Explainer: the locus coeruleus

Critical early site of neurodegeneration

Scaling up to a speck of dust

DNA bricks almost large enough to see with the naked eye

Clot dissolver tPA's tardy twin could aid in stroke recovery

Tissue-type plasminogen activator, meet urokinase-type plasminogen activator. You guys probably know each other.

Explainer: the locus coeruleus

The locus coeruleus is a part of the brain that has been getting a lot of attention recently from Emory neuroscience researchers.

The locus coeruleus is the biggest source of the neurotransmitter norepinephrine in the brain. Located deep in the brainstem, it has connections all over the brain, and is thought to be involved in arousal and attention, stress, memory, the sleep-wake cycle and balance.

Researchers interested in neurodegenerative disease want to look at the locus coeruleus because it may be one of the first structures to degenerate in diseases such as Alzheimer’s and Parkinson’s. In particular, the influential studies of German neuro-anatomist Heiko Braak highlight the locus coeruleus as a key “canary in the coal mine” indicator of neurodegeneration.

That’s why neurologist Dan Huddleston, working with biomedical imaging specialists Xiangchuan Chen and Xiaoping Hu and colleagues at Emory, has been developing a method for estimating the volume of the locus coeruleus by magnetic resonance imaging (MRI). Their procedure uses MRI tuned in such a way to detect the pigment neuromelanin (see panel), which accumulate in both the locus coeruleus and in the substantia nigra. Read more

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Scaling up to a speck of dust

DNA bricks keep getting larger. In 2012, a team of researchers at Harvard described their ability to make self-assembling structures –made completely out of DNA — that were about the size of viruses (80 nanometers across).

Yonggang Ke, PhD

Now they’re scaling up, making bricks that are 1000 times larger and getting close to a size that could be barely visible to the naked eye.

The advances were reported in Nature Chemistry.

Who: a team of researchers at the Wyss Institute at Harvard led by Peng Yin, and including Yonggang Ke, PhD, now an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

How: The DNA brick method uses short, synthetic strands of DNA that work like interlocking Lego® bricks to build complex structures. Structures are first designed using a computer model of a molecular cube, which becomes a master canvas. Each brick is added or removed independently from the 3D master canvas to arrive at the desired shape. The DNA strands that would match up to achieve the desired structure are mixed together and self assemble — with the help of magnesium salts — to achieve the designed crystal structures.

“Therein lies the key distinguishing feature of our design strategy–its modularity,” Ke says. “The ability to simply add or remove pieces from the master canvas makes it easy to create virtually any design.”

What for: As part of this study the team demonstrated the ability to position gold nanoparticles less than two nanometers apart from each other along the crystal structure — a critical feature for future quantum computational devices and a significant technical advance for their scalable production.

More here.

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Clot dissolver tPA’s tardy twin could aid in stroke recovery

Emory researchers led by neurologist Manuel Yepes, MD have identified a protein released by neurons while the brain is recovering from a stroke. The results were published online today in Journal of Neuroscience.

The protein, called urokinase-type plasminogen activator or uPA, has been approved by the FDA to dissolve blood clots in the lungs. It has been tested in clinical trials in some countries as a treatment for acute stroke.

The Emory team’s findings suggest that in stroke, uPA’s benefits may extend beyond the time when doctors’ principal goal is dissolving the blood clot that is depriving the brain of blood.
Instead, uPA appears to help brain cells recover from the injuries induced by loss of blood flow. Treating mice with uPA after an experimental stroke can improve their recovery of motor function, the researchers found.

Read more

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Revisiting landmark folate-autism study

Geneticist Joe Cubells is doing some monumental work re-examining a Chinese study of folic acid supplementation during pregnancy and its impact on autism risk. He is also the Medical Director at the Emory Autism Center. Please see SFARI to check it out.

 

 

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Need a really small number?

Biomedical engineer Yonggang Ke‘s “DNA origami” artwork appears on the cover of NKe-image-300x265ature Methods, as part of a celebration of the journal’s 10th anniversary. Ke designed self-assembling DNA strands that would form a cylinder and a ring structure, let them assemble, and obtained images with transmission electron microscopy. The height of the final image is 120 nanometers, smaller than the wavelengths of visible light and about the size of an influenza or HIV virion.

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Many colors in the epigenetic palette

Methylation, an epigenetic modification to DNA, can be thought of as a highlighting pen applied to DNA’s text, adding information but not changing the actual letters of the text.

Are you still with me on the metaphors? If so, consider this wrinkle. (If not, more explanation here.)

Emory geneticist Peng Jin and his colleagues have been a key part of the discovery in the last few years that methylation comes in several colors. His lab has been mapping where 5-hydroxymethylcytosine or 5hmC appears in the genome and inferring how it functions. 5-hmC is particularly abundant in the brain.D5405-2

Methylation, in the form of 5-methylcytosine or 5mC, is both a control button for turning genes off and a sign of their off state. 5hmC looks like 5mC, except it has an extra oxygen. That could be a tag for a removal, or a signal that a gene is poised to be turned on.

Two recent papers on this topic:

Please recall that an enriched environment (exercise and mental stimulation) is good for learning and memory, for young and old. In the journal Genomics, Jin and his team show that exposing mice to an enriched environment  — a running wheel and a variety of toys — leads to a 60 percent reduction in 5hmC in the hippocampus, a region of the brain critical for learning and memory.  The changes in 5hmC were concentrated in genes having to do with axon guidance. Hat tip to the all-things-epigenetic site Epigenie.

In Genes and Development, structural biologist Xiaodong Cheng and colleagues demonstrate that two regulatory proteins that bind DNA (Egr1 and WT1) respond primarily to oxidation of their target sequences rather than methylation. These proteins like plain old C and 5mC equally, but they don’t like 5hmC or other oxidized forms of 5mC. “Gene activity could plausibly be controlled on a much finer scale by these modifications than simply ‘on or ‘off’,” the authors write.

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Bits from HIV + Aging conference

What conferences like the HIV + Aging meeting recently held by Emory in Decatur offer the visiting writer: anecdotes that illustrate issues of clinical care.

To illustrate her point that assumptions about who is likely to develop a new HIV infection may lead doctors to miss possible diagnoses, keynote speaker Amy Justice from Yale described a patient who was seen last year at Yale-New Haven Hospital.

A 60 year old man reported fatigue and had lost 40 pounds over the course of a year. Despite those symptoms, and the discovery of fungal and viral infections commonly linked to HIV/AIDS, it took nine months before a HIV test was performed on the patient, a delay Justice deplored.

Sex and substance abuse do not end at age 50, she said, citing data showing that the risk of HIV transmission can be greater among older adults, and that substance abuse is more likely among adults who are HIV positive compared to those who are HIV negative.

Justice also highlighted the issue of polypharmacy (interactions between prescription drugs at the same time), a concern even in people who are not living with HIV. Common blood pressure medications taken by older adults to prevent heart disease have been suspected of increasing the risk for falls. That’s a problem especially for people living with HIV, because HIV infection has been linked to weakened bone. Read more

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Nobel Prize for place cells + grid cells

Congratulations to John O’Keefe, May-Britt Moser and Edvard Moser for receiving the 2014 Nobel Prize in Medicine. The prize is for discovering “the brain’s navigation system”: place cells, cells in the hippocampus which are active whenever a rat is in a particular place, and grid cells, cells in the entorhinal cortex which are active when the animal is at multiple locations in a grid pattern.

Former Yerkes researcher Beth Buffalo and her graduate student Nathan Killian were the first to directly detect, via electrode recordings, grid cells in the brains of non-human primates. Buffalo is now at the University of Washington and Killian is at Harvard Medical School.

A significant difference about their experiments was that they could identify grid cells when monkeys were moving their eyes, suggesting that primates don’t have to actually visit a place to construct the same kind of mental map. Another aspect of grid cells in non-human primates not previously seen with rodents is that the cells’ responses change when monkeys are seeing an image for the second time.

Following that report, grid cells were also directly detected in human epilepsy patients. The Mosers themselves noted in a 2014 review, “It will be interesting to see whether the same cells that respond to visual movement in monkeys also respond to locomotion, or whether there is a separate system of grid cells that is responsive to locomotion.”

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Refining tools for Big Data

You may have been hearing about the advent of Big Data: truckloads of information coming from cell phones, satellites, microscopes, and perhaps someday, wearable health monitoring devices.

At Emory, specialists in biomedical informatics have been in the forefront of efforts to design software that will allow scientists to learn from these mountains of data. Fusheng Wang was recently named as co-PI on a five-year $5 million National Science Foundation grant to create MIDAS (Middleware for Data-Intensive Analytics and Science), part of the NSF’s Data Infrastructure Building Blocks program. For this grant, the team consists of seven institutions: Indiana University (lead — Geoffrey Fox), Arizona State, Emory, Kansas, Rutgers, Utah and Virginia Tech.

Wang also recently received a NSF Career award in this same area.

The MIDAS project addresses major data challenges in seven different communities: biomolecular simulations, network and computational social science, epidemiology, computer vision, spatial geographical information systems, remote sensing for polar science, and pathology informatics. Wang is responsible for pathology informatics and geospatial, gathering requirements from those communities and implementing the spatial query and parts of the image analysis library. The libraries are supposed to be interoperable across a range of computing systems including clouds, clusters and supercomputers. The project includes a plan to develop a open online course (MOOC), according to the NSF.

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From Berlin to Yerkes

Yerkes immunologist Guido Silvestri and colleagues have a paper in PLOS Pathogens shedding light on the still singular example of Timothy Brown, aka “the Berlin patient”, the only human cured of HIV. Hat tip to Jon Cohen of Science, who has a great explanatory article.

Recall that Brown had lived with HIV for several years, controlling it with antiretroviral drugs, before developing acute myeloid leukemia. In Berlin, as treatment for the leukemia, he received a bone marrow transplant — and not just from any donor; the donor had a HIV-resistance mutation. What was the critical ingredient that enabled HIV to be purged from his body?

Conditioning: the chemotherapy/radiation treatment that eliminates the recipient’s immune system before transplant? HIV-resistant donor cells? Or graft-vs-host disease: the new immune system attacking the old?

Silvestri and colleagues performed experiments with SHIV-infected non-human primates that duplicate most, but not all, of the elements of Brown’s odyssey. The results demonstrate that conditioning, by itself, does not eliminate the virus from the body. But in one animal, it came close. Frustratingly, that animal’s kidneys failed and researchers had to euthanize it. In two others, the virus came back after transplant.

A critical difference from Brown’s experience is that monkeys received their own virus-free blood-forming stem cells instead of virus-resistant cells. Cohen reports that Silvestri hopes to do future monkey experiments that test more of these variables, including transplanting the animals with viral-resistant blood cells that mimic the ones that Brown received. 

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