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>.
August 15, 2016
University of Pittsburgh Schools of the Health Sciences
Neuroscientists have identified the neural networks that connect the cerebral cortex to the adrenal medulla, which is responsible for the body’s rapid response in stressful situations. These findings provide evidence for the neural basis of a mind-body connection. Specifically, the findings shed new light on how stress, depression and other mental states can alter organ function, and show that there is a real anatomical basis for psychosomatic illness.
Neuroscientists at the University of Pittsburgh have identified the neural networks that connect the cerebral cortex to the adrenal medulla, which is responsible for the body’s rapid response in stressful situations. These findings, reported in the online Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS), provide evidence for the neural basis of a mind-body connection.
Specifically, the findings shed new light on how stress, depression and other mental states can alter organ function, and show that there is a real anatomical basis for psychosomatic illness. The research also provides a concrete neural substrate that may help explain why meditation and certain exercises such as yoga and Pilates can be so helpful in modulating the body’s responses to physical, mental and emotional stress.
“Our results turned out to be much more complex and interesting than we imagined before we began this study,” said senior author Peter L. Strick, Ph.D., Thomas Detre Chair of the Department of Neurobiology and scientific director of the University of Pittsburgh Brain Institute.
In their experiments, the scientists traced the neural circuitry that links areas of the cerebral cortex to the adrenal medulla (the inner part of the adrenal gland, which is located above each kidney). The scientific team included lead author Richard P. Dum, Ph.D., research associate professor in the Department of Neurobiology; David J. Levinthal, M.D., Ph.D., assistant professor in the Department of Medicine; and Dr. Strick.
The scientists were surprised by the sheer number of neural networks they uncovered. Other investigators had suspected that one or, perhaps, two cortical areas might be responsible for the control of the adrenal medulla. The actual number and location of the cortical areas were uncertain. In the PNAS study, the Strick laboratory used a unique tracing method that involves rabies virus. This approach is capable of revealing long chains of interconnected neurons. Using this approach, Dr. Strick and his colleagues demonstrated that the control of the adrenal medulla originates from multiple cortical areas. According to the new findings, the biggest influences arise from motor areas of the cerebral cortex and from other cortical areas involved in cognition and affect.
Why does it matter which cortical areas influence the adrenal medulla? Acute responses to stress include a wide variety of changes such as a pounding heart, sweating and dilated pupils. These responses help prepare the body for action and often are characterized as “fight or flight responses.” Many situations in modern life call for a more thought-out reaction than simple “fight or flight,” and it is clear that we have some cognitive control (or what neuroscientists call “top-down” control) over our responses to stress.
“Because we have a cortex, we have options,” said Dr. Strick. “If someone insults you, you don’t have to punch them or flee. You might have a more nuanced response and ignore the insult or make a witty comeback. These options are part of what the cerebral cortex provides.”
Another surprising result was that motor areas in the cerebral cortex, involved in the planning and performance of movement, provide a substantial input to the adrenal medulla. One of these areas is a portion of the primary motor cortex that is concerned with the control of axial body movement and posture. This input to the adrenal medulla may explain why core body exercises are so helpful in modulating responses to stress. Calming practices such as Pilates, yoga, tai chi and even dancing in a small space all require proper skeletal alignment, coordination and flexibility.
The PNAS study also revealed that the areas of the cortex that are active when we sense conflict, or are aware that we have made an error, are a source of influence over the adrenal medulla. “This observation,” said Dr. Strick, “raises the possibility that activity in these cortical areas when you re-imagine an error, or beat yourself up over a mistake, or think about a traumatic event, results in descending signals that influence the adrenal medulla in just the same way as the actual event.” These anatomical findings have relevance for therapies that deal with post-traumatic stress.
Additional links with the adrenal medulla were discovered in cortical areas that are active during mindful mediation and areas that show changes in bipolar familial depression. “One way of summarizing our results is that we may have uncovered the stress and depression connectome,” says Dr. Strick.
Overall, these results indicate that circuits exist to link movement, cognition and affect to the function of the adrenal medulla and the control of stress. This circuitry may mediate the effects of internal states like chronic stress and depression on organ function and, thus, provide a concrete neural substrate for some psychosomatic illness.
The above post is reprinted from materials provided by University of Pittsburgh Schools of the Health Sciences. Note: Content may be edited for style and length.
- Richard P. Dum, David J. Levinthal, Peter L. Strick. Motor, cognitive, and affective areas of the cerebral cortex influence the adrenal medulla.Proceedings of the National Academy of Sciences, 2016; 201605044 DOI:10.1073/pnas.1605044113
Source: University of Pittsburgh Schools of the Health Sciences. “New insights into how the mind influences the body.” ScienceDaily. ScienceDaily, 15 August 2016. <www.sciencedaily.com/releases/2016/08/160815185555.htm>.
August 15, 2016
Scripps Research Institute
Scientists have succeeded in creating a ribozyme that can basically serve both to amplify genetic information and generate functional molecules, a big step toward the laboratory re-creation of the ‘RNA world’ generally believed to have preceded modern life forms based on DNA and proteins.
Scientists at The Scripps Research Institute (TSRI) have taken a big step toward the laboratory re-creation of the “RNA world,” which is generally believed to have preceded modern life forms based on DNA and proteins.
“This is probably the first time some of these complex RNA molecules have been synthesized with a ribozyme [a special RNA enzyme] since the end of the RNA world four billion years ago,” said TSRI Professor Gerald F. Joyce, the senior author of the study.
The results from the study, reported this week in the online Early Edition of the Proceedings of the National Academy of Sciences, show the scientists have succeeded in creating a ribozyme that can basically serve both to amplify genetic information and to generate functional molecules.
The new ribozyme can replicate short lengths of RNA efficiently and perform transcription on even longer RNAs to make functional RNA molecules with complex structures — coming close to what scientists imagine in terms of an RNA replicator that could have supported life before modern biology, where protein enzymes now handle gene replication and transcription.
Taking Up a Decades-Old Challenge
In the new study, Joyce and TSRI Research Associate David P. Horning set out to use test-tube evolution techniques to tackle the decades-old challenge of creating an enzyme that could both replicate and transcribe RNA and thus support an RNA world.
The team started with an enzyme that had been developed and improved upon by other researchers since the early 1990s. The class I RNA polymerase ribozyme, as it has come to be known, can perform the basic task of RNA synthesis — required for transcribing an RNA template into a functional RNA molecule — by binding to a strand of RNA and using it as a template to stitch together a complementary RNA strand.
But prior forms of the ribozyme had been very limited in the RNA sequences they could handle, and couldn’t transcribe RNAs that have even moderately complex structures. Because of those limitations, they also could not perform full replication of RNA, which requires the transcription of a complementary strand back into a copy of the original.
Horning and Joyce drew upon several improvements described in previous research and then added random mutations to create a population of roughly 100 trillion distinct variants of the molecule. Mimicking the evolutionary process of natural selection, they set up a system to isolate only the variant ribozymes that could synthesize — from the respective RNA templates — two different and challenging RNA molecules, which have mixed sequences and complex structures, and have functions in the sense that they bind tightly to specific target molecules.
“The selection was based on the ability of these newly synthesized RNAs to actually function by binding to their targets,” said Horning. “To be able to make these functional RNAs, the ribozyme effectively had to evolve to become versatile in terms of the sequence and the structure of the RNA it could handle.”
The best performer after two dozen rounds of selection, polymerase ribozyme 24-3, proved capable of synthesizing not only the two target-binding RNAs but also several other structurally complex RNA molecules that exist in nature — as functional remnants of the ancient RNA world — including a yeast version of a “transfer RNA” molecule that has an essential protein-making role in all cells.
“We found that the new ribozyme can handle most sequences and all but the most difficult structures, so we can use it to make a variety of functional RNA molecules,” Joyce said.
Even when synthesizing the limited RNA sequences that the original class I RNA polymerase ribozyme could handle, ribozyme 24-3 proved capable of stitching them together about 100 times faster than its ancestor could.
Turning to the much harder task of replication, the TSRI researchers found that ribozyme 24-3 could copy RNAs of up to two dozen nucleotides, achieving what biologists call “exponential replication” and creating as many as 40,000 copies of a target RNA within 24 hours.
The 24-3 ribozyme is thus the first ever to combine the two basic capabilities — RNA synthesis and RNA replication — necessary for a pre-protein, pre-DNA world of RNA life.
To generate and sustain a true “RNA world,” the new ribozyme will have to be improved further to enable the replication of longer, more complex RNA molecules — crucially including the polymerase ribozyme itself. The Joyce laboratory is now driving its ribozyme toward that goal with further test-tube evolution experiments.
“A polymerase ribozyme that achieves exponential amplification of itself will meet the criteria for being alive,” Joyce said. “That’s a summit that’s now within sight.”
- David P. Horning and Gerald F. Joyce. Amplification of RNA by an RNA polymerase ribozyme. PNAS, 2016 DOI:10.1073/pnas.1610103113
Source: Scripps Research Institute. “Scientists take big step toward recreating primordial ‘RNA world’ of 4 billion years ago.” ScienceDaily. ScienceDaily, 15 August 2016. <www.sciencedaily.com/releases/2016/08/160815185822.htm>.
August 11, 2016
University of Cambridge
Study of bee-manipulating plant virus reveals a ‘short-circuiting’ of natural selection. Researchers suggest that replicating the scent caused by infection could encourage declining bee populations to pollinate crops — helping both bee and human food supplies.
Plant scientists at the University of Cambridge have found that the cucumber mosaic virus (CMV) alters gene expression in the tomato plants it infects, causing changes to air-borne chemicals — the scent — emitted by the plants. Bees can smell these subtle changes, and glasshouse experiments have shown that bumblebees prefer infected plants over healthy ones.
Scientists say that by indirectly manipulating bee behaviour to improve pollination of infected plants by changing their scent, the virus is effectively paying its host back. This may also benefit the virus: helping to spread the pollen of plants susceptible to infection and, in doing so, inhibiting the chance of virus-resistant plant strains emerging.
The authors of the new study, published in the journal PLOS Pathogens, say that understanding the smells that attract bees, and reproducing these artificially by using similar chemical blends, may enable growers to protect or even enhance yields of bee-pollinated crops.
“Bees provide a vital pollination service in the production of three-quarters of the world’s food crops. With their numbers in rapid decline, scientists have been searching for ways to harness pollinator power to boost agricultural yields,” said study principal investigator Dr John Carr, Head of Cambridge’s Virology and Molecular Plant Pathology group.
“Better understanding the natural chemicals that attract bees could provide ways of enhancing pollination, and attracting bees to good sources of pollen and nectar — which they need for survival,” Carr said.
He conducted the study with Professor Beverley Glover, Director of Cambridge University Botanic Garden, where many of the experiments took place, and collaborators at Rothamsted Research.
CMV is transmitted by aphids — bees don’t carry the virus. It’s one of the most prevalent pathogens affecting tomato plants, resulting in small plants with poor-tasting fruits that can cause serious losses to cultivated crops.
Not only is CMV one of the most damaging viruses for horticultural crops, but it also persists in wild plant populations, and Carr says the new findings may explain why: “We were surprised that bees liked the smell of the plants infected with the virus — it made no sense. You’d think the pollinators would prefer a healthy plant. However, modelling suggested that if pollinators were biased towards diseased plants in the wild, this could short-circuit natural selection for disease resistance,” he said.
“The virus is rewarding disease-susceptible plants, and at the same time producing new hosts it can infect to prevent itself from going extinct. An example, perhaps, of what’s known as symbiotic mutualism.”
The increased pollination from bees may also compensate for a decreased yield of seeds in the smaller fruits of virus-infected plants, say the scientists.
The findings also reveal a new level of complexity in the evolutionary ‘arms race’ between plants and viruses, in which it is classically believed that plants continually evolve new forms of disease-resistance while viruses evolve new ways to evade it.
“We would expect the plants susceptible to disease to suffer, but in making them more attractive to pollinators the virus gives these plants an advantage. Our results suggest that the picture of a plant-pathogen arms race is more complex than previously thought, and in some cases we should think of viruses in a more positive way,” said Carr.
Plants emit ‘volatiles’, air-borne organic chemical compounds involved in scent, to attract pollinators and repulse plant-eating animals and microbes. Humans have used them for thousands of years as perfumes and spices.
The researchers grew plants in individual containers, and collected air with emissions from CMV-infected plants, as well as ‘mock-infected’ control plants.
Through mass spectrometry, researchers could see the change in emissions induced by the virus. They also found that bumblebees could smell the changes. Released one by one in a small ‘flight arena’ in the Botanic Gardens, and timed with a stopwatch by researchers, the bees consistently headed to the infected plants first, and spent longer at those plants.
“Bees are far more sensitive to the blends of volatiles emitted by plants and can detect very subtle differences in the mix of chemicals. In fact, they can even be trained to detect traces of chemicals emitted by synthetic substances, including explosives and drugs,” said Carr.
Analysis revealed that the virus produces a factor called 2b, which reprograms genetic expression in the tomato plants and causes the change in scent.
Mathematical modelling by plant disease epidemiologist Dr Nik Cunniffe, also in the Department of Plant Sciences at Cambridge, explored how the experimental findings apply outside the glasshouse. The model showed how pollinator bias for infected plants can cause genes for disease-susceptibility to persist in plant populations over extremely large numbers of generations.
The latest study is the culmination of work spanning almost eight years (and multiple bee stings). The findings will form the basis of a new collaboration with the Royal Horticultural Society, in which they aim to increase pollinator services for cultivated crops.
With the global population estimated to reach nine billion people by 2050, producing enough food will be one of this century’s greatest challenges. Carr, Glover and Cunniffe are all members of the Cambridge Global Food Security Initiative at Cambridge, which is involved in addressing the issues surrounding food security at local, national and international scales.
- Simon C. Groen, Sanjie Jiang, Alex M. Murphy, Nik J. Cunniffe, Jack H. Westwood, Matthew P. Davey, Toby J. A. Bruce, John C. Caulfield, Oliver J. Furzer, Alison Reed, Sophie I. Robinson, Elizabeth Miller, Christopher N. Davis, John A. Pickett, Heather M. Whitney, Beverley J. Glover, John P. Carr. Virus Infection of Plants Alters Pollinator Preference: A Payback for Susceptible Hosts?PLOS Pathogens, 2016; 12 (8): e1005790 DOI: 10.1371/journal.ppat.1005790
Source: University of Cambridge. “Virus attracts bumblebees to infected plants by changing scent.” ScienceDaily. ScienceDaily, 11 August 2016. <www.sciencedaily.com/releases/2016/08/160811143524.htm>.