Guardian of the Cell


Scientists unravel the structure, key features of a human immune-surveillance protein, setting the stage for more-precise immune therapies

protein structure
Scientists have identified the key structural and functional features of a critical immune protein in humans that guards against cancer, viral and bacterial infections.

 

The human body is built for survival. Each one of its cells is closely guarded by a set of immune proteins armed with nearly foolproof radars that detect foreign or damaged DNA.

One of the cells’ most critical sentinels is a “first responder” protein known as cGAS, which senses the presence of foreign and cancerous DNA and initiates a signaling cascade that triggers the body’s defenses.

The 2012 discovery of cGAS ignited a firestorm of scientific inquiry, resulting in more than 500 research publications, but the structure and key features of the human form of the protein continued to elude scientists.

Now, scientists at Harvard Medical School and Dana-Farber Cancer Institute have, for the first time, identified the structural and functional differences in human cGAS that set it apart from cGAS in other mammals and underlie its unique function in people.

A report on the team’s work, published July 12 in Cell, outlines the protein’s structural features that explain why and how human cGAS senses certain types of DNA, while ignoring others.

“The structure and mechanism of action of human cGAS have been critical missing pieces in immunology and cancer biology,” said senior investigator Philip Kranzusch, assistant professor of microbiology and immunobiology at Harvard Medical School and Dana-Farber Cancer Institute. “Our findings detailing the molecular makeup and function of human cGAS close this critical gap in our knowledge.” Importantly, the findings can inform the design of small-molecule drugs tailored to the unique structural features of the human protein—an advance that promises to boost the precision of cGAS-modulating drugs that are currently in development as cancer therapies. “Several promising experimental immune therapies currently in development are derived from the structure of mouse cGAS, which harbors key structural differences with human cGAS,” Kranzusch said. “Our discovery should help refine these experimental therapies and spark the design of new ones. It will pave the way toward structure-guided design of drugs that modulate the activity of this fundamental protein.”

The team’s findings explain a unique feature of the human protein—its capacity to be highly selective in detecting certain types of DNA and its propensity to get activated far more sparingly, compared with the cGAS protein in other animals.

Specifically, the research shows that human cGAS harbors mutations that make it exquisitely sensitive to long lengths of DNA but render it “blind” or “insensitive” to short DNA fragments.

“Human cGAS is a highly discriminating protein that has evolved enhanced specificity toward DNA,” said co-first author Aaron Whiteley, a postdoctoral researcher in the Department of Microbiology and Immunobiology at Harvard Medical School. “Our experiments reveal what underlies this capability.”

Location, location, location

In all mammals, cGAS works by detecting DNA that’s in the wrong place. Under normal conditions, DNA is tightly packed and protected in the cell’s nucleus—the cellular “safe”—where genetic information is stored. DNA has no business roaming freely around the cell. When DNA fragments do end up outside the nucleus and in the cell’s cytosol, the liquid that encases the cell’s organelles, it’s usually a sign that something ominous is afoot, such as damage coming from within the cell or foreign DNA from viruses or bacteria that has made its way into the cell.

The cGAS protein works by recognizing such misplaced DNA. Normally, it lies dormant in cells. But as soon as it senses the presence of DNA outside the nucleus, cGAS springs into action. It makes another chemical—a second messenger—called cGAMP, thus setting in motion a molecular chain reaction that alerts the cell to the abnormal presence of DNA. At the end of this signaling reaction, the cell either gets repaired or, if damaged beyond repair, it self-destructs.

But the health and integrity of the cell are predicated on cGAS’ ability to distinguish harmless DNA from foreign DNA or self-DNA released during cell damage and stress. “It’s a fine balancing act that keeps the immune system in equilibrium. An overactive cGAS can spark autoimmunity, or self-attack, while cGAS that fails to detect foreign DNA can lead to tumor growth and cancer development,” said co-first author Wen Zhou, a postdoctoral researcher at Harvard Medical School and Dana-Farber Cancer Institute.

The current study reveals the evolutionary changes to the protein’s structure that allow human cGAS to ignore some DNA encounters while responding to others.

A foe, an accomplice

For their work, the team turned to an unlikely collaborator—Vibrio cholerae, the bacterium that causes cholera, one of humankind’s oldest scourges.

Taking advantage of a cholera enzyme that shares similarities with cGAS, the scientists were able to recreate the function of both human and mouse cGAS in the bacterium.

Teaming up with colleagues from the lab of Harvard Medical School bacteriologist John Mekalanos, the scientists designed a chimeric, or hybrid, form of cGAS that included genetic material from both the human and mouse forms of the protein. Then they compared the ability of the hybrid cGAS to recognize DNA against both the intact mouse and intact human versions of the protein.

In a series of experiments, the scientists observed activation patterns between the different types of cGAS, progressively narrowing down the key differences that accounted for differential DNA activation among the three.

The experiments revealed that out of the 116 amino acids that differ in human and mouse cGAS, only two accounted for the altered function of human cGAS. Indeed, human cGAS was capable of recognizing long DNA with great precision but it ignored short DNA fragments. The mouse version of the protein, by contrast, did not differentiate between long and short DNA fragments

“These two tiny amino acids make a world of difference,” Whiteley said. “They allow the human protein to be highly selective and respond only to long DNA, while ignoring short DNA, essentially rendering the human protein more tolerant of DNA presence in the cytosol of the cell.”

Plotting the genetic divergence on an evolutionary timescale, the scientists determined that the human and mouse cGAS genes parted ways sometime between 10 million and 15 million years ago.

The two amino acids responsible for sensing long DNA and tolerating short DNA are found solely in humans and nonhuman primates, such as gorillas, chimps and bonobos. The scientists hypothesize that the ability to ignore short DNA but recognize long DNA must have conferred some evolutionary benefits. “It could be a way to guard against an overactive immune system and chronic inflammation,” Kranzusch said. “Or it could be that the risk of certain human diseases is lowered by not recognizing short DNA.”

In a final set of experiments, the team determined the atomic structure of the human cGAS in its active form as it binds to DNA. To do so, they used a visualization technique known as X-ray crystallography, which reveals the molecular architecture of protein crystals based on a pattern of scattered X-ray beams.

Profiling the structure of cGAS “in action” revealed the precise molecular variations that allowed it to selectively bind to long DNA, while ignoring short DNA.

“Understanding what makes the structure and function of human cGAS different from those in other species was the missing piece,” Kranzusch said. “Now that we have it, we can really start designing drugs that work in humans, rather than mice.”

Other investigators included Carina de Oliveira Mann, Benjamin Morehouse, Radosław Nowak, Eric Fischer, and Nathanael Gray. The work was supported by the Claudia Adams Barr Program for Innovative Cancer Research, by the Richard and Susan Smith Family Foundation, by the Charles H. Hood Foundation, by a Cancer Research Institute CLIP Grant, by the National Institute of Allergy and Infectious Diseases grant AI-01845, by National Cancer Institute grant R01CA214608, by the Jane Coffin Childs Memorial Fund for Medical Research, by a Cancer Research Institute Eugene V. Weissman Fellow award, and by a National Institutes of Health T32 grant 5T32CA207021-02.

Relevant Disclosures: The Dana-Farber Cancer Institute and Harvard Medical School have patents pending for human cGAS technologies, on which the authors are inventors.

Harvard Medical School Harvard Medical School (http://hms.harvard.edu) has more than 11,000 faculty working in 10 academic departments located at the School’s Boston campus or in hospital-based clinical departments at 15 Harvard-affiliated teaching hospitals and research institutes: Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Cambridge Health Alliance, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care Institute, Hebrew SeniorLife, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, McLean Hospital, Mount Auburn Hospital, Spaulding Rehabilitation Network and VA Boston Healthcare System.

NASA’s Age Reversing Pill Begins Human Testing Within 6 Months


Scientists have made a discovery that could lead to a revolutionary drug that reverses ageing.

Experiments from a team at the University of New South Walessuggest a treatment is possible to repair DNA damage from both ageing and radiation. The ‘call signaling’ molecule is called NAD+. NAD+ is naturally in every cell of the body and posseses a key role in protein interactions (which control DNA repair.).

When treating mice with an NAD+ ‘booster’ called NMN  , studies showed improvement in the cells’ ability to repair the damaged DNA.

“This is the closest we are to a safe and effective anti-ageing drug that’s perhaps only three to five years away from being on the market if the trials go well. In the study,  cells of old mice were indistinguishable from the young mice after just one week of treatment,” said lead author Professor David Sinclair.

Professor Sinclair pictured in the middle. 

The work has also drawn the attention of NASA which is interested in its uses in the challenge of keeping astronauts healthy while in space.  On short missions, astronauts experience accelerated ageing due to exposure from cosmic radiation, suffering from muscle weakness, memory loss and other symptoms when they return. On longer missions, like a trip to Mars, the situation would be far worse. Five per cent of the astronauts’ cells would die and their chances of cancer would approach near 100 per cent.

Professor Sinclair and his colleague Dr Lindsay Wu were winners in NASA’s iTech competition in December last year:

‘We came in with a solution for a biological problem and it won the competition out of 300 entries,’ Dr Wu said.

Cosmic radiation isn’t an issue exclusive to astronauts.  We are all exposed to radiation aboard aircraft. A London-Singapore-Melbourne flight is equivalent in radiation to a chest x-ray.

The other group that could benefit from this work is survivors of childhood cancers. 96 percent of childhood cancer survivors suffer a chronic illness by age 45. This includes cardiovascular disease, Type 2 diabetes, Alzheimer’s disease, and certain forms of cancer.

The human trials for the anti ageing pill will begin this year at Brigham and Women’s Hospital, in Boston.

Source:www.minds.com

New means of growing intestinal stem cells.


The small intestine, like most other body tissues, has a small store of immature adult stem cells that can differentiate into more mature, specialized cell types. Until now, there has been no good way to grow large numbers of these stem cells, because they only remain immature while in contact with a type of supportive cells called Paneth cells.

New means of growing intestinal stem cells

In a new study appearing in the Dec. 1 online edition of Nature Methods, the researchers found a way to replace Paneth cells with two small molecules that maintain stem cells and promote their proliferation. Stem cells grown in a lab dish containing these molecules can stay immature indefinitely; by adding other molecules, including inhibitors and activators, the researchers can control what types of cells they eventually become.

“This opens the door to doing all kinds of things, ranging from someday engineering a new gut for patients with intestinal diseases to doing drug screening for safety and efficacy. It’s really the first time this has been done,” says Robert Langer, the David H. Koch Institute Professor, a member of MIT‘s Koch Institute for Integrative Cancer Research, and one of the paper’s senior authors.

Jeffrey Karp, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, is also a senior author of the paper. The paper’s lead author is Xiaolei Yin, a postdoc at the Koch Institute and Brigham and Women’s Hospital.

From one cell, many

The inner layer of the intestines has several critical functions. Some cells are specialized to absorb nutrients from digested food, while others form a barrier that secretes mucus and prevents viruses and bacteria from entering cells. Still others alert the immune system when a foreign pathogen is present.

This layer, known as the intestinal epithelium, is coated with many small indentations known as crypts. At the bottom of each crypt is a small pool of epithelial stem cells, which constantly replenish the specialized cells of the intestinal epithelium, which only live for about five days. These stem cells can become any type of intestinal epithelial cell, but don’t have the pluripotency of , which can become any cell type in the body.

If scientists could obtain large quantities of intestinal epithelial stem cells, they could be used to help treat gastrointestinal disorders that damage the epithelial layer. Recent studies in animals have shown that intestinal stem cells delivered to the gut can attach to ulcers and help regenerate healthy tissue, offering a potential new way to treat ulcerative colitis.

Using those stem cells to produce large populations of specialized cells would also be useful for drug development and testing, the researchers say. With large quantities of goblet cells, which help control the immune response to proteins found in food, scientists could study food allergies; with enteroendocrine cells, which release hunger hormones, they could test new treatments for obesity.

“If we had ways of performing high-throughput screens on large numbers of these very specific cell types, we could potentially identify new targets and develop completely new drugs for diseases ranging from inflammatory bowel disease to diabetes,” Karp says.

Controlling cell fate

In 2007, Hans Clevers, a professor at the Hubrecht Institute in the Netherlands, identified a marker for intestinal epithelial stem cells—a protein called Lgr5. Clevers, who is an author of the new Nature Methods paper, also identified growth factors that enable these stem cells to reproduce in small quantities in a lab dish and spontaneously differentiate into , forming small structures called organoids that mimic the natural architecture of the intestinal lining.

In the new study, the researchers wanted to figure out how to keep stem cells proliferating but stop them from differentiating, creating a nearly pure population of stem cells. This has been difficult to do because stem cells start to differentiate as soon as they lose contact with a Paneth cell.

Paneth cells control two signaling pathways, known as Notch and Wnt, which coordinate cell proliferation, especially during embryonic development. The researchers identified two small molecules, valproic acid and CHIR-99021, that work together to induce stem cells to proliferate and prevent them from differentiating into mature cells.

When the researchers grew mouse intestinal stem cells in a dish containing these two small molecules, they obtained large clusters made of 70 to 90 percent stem cells.

Once the researchers had nearly pure populations of stem cells, they showed that they could drive them to develop into particular types of  by adding other factors that influence the Wnt and Notch pathways. “We used different combinations of inhibitors and activators to drive stem cells to differentiate into specific populations of mature cells,” Yin says.

This approach also works in mouse stomach and colon cells, the researchers found. They also showed that the small molecules improved the proliferation of human intestinal stem cells. They are now working on engineering intestinal tissues for patient transplant and developing new ways to rapidly test the effects of drugs on intestinal cells.

Another potential use for these cells is studying the biology that underlies stem cells’ special ability to self-renew and to develop into other cell types, says Ramesh Shivdasani, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute.

“There are a lot of things we don’t know about ,” says Shivdasani, who was not part of the research team. “Without access to large quantities of these cells, it’s very difficult to do any experiments. This opens the door to a systematic, incisive, reliable way of interrogating intestinal stem cell biology.”

Completely Blind People Still Able To React To Light.


Photo credit: gun4hire

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Humans need light for a variety of reasons. Beyond allowing us to perceive our environment with sight, light also activates activity in the brain. A recent study has unexpectedly shown that even individuals who are completely blind are influenced by the presence of light. The presence or absence of light controls many bodily functions, including heart rate, attentiveness, mood, and reflexes. The study will be published in an upcoming edition of Journal of Cognitive Neuroscience. The work is a collaboration between a research team at the University of Montreal and the Brigham and Women’s Hospital in Boston.

The experiment was performed by exposing people who are completely blind to a blue light. The light was turned on and off and the participants were asked whether the light was on or off. The participants were shown to have a non-conscious response to the light, despite not being able to see it. There were more positive identifications made than could be explained by chance alone, though the awareness was non-conscious. This light perception comes from ganglion cells in the retina, which are different from the rod and cone cells that process light for sight.

Next, researchers tested if attentiveness was affected by the presence of light. For this activity, participants had to match sounds with lights on or off. Even though the participants could not visualize the light, they showed an increased attentiveness when light was shining into their eyes.

Finally, the test participants completed a brain scan with functional MRI (fMRI) to measure alertness, memory, and cognition recognition while performing tasks of matching sounds. Across the board, the tasks were completed more efficiently when light was present.

Because of these results, the researchers are speculating that light perception is part of the default mode network. This is the name for the brain activity that occurs non-consciously in the background, while other tasks take priority. They speculate that the ability to perceive light even without actively converting it into images is done to continually pay attention to and monitor the environment. If this is correct, it might help explain why cognitive performance is improved in the presence of light.

– See more at: http://www.iflscience.com/brain/completely-blind-people-still-able-react-light#sthash.KvGYh5Ew.dpuf

New designer compound treats heart failure by targeting cell nucleus.


Cell paper highlights entirely new approach to heart protection, addressing major unmet need

Researchers from Case Western Reserve University School of Medicine and Dana-Farber Cancer Institute have made a fundamental discovery relevant to the understanding and treatment of heart failure – a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.

In contrast to standard therapies for heart failure, JQ1 works directly within the cell’s command center, or nucleus, to prevent damaging stress responses. This groundbreaking research lays the foundation for an entirely new way of treating a diseased heart. The study is published in the August 1 issue of Cell.

“As a practicing cardiologist, it is clear that current heart failure drugs fall alarmingly short for countless patients. Our discovery heralds a brand new class of drugs which work within the cell nucleus and offers promise to millions suffering from this common and lethal disease,” said Saptarsi Haldar, MD, senior author on the paper, assistant professor of medicine at Case Western Reserve and cardiologist at University Hospitals Case Medical Center.

Heart failure occurs when the organ’s pumping capacity cannot meet the body’s needs. Existing drugs, most of which block hormones such as adrenaline at the cell’s outer surface, have improved patient survival. Unfortunately, several clinical studies have demonstrated that heart failure patients taking these hormone-blocking drugs still succumb to high rates of hospitalization and death. Leveraging a new approach, the research team turned their attention from the cell’s periphery to the nucleus – the very place that unleashes sweeping damage-control responses which, if left unchecked, ultimately destroy the heart.

The team found that a new family of genes, called BET bromodomains, cause heart failure because they drive hyperactive stress responses in the nucleus. Prior research linking BET bromodomains to cancer prompted the laboratory of James Bradner, MD, the paper’s senior author and a researcher at Dana-Farber, to develop a direct-acting BET inhibitor, called JQ1. In models of cancer, JQ1 functions to turn off key cancer-causing genes occasionally prompting cancer cells to “forget” they are cancer. In models of heart failure, JQ1 silences genetic actions causing enlargement of and damage to the heart – even in the face of overwhelming stress.

“While it’s been known for many years that the nucleus goes awry in heart failure, potential therapeutic targets residing in this part of the cell are often dubbed as ‘undruggable’ given their lack of pharmacological accessibility,” said Jonathan Brown, MD, cardiologist at Brigham and Women’s Hospital and co-first author on the paper. “Our work with JQ1 in pre-clinical models shows that this can be achieved successfully and safely.”

The team led by principal investigators Haldar and Bradner studied mice who develop classic features of human heart failure, including massively enlarged hearts that are full of scar tissue and have poor pumping function.

For one month, the team administered a single daily dose of JQ1 to the sick mice. The treated mice were protected from precipitous declines in heart function in a matter of days. Animals who received the compound saw a 60 percent improvement, as compared to an untreated control group.

“Remarkably, at the end of the experiment, the hearts of many JQ1 treated mice appeared healthy and vigorous, despite being exposed to persistent and severe stress,” said Priti Anand, a researcher in Haldar’s lab and co-first author on the paper. “We knew we were on to something big the first time we saw this striking response.”

This collaboration started when Haldar read Bradner’s landmark 2010 Nature paper describing the creation of JQ1 and its ability to transform cancer cells into healthy ones. Following an open-source approach to drug development, Bradner elected to make JQ1’s chemical recipe publicly available to accelerate the creation of new treatments for patients. This synergistic approach to discovery opened the door for Haldar to work with Bradner to probe the role of BET bromodomains in the heart.

“So much has been learned from this molecule,” noted Bradner. “The fundamental similarity between the biology of cancer cell growth and heart enlargement following extraordinary stress connects these mature fields of study in new and exciting ways, of immediate relevance to drug development. This study best exemplifies the power of open-source approaches to drug discovery.”

In the coming months, the team will test JQ1 in preclinical models of heart failure and other cardiovascular conditions. With the jumpstart offered by Bradner’s creation of JQ1, the research team hopes to one day move to clinical trials.

Source:DFCI

Cocoa, Even With Few Flavonoids, Boosts Cognition.


Drinking cocoa, whether rich in flavonoids or not, appears to boost the effect of blood flow on neuronal activity in the brain, known as neurovascular coupling (NVC).

A new study shows not only that drinking flavonoid-rich or flavonoid-poor cocoa improves NVC but also that higher NVC is associated with better cognitive performance and greater cerebral white matter structural integrity in elderly patients with vascular risk factors.

As researchers search for ways to detect dementia at the earliest possible stage, the study results could pave the way for using NVC as a biomarker for vascular function in those at high risk for dementia, said lead author Farzaneh A. Sorond, MD, PhD, Department of Neurology, Stroke Division, Brigham and Women’s Hospital, Boston, Massachusetts.

“Our study shows that NVC is modifiable and can be enhanced with cocoa consumption,” said Dr. Sorond.

Tight Correlation

The double-blind proof-of-concept study included 60 community-dwelling participants, mean age 72.9 years. About 90% of the participants were hypertensive, but with well-controlled blood pressure, and half had diabetes mellitus type 2 with reasonably good control. Three quarters were overweight or obese.

Participants were randomly assigned to 2 cups a day of cocoa rich in flavonoids (609 mg per serving) or cocoa with little flavonoids (13 mg per serving). Diets were adjusted to incorporate the cocoa, each cup of which contained 100 calories. Participants were also asked to abstain from eating chocolate.

Researchers measured cerebral blood flow in these participants using transcranial Doppler ultrasonography. Among other things, they documented changes in the middle cerebral artery and blood flow velocity at rest and in response to cognitive tasks (NVC).

The study showed that NVC was tightly correlated with cognition; scores for Trail making Test B, a test of executive function, were significantly better in those with intact NVC (89 seconds vs 167 seconds; P = .002). Participants with intact NVC also had significantly better performance on the 2-Back Task, a test for both attention and memory (82% vs 75%; P = .02).

“The higher you increase your blood flow during a cognitive task, the better your cognitive performance,” commented Dr. Sorond, adding that this is something that has never been shown before.

NVC was also correlated with cerebral white matter structural integrity. Higher NVC was associated with overall less white matter macro- and micro-structural damage. In general, those with intact NVC had a greater volume of normal white matter and smaller volume of white matter hyperintensities, higher fractional anisotropy, and lower mean diffusivity in the normal white matter and WMH.

Therapeutic Target

These results suggest that NVC could be an important therapeutic target. But before NVC can be considered a biomarker, it has to be shown to be changeable, and the clinical importance of the modification must be shown.

To that end, the study authors opted to use cocoa. They could have chosen many other potential modifiers but chose cocoa because the literature has shown the beneficial effects of cocoa on brain health and also because it’s something that many people enjoy, said Dr. Sorond.

The study found that blood pressure, blood flow, and change in NVC were not significantly different between the 2 cocoa groups. In the combined cocoa groups, 30-day blood pressures were not significantly different from baseline (P > .5).

In contrast, response to cocoa differed significantly depending on NVC status. Cocoa had a significant effect on NVC in those with impaired (<5%) coupling at baseline. Of those with impaired NVC, 89% responded to 30 days of cocoa consumption and increased NVC compared with only 36% of those with intact NVC (P = .0002). In those with impaired baseline coupling, cocoa consumption was associated with an 8.3% (P < .0001) increase in NVC at 30 days.

The effect of cocoa consumption on Trail B scores was also significantly dependent on NVC status.

The authors were surprised at the lack of effect of flavonoids because previous research had indicated a dose-response with respect to cognitive performance. It could be something other than flavonoids in the cocoa, possibly caffeine, that improves NVC, or it could be that the 13 mg in the low-flavonoid cocoa group was enough to have an effect.

“I think there are effects of flavonol on brain blood flow no matter how low it is,” said Dr. Sorond, adding that perhaps only a tiny amount is needed to activate an enzyme or some other trigger.

It’s important to identify the component or mechanism, whatever it is, because just telling patients to drink cocoa could be risky, said Dr. Sorond. “Patients with diabetes or hypertension really don’t need the extra sugar, extra calories, and extra fat that come with it.”

Dr. Sorond thinks NVC could be measured in high-risk patients seen in the clinic. “I think this could be an easy, in-clinic quick test of vascular brain function that pertains to cognitive performance.”

The ideal next step would be to carry out a larger study in patients with mild cognitive impairment that includes more detailed cognitive profiles and more control groups. “We need a cocoa arm; we need a caffeine arm; we need maybe other arms, to make sure that we understand this, and maybe look at some of the metabolites in the blood as a result of cocoa consumption that correlates with these things,” said Dr. Sorond.

Remarkable First Step

In an accompanying editorial, Paul B. Rosenberg, MD, associate professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, and Can Ozan Tan, PhD, Harvard Medical School, Boston, write that in many ways, the study represents a “remarkable first step.”

For one thing, it demonstrates the practical utility of a simple, inexpensive, and noninvasive technique for measuring NVC that has several advantages over functional MRI and other means of measuring blood brain flow during cognitive tasks.

In demonstrating a link between NVC and cerebral white matter structural integrity, the study provides an important validation for the association between vascular and cognitive function, according to Dr. Rosenberg.

The study demonstrates that NVC “hangs together” as a measure of vascular function, which could be used in studies targeting vascular interventions, said Dr. Rosenberg in an interview with Medscape Medical News. In this way, he added, the study is “promising for the development of new treatments for vascular dementia.”

The study suggests that the vascular effects of cocoa are not due to its flavonol content, noted Dr. Rosenberg.”It could be a placebo effect.”

Dr. Rosenberg pointed out several strengths of the study, including its relatively large size for a pilot study and its “well-chosen” measures.

Among its weaknesses are that it’s not a placebo-controlled study and the hypothesis that flavonoid-rich cocoa would work better than flavonoid-poor cocoa didn’t pan out. The study may also not have been long enough, said Dr. Rosenberg. “It’s nice to see a drug work for 30 days, but you really need a longer study.”

The study didn’t include patients with mild cognitive impairment who are at risk of developing dementia, which Dr. Rosenberg sees as another weakness. “It’s one thing to show an effect in cognitively healthy older people; it’s a very different thing to show an effect in people who have a brain disease,” he said.

The Alzheimer’s Association also sees weaknesses in the study. Not only is it a very small and very preliminary study, but it was also not well designed as a test of an intervention or therapy because it didn’t include a control group for comparison with the group that drank cocoa, said Maria Carrillo, PhD, Alzheimer’s Association vice president of medical and scientific relations.

Further, said Dr. Carrillo, it didn’t appear that other factors that could possibly affect brain blood flow and/or cognition were controlled for, tracked, or accounted for in the study.

“There is no information on what else the 18 people with impaired cerebral blood flow did during the trial that might have improved their cerebral blood flow or cognitive performance: exercise, for example. A well-designed intervention trial anticipates, tracks, and accounts for these possible confounding factors to help ensure the credibility of the findings.”

Source: Neurology

 

Cardiac disease linked to mild cognitive impairment.


Cardiac disease is associated with increased risk of mild cognitive impairment such as problems with language, thinking and judgment, according to a study.
The study by researchers with the Mayo Clinic found the connection was significant in women with heart disease more so than in men.

Known as nonamnestic because it does not include memory loss, this type of mild cognitive impairment may be a precursor to vascular and other non-Alzheimer’s dementias, the researchers noted. Mild cognitive impairment is an important stage for early detection and intervention in dementia, said Rosebud Roberts, MB, ChB, the study’s lead author and a health sciences researcher at the Mayo Clinic.

“Prevention and management of cardiac disease and vascular risk factors are likely to reduce the risk,” Roberts said in a news release.

The researchers evaluated 2,719 people ages 70 to 89 at the beginning of the study and every 15 months after. Of the 1,450 without mild cognitive impairment at the beginning, 669 had heart disease and 59 (8.8%) developed nonamenestic mild cognitive impairment. In comparison 34 (4.4%) of 781 who did not have heart disease developed nonamenestic mild cognitive impairment.

The association varied by sex, with cardiac disease and mild cognitive impairment appearing together more often among women than men.

Source: JAMA

 

 

Low Melatonin Levels Linked to Diabetes, Study Finds.


Image112EMR-Melatonin-Cherry26jul00f1Having low levels of melatonin, a hormone that regulates sleep, may put you at risk for type 2 diabetes, according to a new study.

By Amir Khan, Everyday Health Staff Writer

People with low levels of melatonin, a hormone that helps regulate sleep and circadian rhythm, may be at a higher risk for type 2 diabetes than people with high levels, according to a new study published in the Journal of the American Medical Association.

Researchers from Brigham and Women’s Hospital in Boston looked at 370 women who developed diabetes while taking part in the Nurses’ Health Study, a long-term study on women’s health, alongside 370 healthy controls, and found that study participants with low levels of melatonin were at approximately twice the risk of developing type 2 diabetes when compared to participants with high levels, even after the researchers adjusted for other diabetes risk factors such as smoking, diet, and exercise.

“This is the first time that an independent association has been established between nocturnal melatonin secretion and type 2 diabetes risk,” Ciaran McMullan, MD, study author and researcher in the renal division at Brigham and Women’s Hospital, said in a statement. “Hopefully this study will prompt future research to examine what influences a person’s melatonin secretion and what is melatonin’s role in altering a person’s glucose metabolism and risk of diabetes.”

Previous research done in rats has shown that taking a melatonin supplement protected them against diabetes, the researchers said, but they could not say for sure that it would have the same effect in humans.

Melatonin is produced in the pineal gland, which is located in the center of the brain, and can be measured through a blood, urine or saliva test. The hormone is only produced in the dark, and low levels have been linked to various conditions, including breast cancerovarian cancer, andinsomnia.

“Melatonin receptors have been found throughout the body in many tissues including pancreatic islet cells,” the researchers wrote in the study, “reflecting the widespread effects of melatonin on physiological functions such as energy metabolism and the regulation of body weight.”

While the researchers could not say for sure that there was a causal link between low melatonin levels and type 2 diabetes, they said previous research has shown that melatonin can play a role helping to regulate sugar levels in the body. When melatonin levels are low, the researchers continued, your blood sugar levels could be thrown off, raising your risk for diabetes.

In addition, they said that since melatonin helps regulate sleep and circadian rhythm, it’s possible that people with low melatonin levels wake up frequently during the night and sleep fewer hours, which could increase their risk.

“Sleep disruption may also be associated with diabetes,” the researchers wrote in the study. “For example, men who reported sleeping less than five hours per night were twice as likely to develop diabetes as those who reported sleeping seven hours per night.”

Although this is the first study to link melatonin to diabetes risk, some doctors use melatonin to treat patients who are already diagnosed with the condition. Michael Wald, MD, director of nutritional services at Integrated Medicine of Mount Kisco in Mount Kisco, NY, routinely gives his diabetic patients melatonin, and said it helps bring their blood sugar levels back into line.

“Several studies have noted that diabetes often have insomnia and it is this subgroup of diabetes that may benefit the most from melatonin supplementation,” said Dr. Wald. “In diabetics with low melatonin, taking slow-release melatonin seems to improve blood sugar levels. The diabetic blood sugar test, called hemoglobin A1c, is reduced in diabetics who take between 1 to 2 mg of melatonin two hours before bedtime.”

Giving patients melatonin, he added, not only helps their blood sugar levels, but also helps them sleep better, which can reduce the risks of other diseases as well.

“By improving sleep quality, melatonin may reduce the risk of many diseases that are associated with poor sleep quality,” Wald said, “including, but not limited to, cardiovascular disease, sleep apnea, nerve problems, depression and pain.”

Salt Linked to Autoimmune Diseases .


 

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Nanowires used to disarm single genes in cells without harming or altering them were used to reveal that sodium chloride might cause harmful T cell growth

The incidence of autoimmune diseases, such as multiple sclerosis and type 1 diabetes, has spiked in developed countries in recent decades. In three studies published today in Nature, researchers describe the molecular pathways that can lead to autoimmune disease and identify one possible culprit that has been right under our noses — and on our tables — the entire time: salt.

To stay healthy, the human body relies on a careful balance: too little immune function and we succumb to infection, too much activity and the immune system begins to attack healthy tissue, a condition known as autoimmunity. Some forms of autoimmunity have been linked to overproduction of TH17 cells, a type of helper T cell that produces an inflammatory protein called interleukin-17.

But finding the molecular switches that cause the body to overproduce TH17 cells has been difficult, in part because conventional methods of activating native immune cells in the laboratory often harm the cells or alters the course of their development.

So when researchers heard a talk by Hongkun Park, a physicist at Harvard University in Cambridge, Massachusetts, about the use of silicone nanowires to disarm single genes in cells, they approached him immediately, recalls Aviv Regev, a biologist at the Massachusetts Institute of Technology (also in Cambridge) and a co-author on two of the studies.

Park showed last year that these nanowires can be used to manipulate genes in immune cells without affecting the cells’ functions. For the first of the Nature studies, Regev and her colleagues used Park’s technology to piece together a functional model of how TH17 cells are controlled, she says. “Otherwise,” she says, they would have been only “guessing in the dark.”

In the second study, an affiliated team of researchers observed immune cell production over 72 hours. One protein kept cropping up as a TH17-signal: serum glucocorticoid kinase 1 (SGK1), which is known to regulate salt levels in other types of cells. The researchers found that mouse cells cultured in high-salt conditions had higher SGK1 expression and produced more TH17 cells than those grown in normal conditions.

“If you incrementally increase salt, you get generation after generation of these TH17 cells,” says study co-author Vijay Kuchroo, an immunologist at Brigham and Women’s Hospital in Boston, Massachusetts.

In the third study, researchers confirmed Kuchroo’s findings, in mouse and human cells. It was “an easy experiment — you just add salt”, says David Hafler, a neurologist at Yale University in New Haven, Connecticut, who led the research.

But could salt change the course of autoimmune disease? Both Kuchroo and Hafler found that in a mouse model of multiple sclerosis, a high-salt diet accelerated the disease’s progression.

All this evidence, Kuchroo says, “is building a very interesting hypothesis [that] salt may be one of the environmental triggers of autoimmunity”.

But Kuchroo and other researchers say that evidence so far cannot predict the effect of salt on human autoimmunity. “As a physician, I’m very cautious,” Hafler says. “Should patients go on a low-salt diet? Yes,” he says, adding that “people should probably already be on a low-salt diet” for general health concerns.

Other experts are intrigued by the findings. “They have a very clear effect in vitro,” says John O’Shea, scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program in Bethesda, Maryland. But Hafler and others note that there are likely many cell types and environmental factors involved in triggering autoimmunity.

The results offer tantalizing leads for drug targets for autoimmune conditions. But O’Shea notes that it is unclear whether TH17 proliferation is a factor in all autoimmune disease. A targeted drug that might work to relieve psoriasis might not subdue rheumatoid arthritis. “When we say autoimmunity, we’re implying that it’s one thing,” O’Shea says. “But it’s not one thing — it’s heterogeneous.”

Source: Scientific American.

Transplant doc, Nobel winner Murray dies in Boston.


Dr. Joseph E. Murray, who performed the world’s first successful kidney transplant and won a Nobel Prize for his pioneering work, has died at age 93.

Murray suffered a stroke at his suburban Boston home on Thanksgiving and died at Brigham and Women’s Hospital on Monday, hospital spokesman Tom Langford said.

Since the first kidney transplants on identical twins, hundreds of thousands of transplants on a variety of organs have been performed worldwide. Murray shared the Nobel Prize in Physiology or Medicine in 1990 with Dr. E. Donnall Thomas, who won for his work in bone marrow transplants.

“Kidney transplants seem so routine now,” Murray told The New York Times after he won the Nobel. “But the first one was like Lindbergh’s flight across the ocean.”

Murray’s breakthroughs did not come without criticism, from ethicists and religious leaders. Some people “felt that we were playing God and that we shouldn’t be doing all of these, quote, experiments on human beings,” he told The Associated Press in a 2004 interview in which he also spoke out in favor of stem cell research.

In the early 1950s, there had never been a successful human organ transplant. Murray and his associates at Boston’s Peter Bent Brigham Hospital, now Brigham and Women’s Hospital, developed new surgical techniques, gaining knowledge by successfully transplanting kidneys in dogs. In December 1954, they found the right human patients, 23-year-old Richard Herrick, who had end-stage kidney failure, and his identical twin, Ronald Herrick.

Because of their identical genetic background, they did not face the biggest problem with transplant patients, the immune system’s rejection of foreign tissue.

After the operation, Richard had a functioning kidney transplanted from Ronald. Richard lived another eight years, marrying a nurse he met at the hospital and having two children.

Murray performed more transplants on identical twins over the next few years and tried kidney transplants on other relatives, including fraternal twins, learning more about how to suppress the immune system’s rejection of foreign tissue. One patient who received a kidney transplant from a fraternal twin in 1959, plus radiation and a bone marrow transplant to suppress his immune response, lived for 29 more years.

But it was the development of drugs to suppress the body’s immune response, a less radical approach than radiation, that made real breakthroughs in transplants possible. In 1962, Murray and his team successfully completed the first organ transplant from an unrelated donor. The 23-year-old patient, Mel Doucette, received a kidney from a man who had died.

Murray continued a long career in plastic surgery, his original specialty, and transplants. He was guided by his own deep religious convictions.

“Work is a prayer,” he told the Harvard University Gazette in 2001. “And I start off every morning dedicating it to our Creator.”

Murray told the Journal of the American Medical Association in 2004 that he continued to get letters from patients he helped years earlier and from relatives of those who died during the early efforts.

“They often say … that they are happy to have played some small part in the eventual success of organ transplants,” he said, praising the courage of his patients and their families.

Murray was honored at the 2004 Transplant Games, for athletes who have received organ transplants, along with Ronald Herrick, the man who had donated a kidney to his twin brother a half-century earlier.

Murray continued to support and mentor others at Brigham and Women’s Hospital after his retirement, hospital president Dr. Elizabeth Nabel said. An exhibit in the hospital’s library housing his Nobel Prize, she said, is framed by his own words: “Service to society is the rent we pay for living on this planet.”

Murray’s interest in transplants developed during his time in the Army during World War II when he was assigned to Valley Forge General Hospital in Pennsylvania while awaiting overseas duty. The hospital performed reconstructive surgery on troops who had been injured in battle.

The burn patients, who often were treated with skin grafts from other people, intrigued Murray.

“The slow rejection of the foreign skin grafts fascinated me,” Murray wrote in autobiography for the Nobel Prize ceremony. “How could the host distinguish another person’s skin from his own?”

The hospital’s chief of plastic surgery had performed skin grafts on civilians and noticed that the closer the donor and recipient were related, the slower the tissue was rejected. A skin graft between identical twins had taken permanently.

Murray said that was “the impetus” of his study of organ transplantation.

Murray was ever the optimist and kept on his desk a quotation, “Difficulties are opportunities,” his son Rick Murray said.

“It reflects the unwavering optimism of a great man who was generous, curious, and always humble,” Rick Murray said in a statement released by the hospital.

Source: Yahoo News