Science Daily.com April 2018. Also see further down: Using a homemade, high-tech microscope, scientists have revealed how a cancer-causing virus anchors itself to our DNA. That discovery could pave the way for doctors to cure incurable diseases by flushing out viruses, including HPV and Epstein-Barr, that now permanently embed themselves in our cells
Older adults who take a novel antioxidant that specifically targets cellular powerhouses, or mitochondria, see age-related vascular changes reverse by the equivalent of 15 to 20 years within six weeks, according to new University of Colorado Boulder research.
The study, published this week in the American Heart Association journal Hypertension, adds to a growing body of evidence suggesting pharmaceutical-grade nutritional supplements, or nutraceuticals, could play an important role in preventing heart disease-the nation’s No. 1 killer. It also resurrects the notion that oral antioxidants, which have been broadly dismissed as ineffective in recent years, could reap measurable health benefits if properly targeted, the authors say.
“This is the first clinical trial to assess the impact of a mitochondrial-specific antioxidant on vascular function in humans,” said lead author Matthew Rossman, a postdoctoral researcher in the department of integrative physiology. “It suggests that therapies like this may hold real promise for reducing the risk of age-related cardiovascular disease.”
For the study, Rossman and senior author Doug Seals, director of the Integrative Physiology of Aging Laboratory, recruited 20 healthy men and women age 60 to 79 from the Boulder area.
Half took 20 milligrams per day of a supplement called MitoQ, made by chemically altering the naturally-occurring antioxidant Coenzyme Q10 to make it cling to mitochondria inside cells.
The other half took a placebo.
After six weeks, researchers assessed how well the lining of blood vessels, or the endothelium, functioned, by measuring how much subjects’ arteries dilated with increased blood flow.
Then, after a two-week “wash out” period of taking nothing, the two groups switched, with the placebo group taking the supplement, and vice versa. The tests were repeated.
The researchers found that when taking the supplement, dilation of subjects’ arteries improved by 42 percent, making their blood vessels, at least by that measure, look like those of someone 15 to 20 years younger. An improvement of that magnitude, if sustained, is associated with about a 13 percent reduction in heart disease, Rossman said. The study also showed that the improvement in dilation was due to a reduction in oxidative stress.
In participants who, under placebo conditions, had stiffer arteries, supplementation was associated with reduced stiffness.
Blood vessels grow stiff with age largely as a result of oxidative stress, the excess production of metabolic byproducts called free radicals which can damage the endothelium and impair its function. During youth, bodies produce enough antioxidants to quench those free radicals. But with age, the balance tips, as mitochondria and other cellular processes produce excess free radicals and the body’s antioxidant defenses can’t keep up, Rossman said.
Oral antioxidant supplements like vitamin C and vitamin E fell out of favor after studies showed them to be ineffective.
“This study breathes new life into the discredited theory that supplementing the diet with antioxidants can improve health,” said Seals. “It suggests that targeting a specific source-mitochondria-may be a better way to reduce oxidative stress and improve cardiovascular health with aging.”
The study was funded by the National Institutes of Health. MitoQ Limited provided supplements and some financial support.
This summer, Rossman and Seals plan to launch a three-month follow-up study to confirm the findings in a larger number of subjects and look more closely at the impact the compound has on mitochondria.
The same lab published another study recently, showing that a compound called nicotinamide riboside may also be able to reverse vascular aging in healthy subjects.
“Exercise and eating a healthy diet are the most well-established approaches for maintaining cardiovascular health,” said Seals. “But at the public health level, not enough people are willing to do that. We’re looking for complementary, evidence-based options to prevent age-related changes that drive disease. These supplements may be among them.”
Journal Reference: Matthew J. Rossman, Jessica R. Santos-Parker, Chelsea A.C. Steward, Nina Z. Bispham, Lauren M. Cuevas, Hannah L. Rosenberg, Kayla A. Woodward, Michel Chonchol, Rachel A. Gioscia-Ryan, Michael P. Murphy, Douglas R. Seals. Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. Hypertension, 2018; HYPERTENSIONAHA.117.10787 DOI: 10.1161/HYPERTENSIONAHA.117.10787
Using a homemade, high-tech microscope, scientists have revealed how a cancer-causing virus anchors itself to our DNA. That discovery could pave the way for doctors to cure incurable diseases by flushing out viruses, including HPV and Epstein-Barr, that now permanently embed themselves in our cells.
“The reason we can’t get rid of these [viruses] is because we can’t figure out a way to get their DNA out of the nucleus, out of the cell,” explained UVA researcher Dean H. Kedes, MD, PhD. “They depend on this ‘tether’ to remain anchored to the DNA within our cells, and to remain attached even as the cells divide. This tether is a key factor to disrupt in devising a cure.”
Now that scientists can understand this vital infrastructure, they can work to disassemble it. “Without it,” Kedes noted, “the virus is going to lose its hold in the body. … Bad for the virus, but very good for the patient.”
The researchers used the microscope built by fellow investigator M. Mitchell Smith, PhD, to reveal the structure of the tether used by a virus called Kaposi’s sarcoma-associated herpesvirus (KSHV). Until now, such tethers have largely eluded scientists because they are so diabolically small, defying even the most high-tech approaches to determining their form. “We’re seeing things on the order of 8,000 times smaller than a human hair,” said Smith, who built UVA’s microscope piece-by-piece based on one pioneered in the Physics and Astronomy Department at the University of Maine.
Smith’s microscope is nothing like the simple light microscope seen in every high school biology class. It’s a stunning marriage of stainless steel and laser beams, looking much like an oversized sci-fi Erector set. It sits on a table that almost fills a small room.
“It’s a set of lasers, a bunch of optics that focus and filter the lasers,” Smith explained, gesturing to various components. “I’m trained as a molecular geneticist, not as an optical physicist … so we worked on it for maybe three years. But it’s continually a work in progress.”
The device has already proved a game-changer, allowing him and Kedes to unveil the viral tether. The researchers — in UVA’s Department of Microbiology, Immunology and Cancer Biology — used fluorescent antibodies to mark individual molecules on the tether and then recorded their location in space. They then combined the resulting images to create an outline of the shape, a bit like mapping a city from thousands of GPS signals.
To complete their 3D portrait, they combined their results with information drawn from other imaging techniques, such as X-ray crystallography. The result is the most complete portrait of the tether ever created. And that information likely will prove vital for cutting the rope on the virus’ grappling hook.
The researchers envision using the approach for many other stubborn viruses, such as Epstein-Barr (the virus that causes infectious mononucleosis) and HPV (human papillomavirus). Further, they suspect that such viruses’ tethers may share similarities with the one they revealed. “Now, for the first time,” Kedes said, “it’s OK to say, ‘Let’s focus on structures that are vital to the virus that before were below the limits of our standard methods of detection within infected cells.'”
The researchers have published their findings in the scientific journal PNAS, the Proceedings of the National Academy of Sciences. The research team consisted of Margaret J. Grant, Matthew S. Loftus, Aiola P. Stoja, Kedes and Smith.
The work was supported by the University of Virginia Cancer Center, grant P30CA044579; the National Institutes of Health’s National Institute of Dental and Craniofacial Research, grant R01DE022291; and the NIH’s National Institute of General Medical Sciences, grants RC1GM091175 and R01GM116994.
Journal Reference: Margaret J. Grant, Matthew S. Loftus, Aiola P. Stoja, Dean H. Kedes, M. Mitchell Smith. Superresolution microscopy reveals structural mechanisms driving the nanoarchitecture of a viral chromatin tether. Proceedings of the National Academy of Sciences, 2018; 201721638 DOI: 10.1073/pnas.1721638115
Those diseases are: systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes. Combined, these seven diseases affect nearly 8 million people in the U.S.
Study results published April 12 in the journal Nature Genetics. The project was led by three scientists: John Harley, MD, PhD, Director of the Center for Autoimmune Genomics and Etiology (CAGE) at Cincinnati Children’s and a faculty member of the Cincinnati VA Medical Center; Leah Kottyan, PhD, an immunobiology expert with CAGE; and Matthew Weirauch, PhD, a computational biologist with the center. Critical contributions were provided by Xiaoting Chen, PhD, and Mario Pujato, PhD, both also in CAGE.
The study shows that a protein produced by the Epstein-Barr virus, called EBNA2, binds to multiple locations along the human genome that are associated with these seven diseases.
Overall, the study sheds new light on how environmental factors, such as viral or bacterial infections, poor diet, pollution or other hazardous exposures, can interact with the human genetic blueprint and have disease-influencing consequences. “Now, using genomic methods that were not available 10 years ago, it appears that components made by the virus interact with human DNA in the places where the genetic risk of disease is increased,” Harley says. “And not just for lupus, but all these other diseases, too.”
The full impact of this study could take years to explore. Here are some of the initial implications:
New concern about the ‘kissing disease’
EBV is a strikingly common virus. In the US and other developed nations, more than 90 percent of the population becomes infected by age 20. In less-developed nations, 90 percent of people become infected by age 2. Once infected, the virus remains in people for their entire lives.
Mononucleosis, which causes weeks of extreme fatigue, is the most common illness caused by EBV. Mono was nicknamed the “kissing disease” years ago because the virus spreads primarily via contact with saliva.
Over the years, scientists have linked EBV to a few other rare conditions, including certain cancers of the lymphatic system. Harley, who has devoted much of his career to studying lupus, found possible connections between lupus and EBV years ago. That work includes proposing mechanisms that the immune system uses in response to the virus that lead to lupus, and showing that children with lupus almost always are infected with EBV.
Today’s study adds weight to those lupus findings and adds six more well-known diseases to the list.
“This discovery is probably fundamental enough that it will spur many other scientists around the world to reconsider this virus in these disorders,” Harley says. “As a consequence, and assuming that others can replicate our findings, that could lead to therapies, ways of prevention, and ways of anticipating disease that don’t now exist.” So far, no vaccine exists that will prevent EBV infection.
“I think we’ve come up with a really strong rationale for encouraging people to come up with more of an effort,” Kottyan says. “Some EBV vaccines are under development. I think this study might well encourage them to push forward faster and with rededicated effort.”
How EBV hijacks our immune system
When viral and bacterial infections strike, our bodies respond by commanding B cells within our immune systems to crank out antibodies to battle the invaders. However, when EBV infections occur, something unusual happens.
The EBV virus invades the B cells themselves, re-programs them, and takes over control of their functions. The Cincinnati Children’s research team has discovered a new clue about how the virus does this, a process that involves tiny proteins called transcription factors.
Our bodies have about 1,600 known transcription factors at work within our genome. Each cell uses a subset of these to become what they are and to respond to their environment. These proteins constantly move along the strands of our DNA, turning specific genes on and off to make sure cells function as expected.
However, when the transcription factors change what they do, the normal functions of the cell can also change, and that can lead to disease. The Cincinnati Children’s team suspects that the EBNA2 transcription factor from EBV is helping change how infected B cells operate, and how the body responds to those infected cells.
The new paper shows that seven seemingly unrelated disease states actually share a common set of abnormal transcription factors, each affected by the EBNA2 protein from the Epstein-Barr virus. When these EBNA2-related clusters of transcription factors attach themselves to one portion of the genetic code, the risk of lupus appears to rise. When those same transcription factors land on another part of the code, the risk of multiple sclerosis appears to rise. And so on.
“Normally, we think of the transcription factors that regulate human gene expression as being human,” Kottyan says. “But in this case, when this virus infects cells, the virus makes its own transcription factors, and those sit on the human genome at lupus risk variants (and at the variants for other diseases) and that’s what we suspect is increasing risk for the disease.”
New leads emerge for improving treatment
It remains unclear how many cases of the seven diseases listed in the study can be traced to prior EBV infection. More genomic analyses involving many more patients with these diseases will be required to make reliable estimates.
“The impact of the virus is likely to vary across the diseases,” Harley says. “In lupus and MS, for example, the virus could account for a large percentage of those cases. We do not have a sense of the proportion in which the virus could be important in the other EBNA2-associated diseases.”
However, the breakthrough identification of specific transcription factors connected to EBV infections opens new lines of study that could accelerate efforts to find cures.
“This same cast of characters is a villain in multiple immune-related diseases,” Weirauch says. “They’re playing that role through different ways, and doing it at different places in your genome, but it’s the same sinister characters. So if we could develop therapies to stop them from doing this, then it would help multiple diseases.”
A number of compounds — some experimental, some approved as medications for other conditions — already are known to be capable of blocking some of the high-risk transcription factors listed in the paper, Weirauch says. Teams at Cincinnati Children’s have begun deeper studies of some of these compounds.
Findings go far, far beyond EBV
While the EBV-related findings involved more than 60 human proteins linked to seven diseases, the Cincinnati Children’s research team already has taken a huge next step. They applied the same analytic techniques to tease out connections between all 1,600 known transcription factors and the known gene variants associated with more than 200 diseases.
The results of that massive cross-analysis also appear in today’s study. Intriguing associations were documented involving 94 conditions.
“Our study has uncovered potential leads for many other diseases, including breast cancer,” Harley says. “We cannot possibly follow up on all of these, but we are hoping that other scientists will.”
After devoting decades of research to hunting down the causes of lupus, Harley says this study represents the most important discovery of his career. “I’ve been a co-author in almost 500 papers. This one is more important than all of the rest put together. It is a capstone to a career in medical research,” he says.
Software behind discoveries to be made public
Detecting and tracking the activities of these transcription factors took years of work involving dozens of laboratory and computational experts.
The project required gathering massive sets of genetic data, then analyzing every genetic change affecting the activity of the virus. Doing this required creating two new algorithms, called RELI and MARIO, which were developed at Cincinnati Children’s by Weirauch and colleagues.
Both software tools and a related website will be made publicly available.
“We are going to great lengths to not only make the computer code available, but all of the data and all of the results,” Weirauch says. “We think it’s an interesting approach that could have implications for many diseases, so we’re contacting experts on the various diseases and sharing the results and seeing if they want to collaborate to follow up on them.”
GLOSSARY OF TERMS
What is the Epstein-Barr virus?
The Epstein-Barr virus (EBV) is an extremely common virus usually spread by saliva. EBV causes mononucleosis, and has been associated with a growing number of other diseases. A study led by Cincinnati Children’s, published today in Nature Genetics, adds seven diseases to that list.
What is mononucleosis?
Also known as “mono,” and nicknamed the “kissing disease,” the symptoms of this condition include extreme fatigue, fever, sore throat, head and body aches, swollen lymph nodes in the neck and armpits, swollen liver or spleen or both, and rash, according to the Centers for Disease Control and Prevention. Most people get better in two to four weeks. However, some people may feel fatigued for several more weeks.
What is a B cell?
B cells are a type of white blood cell found in the immune system. These cells produce antibodies in reaction to infections by bacteria, viruses and other invaders. Epstein-Barr virus infects a small proportion of these cells.
What is a transcription factor?
Transcription factors are proteins that “turn on and turn off” genes. These proteins help direct cell growth, division, and death. They also control cell migration and organization. There are about 1,600 known human transcription factors that do their work along the human genome. These proteins change the expression of genes to make RNA, which in many cases results in forming other proteins that change how cells form and function.
What is a DNA variant?
The DNA genome of every person contains over 3 billion DNA bases. Most of the bases are exactly the same for every person. However, about 1 percent of the bases can be different and these create diversity between people. The variants can change the way proteins are made or change the regulatory processes that lead to protein production.
What is a genetic risk variant?
When a DNA variant is known to increase risk for a disease, it is called a genetic risk variant. Some variants increase risk for multiple diseases, and some variants are specific to a single disease.
Journal Reference: John B. Harley, Xiaoting Chen, Mario Pujato, Daniel Miller, Avery Maddox, Carmy Forney, Albert F. Magnusen, Arthur Lynch, Kashish Chetal, Masashi Yukawa, Artem Barski, Nathan Salomonis, Kenneth M. Kaufman, Leah C. Kottyan, Matthew T. Weirauch. Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nature Genetics, 2018; DOI: 10.1038/s41588-018-0102-3
A shooting is defined as a “mass shooting” when four or more people are killed (excluding the shooter). Sporadic school shootings have occurred at various points in the history of the US. For example, in 1940 a junior high school principal killed six adults including the school’s district business manager. No similar mass shootings occurred in the 1950s and 1960s. However, school shootings have been steadily increasing since 1979. Overall, the death toll from mass school shootings was 12 in the 1980s and 36 in the 1990s.
During the 20th century, mass school shootings killed 55 people and injured 260 others at schools especially in America’s Western region. Most of the 25 shooters involved were white males who acted alone, and only nine were diagnosed as suffering from mental illnesses at the time. Sixty percent of shooters were between 11 and 18 years old.
Since the start of the 21st century there have already been 13 incidents involving lone shooters; they have killed 66 people and injured 81 others.
“In less than 18 years, we have already seen more deaths related to school shootings than in the whole 20th century. One alarming trend is that the overwhelming majority of 21st-century shooters were adolescents, suggesting that it is now easier for them to access guns, and that they more frequently suffer from mental health issues or limited conflict resolution skills,” says Katsiyannis.
The authors explain that such violence can be mitigated through deliberate and sensible policy and legislative actions. These include expanded background checks of potential gun owners, and a ban on assault weapons. Mental health issues among adolescent students and adults should also be addressed more thoroughly. School personnel should also implement tiered models of support and school-based mental health services to support students’ social, emotional, and behavioral well-being and prevent school violence. “Preventative efforts not only require policy and legislative action but increased and targeted funding across federal, state, local and private sectors,” adds Katsiyannis.
Journal Reference: Antonis Katsiyannis, Denise K. Whitford, Robin Parks Ennis. Historical Examination of United States Intentional Mass School Shootings in the 20th and 21st Centuries: Implications for Students, Schools, and Society. Journal of Child and Family Studies, 2018; DOI: 10.1007/s10826-018-1096-2