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My baby, my… virus? Stanford researchers find viral proteins in human embryonic cells

My baby, my... virus? Stanford researchers find viral proteins in human embryonic cells

Wysocka - 560

One thing I really enjoy about my job is the opportunity to constantly be learning something new. For example, I hadn’t realized that about eight percent of human DNA is actually left-behind detritus from ancient viral infections. I knew they were there, but eight percent? That’s a lot of genetic baggage.

These sequences are often inactive in mature cells, but recent research has shown they can become activated in some tumor cells or in human embryonic stem cells. Now developmental biologist Joanna Wysocka, PhD, and graduate student Edward Grow, have shown that some of these viral bits and pieces spring back to life in early human embryos and may even affect their development.

Their research was published today in Nature. As I describe in our press release:

Retroviruses are a class of virus that insert their DNA into the genome of the host cell for later reactivation. In this stealth mode, the virus bides its time, taking advantage of cellular DNA replication to spread to each of an infected cell’s progeny every time the cell divides. HIV is one well-known example of a retrovirus that infects humans.

When a retrovirus infects a germ cell, which makes sperm and eggs, or infects a very early-stage embryo before the germ cells have arisen, the viral DNA is passed along to future generations. Over evolutionary time, however, these viral genomes often become mutated and inactivated. About 8 percent of the human genome is made up of viral sequences left behind during past infections. One retrovirus, HERVK, however, infected humans repeatedly relatively recently — within about 200,000 years. Much of HERVK’s genome is still snuggled, intact, in each of our cells.

Wysocka and Grow found that human embryonic cells begin making viral proteins from these HERVK sequences within just a few days after conception. What’s more, the non-human proteins have a noticeable effect on the cells, increasing the expression of a cell surface protein that makes them less susceptible to subsequent viral infection and also modulating human gene expression.

More from our release:

But it’s not clear whether this sequence of events is the result of thousands of years of co-existence, a kind of evolutionary symbiosis, or if it represents an ongoing battle between humans and viruses.

“Does the virus selfishly benefit by switching itself on in these early embryonic cells?” said Grow. “Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

Wysocka describes the findings as “fascinating, but a little creepy.” I agree. But I can’t wait to hear what they discover next.

Previously: Viruses can cause warts on your DNA, Stanford researcher wins Vilcek Prize for Creative Promise in Biomedical Science and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Photo of Joanna Wysocka by Steve Fisch

Cancer, Genetics, Patient Care, Research, Science, Stanford News

Identifying relapse in lymphoma patients with circulating tumor DNA

Identifying relapse in lymphoma patients with circulating tumor DNA

3505577004_6fc17ba8c2_zCancer patients in remission often live on a knife’s edge, wondering if their disease will recur. This possibility is more likely in some types of cancers than in others. One of these is diffuse large B-cell lymphoma, which is the most common blood cancer in this country. It’s often successfully treated, but a significant minority of patients will relapse. Detecting these relapses early is critical, but difficult.

Hematologist and oncologists Ash Alizadeh, MD, PhD, and David Kurtz, MD, and former postdoctoral scholar Michael Green, PhD, wanted to find a better way to track disease progression in these patients. They’ve developed a new technique, published Friday in the journal Blood, that is more accurate and can detect relapses earlier than conventional methods.

“As a clinician, I care for many of these patients,” Alizadeh explained to me. “Detecting relapse can be very difficult. It would be a major step forward to develop a way to identify these patients before they become sick again.”

Detecting relapse can be very difficult. It would be a major step forward to develop a way to identify these patients before they become sick again.

The researchers turned to what’s known as circulating tumor DNA in the blood. The approach, which was pioneered by Stanford bioengineer Stephen Quake, PhD, relies on the idea that when the cells in our body die, they rupture and release their contents, including their DNA, into our bloodstream. Tracking the rise and fall of the levels of these tiny snippets of genetic information can give insight into what is happening throughout the body.

When a B cell becomes cancerous, it begins to divide uncontrollably. Each of these cancer cells shares the DNA sequence of the original cell; as the cells multiply, so does the overall amount of that DNA sequence in the body. Alizadeh and his colleagues wondered whether tracking the levels of cancer-specific DNA in a patient’s blood could help them identify those patients in the early stages of relapse.

Currently patients in remission are monitored for relapse with regular physical exams and blood tests. Imaging techniques such as PET or CT scans can be used to look for residual disease, but they don’t detect every case, and often deliver false positive results. They are also costly and expose the patient to DNA-damaging radiation that could potentially cause secondary cancers years later.

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Research, Science, Stanford News, Surgery

Will scars become a thing of the past? Stanford scientists identify cellular culprit

Will scars become a thing of the past? Stanford scientists identify cellular culprit

346801775_c5a1e37a6d_zI have a scar on my chin from a fall I took while rollerskating when I was about 12. One minute I was blithely zooming along to Bob Seger’s hit Against the Wind (earworm alert!), reveling in my new ability to skillfully cross one foot in front of the other and thinking about that cute boy by the snack counter, and the next I was chin down skidding across the flat, grey and (I then realized) very hard floor to come to rest against the wooden wall in an ignominious heap.

Although the experience left an impression on my psyche, as well as my skin, I can’t claim any long-lasting problem from the thin line on my chin. After all, nearly all of us have something similar. But scars can also be debilitating and even dangerous.

Now plastic and reconstructive surgeon Michael Longaker, MD, and pathologist and stem cell expert Irving Weissman, MD, have identified the cell type in mice that is responsible for much of the development of a scar. They’ve shown that blocking this cell’s activity with a small molecule can reduce the degree of scarring. Because a similar drug molecule is already approved for use in humans to treat Type 2 diabetes, the researchers are hopeful that they can begin clinical trials in humans soon. The research was published today in Science.

As Longaker explained in our release on the study:

The biomedical burden of scarring is enormous. About 80 million incisions a year in this country heal with a scar, and that’s just on the skin alone. Internal scarring is responsible for many medical conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and even the damage left behind after a heart attack.

Longaker and his colleagues found that a subset of a skin cell called a fibroblast is responsible for much of the collagen deposition that leads to scarring. Inhibiting the activity of a protein on the surface of the cells significantly reduced the amount of scarring during wound healing in laboratory mice – from about 30 percent of the original wound area down to about 5 percent -the researchers found. Furthermore, they showed the cells are also involved in the thickening and darkening of skin exposed to radiation therapy for cancer, as well as the spread of melanoma cancer cells in the animals.

Longaker’s been interested in how the skin heals for decades–ever since he learned as a student that, prior to the third trimester, human fetuses heal from trauma or surgery without any scarring. Now he’s excited to learn whether there’s a way to recapture that long-lost ability as adults and at least reduce the degree of scarring during skin repair.

“I’ve been obsessed with scarring for 25 years,” Longaker told me. “Now we’re bringing together the fields of wound healing and tumor development in remarkable new ways. It’s incredibly exciting.”

Longaker and Weissman are both also members of the Stanford Cancer Institute.

Previously: New medicine? A look at advances in wound healing, Stanford-developed device shown to reduce the size of existing scars in clinical trial and Mast cells not required for wound healing, according to Stanford study
Photo by Paulo Alegria

Genetics, Research, Science, Stanford News

When X+X = X: Stanford scientists shed light on X-inactivation

When X+X = X: Stanford scientists shed light on X-inactivation

2189014070_339cb830f9_z-1With apologies to some of my colleagues (cough, Margarita Gallardo, cough), I’ve never really enjoyed the Garfield comic strip. The rotund cartoon cat and his insatiable lasagna cravings has always seemed odd to me. Plus, most orange and black cats are female, due to a curious biological phenomenon called X inactivation.

The inactivation of one X chromosome in female animals (and humans) is necessary to ensure that both sexes end up with roughly the same dosage of X-chromosome associated genes. In most species, the chromosome to be inactivated is selected randomly in each cell early in development, and the selected chromosome remains inactive in all of the cell’s subsequent progeny. Researchers believe that X inactivation might explain at least in part why some diseases are more prevalent or severe in one gender than the other.

Now dermatologist Howard Chang, MD, PhD, and former graduate student Ci Chu, PhD, have shed some light on the process, which occurs through the action of a regulatory RNA molecule called Xist. Their research was published today in Cell.

From our release:

[The researchers] have outlined the molecular steps of inactivation, showing that it occurs in an orderly and directed fashion as early embryonic cells begin to differentiate into more specialized tissues. They’ve identified more than 80 proteins in mouse cells that bind to Xist to help it do its job. They hope their findings will shed light on conditions in humans that are typically more severe in one gender than the other.

“We see some very interesting phenomena with X-linked diseases in humans,” said [Chang]. “Often, when the faulty gene is on the X chromosome, the condition is more severe in boys. This happens in hemophilia, for example. In contrast, women are far more likely than men to suffer from autoimmune diseases, for reasons we don’t yet understand. This research opens the door to possibly understanding the biological basis for these differences.”

The researchers were able to pinpoint the protein partners of Xist only after Chu developed an entirely new technique. More from our release:

Chu’s technique, which the researchers call CHIRP-MS for “comprehensive identification of RNA-binding proteins by mass spectrometry,” allowed the researchers to identify the sequential interaction of over 80 proteins with Xist during X inactivation. Many of these proteins have never before been associated with that process. It’s thought that they may help target and anchor Xist to active genes along the length of the X chromosome like burrs on a shoelace after a hike in the woods.

“If you lay all the copies of Xist in a cell end to end, they are not long enough to coat the entire X chromosome,” said Chang. “Instead, Xist spreads judiciously, finding active genes and shutting them down. It also must stay anchored to the chromosome and not float over to any other chromosomes in the nucleus. This requires an elaborate set of machinery that we believe acts in a sequential fashion.”

Specifically, the researchers suspect that some proteins help Xist locate and silence active genes, while others work to maintain that silencing once it has been established.

Clearly X inactivation is a complex process. But are you still wondering about Garfield? Because the genes for “orange” or “black” fur occur on the X chromosome, female cats that carry one of each version can be a patchwork of the two colors, depending on which chromosome is inactivated. Blobs of orange fur indicate an ancestor cell in which the chromosome with the black fur gene was inactivated, and vice versa. But a male cat, with only one X chromosome can only be orange or black, but not both.

An exception would be a male cat who had inherited two X chromosomes and one Y (in humans, this is called Klinefelter syndrome). This genetic anomaly, which is found in about one of every 3,000 calico cats, would likely have other oddities, however. Perhaps even a craving for pasta, cheese and tomato sauce?

Previously: Tomayto, tomahto: Separate genes exert control over differential male and female behaviors, Does it matter which parent your “brain genes” came from? and Stanford professor encourages researchers to take gender into account
Photo by Jerry Knight

Research, Science, Stanford News, Stem Cells

Bridging the stem-cell gap: Stanford researchers identify unique transition state

Bridging the stem-cell gap: Stanford researchers identify unique transition state

474026463_87cca6b272_zIn 2006, Shinya Yamanaka, MD, PhD, turned the stem-cell world upside down when he showed it was possible to take mature, specialized cells such as those found in skin and convert them to a pluripotent state simply by exposing them to a few key proteins. The discovery earned Yamanaka the Nobel Prize in Physiology or Medicine in 2012 and sparked an explosion of stem-cell science.

Although the exact steps of the reprogramming process are unknown, scientists have thought it proceeded mostly as a two-step pathway that essentially rewinds the march to specialization that normally occurs during development. Now Marius Wernig, MD, and his colleagues at the Stanford Institute for Stem Cell Biology and Regenerative Medicine have uncovered an intermediary state through which the cells must pass to successfully acquire pluripotency (a term that describes a cell’s ability to become nearly any cell type in the body). The researchers published their findings in today’s  Nature.

As Wernig described in my article on the research:

This [finding] was completely unexpected. It’s always been assumed that reprogramming is simply a matter of pushing mature cells backward along the developmental pathway. These cells would undergo two major changes: they’d turn off genes corresponding to their original identity, and begin to express pluripotency genes. Now we know there’s an intermediary state we’d never imagined before.

Cells in this “bridge” state express cell surface markers that are distinct from those found on fibroblasts (the starting cell type) and on successfully reprogrammed iPS cells. They also express specific transcription factors that likely contribute to the cells’ progression through the reprogramming process.

The researchers believe it may be possible to increase the efficiency of reprogramming in cells that typically resist the process (these cell types include highly specialized cells or cancer cells). But they’re more excited about peeking into the inner workings of a transformation that’s been both revolutionary and mysterious.

“We’re learning more and more about how cells accomplish this really unbelievable task of reverting to pluripotency,” Wernig told me. “Now we know that the cell biology of this process is novel, and this intermediary state is unique.”

Previously: Congratulations to Marius Wernig, named Outstanding Young Investigator by stem cell society, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Human neurons from skin cells without pluripotency?
Photo by Alexis R

Aging, Genetics, Research, Science, Stanford News

“Are we there yet?” Exploring the promise, and the hype, of longevity research

"Are we there yet?" Exploring the promise, and the hype, of longevity research

Brunet photoThe days are getting longer, and it’s no longer dark outside when I drop my teenager at school for her early-bird class. I appreciate the light, of course, and there’s something soothing about the rhythmic change of seasons.

If only we could extend our lifespan in a similar gentle, reliable manner.

The idea of living longer, and healthier, is the theme of my story for the new issue of Stanford Medicine magazine. It’s my favorite kind of article – a dash of juicy science history, a panoply of dedicated scientists and a brand-new animal model (and my newest crush) that may open all kinds of research doors. Best of all, there’s a sense of real progress in the field. From my article:

“Ways of prolonging human life span are now within the realm of possibility,” says professor of genetics and newbie fish keeper Anne Brunet, PhD. Brunet, who is an associate director of Stanford’s Paul F. Glenn Center for the Biology of Aging, focuses her research on genes that control the aging process in animals such as the minnowlike African killifish I’d watched fiercely guarding his territory.

The killifish is especially important to researchers like Brunet because it has an extremely variable, albeit short, life span. One strain from eastern Zimbabwe completes its entire life cycle — birth, maturity, reproduction and death — within about three to four months. Another strain can live up to nine months.

It’s also a vertebrate, meaning it belongs to the same branch of the evolutionary tree as humans. This gives it a backbone up over more squishy models of aging like fruit flies or roundworms — translucent, 1-millimeter-long earth dwellers you could probably find in your compost pile if you felt like digging.

I hope you’ll read the rest of my piece to learn more.

Previously: My funny Valentine – or, how a tiny fish will change the world of aging research, Stanford Medicine magazine reports on time’s intersection with health and Living loooooooonger: A conversation on longevity
Photo of Anne Brunet by Gregg Segal

Cancer, Genetics, In the News, Women's Health

Angelina Jolie Pitt’s New York Times essay praised by Stanford cancer expert

Angelina Jolie Pitt's New York Times essay praised by Stanford cancer expert

4294641229_c78b406658_zYou’ve likely heard today about Angelina Jolie Pitt’s New York Times essay regarding her decision to have her ovaries and fallopian tubes removed. Women who carry mutations in the BRCA1 or BRCA2 genes have a significantly increased risk for breast and ovarian cancer; Jolie carries such a mutation, and in 2013 she shared publicly her decision to have her breasts removed to reduce her risk of cancer.

Jolie Pitt shares her decision-making process and notes that though she won’t be able to have any more children and though she still remains prone to cancer, she feels “at ease with whatever will come.” She closes her latest essay by writing, “It is not easy to make these decisions. But it is possible to take control and tackle head-on any health issue. You can seek advice, learn about the options and make choices that are right for you.”

After reading the piece I reached out to Stanford cancer geneticist Allison Kurian, MD, who told me:

Angelina Jolie made a very courageous decision to share her experience publicly.  The surgery she chose is strongly recommended for all women with BRCA1/2 mutations by age 40, since it’s the only way to prevent an ovarian cancer in these high-risk women, and early detection doesn’t work. This is a life-saving intervention for high-risk women.

Kurian is associate director of the Stanford Program in Clinical Cancer Genetics and a member of the Stanford Cancer Institute. In 2012 she published on online tool to help women with BRCA mutations understand their treatment options.

Previously: Helping inform tough cancer-related decisions, NIH Director highlights Stanford research on breast cancer surgery choices and Breast cancer patients are getting more bilateral mastectomies – but not any survival benefit
Photo by Marco Musso

Ethics, Genetics, History, In the News, Medicine and Society, Microbiology, Stanford News

Stanford faculty lend voices to call for “genome editing” guidelines

Stanford faculty lend voices to call for "genome editing" guidelines

baby feetStanford law professor Hank Greely, JD, and biochemist Paul Berg, PhD, are two of 20 scientists who have signed a letter in today’s issue of Science Express discussing the need to develop guidelines to regulate genome editing tools like the recently discovered Crispr/Cas9. Researchers are particularly concerned that the technology could be used to alter human embryos. From the commentary:

The simplicity of the CRISPR-Cas9 system enables any researcher with knowledge of molecular biology to modify genomes, making feasible many experiments that were previously difficult or impossible to conduct. […]

We recommend taking immediate steps toward ensuring that the application of genome engineering technology is performed safely and ethically.

We’ve written a bit here before about the Crispr system, which essentially lets researchers swap one section of DNA for another with high specificity. The potential uses, for both research or therapy, are touted as nearly endless. But, as Greely pointed out in an email to me: “Making babies using genomic engineering right now would be reckless – it would be unknowably risky to the lives of those babies, none of whom consented to the procedure. For me, those safety issues are paramount in human germ line modification, but there are also other issues that have sparked social concern. It would be prudent for science to slow down while society as a whole discusses all the issues – safety and beyond.”

The list of others who signed the commentary reads like a veritable who’s who of biology and bioethics. It includes Caltech’s David Baltimore, PhD; U.C. Berkeley’s Michael Botchan, PhD; Harvard’s George Church, PhD; and George Q. Daley, MD, PhD; University of Wisconsin bioethicist R. Alta Charo, JD; and Crispr/Cas9 developer Jennifer Doudna, PhD. (Another group of scientists published a similar letter in Nature last Friday.)

The call to action echos one in the 1970s in response to the discovery of the DNA snipping ability of restriction endonucleases, which launched the era of DNA cloning. Berg, who shared the 1980 Nobel Prize in Chemistry for this discovery, organized a historic meeting at Asilomar in 1975 known as the International Congress on Recombinant DNA Molecules to discuss concerns and establish guidelines for the use of the powerful enzymes.

Berg was prescient in an article in Nature in 2008 discussing the Asilomar meeting:

That said, there is a lesson in Asilomar for all of science: the best way to respond to concerns created by emerging knowledge or early-stage technologies is for scientists from publicly-funded institutions to find common cause with the wider public about the best way to regulate — as early as possible. Once scientists from corporations begin to dominate the research enterprise, it will simply be too late.

Previously: Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and The challenge – and opportunity – of regulating new ideas in science and technology
Photo by gabi manashe

Cancer, Dermatology, Research, Science

Common skin cancer evades treatment via specific mutations

Common skin cancer evades treatment via specific mutations

Anthony OroBasal cell carcinoma is the most common type of skin cancer. It is also one of the most treatable. But people with advanced cases of the disease often experience only a temporary response to the drug vismodegib, and their tumors recur within a few months as the cancer becomes resistant to the drug.

Now dermatologists Anthony Oro, MD, PhD; Jean Tang, MD, PhD; and Anne Chang, MD, have identified the specific mutations involved in the development of vismodegib resistance, and identified another treatment that may be successful even on vismodegib resistant tumors. They’ve recently published their findings in Cancer Cell (with an accompanying companion paper and commentary).

From our release:

Approximately 2 million new cases of basal cell carcinoma are diagnosed each year in the United States, making it the most common cancer in the country. About half of patients with advanced basal cell carcinomas will respond to vismodegib, which belongs to a class of drug compounds called Smoothened inhibitors. About 20 percent of these responders will go on to quickly develop resistance to the drug.

Basal cell carcinomas are uniquely dependent on the inappropriate activation of a cellular signaling cascade called the Hedgehog pathway. Blocking signaling along this pathway will stop the growth and spread of the cancer cells. The Hedgehog pathway plays a critical role in normal development. It’s also been found to be abnormally active in many other cancers, including pancreatic, colon, lung and breast cancers, as well as in a type of brain cancer called medulloblastoma.

The researchers found two classes of mutations in the Smoothened gene that inhibit vismodegib’s effectiveness by keeping the Smoothened protein active. Treating the cells with inhibitors that target a portion of the pathway downstream of Smoothened blocked the activation of the pathway even in cells with the mutations. These inhibitors, called Gli antagonists, could be an effective way to treat vismodegib-resistant tumors, the researchers said.

As Oro told me, “This research sheds new light on mechanisms of how tumors evolve to develop drug resistance, and has already helped us with personalized cancer genetics and therapy for our patients. It is now possible for us to identify those people who may benefit from a combination therapy even before they begin treatment.”

Previously: Studies show new drug may treat and prevent basal cell carcinoma, New skin cancer target identified by Stanford researchers and Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers
Photo of Anthony Oro by Steve Fisch

Big data, Genetics, Research, Science, Stanford News

Caribbean skeletons hold slave trade secrets

Caribbean skeletons hold slave trade secrets

5598998640_3c9968b4ac_zI was excited yesterday to see the Los Angeles Times cover a really neat story out of the laboratory of geneticist Carlos Bustamante, PhD. He and his colleagues at the University of Copenhagen used genetic analysis to solve a 300-year-old mystery with origins in the city of Philipsburg on the island of Saint Martin.

Philipsburg is an idyllic retreat for thousands of tourists each year. Not so for three skeletons recently unearthed during a construction project in the city. The skeletons were those of African-born slaves who had been shipped from their homeland more than 300 years ago to the Caribbean island to serve as forced laborers. Like millions of other enslaved Africans, the two men and one woman likely led difficult lives and died young.

Now the researchers have identified the regions in Africa the individuals likely lived before their capture. To do so, they examined tiny, highly fragmented bits of ancient DNA that survived the hot, humid conditions of the tropics in the roots of the skeletons’ teeth.  The research was published this week in the Proceedings of the National Academy of Sciences.

As Bustamante explained in our release:

Through the barbarism of the middle passage, millions of people were forcibly removed from Africa and brought to the Americas. We have long sought to use DNA to understand who they were, where they came from, and who, today, shares DNA with those people taken aboard the ships. This project has taught us that we cannot only get ancient DNA from tropical samples, but that we can reliably identify their ancestry. This is incredibly exciting to us and opens the door to reclaiming history that is of such importance.

Bustamante is co-author of a paper describing the research.The study was led by Hannes Schroeder, PhD, a molecular anthropologist from the University of Copenhagen, and Stanford postdoctoral scholar Maria Avila-Arcos, PhD. The research was initiated in Denmark, and the senior author of the study is Thomas Gilbert, PhD, of the University of Copenhagen. More from our release:

Researchers could tell from the skeletons found in the Zoutsteeg area that the three people were between 25 and 40 years old when they died in the late 1600s. The skulls of each also bore teeth that had been filed down in patterns characteristic of certain African groups. But this alone wasn’t enough to pinpoint where the individuals originated on the African continent.

Schroeder and Avila-Arcos used a technique developed by study co-author Meredith Carpenter, PhD, a postdoctoral scholar in the Bustamante laboratory, to fish out snippets of ancient DNA from the material inside the teeth for sequencing. They then used a different technique called principal component analysis to identify the distinct ethnic groups from which each individual likely originated. The findings illuminate a tumultuous period of time in the Americas and may provide insight into subsequent population patterns and perceived ethnic identities. They also open doors to new advances in genealogy and historical research. As Bustamante told me:

Several years ago, we were part of the team that sequenced the genome of Otzi, the iceman, and we were able to show that the people alive today that most closely match him genetically are Sardinians. This incredible precision was possible because we, as a community, had invested lots of resources in understanding patterns of DNA variation in Europe. I started to talk about the ‘Otzi rule,’ or the idea that we should be able to do for all people alive today what we can do for a 5,000-year-old mummy.

Previously: Melting pot or mosaic? International collaboration studies genomic diversity in Mexico, Caribbean genetic diversity explored by Stanford/ University of Miami researchers and Recent shared ancestry between Southern Europe and North Africa identified by Stanford researchers
Photo by alljengi

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