Changes linked to unstable genomes, cancer and other defects
August 30, 2016
Although genetic variants are scattered throughout the human genome, scientists have largely ignored the stretches of repetitive genetic code known as ‘junk’ DNA in their search for differences that influence human health and disease. Now, researchers have discovered that variation in these overlooked regions can affect the stability of the genome and the proper function of the chromosomes that package our genetic material, leading to an increased risk of birth defects, infertility, and cancer.
All humans are 99.9 percent identical, genetically speaking. But that tiny 0.1 percent variation has big consequences, influencing the color of your eyes, the span of your hips, your risk of getting sick and in some ways even your earning potential.
Although variants are scattered throughout the genome, scientists have largely ignored the stretches of repetitive genetic code once dismissively known as “junk” DNA in their search for differences that influence human health and disease.
A new study shows that variation in these overlooked repetitive regions may also affect human health. These regions can affect the stability of the genome and the proper function of the chromosomes that package genetic material, leading to an increased risk of cancer, birth defects and infertility. The results appear online in the journal Genome Research.
“Variation is not only important for how genes and proteins function, but it can also occur in the noncoding, repetitive portions of the genome,” said Beth A. Sullivan, Ph.D., senior author of the study and associate professor of molecular biology and microbiology at Duke University School of Medicine.
“What we found in this study is probably the tip of the iceberg,” Sullivan said. “There could be all sorts of functional consequences to having variation within the complex, repetitive portion of the genome that we don’t know about yet.”
Even though the sequence of the human genome was declared complete more than a decade ago, it retains several glaring gaps, especially in the repetitive sequences around centromeres, the twisty ties that hold a pair of chromosomes together in a floppy X shape and coordinate their movement during cell division.
These centromere sequences — called satellite DNA — are made up of blocks of exactly 171 A’s, C’s, T’s and G’s, repeated over and over for millions of base-pairs. Researchers once believed that each chromosome contained a single stretch of this satellite DNA, which determined where its centromere would reside. But a few years ago, Sullivan’s lab discovered that many human chromosomes possessed more than one of these regions, and depending on the individual, the centromere could form at either site.
In this study, Sullivan wanted to see how the chromosome decides where to put its centromere, and whether one site builds a “better” centromere than the other. Of the 23 pairs of human chromosomes, she focused on chromosome 17, which is structurally rearranged or mutated in many different cancers and birth defects.
First, Sullivan and her team combined molecular and visual assays, stretching the chromosome out into long chromatin fibers that were painted with fluorescent probes to map the variation in genomic sequence at the two different regions of satellite DNA. Then they looked at each satellite region for the presence of proteins necessary to construct a fully functioning centromere.
The researchers found that genomic variation at one of these satellite DNA regions — either in the size or sequence of its repeated 171 base pair units — ultimately determines whether the centromere is built at the primary site or the alternate site.
When they interrogated samples from a human DNA bank, they found that about 70 percent of humans have little genomic variation at the primary site, while 30 percent have differing degrees of variation. Most of the time, the centromeres aren’t built at the primary site if it contains variation and instead are assembled at the “backup” site nearby. But when this happens, the result may be a dysfunctional centromere that is architecturally unsound and an unstable chromosome that may be present in too many or too few copies.
“It is immensely fascinating to think that there are so many people walking around who are essentially centromere mosaics,” said Sullivan. “One of their centromeres, on one of their chromosomes, has the potential to be dangerously unstable, and it could affect their ability to reproduce, or predispose them to cancer.”
In the future, Sullivan plans to investigate just how big of a risk the variant satellite regions pose for those who carry them, and possibly develop a way to use these sequences as biomarkers for the chromosomal defects that can lead to disease.
- Megan E Aldrup-MacDonald, Molly E Kuo, Lori L Sullivan, Kimberline Chew, Beth A Sullivan. Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles. Genome Research, 2016; gr.206706.116 DOI: 10.1101/gr.206706.116
Source: Duke University. “Variation in ‘junk’ DNA leads to trouble: Changes linked to unstable genomes, cancer and other defects.” ScienceDaily. ScienceDaily, 30 August 2016. <www.sciencedaily.com/releases/2016/08/160830121720.htm>.
August 29, 2016
Queensland University of Technology
An unnatural balance of nutrients threatens biodiversity in a survival of the fittest scenario, according to new research. A global network of researchers who have tested the impact increased nutrient levels is having on grasslands across six continents.
An unnatural balance of nutrients threatens biodiversity in a survival of the fittest scenario, according to the results of a world-first global experiment published in the journal Nature. Professor Jennifer Firn, from QUT’s Science and Engineering Faculty, is part of a global network of researchers who have tested the impact increased nutrient levels is having on grasslands across six continents.
The article is titled “Addition of multiple limiting resources reduces grassland diversity” and was led by Professor Stan Harpole from UFZ and iDIV, Germany.
“As part of the Nutrient Network, researchers tested the Charles Darwin ‘entangled bank’ observation which is used to explain how species can coexist even if they require the same limiting resources.
“This theory explains the mechanism of how a number of species should be competing for resources when they are actually coexisting because of the subtle differences in their resource needs.
“But what we found was that if you change the limiting resources and add an abundance of resources such as nutrients like phosphorus, nitrogen and potassium, it will lead to a favouring of some species over others because competition is then shifted above ground for light.
“This will in turn evoke competition between species, leading to one species dominating the land area.”
The experiment was conducted across 45 grassland sites spanning the multi-continent Nutrient Network.
Professor Firn said the human influence on the nutrient cycle through greater globalisation, was having a damaging effect on ecosystem biodiversity.
“The loss of diversity was not driven by the addition of any single added resource for example nitrogen or potassium, we found greatest diversity loss occurred with the addition of a combination of two or more resources,” she said.
“Simply put, the more nutrients, the less biodiversity.”
She said many of the ecosystem functions that humans need to survive were provided by richly diverse ecosystems, such as oxygen production, water filtration, nutrient cycling, pollination, and carbon sequestration.
“The irreplaceable loss of native biodiversity is accelerating at an alarming rate globally,” she said.
“What this research does is provide tangible evidence that global change is driving environmental conditions beyond our planetary boundaries.”
The Nutrient Network is the only collaborations of its kinds in which individual researchers have set up the same experiments at sites around the world. It is coordinated through the US-based National Science Foundation’s funding to biologists Prof. Elizabeth Borer and Prof. Eric Seabloom of the University of Minnesota.
- W. Stanley Harpole, Lauren L. Sullivan, Eric M. Lind, Jennifer Firn, Peter B. Adler, Elizabeth T. Borer, Jonathan Chase, Philip A. Fay, Yann Hautier, Helmut Hillebrand, Andrew S. MacDougall, Eric W. Seabloom, Ryan Williams, Jonathan D. Bakker, Marc W. Cadotte, Enrique J. Chaneton, Chengjin Chu, Elsa E. Cleland, Carla D’Antonio, Kendi F. Davies, Daniel S. Gruner, Nicole Hagenah, Kevin Kirkman, Johannes M. H. Knops, Kimberly J. La Pierre, Rebecca L. McCulley, Joslin L. Moore, John W. Morgan, Suzanne M. Prober, Anita C. Risch, Martin Schuetz, Carly J. Stevens, Peter D. Wragg. Addition of multiple limiting resources reduces grassland diversity. Nature, 2016; DOI: 10.1038/nature19324
Source: Queensland University of Technology. “An imbalance in nutrients threatens plant biodiversity.” ScienceDaily. ScienceDaily, 29 August 2016. <www.sciencedaily.com/releases/2016/08/160829105742.htm>.
August 25, 2016
Cancer Research UK
Scientists have demonstrated for the first time the ‘perfect storm’ of conditions that cells need to start forming cancer, helping to explain why some organs are more susceptible to developing the disease.
Scientists have demonstrated for the first time the ‘perfect storm’ of conditions that cells need to start forming cancer, helping to explain why some organs are more susceptible to developing the disease, according to a new study published in Cell.
The research, carried out by scientists at Cancer Research UK’s Cambridge Institute at the University of Cambridge and St Jude’s Children’s Research Hospital in the United States, shows that cancers are more likely to start in stem cells — special cells that copy themselves so the body can grow new cells, repair damaged tissue and replace old cells.
But while these stem cells are more susceptible to developing into cancer, they also need to have accumulated DNA mistakes and be replicating to repair damage or wear and tear for cancers to start.
These DNA mistakes can happen randomly as stem cells replicate and they tend to build up with age, which is why cancer gets more common as we get older. They can also be caused by things in our environment such as tobacco smoke or UV radiation.
To find out how cancers start in different organs the researchers tagged one particular group of cells in mice with a fluorescent dye to track their behaviour. They then introduced DNA mistakes linked to different types of cancers into these cells.
Importantly, they found that DNA mistakes by themselves were not enough to cause cancer. In organs where DNA mistakes were introduced into dormant stem cells, there were no signs of cancer.
Yet, in other organs that are exposed to lots of wear and tear — like the bowel — introducing DNA mistakes into the replicating stem cells caused cancer to start.
Professor Richard Gilbertson, lead researcher based at Cancer Research UK’s Cambridge Institute at the University of Cambridge, said: “We can now say that cancer most likely starts in stem cells but is not just down to ‘bad luck’. The development of cancer involves a ‘perfect storm’ of stem cells containing DNA mistakes that are replicating in response to damage or wear and tear.
“Although stem cells can sometimes go wrong by chance, our research shows that things in our environment that lead to more DNA mistakes or that damage organs, causing these stem cells to divide, increases the chances of the ‘perfect storm’ brewing. That’s why behaviours like smoking or UV exposure raise the risk of developing cancer.
“Our work also shows why some types of cancer are more common than others, with tumours more likely to develop in organs with lots of replicating stem cells, for example the bowel.”
“We hope finding out more about the way in which cancer develops will help us, and other scientists around the world, develop new ways to prevent and treat cancer.”
Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “The study looks at the perplexing question of why we get cancer more often in some organs than others. This risk seems to be dictated by a combination of mutations in cancer-causing genes in stem cells, stem cell proliferation and tissue damage — which vary between different organs.”
- Liqin Zhu, David Finkelstein, Culian Gao, Lei Shi, Yongdong Wang, Dolores López-Terrada, Kasper Wang, Sarah Utley, Stanley Pounds, Geoffrey Neale, David Ellison, Arzu Onar-Thomas, Richard James Gilbertson. Multi-organ Mapping of Cancer Risk. Cell, 2016; 166 (5): 1132 DOI: 10.1016/j.cell.2016.07.045
Source: Cancer Research UK. “New research reveals cancers need a ‘perfect storm’ of conditions to develop.” ScienceDaily. ScienceDaily, 25 August 2016. <www.sciencedaily.com/releases/2016/08/160825130559.htm>.
August 24, 2016
American Chemical Society
Millions of Americans with diabetes have to inject themselves regularly with insulin to manage their blood-sugar levels. But scientists are developing a new way of administering the medicine orally with tiny vesicles that can deliver insulin where it needs to go without a shot.
Every day, millions of Americans with diabetes have to inject themselves with insulin to manage their blood-sugar levels. But less painful alternatives are emerging. Scientists are developing a new way of administering the medicine orally with tiny vesicles that can deliver insulin where it needs to go without a shot. Today, they share their in vivo testing results.
The researchers are presenting their work at the 252nd National Meeting & Exposition of the American Chemical Society (ACS).
“We have developed a new technology called a CholestosomeTM,” says Mary McCourt, Ph.D., a leader of the research team. “A CholestosomeTM is a neutral, lipid-based particle that is capable of doing some very interesting things.”
The biggest obstacle to delivering insulin orally is ushering it through the stomach intact. Proteins such as insulin are no match for the harsh, highly acidic environment of the stomach. They degrade before they get a chance to move into the intestines and then the bloodstream where they’re needed.
Some efforts have been made to overcome or sidestep this barrier. One approach packages insulin inside a protective polymer coating to shield the protein from stomach acids and is being tested in clinical trials. Another company developed and marketed inhalable insulin, but despite rave reviews from some patients, sales were a flop. Now its future is uncertain.
McCourt, Lawrence Mielnicki, Ph.D., and undergraduate student Jamie Catalano — all from Niagara University — have a new tactic. Using the patented CholestosomesTM developed in the McCourt/Mielnicki lab, the researchers have successfully encapsulated insulin. The novel vesicles are made of naturally occurring lipid molecules, which are normal building blocks of fats. But the researchers say that they are unlike other lipid-based drug carriers, called liposomes.
“Most liposomes need to be packaged in a polymer coating for protection,” says Mielnicki. “Here, we’re just using simple lipid esters to make vesicles with the drug molecules inside.”
Computer modeling showed that once the lipids are assembled into spheres, they form neutral particles resistant to attack from stomach acids. Drugs can be loaded inside, and the tiny packages can pass through the stomach without degrading. When CholestosomesTM reach the intestines, the body recognizes them as something to be absorbed. The vesicles pass through the intestines, into the bloodstream, and then cells take them in and break them apart, releasing insulin.
The team has delivered multiple molecules with these vesicles into cells in the lab. To pack the most insulin into the CholestosomesTM, the researchers determined the optimal pH and ionic strength of the drug-containing solution. They then moved the most promising candidates on to animal testing. Studies with rats showed that certain formulations of CholestosomesTMloaded with insulin have high bioavailability, which means the vesicles travel into the bloodstream where the insulin needs to be.
Next, the team plans to further optimize the formulations, conduct more animal testing and develop new partnerships to move forward into human trials.
Source: American Chemical Society. “Insulin pill could make diabetes treatment ‘ouchless’.” ScienceDaily. ScienceDaily, 24 August 2016. <www.sciencedaily.com/releases/2016/08/160824084250.htm>.
Spontaneous interconversion between HER2-positive and HER2-negative states could contribute to progression, treatment resistance in breast cancer
August 24, 2016
Massachusetts General Hospital
A new study reveals how spontaneous changes in the molecular characteristics of tumors can lead to tumors with a mixed population of cells requiring treatment with several types of therapeutic drugs.
A study led by Massachusetts General Hospital (MGH) investigators reveals how spontaneous changes in the molecular characteristics of tumors can lead to tumors with a mixed population of cells requiring treatment with several types of therapeutic drugs. In their report in the Sept. 1 issue ofNature, the research team describes finding a mixture of HER2-positive and HER2-negative circulating tumors cells (CTCs) in blood samples from patients who developed metastatic disease after originally being diagnosed with estrogen-receptor (ER)-positive/HER2-negative breast cancer.
“Not only did we observe the acquisition of HER2 positivity in patients with ER-positive/HER2 negative breast tumors, we also found that this population of tumor cells is able to spontaneously oscillate between HER2-positive and HER2-negative states, which contributes to tumor progression and resistance,” says Shyamala Maheswaran, PhD, of the MGH Cancer Center, co-senior author of the report. “We also showed in mouse models the types of therapies that may be most useful for patients with these difficult-to-treat tumors.”
Molecular heterogeneity of tumors has become a confounding factor in cancer treatment in recent years, requiring the use of multiple drugs that specifically target all the different cell populations driving tumor growth. The current study was designed to investigate further the differences in HER2 expression that can occur in individual patients’ tumors and how they affect tumor growth and treatment. Using the CTC-iChip — a microfluidic device developed at the MGH Center for Engineering in Medicine that isolates CTCs from blood samples — the researchers found both HER2-positive and HER2-negative CTCs in samples from 16 out of 18 patients who had developed metastases after treatment for ER-positive/HER2-negative breast cancer.
CTCs isolated from patients with ER-positive/HER2-negative breast cancer and grown in culture also showed a similar pattern of HER2 expression, in which some of the tumor cells expressed HER2 and some did not. Closer examination of these HER2-positive tumor cells showed elevated expression of proteins in several growth signaling pathways, but the level of HER2 expression was not as high as seen in HER2-amplified primary tumors.
These HER2-positive CTCs were no more sensitive to treatment with a HER2-inhibiting drug than were HER2-negative CTCs, but combined treatment with both the HER2 inhibitor and an IGFR1 (insulin-like growth factor receptor 1) inhibitor was toxic to HER2-positive CTCs. In contrast, HER2-negative CTCs had elevated expression of proteins in the Notch developmental pathway and in pathways that respond to DNA damage. Reflecting those differences, HER2-positive CTCs were found to proliferate more rapidly and respond to treatment with standard chemotherapy drugs, while HER2-negative CTCs were more resistant to chemotherapy drugs but sensitive to gamma secretase inhibitors, which are known to suppress Notch signaling.
Injecting either HER2-positive or HER2-negative breast tumor cells into the mammary tissue of mice led to the development of tumors with both types of cells. Treatment of tumors in which HER2-positive cells were predominant with the chemotherapy drug paclitaxel led to rapid tumor shrinkage, followed by recurrence with a greater number of HER2-negative cells, while paclitaxel treatment of tumors with more HER2-negative cells did not have any effect. Treating mice in which tumors had been initiated by a mixture of HER2-positive and HER2-negative tumor cells with a combination of paclitaxel and a gamma secretase inhibitor did delay tumor recurrence significantly, suggesting the potential utility of a combination treatment strategy to eliminate this mixed population of tumor cells.
“The ability of these two populations of tumor cells to convert back and forth highlights the importance of treating tumors with drugs that would simultaneously target both populations,” says Maheswaran, who is an associate professor of Surgery at Harvard Medical School. “Now we need to investigate the mechanisms responsible for this interconversion.”
- Nicole Vincent Jordan, Aditya Bardia, Ben S. Wittner, Cyril Benes, Matteo Ligorio, Yu Zheng, Min Yu, Tilak K. Sundaresan, Joseph A. Licausi, Rushil Desai, Ryan M. O’Keefe, Richard Y. Ebright, Myriam Boukhali, Srinjoy Sil, Maristela L. Onozato, Anthony J. Iafrate, Ravi Kapur, Dennis Sgroi, David T. Ting, Mehmet Toner, Sridhar Ramaswamy, Wilhelm Haas, Shyamala Maheswaran, Daniel A. Haber. HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature, 2016; DOI: 10.1038/nature19328
Source: Massachusetts General Hospital. “Breast cancer cells found to switch molecular characteristics: Spontaneous interconversion between HER2-positive and HER2-negative states could contribute to progression, treatment resistance in breast cancer.” ScienceDaily. ScienceDaily, 24 August 2016. <www.sciencedaily.com/releases/2016/08/160824135041.htm>.
Bubble-wrapped structure requires no mirrors or lenses to focus the sun’s heat
August 22, 2016
Massachusetts Institute of Technology
How do you boil water? Eschewing the traditional kettle and flame, engineers have invented a bubble-wrapped, sponge-like device that soaks up natural sunlight and heats water to boiling temperatures, generating steam through its pores. The design, which the researchers call a ‘solar vapor generator,’ requires no expensive mirrors or lenses to concentrate the sunlight, but instead relies on a combination of relatively low-tech materials to capture ambient sunlight and concentrate it as heat.
How do you boil water? Eschewing the traditional kettle and flame, MIT engineers have invented a bubble-wrapped, sponge-like device that soaks up natural sunlight and heats water to boiling temperatures, generating steam through its pores.
The design, which the researchers call a “solar vapor generator,” requires no expensive mirrors or lenses to concentrate the sunlight, but instead relies on a combination of relatively low-tech materials to capture ambient sunlight and concentrate it as heat. The heat is then directed toward the pores of the sponge, which draw water up and release it as steam.
From their experiments — including one in which they simply placed the solar sponge on the roof of MIT’s Building 3 — the researchers found the structure heated water to its boiling temperature of 100 degrees Celsius, even on relatively cool, overcast days. The sponge also converted 20 percent of the incoming sunlight to steam.
The low-tech design may provide inexpensive alternatives for applications ranging from desalination and residential water heating, to wastewater treatment and medical tool sterilization.
The team has published its results today in the journal Nature Energy. The research was led by George Ni, an MIT graduate student; and Gang Chen, the Carl Richard Soderberg Professor in Power Engineering and the head of the Department of Mechanical Engineering; in collaboration with TieJun Zhang and his group members Hongxia Li and Weilin Yang from the Department of Mechanical and Materials Engineering at the Masdar Institute of Science and Technology, in the United Arab Emirates.
Building up the sun
The researchers’ current design builds on a solar-absorbing structure they developed in 2014 — a similar floating, sponge-like material made of graphite and carbon foam, that was able to boil water to 100 C and convert 85 percent of the incoming sunlight to steam.
To generate steam at such efficient levels, the researchers had to expose the structure to simulated sunlight that was 10 times the intensity of sunlight in normal, ambient conditions.
“It was relatively low optical concentration,” Chen says. “But I kept asking myself, ‘Can we basically boil water on a rooftop, in normal conditions, without optically concentrating the sunlight? That was the basic premise.”
In ambient sunlight, the researchers found that, while the black graphite structure absorbed sunlight well, it also tended to radiate heat back out into the environment. To minimize the amount of heat lost, the team looked for materials that would better trap solar energy.
A bubbly solution
In their new design, the researchers settled on a spectrally-selective absorber — a thin, blue, metallic-like film that is commonly used in solar water heaters and possesses unique absorptive properties. The material absorbs radiation in the visible range of the electromagnetic spectrum, but it does not radiate in the infrared range, meaning that it both absorbs sunlight and traps heat, minimizing heat loss.
The researchers obtained a thin sheet of copper, chosen for its heat-conducting abilities and coated with the spectrally-selective absorber. They then mounted the structure on a thermally-insulating piece of floating foam. However, they found that even though the structure did not radiate much heat back out to the environment, heat was still escaping through convection, in which moving air molecules such as wind would naturally cool the surface.
A solution to this problem came from an unlikely source: Chen’s 16-year-old daughter, who at the time was working on a science fair project in which she constructed a makeshift greenhouse from simple materials, including bubble wrap.
“She was able to heat it to 160 degrees Fahrenheit, in winter!” Chen says. “It was very effective.”
Chen proposed the packing material to Ni, as a cost-effective way to prevent heat loss by convection. This approach would let sunlight in through the material’s transparent wrapping, while trapping air in its insulating bubbles.
“I was very skeptical of the idea at first,” Ni recalls. “I thought it was not a high-performance material. But we tried the clearer bubble wrap with bigger bubbles for more air trapping effect, and it turns out, it works. Now because of this bubble wrap, we don’t need mirrors to concentrate the sun.”
The bubble wrap, combined with the selective absorber, kept heat from escaping the surface of the sponge. Once the heat was trapped, the copper layer conducted the heat toward a single hole, or channel, that the researchers had drilled through the structure. When they placed the sponge in water, they found that water crept up the channel, where it was heated to 100 C, then turned to steam.
Chen and Ni say that solar absorbers based on this general design could be used as large sheets to desalinate small bodies of water, or to treat wastewater. Ni says other solar-based technologies that rely on optical-concentrating technologies typically are designed to last 10 to 20 years, though they require expensive parts and maintenance. This new, low-tech design, he says, could operate for one to two years before needing to be replaced.
“Even so, the cost is pretty competitive,” Ni says. “It’s kind of a different approach, where before, people were doing high-tech and long-term [solar absorbers]. We’re doing low-tech and short-term.”
“What fascinates us is the innovative idea behind this inexpensive device, where we have creatively designed this device based on basic understanding of capillarity and solar thermal radiation. Meanwhile, we are excited to continue probing the complicated physics of solar vapor generation and to discover new knowledge for the scientific community,” Zhang says.
This research was funded, in part, by a cooperative agreement between the Masdar Institute of Science and Technology; and by the Solid-State Solar Thermal Energy Conversion Center, an Energy Frontier Research Center funded by U.S. Department of Energy.
- George Ni, Gabriel Li, Svetlana V. Boriskina, Hongxia Li, Weilin Yang, TieJun Zhang, Gang Chen. Steam generation under one sun enabled by a floating structure with thermal concentration. Nature Energy, 2016; 1: 16126 DOI: 10.1038/nenergy.2016.126
Source: Massachusetts Institute of Technology. “Bubble-wrapped sponge creates steam using sunlight: Bubble-wrapped structure requires no mirrors or lenses to focus the sun’s heat.” ScienceDaily. ScienceDaily, 22 August 2016. <www.sciencedaily.com/releases/2016/08/160822124924.htm>.
August 22, 2016
American Chemical Society
During a heart attack, clots or narrowed arteries block blood flow, harming or killing cells in the heart. But damage doesn’t end after the crushing pain subsides. Instead, the heart’s walls thin out, the organ becomes enlarged, and scar tissue forms. These changes can cause heart failure. Scientists now report they have developed injectable gels to prevent this damage.
During a heart attack, clots or narrowed arteries block blood flow, harming or killing cells within the tissue. But the damage doesn’t end after the crushing pain subsides. Instead, the heart’s walls thin out, the organ becomes enlarged, and scar tissue forms. If nothing is done, the patient can eventually experience heart failure. But scientists now report they have developed gels that, in animal tests, can be injected into the heart to shore up weakened areas and prevent heart failure.
The researchers will present their work today at the 252nd National Meeting & Exposition of the American Chemical Society (ACS).
Heart attacks strike 750,000 people each year in the U.S., according to the American Heart Association. And more than 5 million U.S. residents are living with heart failure, with symptoms that progress from fatigue and shortness of breath to eventual death. “Heart failure is a huge problem, and few therapies are available for these patients,” says Jason A. Burdick, Ph.D., leader of the study.
Treatments include lifestyle changes, medication, implants or heart transplants. Burdick, who is at the University of Pennsylvania (Penn), explains that these options often don’t work well or, in the case of transplants, are hard to come by. So scientists are pursuing other treatment methods. For instance, researchers at other institutions have done animal studies in which they injected cells into the damaged section of the heart to try to repair damage. To prevent the cells from leaking out, those researchers embedded them in biodegradable “hydrogels” — water-swollen networks of polymer chains with a consistency similar to Jell-OTM. But the scientists noticed something odd when they ran control experiments in which they injected the hydrogel without added cells: Some of the animals’ hearts still showed improvement compared with untreated animals.
Based on those findings, a handful of labs are now experimenting with hydrogel treatments, including two materials that are in clinical trials. Neither is from Burdick’s lab, but as he notes, “It’s important we all keep moving forward to figure out how this therapy could be used, because it’s different than any current treatment.” In addition, different types of hydrogels could suit different patients’ needs.
Some experimental heart attack treatments require surgery to open up the chest, but the two hydrogel materials already in clinical trials are injected into the damaged tissue through a long catheter inserted through the skin — eliminating the need for open-chest surgery.
Burdick and his graduate student Christopher B. Rodell, in collaboration with Robert C. Gorman, M.D., also at Penn, are using this same minimally invasive technique in their own work. But his team has gone a step further by identifying properties that would be useful in treating heart attack patients and then designing hydrogels with those properties. For instance, his group developed a hydrogel that forms additional crosslinks between the polymer chains after injection. The resulting material is stiffer and lasts longer than a gel without these additional crosslinks and the gels in clinical trials.
In fact, Burdick’s gel is unique among hydrogels in providing mechanical support to stabilize the damaged area. In sheep studies, this gel limits formation of scar tissue, thinning of the heart’s walls and enlargement of the heart. By preserving the organ’s size, the gels also reduce leakage of blood through the mitral valve. Together, these benefits maintain the heart’s blood-pumping ability and could stave off heart failure.
The team’s materials are based on hyaluronic acid (HA), a type of sugar molecule that occurs naturally in the body. The researchers modified the HA molecules by attaching adamantane and cyclodextrin groups to allow the gels to flow through catheters, and they added thiol and methacrylate groups to enable post-injection cross-linking to stiffen the hydrogel. Once the researchers finalize the hydrogel formulation and delivery method, they hope to partner with a catheter firm to bring a product to market. Burdick’s team and other research groups are also designing hydrogels that contain drugs or cells that can repair heart tissue.
Source: American Chemical Society. “After the heart attack: Injectable gels could prevent future heart failure.” ScienceDaily. ScienceDaily, 22 August 2016. <www.sciencedaily.com/releases/2016/08/160822083246.htm>.
August 18, 2016
University of Arizona
Sea level changes in the Pacific Ocean can be used to estimate future global surface temperatures, according to a new paper. Scientists knew both the rate at which global surface temperature is rising and sea level in the Pacific varied, but had not connected the two phenomena. The researchers estimate by the end of 2016, average surface temperature will increase up to 0.5 F (0.28 C) more than in 2014.
The amount of sea level rise in the Pacific Ocean can be used to estimate future global surface temperatures, according to a new report led by University of Arizona geoscientists.
Based on the Pacific Ocean’s sea level in 2015, the team estimates by the end of 2016 the world’s average surface temperature will increase up to 0.5 F (0.28 C) more than in 2014.
In 2015 alone, the average global surface temperature increased by 0.32 F (0.18 C).
“Our prediction is through the end of 2016,” said first author Cheryl Peyser. “The prediction is looking on target so far.”
Scientists knew that both the rate at which global surface temperature is rising and sea level in the western Pacific varied, but had not connected the two phenomena, said Peyser, a UA doctoral candidate in geosciences.
“We’re using sea level in a different way, by using the pattern of sea level changes in the Pacific to look at global surface temperatures — and this hasn’t been done before,” she said.
Peyser and her colleagues used measurements of sea level changes taken by NASA/NOAA/European satellites starting in 1993.
Using sea surface height rather than sea surface temperatures provides a more accurate reflection of the heat stored in the entire water column, said co-author Jianjun Yin, a UA associate professor of geosciences.
“We are the first to use sea level observations to quantify the global surface temperature variability,” Yin said.
The team found when sea level in the western Pacific rises more than average — as it did from 1998 to 2012 — the rise in global surface temperatures slows.
In contrast, when sea level drops in the western Pacific but increases in the eastern Pacific as it did in 2015, global surface temperatures bump up because the heat stored in the ocean is released, Yin said.
The paper by Peyser, Yin, Felix Landerer of NASA’s Jet Propulsion Laboratory, Pasadena, California, and Julia Cole, a UA professor of geosciences, titled, “Pacific Sea Level Rise Patterns and Global Surface Temperature Variability,” is being published online in Geophysical Research Letters.
People already knew the tropical Pacific Ocean was relatively higher in the west — the trade winds blow from east to west, piling up water on the western side of the Pacific.
However, the degree of the tilt from west to east changes over time, much like a seesaw. Sometimes the western Pacific near Asia is much higher than the ocean’s eastern coast with the Americas. At other times, Pacific sea level in the west is not much greater than sea level in the east.
Others had documented that two different climate cycles, the Pacific Decadal Oscillation and the El Niño/La Niña cycle, affected how much the surface of the Pacific Ocean tilted from west to east.
From 1998 to 2012, the rate at which the global surface temperature increased slowed down — a phenomenon dubbed “the global warming hiatus.” During the same time period, sea level in the western tropical Pacific Ocean increased four times faster than the average global sea level rise.
Yin wondered if the two phenomena — sea level and global surface temperature — were related and asked Peyser, his graduate student, to investigate.
To figure out whether there was a connection, Peyser used state-of-the-art climate models that show what the climate system would do in the absence of global warming.
The models showed that changes in sea level in the western Pacific were correlated with changes in global surface temperature.
Verifying the correlation allowed the researchers to calculate the numerical relationship between amount of tilt and global surface temperature.
Once the researchers had the correlation, they used actual Pacific sea level data from satellites to calculate the Pacific Ocean’s contribution to global surface temperature.
“What I found was that during years when the tilt was steep in the western Pacific, global average temperature was cooler,” she said. “And when the seesaw is tilted more toward the eastern Pacific, it’s warmer.”
“We could say that for a certain amount of change in the tilt, you could expect a certain change in the temperature,” she said. “Natural variability is a really important part of the climate cycle.”
Understanding the variability is crucial for understanding the mechanisms underlying the warming hiatus, Yin said.
During the global warming hiatus, more heat was being stored in the deeper layers of the western Pacific Ocean, muting warming at the surface, the researchers said. Because warmer water expands, that stored heat contributed to the extreme sea level rise in the western Pacific during that time.
Starting in 2014 the ocean’s tilt started to flatten out as the climate cycle changed to an El Niño pattern. The heat previously stored in the ocean was being released, warming Earth’s surface and reducing sea level in the western Pacific.
Yin was surprised to find the Pacific Ocean plays such an important role in the global surface temperature. He said, “Our research shows that the internal variability of the global climate system can conceal anthropogenic global warming, and at other times the internal variability of the system can enhance anthropogenic warming.”
The next step, he said, is figuring out the mechanisms that allow the Pacific to change the global surface temperature so quickly.
- Cheryl E. Peyser, Jianjun Yin, Felix W. Landerer, Julia E. Cole. Pacific sea level rise patterns and global surface temperature variability.Geophysical Research Letters, 2016; DOI: 10.1002/2016GL069401
Source: University of Arizona. “Pacific sea level predicts global temperature changes.” ScienceDaily. ScienceDaily, 18 August 2016. <www.sciencedaily.com/releases/2016/08/160818212759.htm>.
August 18, 2016
The term ‘healthy obesity’ has gained traction over the past 15 years, but scientists have recently questioned its very existence. A new study provides further evidence against the notion of a healthy obese state, revealing that white fat tissue samples from obese individuals classified as either metabolically healthy or unhealthy actually show nearly identical, abnormal changes in gene expression in response to insulin stimulation.
The term “healthy obesity” has gained traction over the past 15 years, but scientists have recently questioned its very existence. A study published August 18 in Cell Reports provides further evidence against the notion of a healthy obese state, revealing that white fat tissue samples from obese individuals classified as either metabolically healthy or unhealthy actually show nearly identical, abnormal changes in gene expression in response to insulin stimulation.
“The findings suggest that vigorous health interventions may be necessary for all obese individuals, even those previously considered to be metabolically healthy,” says first author Mikael Rydén of the Karolinska Institutet. “Since obesity is the major driver altering gene expression in fat tissue, we should continue to focus on preventing obesity.”
Obesity has reached epidemic proportions globally, affecting approximately 600 million people worldwide and significantly increasing the risk of heart disease, stroke, cancer, and type 2 diabetes. Since the 1940s, evidence supporting the link between obesity and metabolic and cardiovascular diseases has been steadily growing. But in the 1970s and 80s, experts began to question the extent to which obesity increases the risk for these disorders. Subsequent studies in the late 90s and early 2000s showed that some obese individuals display a relatively healthy metabolic and cardiovascular profile.
Recent estimates suggest that up to 30% of obese individuals are metabolically healthy and therefore may need less vigorous interventions to prevent obesity-related complications. A hallmark of metabolically healthy obesity is high sensitivity to the hormone insulin, which promotes the uptake of blood glucose into cells to be used for energy. However, there are currently no accepted criteria for identifying metabolically healthy obesity, and whether or not such a thing exists is now up for debate.
To address this controversy, Rydén, Carsten Daub, and Peter Arner of the Karolinska Institutet assessed responses to insulin in 15 healthy, never-obese participants and 50 obese subjects enrolled in a clinical study of gastric bypass surgery. The researchers took biopsies of abdominal white fat tissue before and at the end of a two-hour period of intravenous infusion of insulin and glucose. Based on the glucose uptake rate, the researchers classified 21 obese subjects as insulin sensitive and 29 as insulin resistant.
Surprisingly, mRNA sequencing of white fat tissue samples revealed a clear distinction between never-obese participants and both groups of obese individuals. White fat tissue from insulin-sensitive and insulin-resistant obese individuals showed nearly identical patterns of gene expression in response to insulin stimulation. These abnormal gene expression patterns were not influenced by cardiovascular or metabolic risk factors such as waist-to-hip ratio, heart rate, or blood pressure. The findings show that obesity rather than other common risk factors is likely the primary factor determining metabolic health.
“Our study suggests that the notion of metabolically healthy obesity may be more complicated than previously thought, at least in subcutaneous adipose tissue,” Rydén says. “There doesn’t appear to be a clear transcriptomic fingerprint that differentiates obese subjects with high or low insulin sensitivity, indicating that obesity per se is the major driver explaining the changes in gene expression.”
One limitation of the study is that it examined gene expression profiles only in subcutaneous white fat tissue, not other types of fat tissue or other organs. Moreover, all of the obese subjects were scheduled to undergo bariatric surgery, so the findings may only apply to individuals with severe obesity.
In future research, Rydén and his collaborators will track the study participants after bariatric surgery to determine whether weight loss normalizes gene expression responses to insulin. They will also look for specific genes linked to improved metabolic health in these individuals.
In the meantime, the study has an important take-home message. “Insulin-sensitive obese individuals may not be as metabolically healthy as previously believed,” Rydén says. “Therefore, more vigorous interventions may be necessary in these individuals to prevent cardiovascular and metabolic complications.”
- Rydén et al. The Adipose Transcriptional Response to Insulin Is Determined by Obesity, Not Insulin Sensitivity. Cell Reports, 2016 DOI: 10.1016/j.celrep.2016.07.070
Source: Cell Press. “More evidence that ‘healthy obesity’ may be a myth.” ScienceDaily. ScienceDaily, 18 August 2016. <www.sciencedaily.com/releases/2016/08/160818131127.htm>.
Research into the bacterial interactions in our nasal microbiome suggest novel approaches for preventing Staphylococcus aureus infections without antibiotic use
August 17, 2016
Staphylococcus aureus is a common colonizer of the human body. Although, one quarter of the US population live with the bacteria and never get sick, having S. aureus present in the nostrils is a risk for infections that range in severity from mild skin to life- threatening MRSA infections. Research is providing insight into how harmless Corynebacterium species, bacterial members of the nasal and skin microbiome, help protect humans from disease.
Staphylococcus aureus is a common colonizer of the human body. Although, one quarter of the U.S. population live with the bacteria and never get sick, having S. aureus present in the nostrils is a risk for infections that range in severity from mild skin to life- threatening MRSA infections. Research from the Forsyth Institute is providing insight into how harmlessCorynebacterium species, bacterial members of the nasal and skin microbiome, help protect humans from disease.
A recent study by senior-author Katherine P. Lemon MD, PhD and first-author Matthew M. Ramsey PhD, along with Dr. Marcelo Freire at the Forsyth Institute, and with Rebecca Gabrilska and Dr. Kendra Rumbaugh from Texas Tech University, shows that when the two bacteria interact, Corynebacteriuminhibits the virulence of S. aureus. Further understanding of these interactions is likely to help researchers to develop new treatments for preventing S. aureus infections. In addition, further research on the interactions between benign members of the human microbiome and bacteria, like S. aureus, that exhibit similar dual characteristics of living in harmony with and causing infections of humans, so-called pathobionts, could lead to the development of novel treatments for other diseases.
“Our research helps set the stage for the development of small molecules and, potentially, probiotic therapies for promoting health by actively managing nasal microbiome composition,” says Lemon. “This research identifies a role for Corynebacterium species in suppressing S. aureus virulence, and is an exciting early stage in our exploration of the molecular mechanisms that sculpt the composition of the nasal microbiome and influence colonization by pathobionts. We look forward to an increase in research on commensal-pathobiont interactions within the human microbiome and an ever-increasing understanding of the significance of our beneficial bacteria partners.”
In recent years, the emergence of an antibiotic resistant form of S. aureusinfection (methicillin-resistance S. aureus or MRSA) has been a vexing problem. According to the Centers for Disease Control and Prevention, MRSA caused over 80,000 cases of invasive disease and over 10,000 deaths annually from 2005 through 2011. As more and more species of bacteria become antibiotic resistant, a deeper understanding of the interactions between potentially helpful and harmful bacteria in our microbiomes offers new approaches for treating diseases by harnessing the functions of already-present “beneficial” bacteria. Because pathobiont colonization is a prerequisite for infection and transmission, a possible approach to prevent infections by bacteria such as S. aureus is to limit or decrease their abundance or to shift them towards harmless behavior using either compounds derived from benign/beneficial members of the microbiome or by using these beneficial bacteria themselves as probiotics.
The full paper, titled “Staphylococcus aureus shifts towards commensalism in response to Corynebacterium species” is published in the Frontiers in Microbiology website.
- Matthew M. Ramsey, Marcelo O. Freire, Rebecca A. Gabrilska, Kendra P. Rumbaugh, Katherine P. Lemon. Staphylococcus aureus Shifts toward Commensalism in Response to Corynebacterium Species. Frontiers in Microbiology, 2016; 7 DOI: 10.3389/fmicb.2016.01230
Source: Forsyth Institute. “New findings detail how beneficial bacteria in the nose suppress pathogenic bacteria: Research into the bacterial interactions in our nasal microbiome suggest novel approaches for preventing Staphylococcus aureus infections without antibiotic use.” ScienceDaily. ScienceDaily, 17 August 2016. <www.sciencedaily.com/releases/2016/08/160817091034.htm>.