Eating green veggies improves immune defenses

 by Biomechanism 

Researchers reporting online in the journal Cell, a Cell Press publication, have found another good reason to eat your green vegetables, although it may or may not win any arguments with kids at the dinner table.

It turns out that green vegetables — from bok choy to broccoli — are the source of a chemical signal that is important to a fully functioning immune system. They do this by ensuring that immune cells in the gut and the skin known as intra-epithelial lymphocytes (IELs) function properly.

“It is still surprising to me,” said Marc Veldhoen of The Babraham Institute in Cambridge. “I would have expected cells at the surface would play some role in the interaction with the outside world, but such a clear cut interaction with the diet was unexpected. After feeding otherwise healthy mice a vegetable-poor diet for two to three weeks, I was amazed to see 70 to 80 percent of these protective cells disappeared.”

Those protective IELs exist as a network beneath the barrier of epithelial cells covering inner and outer body surfaces, where they are important as a first line of defense and in wound repair. Veldhoen’s team now finds that the numbers of IELs depend on levels of a cell-surface protein called the aryl hydrocarbon receptor (AhR), which can be regulated by dietary ingredients found primarily in cruciferous vegetables. Mice lacking this receptor lose control over the microbes living on the intestinal surface, both in terms of their numbers and composition.

Earlier studies suggested that breakdown of cruciferous vegetables can yield a compound that can be converted into a molecule that triggers AhRs. The new work finds that mice fed a synthetic diet lacking this key compound experience a significant reduction in AhR activity and lose IELs. With reduced numbers of these key immune cells, animals showed lower levels of antimicrobial proteins, heightened immune activation and greater susceptibility to injury. When the researchers intentionally damaged the intestinal surface in animals that didn’t have normal AhR activity, the mice were not as “quick to repair” that damage.

As an immunologist, Veldhoen says he hopes the findings will generate interest in the medical community, noting that some of the characteristics observed in the mice are consistent with those seen in patients with inflammatory bowel disease.

“It’s tempting to extrapolate to humans,” he said. “But there are many other factors that might play a role.”

For the rest of us, he says, “it’s already a good idea to eat your greens.” Still, the results offer a molecular basis for the importance of cruciferous vegetable-derived phyto-nutrients as part of a healthy diet.

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Scientists reveal surprising picture of how powerful antibody neutralizes HIV by Biomechanism

“The findings advance AIDS vaccine development”

Researchers at The Scripps Research Institute have uncovered the surprising details of how a powerful anti-HIV antibody grabs hold of the virus. The findings, published in Science Express on October 13, 2011, highlight a major vulnerability of HIV and suggest a new target for vaccine development.

Caption: This is the PGT 128 antibody in action. Credit: Wilson lab, The Scripps Research Institute

“What’s unexpected and unique about this antibody is that it not only attaches to the sugar coating of the virus but also reaches through to grab part of the virus’s envelope protein,” said the report’s co-senior author Dennis Burton, a professor at The Scripps Research Institute and scientific director of the International AIDS Vaccine Initiative’s (IAVI) Neutralizing Antibody Center, based on the Scripps Research La Jolla campus.

“We can now start to think about constructing mimics of these viral structures to use in candidate vaccines,” said co-senior author Ian Wilson, who is Hansen Professor of Structural Biology and member of the Skaggs Institute for Chemical Biology at Scripps Research.

Other institutions in the United States, United Kingdom, Japan, and the Netherlands contributed to the research as part of an ongoing global HIV vaccine development effort.

Getting a Better Grip on HIV

Researchers from the current team recently isolated the new antibody and 16 others from the blood of HIV-infected volunteers, in work they reported online in the journal Nature on August 17, 2011. Since the 1990s, Burton, Wilson, and other researchers have been searching for such “broadly neutralizing” antibodies against HIV—antibodies that work against many of the various strains of the fast-mutating virus—and by now have found more than a dozen. PGT 128, the antibody described in the new report, can neutralize about 70 percent of globally circulating HIV strains by blocking their ability to infect cells. It also can do so much more potently—in other words, in smaller concentrations of antibody molecules—than any previously reported broadly neutralizing anti-HIV antibody.

The new report illuminates why PGT 128 is so effective at neutralizing HIV. Using the Wilson lab’s expertise in X-ray crystallography, Robert Pejchal, a research associate in the Wilson lab, determined the structure of PGT 128 joined to its binding site on molecular mockups of the virus, designed in part by Robyn Stanfield and Pejchal in the Wilson group and Bill Schief, now an IAVI principal scientist and associate professor at Scripps Research, and his group. With these structural data, and by experimentally mutating and altering the viral target site, they could see that PGT 128 works in part by binding to glycans on the viral surface.

Thickets of these sugars normally surround HIV’s envelope protein, gp120, largely shielding it from attack by the immune system. Nevertheless, PGT 128 manages to bind to two closely spaced glycans, and at the same time reaches through the rest of the “glycan shield” to take hold of a small part of structure on gp120 known as the V3 loop. This penetration of the glycan shield by PGT 128 was also visualized by electron microscopy with a trimeric form of the gp120/gp41 envelope protein of HIV-1 by Reza Kayat and Andrew Ward of Scripps Research; this revealed that the PGT 128 epitope appears to be readily accessible on the virus.

“Both of these glycans appear in most HIV strains, which helps explain why PGT 128 is so broadly neutralizing,” said Katie J. Doores, a research associate in the Burton lab who was one of the report’s lead authors. PGT 128 also engages V3 by its backbone structure, which doesn’t vary as much as other parts of the virus because it is required for infection.

PGT 128′s extreme potency is harder to explain. The antibody binds to gp120 in a way that presumably disrupts its ability to lock onto human cells and infect them. Yet it doesn’t bind to gp120 many times more tightly than other anti-HIV antibodies. The team’s analysis hints that PGT 128 may be extraordinarily potent because it also binds two separate gp120 molecules, thus tying up not one but two cell-infecting structures. Other mechanisms may also be at work.

Toward an AIDS Vaccine

Researchers hope to use the knowledge of these antibodies’ binding sites on HIV to develop vaccines that stimulate a long-term—perhaps lifetime—protective antibody response against those same vulnerable sites.

“We’ll probably need multiple targets on the virus for a successful vaccine, but certainly PGT 128 shows us a very good target,” said Burton.

Intriguingly, the basic motif of PGT 128′s target may mark a general vulnerability for HIV. “Other research is also starting to suggest that you can grab onto two glycans and a beta strand and get very potent and broad neutralizing antibodies against HIV,” Wilson said.

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The research was supported by the International AIDS Vaccine Initiative, National Institutes of Health, the U.S. Department of Energy, the Canadian Institutes of Health Research, the UK Research Councils, the Ragon Institute, and other organizations.

From Blue Whales to Earthworms, a Common Mechanism Gives Shape to Living Beings

This is a diagram of the mechanism for form. The blue whale and the earth worm owe their form to the same biological mechanism. EPFL researchers have discovered the secret. (Credit: Infographic courtesy of Pascal Coderay, EPFL)

Science Daily  — Why don't our arms grow from the middle of our bodies? The question isn't as trivial as it appears. Vertebrae, limbs, ribs, tailbone ... in only two days, all these elements take their place in the embryo, in the right spot and with the precision of a Swiss watch. Intrigued by the extraordinary reliability of this mechanism, biologists have long wondered how it works. Now, researchers at EPFL (Ecole Polytechnique Fédérale de Lausanne) and the University of Geneva (Unige) have solved the mystery.

The embryo is built one layer at a time

Their discovery will be published October 13, 2011 in the journalScience.

During the development of an embryo, everything happens at a specific moment. In about 48 hours, it will grow from the top to the bottom, one slice at a time -- scientists call this the embryo's segmentation. "We're made up of thirty-odd horizontal slices," explains Denis Duboule, a professor at EPFL and Unige. "These slices correspond more or less to the number of vertebrae we have."

Every hour and a half, a new segment is built. The genes corresponding to the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae and the tailbone become activated at exactly the right moment one after another. "If the timing is not followed to the letter, you'll end up with ribs coming off your lumbar vertebrae," jokes Duboule. How do the genes know how to launch themselves into action in such a perfectly synchronized manner? "We assumed that the DNA played the role of a kind of clock. But we didn't understand how."

When DNA acts like a mechanical clock

Very specific genes, known as "Hox," are involved in this process. Responsible for the formation of limbs and the spinal column, they have a remarkable characteristic. "Hox genes are situated one exactly after the other on the DNA strand, in four groups. First the neck, then the thorax, then the lumbar, and so on," explains Duboule. "This unique arrangement inevitably had to play a role."

The process is astonishingly simple. In the embryo's first moments, the Hox genes are dormant, packaged like a spool of wound yarn on the DNA. When the time is right, the strand begins to unwind. When the embryo begins to form the upper levels, the genes encoding the formation of cervical vertebrae come off the spool and become activated. Then it is the thoracic vertebrae's turn, and so on down to the tailbone. The DNA strand acts a bit like an old-fashioned computer punchcard, delivering specific instructions as it progressively goes through the machine.

"A new gene comes out of the spool every ninety minutes, which corresponds to the time needed for a new layer of the embryo to be built," explains Duboule. "It takes two days for the strand to completely unwind; this is the same time that's needed for all the layers of the embryo to be completed."

This system is the first "mechanical" clock ever discovered in genetics. And it explains why the system is so remarkably precise.

This discovery is the result of many years of work. Under the direction of Duboule and Daniël Noordermeer, the team analyzed thousands of Hox gene spools. With assistance from the Swiss Institute for Bioinformatics, the scientists were able to compile huge quantities of data and model the structure of the spool and how it unwinds over time.

The snake: a veritable vertebral assembly line

The process discovered at EPFL is shared by numerous living beings, from humans to some kinds of worms, from blue whales to insects. The structure of all these animals -- the distribution of their vertebrae, limbs and other appendices along their bodies -- is programmed like a sheet of player-piano music by the sequence of Hox genes along the DNA strand.

The sinuous body of the snake is a perfect illustration. A few years ago, Duboule discovered in these animals a defect in the Hox gene that normally stops the vertebrae-making process.

"Now we know what's happening. The process doesn't stop, and the snake embryo just keeps on making vertebrae, all identical, until the process just runs out of steam."

The Hox clock is a demonstration of the extraordinary complexity of evolution. One notable property of the mechanism is its extreme stability, explains Duboule. "Circadian or menstrual clocks involve complex chemistry. They can thus adapt to changing contexts, but in a general sense are fairly imprecise. The mechanism that we have discovered must be infinitely more stable and precise. Even the smallest change would end up leading to the emergence of a new species."