecule imaging. That's the technical challenge." The scientific challenges for the future, Yan says, "are how to make the spider walk faster and how to make it more programmable, so it can follow many commands on the track and make more decisions, implementing logical behavior."

"In the current system," says Stojanovic, "interactions are restricted to the walker and the environment. Our next step is to add a second walker, so the walkers can communicate with each other directly and via the environment. The spiders will work together to accomplish a goal." Adds Winfree, "The key is how to learn to program higher-level behaviors through lower-level interactions."

Such collaboration ultimately could be the basis for developing molecular-scale reconfigurable robots—complicated machines that are made of many simple units that can reorganize themselves into any shape—to accomplish different tasks, or fix themselves if they break. For example, it may be possible to use the robots for medical applications. "The idea is to have molecular robots build a structure or repair damaged tissues," says Stojanovic.

"You could imagine the spider carrying a drug and bonding to a two-dimensional surface like a cell membrane, finding the receptors and, depending on the local environment," adds Yan, "triggering the activation of this drug."

Such applications, while intriguing, are decades or more away. "This may be 100 years in the future," Stojanovic says. "We're so far from that right now."

"But," Walter adds, "just as researchers self-assemble today to solve a tough problem, molecular nanorobots may do so in the future."

(Photo: Paul Michelotti)

The California Institute of Technology

STUDY UNCOVERS WHY JURORS REWARD THE GOOD-LOOKING, PENALIZE THE UNBEAUTIFUL

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It's the last place you want to be judged on your looks. But in a court of law, it pays to be attractive, according to a new Cornell study that has found that unattractive defendants tend to get hit with longer, harsher sentences -- on average 22 months longer in prison.

The study also identified two kinds of jurors: Those who reason emotionally and give harsher verdicts to unattractive defendants and those who reason rationally and focus less on defendants' looks.

Psycho-legal literature has reported for decades that juries tend to show a bias in favor of good-looking defendants. Two Cornell researchers set out to determine why.

"Our hypothesis going in was that jurors inclined to process information in a more emotional/intuitive manner would be more prone to make reasoning errors when rendering verdicts and recommending sentences as opposed to rational processors. The results bore out our hypothesis on all measures," said lead author Justin Gunnell '05, J.D. '08, who began working on the study as a policy analysis and management major with co-author Stephen Ceci, Cornell's Helen L. Carr Professor of Developmental Psychology.

The study, "When Emotionality Trumps Reason," to be published in an upcoming issue of Behavioral Sciences and the Law, may contribute to new refinements in jury selection.

Borrowing a theory from personality psychology, the researchers sought to identify emotional and rational thinkers. One processes information based on facts, analysis and logic. The other reasons emotionally and may consider such legally irrelevant factors as a defendant's appearance, race, gender and class and report that the less-attractive defendant appeared more like the "type of person" that would commit a crime.

American attorneys, depending on jurisdiction and the type of case, are permitted to screen out jurors for a number of reasons. In cases where the evidence strongly favors one side, a lawyer might want to choose rational jurors. But in a case with an emotional tug (e.g., a poor defendant with several children, for example), a defense attorney might try to screen out highly rational jurors.

Study participants -- 169 Cornell psychology undergraduates -- took an online survey to determine the degree to which they processed information rationally or emotionally. They were then given a case study with a photograph of an actual defendant and his or her general profile. They read real jury instructions and listened to the cases' closing arguments.

While both groups convicted attractive defendants at similar rates and were less biased in the face of strong evidence or very serious offences, the jurors' reasoning style tended to play out "in cases where the evidence is ambiguous and the charged offense is somewhat minor," said Gunnell, who practices commercial litigation in New York City.

"Every person is capable of reasoning via either system and likely uses each system to some degree depending on context," Gunnell said. "The degree to which one system predominates the other is a factor that varies, depending on the individual's natural preference and style."

He said the findings are important in that "22 months may not seem like a lot to an outsider, but I guarantee that to the person serving the sentence it will seem like a lot."

"It is our obligation to look at areas of the judicial process that may be prone to weakness, at least under certain circumstances, or where improvements can be made. How jurors think, process and reason are an important step in understanding potential flaws in the American justice system, as crucial decisions ultimately rest in their hands," he concluded.

(Photo: Cornell U.)

Cornell University

QUANTUM MECHANICS REVEALS NEW DETAILS OF DEEP EARTH

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Scientists have used quantum mechanics to reveal that the most common mineral on Earth is relatively uncommon deep within the planet.

Using several of the largest supercomputers in the nation, a team of physicists led by Ohio State University has been able to simulate the behavior of silica in a high-temperature, high-pressure form that is particularly difficult to study firsthand in the lab.

The resulting discovery -- reported in this week’s early online edition of the Proceedings of the National Academy of Sciences (PNAS) -- could eventually benefit science and industry alike.

Silica makes up two-thirds of the Earth’s crust, and we use it to form products ranging from glass and ceramics to computer chips and fiber optic cables.

“Silica is all around us," said Ohio State doctoral student Kevin Driver, who led this project for his doctoral thesis. “But we still don’t understand everything about it. A better understanding of silica on a quantum-mechanical level would be useful to earth science, and potentially to industry as well.”

Silica takes many different forms at different temperatures and pressures -- not all of which are easy to study, Driver said.

"As you might imagine, experiments performed at pressures near those of Earth’s core can be very challenging. By using highly accurate quantum mechanical simulations, we can offer reliable insight that goes beyond the scope of the laboratory.”

Over the past century, seismology and high-pressure laboratory experiments have revealed a great deal about the general structure and composition of the earth. For example, such work has shown that the planet’s interior structure exists in three layers called the crust, mantle, and core. The outer two layers -- the mantle and the crust -- are largely made up of silicates, minerals containing silicon and oxygen.

Still, the detailed structure and composition of the deepest parts of the mantle remain unclear. These details are important for geodynamical modeling, which may one day predict complex geological processes such as earthquakes and volcanic eruptions.

Even the role that the simplest silicate -- silica -- plays in Earth's mantle is not well understood.

“Say you’re standing on a beach, looking out over the ocean. The sand under your feet is made of quartz, a form of silica containing one silicon atom surrounded by four oxygen atoms. But in millions of years, as the oceanic plate below becomes subducted and sinks beneath the Earth’s crust, the structure of the silica changes dramatically,” Driver said.

As pressure increases with depth, the silica molecules crowd closer together, and the silicon atoms start coming into contact with oxygen atoms from neighboring molecules. Several structural transitions occur, with low-pressure forms surrounded by four oxygen atoms and higher-pressure forms surrounded by six. With even more pressure, the structure collapses into a very dense form of the mineral, which scientists call alpha-lead oxide.

It’s this form of silica that likely resides deep within the earth, in the lower part of the mantle, just above the planet’s core, Driver said.

When scientists try to interpret seismic signals from that depth, they have no direct way of knowing what form of silica they are dealing with. So they must simulate the behavior of different forms on computer, and then compare the results to the seismic data. The simulations rely on quantum mechanics.

In PNAS, Driver, his advisor John Wilkins, and their coauthors describe how they used a quantum mechanical method to design computer algorithms that would simulate the silica structures. When they did, they found that the behavior of the dense, alpha-lead oxide form of silica did not match up with any global seismic signal detected in the lower mantle.

This result indicates that the lower mantle is relatively devoid of silica, except perhaps in localized areas where oceanic plates have subducted, Driver explained.

Wilkins, Ohio Eminent Scholar and professor of physics at Ohio State, cited Driver’s determination and resourcefulness in making this study happen. The physicists used a method called quantum Monte Carlo (QMC), which was developed during atomic bomb research in World War II. To earn his doctorate, Driver worked to show that the method could be applied to studying minerals in the planet’s deep interior.

"This work demonstrates both the superb contributions a single graduate student can make, and that the quantum Monte Carlo method can compute nearly every property of a mineral over a wide range of pressure and temperatures,” Wilkins said. He added that the study will “stimulate a broader use of quantum Monte Carlo worldwide to address vital problems.”

While these algorithms have been around for over half a century, applying them to silica was impossible until recently, Driver said. The calculations were simply too labor-intensive.

Even today, with the advent of more powerful supercomputers and fast algorithms that require less computer memory, the calculations still required using a number of the largest supercomputers in the United States, including the Ohio Supercomputer Center in Columbus.

“We used the equivalent of six million CPU hours or more, to model four different states of silica” Driver said.

He and his colleagues expect that quantum Monte Carlo will be used more often in materials science in the future, as the next generation of computers goes online.

(Photo: OSU)

Ohio State

RESEARCH SHOWS CHEMICALS FROM SEAWEED CAN KILL CORAL ON CONTACT

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Field studies have shown for the first time that several common species of seaweeds in both the Pacific and Caribbean Oceans can kill corals upon contact using chemical means.

While competition between seaweed and coral is just one of many factors affecting the decline of coral reefs worldwide, this chemical threat may provide a serious setback to efforts aimed at repopulating damaged reefs. Seaweeds are normally kept in check by herbivorous fish, but in many areas overfishing has reduced the populations of these plant-consumers, allowing seaweeds to overpopulate coral reefs.

A study documenting the chemical effects of seaweeds on corals was published May 10, 2010, in the early edition of the journal Proceedings of the National Academy of Sciences (PNAS). The research was supported by the National Institutes of Health, the National Science Foundation, and the Teasely Endowments at the Georgia Institute of Technology.

"Between 40 and 70 percent of the seaweeds we studied killed corals," said Mark Hay, a professor in the School of Biology at Georgia Tech. "We don't know how significant this is compared to other problems affecting coral, but we know this is a growing problem. For reefs that have been battered by human use or overfishing, the presence of seaweeds may prevent natural recovery from happening at all."

Coral reefs are declining worldwide, and scientists studying the problem had suspected that proliferation of seaweed was part of the cause -- perhaps by crowding out the coral or by damaging it physically.

Using racks of coral being transplanted as part of repopulation efforts, Hay and graduate student Douglas Rasher compared the fate of corals from two different species when they were placed next to different types of seaweed common around Fijian reefs in the Pacific -- and Panamanian reefs in Caribbean. They planted the seaweeds next to coral being transplanted -- and also placed plastic plants next to some of the coral to simulate the effects of shading and mechanical damage. Other coral in the racks had neither seaweeds nor plastic plants near them.

The researchers revisited the coral two days, 10 days and 20 days later. In as little as two days, corals in contact with some seaweed species bleached and died in areas of direct contact. In other cases, the effects took a full 20 days to appear -- or for some seaweed species, no damaging effects were noted during the 20-day period. Ultimately, as much as 70 percent of the seaweed species studied turned out to have harmful effects -- but only when they were in direct contact with the coral.

To confirm that chemical factors were responsible, Hay and Rasher extracted chemicals from the seaweeds -- and from only the surfaces of the seaweeds. They then applied both types of chemicals to corals by placing the chemicals into gel matrix bound to a strip of window screen, forming something similar to a gauze bandage and applying that directly to the corals. To a control group of corals, they applied the gel and screen without the seaweed chemicals.

The effects confirmed that chemicals from both the surface of certain seaweeds and extracts from those entire plants killed corals.

"In all cases where the coral had been harmed, the chemistry appeared to be responsible for it," said Hay. "The evolutionary reasons why the seaweeds have these compounds are not known. It may be that these compounds protect the seaweeds against microbial infection, or that they help compete with other seaweeds. But it's clear now that they also harm the corals, either by killing them or suppressing their growth."

The researchers studied coral of different species in the Pacific and Caribbean, matching them up against different species of seaweed common to their geographic areas. The coral species chosen – Porites porites in Panama and Porites cylindrica in Fiji -- are among the hardiest of coral, suggesting that other species may be even more dramatically affected by the seaweed compounds.

In the Caribbean, five of the seven seaweeds studied caused bleaching of the coral, while in the Pacific, three of eight species studied caused the effect.

The harmful chemicals affect only coral in direct contact with the seaweed, suggesting the compounds are not soluble in water, Hay noted. The effects -- which were measured through photographic image analysis and Pulse-Amplitude-Modulated fluorometry -- also varied considerably, with certain seaweeds showing stronger impacts than others.

Conducted during 2008 and 2009, the study adds new information about the decline of reefs worldwide, and reinforces the importance of maintaining a healthy ecosystem that includes enough herbivorous fish to keep seaweed under control.

"Removing the herbivorous fishes really sets up a cascade of effects," said Hay, who holds the Harry and Linda Teasely Chair in the Georgia Tech School of Biology. "The more you fish, the more seaweeds there are. The more seaweeds there are, the more damage is done to the coral. The less coral there is, the fewer fish will be recruited to an area. If there are fewer fish, the seaweeds outgrow the coral. It's a downward death spiral that may be difficult to recover from."

In earlier research, Hay and other researchers demonstrated that keeping fish away from coral reefs fuels the growth of seaweeds, and that certain fish are responsible for eating specific seaweed species. That information could help guide fisheries management by encouraging protection of fish that control the most harmful seaweeds.

"The most damaging seaweed in our study is eaten voraciously by one species of fish, and no other species will touch it," Hay said. "Now that we know that seaweeds can kill coral through these chemical means, it is even more important to understand which herbivores control which seaweeds so we can consider additional protections for these critical fish species, even outside of normal marine protected areas."

(Photo: GIT)

Georgia Tech

LATINO GENOMES ARE EXCEEDINGLY DIVERSE, REFLECTING HISTORY'S MIGRATIONS

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The term Hispanic/Latino "encompasses a huge amount of genetic diversity," says a Cornell researcher whose new study shows that populations geographically close to historical slave trade routes and ports have more African ancestry than more distant or inland Latin Americans, who show more Native American influences.

The genetics study by researchers from Cornell, the New York University School of Medicine, the University of Arizona and Stanford University, appears online in the Proceedings of the National Academy of Sciences Early Edition May 5.

"The study reveals unique patterns of ancestry across these populations," said Katarzyna Bryc, graduate student in biological statistics and computational biology and co-lead author of the paper with New York University medical student Christopher Velez. The genes of "these Latino populations tell us about the complexity of migration events involved in the histories of Hispanics/Latinos," Bryc added.

The research also found a sex bias in ancestry contributions in the sample of 100 individuals from Ecuador, Colombia, Dominican Republic and Puerto Rico and 112 Mexicans: All of the studied populations show greater proportions of Native American female and European male ancestries.

The findings have implications for using a genomic perspective in medicine, where knowledge of ancestries may reveal tendencies toward chronic inherited diseases. Previous studies have shown that Latinos with greater European ancestry have a higher risk of breast cancer, while European ancestry correlates with higher susceptibility to asthma in Puerto Ricans, compared with Mexicans, for example.

The genetic analysis shows that individuals from the Dominican Republic, Puerto Rico and to some extent Colombia have more African ancestry, reflecting migrations along the historical slave trade routes. In contrast, Mexicans and Ecuadorians have more Native American ancestry.

When compared with eight sampled Native American populations, the researchers also found that the Native American segments of genomes of North American Hispanics/Latinos (from Mexico, Puerto Rico and Dominican Republic) are genetically more similar to those of the Nahua people (indigenous of Mexico and Central America), while the Native American segments of genomes of South American populations (of Colombia and Ecuador) were most similar to those of the Quechua people.

The term Hispanic or Latino encompasses many different countries, hundreds of millions of individuals, and populations that underwent "different rates of migration from Europe and enslavement from Africa," said Velez. "This, in conjunction with the uneven distribution of native populations throughout the Americas prior to the arrival of the Spanish and Portuguese, has led to marked differences not only between countries in Latin America, but also within them," he added.

The researchers used data on 100 individuals from Ecuador, Colombia, Dominican Republic and Puerto Rico from a repository collected for the New York Cancer Project and housed at North Shore-Long Island Jewish Medical Center, and 112 Mexicans from a dataset collected by GlaxoSmithKline for the Population Reference Sample, a resource for population, disease and pharmacological genetics research.

Cornell University

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