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2013年6月16日星期日

A peptide to protect brain function

Now Prof. Illana Gozes of Tel Aviv University's Sackler Faculty of Medicine has developed a new peptide in her lab, called NAP or Davunetide, that has the capacity to both protect and restore microtubule function. The peptide is a compound derived from the protein ADNP, which regulates more than 400 genes and is essential for brain formation, memory, and behavior.

Prof. Gozes and her team of researchers, including Dr. Yan Jouroukhin and graduate student Regin Ostritsky of TAU, observed that in animal models with microtubule damage, NAP was able to maintain or revive the transport of proteins and other materials in cells, ameliorating symptoms associated with neurodegeneration. These findings, which were reported in the journal Neurobiology of Disease, indicate that NAP could be an effective tool in fighting some of the most debilitating effects of neurodegenerative diseases.

Prof. Gozes is the director of TAU's Adams Super Center for Brain Studies and holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors.

Securing passage through the brain

In their investigation, the researchers used two different animal models with microtubule damage. The first group was made up of normal mice whose microtubule system was broken down through the use of a compound. The second group were genetically-engineered mouse models of ALS, in which the microtubule system was chronically damaged. In both groups, half the mice were given a single NAP injection, while the control half were not.

To determine the impact of NAP on nerve cell communications, the researchers administered the chemical element manganese to all animal models and tracked its movement through the brain using an MRI. In the mice treated with NAP, researchers observed that the manganese was able to travel through the brain normally -- the microtubule system had been protected from damage or restored to normal use. Those mice that did not receive the peptide experienced the usual breakdown or continued dysfunction of the microtubule system.

These findings were corroborated by a subsequent study conducted in the UK, published in the journal Molecular Psychiatry, which found that NAP was able to ameliorate damage in fruit fly models of microtubule deficiency, repairing nerve cell dysfunction.

Slowing down cognitive dysfunction

NAP appears to have widespread potential in terms of neuroprotection, says Prof. , Gozes who was recently awarded the Meitner-Humblodt Research Award for her lifelong contribution to the field of brain sciences.

Previous studies on the peptide, conducted through a collaboration between Allon Therapeutics and Ramot, TAU's technology transfer arm, have shown that patients suffering from cognitive dysfunction -- a precursor to Alzheimer's Disease -- showed significant improvements in their cognitive scores when treated with NAP. Additional studies have also shown that NAP has a positive impact on rectifying microtubule deficiencies in schizophrenia patients.

Prof. Gozes notes that more research must be conducted to discover how to optimize the use of NAP as a treatment, including which patients can benefit most from the intervention.

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New fluorescent protein from eel improves key clinical assay

Science from kitchen to lab to clinic

Best known as a culinary delicacy in Japan, the freshwater eel Unagi (Anguilla japonica) and related species have seen a worldwide decrease in population, probably due to the effects of global warming, and Unagi is on the brink of extinction in Japan. Yet almost nothing is know about the biology of the eel.

Drs. Atsushi Miyawaki, Akiko Kumagai and their team cloned a gene from Unagi for an unusual fluorescent protein they named UnaG, for Unagi Green protein, that allows eels to glow in the dark . UnaG is the first fluorescent protein found in vertebrates; previously they were thought to exist only in simple animals like jellyfish.

But what makes UnaG truly unique in nature is that it needs a natural chemical to activate its powerful green light emission. In a surprise twist, the compound was identified by the authors to be bilirubin, a slippery molecule universally used in clinical labs around the world as a human blood marker for liver function.

New clinical test for bilirubin

Bilirubin is the breakdown product of blood hemoglobin and is toxic if present in excess in the body like in the characteristic yellow skin and eye color conditions seen in newborn babies, jaundice and kernicterus. It is also a common marker in blood tests where bilirubin is used by doctors to assess liver function and for the assessment of health, including hemolysis, the loss of red blood cells in anemia.

By analyzing the structure of UnaG, the team discovered a novel mechanism of fluorescence enabling bilirubin to bind to UnaG and activate its light emission. With this property, they developed a superior new assay for bilirubin with high sensitivity, accuracy and speed that may become the global clinical standard, and can be used in developing countries where child liver health is a major issue.

Role of UnaG in eel conservation

Japanese freshwater eels have a long-distance migration life cycle, growing in inland rivers and swimming far into the sea to spawn. The authors identified UnaG and bilirubin in the muscle cells of Japanese, American, and European eels where they may aid in endurance swimming during migration. The unexpected discovery of UnaG may initiate legislation to conserve endangered eel species.

"We believe that UnaG provides an unexpected foothold into several important but currently obscure areas of human health including bilirubin metabolism and muscle physiology during endurance exercise," Miyawaki concludes. "Before the discovery of UnaG, I couldn't imagine that basic science could have such a direct impact on human health. From a simple eel, we found a new path to the clinic."

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Programming blood forming stem cells

The study, titled, "Induction of a Hemogenic Program in Mouse Fibroblasts," was published online in Cell Stem Cell on June 13. Mount Sinai researchers screened a panel of 18 genetic factors for inducing blood-forming activity and identified a combination of four transcription factors, Gata2, Gfi1b, cFos, and Etv6 as sufficient to generate blood vessel precursor cells with the subsequent appearance of hematopoietic cells. The precursor cells express a human CD34 reporter, Sca1 and Prominin1 within a global endothelial transcription program.

"The cells that we grew in a petri dish are identical in gene expression to those found in the mouse embryo and could eventually generate colonies of mature blood cells," said the first author of the study, Carlos Filipe Pereira, PhD, Postdoctoral Fellow of Developmental and Regenerative Biology at the Icahn School of Medicine.

Other leaders of the research team that screened the genetic factors to find the right combination included Kateri Moore, DVM, Associate Professor of Developmental and Regenerative Biology at the Icahn School and Ihor R. Lemischka, PhD, Professor of Developmental and Regenerative Biology, Pharmacology and Systems Therapeutics and Director of The Black Family Stem Cell Institute at The Mount Sinai Medical Center.

"The combination of gene factors that we used was not composed entirely of the most obvious or expected proteins," said Dr. Lemischka. "Many investigators have been trying to grow hematopoietic stem cells from embryonic stem cells, but this process has been problematic. Instead, we used mature mouse fibroblasts, picked the right combination of proteins, and it worked."

"This discovery is just the beginning of something new and exciting and can hopefully be used to identify a treatment for blood disorders," said Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai and Executive Vice President for Academic Affairs at The Mount Sinai Medical Center.

According to Dr. Pereira, there is a critical shortage of suitable donors for blood stem cell transplants. Donors are currently necessary to meet the needs of patients suffering from blood diseases such as leukemia, aplastic anemia, lymphomas, multiple myeloma and immune deficiency disorders. "Programming of hematopoietic stem cells represents an exciting alternative," said Pereira.

"Dr. Lemischka and I have been working together for over 20 years in the fields of hematopoiesis and stem cell biology," said Dr. Moore, senior author of the study. "It is truly exciting to be able to grow these blood forming cells in a culture dish and learn so much from them. We have already started applying this new approach to human cells and anticipate similar success."

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Genetics of dyslexia and language impairment unraveled

The study is published online and in the July print issue of the American Journal of Human Genetics. Senior author Dr. Jeffrey R. Gruen, professor of pediatrics, genetics, and investigative medicine at Yale, and colleagues analyzed data from more than 10,000 children born in 1991-1992 who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) conducted by investigators at the University of Bristol in the United Kingdom.

Gruen and his team used the ALSPAC data to unravel the genetic components of reading and verbal language. In the process, they identified genetic variants that can predispose children to dyslexia and language impairment, increasing the likelihood of earlier diagnosis and more effective interventions.

Dyslexia and language impairment are common learning disabilities that make reading and verbal language skills difficult. Both disorders have a substantial genetic component, but despite years of study, determining the root cause had been difficult.

In previous studies, Gruen and his team found that dopamine-related genes ANKK1 and DRD2 are involved in language processing. In further non-genetic studies, they found that prenatal exposure to nicotine has a strong negative affect on both reading and language processing. They had also previously found that a gene called DCDC2 was linked to dyslexia.

In this new study, Gruen and colleagues looked deeper within the DCDC2 gene to pinpoint the specific parts of the gene that are responsible for dyslexia and language impairment. They found that some variants of a gene regulator called READ1 (regulatory element associated with dyslexia1) within the DCDC2 gene are associated with problems in reading performance while other variants are strongly associated with problems in verbal language performance.

Gruen said these variants interact with a second dyslexia risk gene called KIAA0319. "When you have risk variants in both READ1 and KIAA0319, it can have a multiplier effect on measures of reading, language, and IQ," he said. "People who have these variants have a substantially increased likelihood of developing dyslexia or language impairment."

"These findings are helping us to identify the pathways for fluent reading, the components of those pathways; and how they interact," said Gruen. "We now hope to be able to offer a pre-symptomatic diagnostic panel, so we can identify children at risk before they get into trouble at school. Almost three-quarters of these children will be reading at grade level if they get early intervention, and we know that intervention can have a positive lasting effect."

Other authors on the study include Natalie R. Powers, John D. Eicher, Falk Butter, Yong Kong, Laura L. Miller, Susan M. Ring, and Matthias Mann.

This work was supported by the UK medical research council, the Wellcome Trust (092731), the Yale Center for Genome Analysis; and the National Institutes of Health (R01 NS043530 and F31 DC012270)

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Black locust tree shows promise for biomass potential

"For now the only thing you can do with it is use it for direct combustion," Kling said. "But if it becomes a major crop other researchers could start working on the process of how to break it down," he said. "The EBI is working on how to get the sugars out of plants and how to turn those to alcohols. It is a very tough thing to do. It's typically been tough to break down the biomass in woody plants to make it useful for alcohol production. Our plan is to be able to take anything we grow and convert it into a drop-in fuel."

Kling said he and his team's role in the EBI's feedstock production/agronomy program, is to improve the production aspects of bioenergy crops. While other researchers in the program have evaluated miscanthus, switchgrass, and prairie cord grass, Kling is examining which short-rotation woody crops grow best in the Midwest.

"Robinia pseudoacacia is showing great potential as a biomass crop for Midwestern energy production, out-yielding the next closest species by nearly three-fold," Kling said. "We picked the best crops and moved those forward. Other crops may catch up, but black locust was the fastest out of the gate. We will pursue other crops as well for a number of years, but we want to move to the next step which is on to improved selections."

As part of the initial study, two-year old seedlings were planted in the spring of 2010, grown over the summers of 2010 and 2011, and were then coppiced in the winter of 2011-2012. By coppicing the plants after a period of growth, or cutting the plants back from a single stem just a few inches from the ground, Kling explained that this process allows the plant to grow back with multiple stems coming from the base and shoots coming up from underground root systems.

"Black locust is effective at colonizing an area, because it freely branches like that," Kling said. "It's a good candidate for this kind of treatment, but not all plants will tolerate this process. It forces the plants to essentially grow up as shrubs, with more frequent harvests. By planting much closer together and causing them to branch like that, you are able to fill up available space, intercept light more quickly, and use the field resources more efficiently."

Researchers assumed they would harvest 3 to 5 years after coppicing, which is comparable to woody crops such as the willow. "After that first coppicing in February 2012, and then after last year's very early spring, the black locust was growing quite rapidly. It was already a foot tall when we had that freeze in the middle of April, which froze them back to the ground. They began to regrow and put out new shoots in May. By the end of last season, the plants were nearly equivalent to the first two years' growth," he said.

This spring, a preliminary check on the black locust crops, which included harvesting 3 plants from the edge of the field, produced a yield of 12 to 13 mega grams per hectare (Mg ha-1), which exceeded what was produced over the first two years' growth, Kling said.

This rapid growth is what distinguished the black locust from other woody plants in the study.

"We are now looking at harvesting every 2 years rather than every 3 to 5 years as we first assumed," Kling explained. "This would allow producers to get some payback a lot quicker from their investment."

Based on these encouraging findings, Kling said two new experiments were started this spring, through the EBI, both looking at different germplasm for black locust crops. In the first, Kling said seedlings were ordered from 10 different commercial sources across 8 states.

"We wanted to sample as much commercial germplasm as we could to see if some are faster growing," he said. "For example, in Hungary, with appropriate selection, researchers were able to improve yield by approximately 25 percent compared to unimproved black locust. We're certainly in our infancy yet in terms of trying to improve and select for improved yield, but you've got to start somewhere and looking at different germplasm sources is one way to do that."

The second experiment involved obtaining seed sources internationally through the USDA, including seeds from Afghanistan, Uzbekistan, and Iran. Seeds were also taken from the site of a remediated quarry area in Vermillion County where they found native black locust growing.

The seeds and seedlings for the two new evaluations were treated in greenhouses over the winter, and then planted in EBI fields this spring. Kling said he and the other researchers will evaluate whether to coppice the plants at the end of 1 or 2 years.

"Illinois has a lot of land that is subpar for corn and soybeans, such as the southern part of state and northern parts of the state along rivers. Black locust could be cultivated along some of that area in large acreage. This would be well-suited to smaller producers who want to generate some of their own fuel," he said. "We do have some producers out there who are looking at alternatives, and there are a lot of farmers who have riparian areas that could potentially grow black locust as a minor crop, in central Illinois we're not going to see 100-acre lots of black locust growing, though."

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Secrets of biological soil crusts uncovered

"We found a way to measure from start to finish in real unaltered samples the molecular events behind the response of cyanobacterium to wetting and drying in a desert BSC," says Aindrila Mukhopadhyay, a biologist with Berkeley Lab's Physical Biosciences Division. "Not only did we get a good view of the genetic machinery that wakes the microbes up, but we also got a good sense of what constitutes a healthy BSC."

Mukhopadhyay and Trent Northen, a chemist with Berkeley Lab's Life Sciences Division, are the corresponding authors of a paper describing this research in the journal of the International Society for Microbial Ecology. The paper is titled "Dynamic cyanobacterial response to hydration and dehydration in a desert biological soil crust."

Arid and semi-arid deserts make up about 40-percent of Earth's total land mass. Much of the undisturbed soil crust in these deserts is a living mantle of microbes and their by-products, with the predominant inhabitants being cyanobacteria, microorganisms that use photosynthesis for energy. To survive dry spells that can go on for years, BSC microorganisms must enter a dormant state but they must also be poised for rapid resuscitation to utilize short periods of precipitation. For a better understanding of how the microbes are able to do this, the Berkeley Lab research team studied the cyanobacterium Microcoleus vaginatus.

"M. vaginatus is the early BSC colonizer, an ecosystem pioneer that fixes carbon and binds the soil together allowing the community to develop while preventing wind erosion," says Northen. "It is globally distributed in regions where water is scarce, including not only hot deserts but the arctic as well."

Working with the research group of Ferran Garcia-Pichel at Arizona State University, the Berkeley Lab team collected pie-sized samples of soil crust from the cold desert area near Moab, Utah. These samples were subjected to in situ wetting and drying over a period of six days, including two diel (day/night) cycles. The wetting simulated conditions that would be brought about by the passage of a rain front. During the study, the researchers performed whole-genome transcriptional analysis and precise biochemical measurements.

"Simulated weather conditions and sampling in a temporal manner over the six day experimental period allowed us to track key transcriptional and metabolic responses as they occurred," says Mukhopadhyay. "We found that within three minutes after wetting began, metabolic processes in the dormant microbial cells came alive. Within one hour, photosynthesis began, accompanied by carbon dioxide up-take. During this time we saw specific genes get turned on/off and specific gene expressions be elevated or depressed."

The rain episode lasted three days. Although rare, such conditions do occur in the desert and enabled the researchers to differentiate between wetting-up and drying-down responses from diel cycle responses. They discovered that when dehydration of the soil resumed, the mechanisms triggered by wetting were mirrored in the reverse direction, suggesting that the M. vaginatus microbes were preparing themselves to re-enter desiccation-induced dormancy.

"These BSC microbes are highly attuned to their environment and they respond very quickly to changes," Mukhopadhyay says. "Their responses, however, are highly sensitive to physical disturbances and alterations in temperature."

In their paper, the Berkeley Lab researchers say that a better understanding of how environmental factors influence the growth and metabolism of M. vaginatus and other BSC microbes should improve our ability to predict the impacts of climate or land-use change on BSC systems. This knowledge should also help in the development of management strategies for restoring BSCs following large-scale disturbances.

"BSC systems represent the world's largest biofilms, and the demise of such systems could release carbon, and probably more importantly, dust into the atmosphere, changing the albedo of snow-packs," says Northen. "Restoring or protecting BSCs through changes in land-use could help pull carbon out of the atmosphere and reduce dust."

A better understanding of BSCs could also deepen our understanding of the carbon cycle, which could improve the accuracy of climate models, as Mukhopadhyay explains.

"In most climate models there is little or no accounting for the carbon fixed by soil microbes," she says. "BSC cyanobacteria are the photosynthetic organism for deserts and understanding their role in the carbon-cycle will help fill in current climate model gaps. This should help improve the accuracy of these models."

The Berkeley Lab team would like to expand their efforts to examine other BSC systems around the world. Among other issues, they would like to identify the signaling mechanisms that inform dormant BSC microbes that moisture is present or that the temperature is changing and it is time to respond.

"BSCs are sentinels for marking the health or decline of the world's deserts, one of Earth's major ecosystems," Mukhopadhyay says. "It is vital that we understand them."

Co-authoring the paper "Dynamic cyanobacterial response to hydration and dehydration in a desert biological soil crust" were Lara Rajeev, Ulisses Nunes da Rocha, Niels Klitgord, Eric Luning, Julian Fortney, Seth Axen, Patrick Shih, Nicholas Bouskill, Benjamin Bowen, Cheryl Kerfeld, Ferran Garcia-Pichel and Eoin Brodie.

This research was funded through Berkeley Lab's Laboratory Directed Research and Development program.

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New findings regarding DNA damage checkpoint mechanism in oxidative stress

For example, few of us realize that, while our cells' DNA is constantly being damaged by reactive oxygen species (as well as by other forces), there are also complex mechanisms that constantly assess that damage and make repairs to our fragile genetic material at least 10,000 times a day in every cell in our bodies. The vital biochemical processes by which this constant DNA repair takes place are still only partially understood because of their complexity, speed, and the difficulty of studying complex interactions within living cells. Moreover, it remains unknown how cells sense the oxidatively damaged DNA in the first place.

In an article published in the Proceedings of the National Academy of Sciences (PNAS) a research team from University of North Carolina at Charlotte announced that they had uncovered a previously unknown surveillance mechanism, known as a DNA damage checkpoint, used by cells to monitor oxidatively damaged DNA. The finding, first-authored by UNC Charlotte biology graduate student Jeremy Willis and undergraduate honors student Yogin Patel, was also co-authored by undergraduate honors student Barry L. Lentz and assistant professor of biology Shan Yan.

"DNA damage is the underlying pathology in many major human diseases, including cancers and neurodegenerative disorders such as Alzheimer's and Parkinson's, so arriving at a full understanding of the sophisticated mechanisms that cells usually employ to avoid such disastrous outcomes is important," Yan noted.

Two biochemical pathways, known as ATM-Chk2 and ATR-Chk1, govern the cell's response and repair of double-strand DNA breaks and other types of DNA damage or replication stress respectively. The molecular mechanisms underlying the ATR-Chk1 checkpoint activation include the uncoupling of DNA helicase and polymerase activities and DNA end resection of double-strand breaks.

"The significance of what we have found is that there is a third, previously unknown trigger for ATR-Chk1 checkpoint pathway, and this novel mechanism is discovered in the context of oxidative stress," Yan said.

In particular, Yan's team discovered that under conditions of oxidative stress (in the presence of hydrogen peroxide) a base excision repair protein known as APE2 plays unexpected roles in the checkpoint response: single-strand DNA generation and Chk1 association. The protein was previously known to be involved in the DNA repair of oxidative damage, but not to extent revealed in the study's findings. The distinct role of APE2 in the single-stand DNA generation in 3' to 5' direction is referred to as single-strand break end resection ("SSB end resection") by the authors.

The study involved experiments performed with Xenopus laves (the African clawed frog, a species commonly used as a lab animal) egg extracts -- an experimental system that Yan's lab has developed for studying DNA repair and checkpoint mechanisms in a cell-free conditions. Xenopus is useful because it is a vertebrate (and thus quite similar to humans in cell biology), and its egg cells can be easily produced and manipulated.

Yan is hopeful that this research will open new avenues to pharmacological strategies in drug development for cancer and neurodegenerative diseases.

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Autonomous energy-scavenging micro devices will test water quality, monitor bridges, more

Researchers at the University of Waterloo in Ontario are using optics and photonics in their quest to "bring the lab to the sample," said lead researcher Vassili Karanassios, director of the university's Institute for Nanotechnology. A major aspect of his team's solution, reported in a conference and publication by SPIE, the international society for optics and photonics, is scavenging energy from various sources to power instruments at the sample site.

While energy harvesting utilizes sources such as wind power, energy scavenging involves re-using discarded energy, such as the electric light that runs a calculator, Karanassios said.

The team is incorporating wake-up systems in the devices to support energy autonomy, the ability to be powered as needed without an external source, without losing selectivity, the ability to gather and accurately analyze relevant data.

An important feature of his lab's approach is the integration of several features of full-scale laboratory instruments.

"People have experimented with sensors and with lab-on-a-chip devices for a long time," Karanassios said. "But taking an entire instrument to the field in a hand-held device is new. Not many research groups have the expertise to integrate it all, to go from the sensor level to the micro-instrument level."

The team is also working to reduce the power required for miniature instruments that perform optical emission spectrometry -- using light to generate the spectral patterns that are intrinsically unique to materials -- with very small samples. The resulting spectral "signature" is used to identify what is in the sample, for example, in on-site monitoring of water quality.

Among power source optics, sunlight is one obvious answer, Karanassios said, but limited by clouds and brief daylight in some regions. Additional possible sources and applications for energy scavenging are:

Plugging in to human body heat, unobtrusively scavenging energy in the form of otherwise-wasted heat generated by a person while walking, to power instruments for testing water quality or wearable biomedical monitors.
Harnessing animal body heat, to recharge implanted tracking devices. "When tagging and tracking animals in the wild, you do not want to have to catch the same animal one more time just to replace the battery that powers its sensors," Karanassios noted.
Charging up a bridge sensor using mechanical energy generated in a spring-loaded device in the road, activated by vehicles crossing the bridge.

Because smaller sensors and instruments require less power, Karanassios' lab is working toward "shirt-pocket size" micro-instruments that eventually will deliver performance comparable to full-size lab versions.

They have experimented with a device the size of sugar cube that can be used along with a portable spectrometer for rapid screening of environmental contaminants, using spectral lines generated by wavelengths in the visible light and ultraviolet regions.

A paper detailing the work by Karanassios and Waterloo colleagues Donghyun Lee and Gurjit Dulai was published 28 May in the SPIE Digital Library, and presented in a conference on Energy Harvesting and Storage at SPIE defense, securit, and sensing meeting DSS 2013 last month in Baltimore. Titled "Survey of energy harvesting and energy scavenging approaches for on-site powering of wireless sensor- and microinstrument-networks," the paper is available via open access through 31 August 2013.

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Depression in postmenopausal women may increase diabetes and cardiovascular disease risk

The UMMS study investigated whether elevated depressive symptoms and antidepressant use are associated with biomarkers for glucose dysregulation and inflammation, BMI and waist circumference. The three main findings indicate that both elevated depressive symptoms and antidepressant use are each significantly associated with higher BMI and waist circumference; elevated depressive symptoms are associated with increased levels of insulin and insulin resistance; and antidepressant use is associated with increased C-reactive protein (CRP) levels, a marker of inflammation, which increases the risk of type 2 diabetes and cardiovascular disease.

"It may be prudent to monitor post-menopausal women who have elevated depression symptoms or are taking antidepressant medication to prevent diabetes and cardiovascular disease," said Dr. Ma, associate professor of medicine, who with UMMS colleagues analyzed data from the landmark Women's Health Initiative (WHI).

Postmenopausal women were recruited into the WHI from 1993 to 1998, and data for this analysis were collected at regular intervals through 2005. Using data from 1,953 women who completed all relevant WHI assessments, the study found that elevated depressive symptoms were found to be significantly associated with increased insulin levels and measures of insulin resistance. Significantly, throughout the entire 7.6 years on average that women were enrolled in the WHI, those who had elevated depressive symptoms or were using antidepressants had higher average BMI and waist circumference than did women not using antidepressants or without depressive symptoms among 71,809 women. However, the associations were stronger for waist circumference.

Analysis of data from 2,242 women showed that both elevated depressive symptoms and antidepressant use was associated with higher CRP levels, a marker of inflammation.

"Identifying these markers in women is important for diabetes prevention because they can be monitored for possible action before progression to full-blown diabetes," said Ma.

Few studies have examined the association of BMI, waist circumference and biomarkers of glucose dysregulation and inflammation with depression, antidepressant medication use, or both. The UMMS study included a large, racially and ethnically diverse sample of post-menopausal women. Because the analysis was epidemiological, it could not determine a causal relationship, so further study is needed to confirm the results through clinical trials.

"Given that diabetes and cardiovascular disease can be effectively prevented or delayed in high-risk individuals with lifestyle modifications or pharmacological interventions, our findings indicate the prudence of monitoring BMI, waist circumference, along with established biomarkers for diabetes and cardiovascular risk including serum glucose, insulin resistance, and CRP among women with elevated depression symptoms, or who are taking antidepressant medication, to prevent diabetes and cardiovascular disease," adds Dr. Simin Liu, professor of epidemiology and medicine at Brown University, a WHI investigator and study coauthor. "Further intervention trial is needed to confirm our findings and identify the specific patterns of change associated with diabetic and cardiovascular disease risk markers and individual antidepressants and depression."

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Sugar overload can damage heart

June 14, 2013 — Too much sugar can set people down a pathway to heart failure, according to a study led by researchers at The University of Texas Health Science Center at Houston (UTHealth).

A single small molecule, the glucose metabolite glucose 6-phosphate (G6P), causes stress to the heart that changes the muscle proteins and induces poor pump function leading to heart failure, according to the study, which was published in the May 21 issue of the Journal of the American Heart Association. G6P can accumulate from eating too much starch and/or sugar.

Heart failure kills 5 million Americans a year, according to the Centers for Disease Control. The one-year survival rate after diagnosis is 50 percent and there are 550,000 new patients in the United States diagnosed with heart failure each year.

"Treatment is difficult. Physicians can give diuretics to control the fluid, and beta-blockers and ACE inhibitors to lower the stress on the heart and allow it to pump more economically," said Heinrich Taegtmeyer, M.D., D.Phil., principal investigator and professor of cardiology at the UTHealth Medical School. "But we still have these terrible statistics and no new treatment for the past 20 years."

Taegtmeyer performed preclinical trials in animal models, as well as tests on tissue taken from patients at the Texas Heart Institute who had a piece of the heart muscle removed in order to implant a left ventricle assist device by O.H. "Bud" Frazier, M.D., and his team. Both led to the discovery of the damage caused by G6P.

"When the heart muscle is already stressed from high blood pressure or other diseases, and then takes in too much glucose, it adds insult to injury," Taegtmeyer said.

The study has opened doors to possible new treatments. Two drugs, rapamycin (an immunosuppressant) and metformin (a diabetes medication) disrupt signaling of G6P and improved cardiac power in small animal studies.

"These drugs have a potential for treatment and this has now cleared a path to future studies with patients," Taegtmeyer said.

The study was supported in part by grants from the National Institutes of Health (R01 HL061483, TL1RR024147, R21 HL102627 and R01 HL08972).

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