‘Genetic doppelgangers:’ Emory research provides insight into two neurological puzzles

An international team led by Emory scientists has gained insight into the pathological mechanisms behind two devastating neurodegenerative diseases. The scientists compared the most common inherited form of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) with a rarer disease called spinocerebellar ataxia type 36 (SCA 36). Both of the diseases are caused by abnormally expanded and strikingly similar DNA repeats. However, ALS progresses quickly, typically killing patients within a year or two, while the disease Read more

Emory launches study on COVID-19 immune responses

Emory University researchers are taking part in a multi-site study across the United States to track the immune responses of people hospitalized with COVID-19 that will help inform how the disease progresses and potentially identify new ways to treat it.  The study is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The study – called Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) – launched Friday. Read more

Marcus Lab researchers make key cancer discovery

A new discovery by Emory researchers in certain lung cancer patients could help improve patient outcomes before the cancer metastasizes. The researchers in the renowned Marcus Laboratory identified that highly invasive leader cells have a specific cluster of mutations that are also found in non-small cell lung cancer patients. Leader cells play a dominant role in tumor progression, and the researchers discovered that patients with the mutations experienced poorer survival rates. The findings mark the first Read more

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Why humans develop gout

Thanks to prolific UK science writer Ed Yong for picking up on a recent paper in PNAS from Eric Gaucher’s lab at Georgia Tech and Eric Ortlund’s at Emory.

Gaucher and Ortlund teamed up to “resurrect” ancient versions of the enzyme uricase, in search of an explanation for why humans develop gout. Yong explains:

The substance responsible for the condition [gout] is uric acid, which is normally expelled by our kidneys, via urine. But if there’s too much uric acid in our blood, it doesn’t dissolve properly and forms large insoluble crystals that build up in our joints. That explains the http://www.raybani.com/ painful swellings. High levels of uric acid have also been linked to obesity, diabetes, and diseases of the heart, liver and kidneys. Most other mammals don’t have this problem. In their bodies, an enzyme called uricase converts uric acid into other substances that can be more easily excreted.

Uricase is an ancient invention, one that’s shared by bacteria and animals alike. But for some reason, apes have abandoned it. Our uricase gene has mutations that stop us from making the enzyme at all. It’s a “pseudogene”—the biological version of a corrupted computer file. And it’s the reason that our blood contains 3 to 10 times more uric acid than that of other mammals, predisposing us to gout.

“Our role* on the project was to solve the three dimensional structure of this enzyme using X-ray crystallography to figure out how these ancient mutations led to a decline in uricase activity in humans and apes,” Ortlund says. “We were interested in how this enzyme lost function, and for the future, how we can restore function to this enzyme to create a more “human-like” (and thus less immunogenic) protein than the current available bacterial or baboon-pig uricase chimeras.”

(There’s even a patent on this ancient uricase as a potential treatment for gout, and a start-up company named General Genomics)

Their paper also explores what advantage humans might have gained from losing functional uricase. The proposal is: by disabling uricase, ancient primates became more efficient at Ray Ban outlet turning fructose, the sugar found in fruit, into fat. Their results provide some support for the “thrifty gene hypothesis:” the idea that humans are evolutionarily adapted to being able to survive an erratic food supply, which is not so great now that people in developed countries have access to lots of food. The authors write:

The loss of uricase may have provided a survival advantage by amplifying the effects of fructose to enhance fat stores, and by the ability of uric acid to stimulate foraging, while also increasing blood pressure in response to salt. Thus, the loss of uricase may represent the first example of a “thrifty gene” to explain the current epidemic of obesity and diabetes, except that it is the loss of a gene, and not the acquisition of a new gene, that has ray ban da sole outlet increased our susceptibility to these conditions. 

*Ortlund’s former postdoc Michael Murphy was involved in this part.

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Antioxidants are no panacea

Derek Lowe, a respected science blogger and drug discovery expert who was blogging when this writer was still working in the laboratory, today has a roundup of a concept that anyone hanging around Emory might have clued into already.

Namely, antioxidants aren’t all they’re cracked up to be. Judging from the messages Gafas Ray Ban outlet to shoppers in the supermarket vitamin aisle, everybody needs more antioxidants. But evidence is accumulating that in some situations, antioxidants can be harmful: negating the adaptive effects of exercise on muscle tissue or even encouraging tumor growth, Lowe writes.

At Emory, Dean Jones has been patiently explaining for years that cells are not simply big bags with free radicals, thiols and antioxidants sloshing around indiscriminately. Instead, cells and oxidation-sensitive components are highly compartmentalized. Take for example, this recent paper in Molecular & Cellular Proteomics from Jones and Young-mi Go. Two major antioxidant systems in cells, glutathione and thioredoxin, function distinctly and independently, they show.

In a related vein, Kathy Griendling’s and David Lambeth’s labs were at the center of the discovery that reactive oxygen species are not only poisons that overflow from mitochondria, but important signals involved in many aspects of cell biology.

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Talking to members of Congress: how-to for scientists

It’s OK to use the term “pH” when talking with a member of Congress – but not the word “intracellular.”

This was one of the rules of thumb that emerged from Adam Katz’ talk at the GDBBS Student Research Symposium Friday afternoon. Katz, a public policy specialist at Research America, was advising Emory graduate students and faculty on the best ways to advocate for biomedical research. His theme: get personal.

That is, he advised scientists to meet in person with members of Congress or people on their staffs, try to get them to remember you, and invite them to come visit your laboratory. Make a personal connection. Read more

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Odd couples and persistence

When doctors treat disease-causing bacteria with antibiotics, a few bacteria can survive even if they do not have a resistance gene that defends them from the antibiotic. These rare, slow-growing or hibernating cells are called “persisters.”

Microbiologists see understanding persistence as a key to fighting antibiotic resistance and possibly finding new antibiotics. Persistence appears to be regulated by constantly antagonistic pairs of proteins called toxin-antitoxins.

Basically, the toxin’s job is to slow down bacterial growth by interfering with protein production, and the antitoxin’s job is to restrain the toxin until stress triggers a retreat by the antitoxin. Some toxins chew up protein-encoding RNA messages docked at ribosomes, but there are a variety of mechanisms. The genomes of disease-causing bacteria are chock full of these battling odd couples, yet not much was known about how they work in the context of persistence.

Biochemist Christine Dunham reports that several laboratories recently published papers directly implicating toxin-antitoxin complexes in both persistence and biofilm formation. Her laboratory has been delving into how the parts of various toxin-antitoxin complexes interact.HigBA smaller

BCDB graduate student Marc Schureck and colleagues have determined the structure of a complex of HigBA toxin-antitoxin proteins from Proteus vulgaris bacteria via X-ray crystallography. The results were recently published in Journal of Biological Chemistry.

While Proteus vulgaris is known for causing urinary tract and wound infections, the HigBA toxin-antitoxin pair is also found in several other disease-causing bacteria such as V. cholera, P. aeruginosa, M. tuberculosis, S. pneumoniae etc.

“We have been directly comparing toxin-antitoxin systems in E. coli, Proteus and M. tuberculosis to see if there are commonalities and differences,” Dunham says.

The P. vulgaris HigBA structure is distinctive because the antitoxin HigA does not wrap around and mask the active site of HigB, which has been seen in other toxin-antitoxin systems. Still, HigA clings onto HigB in a way that prevents it from jamming itself into the ribosome.

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Cellular response to stress: autophagy

Update: Yoshinori Ohsumi’s 2016 Nobel Prize was for the study of autophagy. Hepatologist Mark Czaja, who came to Emory in 2015, is well known for his work on autophagy in the liver.

Feeling hungry? For this month’s Current Concept feature, lets take a look at the term autophagy. Taken literally, its Greek roots mean “self-digestion”.

Autophagy in mouse liver cells — the autophagic vesicles are green (Image from PNAS)

Autophagy is a basic response of cells to not having enough nutrients or other forms of stress: they begin to break down parts of the cell that are broken or not needed. The term autophagy was coined by Belgian biochemist Christian de Duve in the 1960s. He discovered lysosomes, the parts of the cell where breakdown can take place.

Autophagy comes up in many contexts in biomedical research. Indeed, there is an entire scientific journal devoted to the topic. At Emory, researchers interested in cancer, Parkinson’s, stroke and liver disease all have touched upon the process of autophagy.  Read more

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How beneficial bacteria talk to intestinal cells

Guest post from Courtney St Clair Ardita, MMG graduate student and co-author of the paper described. Happy Halloween!

In the past, reactive oxygen species were viewed as harmful byproducts of breathing oxygen, something that aerobic organisms just have to cope with to survive. Not any more. Scientists have been finding situations in humans and animals where cells create reactive oxygen species (ROS) as signals that play important parts in keeping the body healthy.

One example is when commensal or good bacteria in the gut cause the cells that line the inside of the intestines to produce ROS. Here, ROS production helps repair wounds in the intestinal lining and keeps the environment in the gut healthy. This phenomenon is not unique to human intestines. It occurs in organisms as primitive as fruit flies and nematodes, so it could be an evolutionarily ancient response. Examples of deliberately created and beneficial ROS can also be found in plants, sea urchins and amoebas.

Researchers led by Emory pathologist Andrew Neish have taken these findings a step further and identified the cellular components responsible for producing ROS upon encountering bacteria. Postdoctoral fellow Rheinallt Jones is first author on the paper that was recently published in The EMBO Journal. Read more

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Visualizing retrograde flow

This month’s intriguing image is a set of videos produced by cell biologist James Zheng’s laboratory. Looking at this video of a cell can be mesmerizing. The edges of the cell appear to be flowing inward, like a waterfall. Zheng explains that this is a phenomenon called “actin retrograde flow.”

Actin is a very abundant protein found in animals, plants and fungi that forms filaments, making up the cell’s internal skeleton. What we are seeing with retrograde flow is that molecules of actin are being added to one end of the filaments while coming loose from the other end.Actin

Zheng’s laboratory is studying a protein called cofilin, which disassembles actin filaments. Using a technique called CALI (chromophore-assisted laser inactivation) the scientists http://www.troakley.com/ used a laser to blast cofilin, inactivating it. This is why, partway through the loop, after the word CALI appears, the flow slows down. Postdoctoral fellow Eric Vitriol is the lead author on a paper in Molecular Biology of the Cell that includes these videos.

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Gene duplication leads to obesity in childhood syndrome

A team of researchers has discovered a genetic syndrome that causes childhood obesity, intellectual disability and seizures. The syndrome comes from an “unbalanced” chromosomal translocation: affected individuals have additional copies of genes from one chromosome and fewer copies of genes from another.

The results were published this week in Proceedings of the National Academy of Sciences, Early Edition.

Katie Rudd, PhD, assistant professor of human http://www.raybanoutletes.com/ genetics at Emory University School of Medicine, is senior author of the paper. Research specialist Ian Goldlust, now a graduate student in the NIH-Oxford-Cambridge Scholars Program, is the first author. Co-authors include investigators from around the USA and Australia.

Rudd’s team was able to connect the contribution of one gene, GNB3, among many involved in the translocation, to the obesity aspect of the syndrome. Her lab created a mouse model with an extra copy of the GNB3 gene and found that the mice are obese. The mice are on average 6 percent (males) or 10 percent (females) heavier.

Rudd says her work was greatly assisted by collaboration with the Unique Rare Chromosome Disorder Support Group, a UK-based charity. Within Unique, a few parents had together found that their children had translocations involving the same chromosomes and similar symptoms. They contacted Rudd and helped her find additional affected families. Her study includes seven unrelated patients.

“It really was a group effort, and Unique was the linchpin,” she says. “Managing to find seven families with exactly the same rare translocation would have been extremely difficult otherwise.”

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Exception from informed consent: what patients say

Informed consent is a basic principle of clinical research. Doctors are required to make sure that patients understand what’s involved with experimental treatments, and patients should only participate if they provide consent.

However, an important area of clinical research takes place outside of this general rule, because some life-threatening conditions – seizures, traumatic brain injury and cardiac arrest, as examples — make it impossible for the patient to learn about a clinical trial and make a decision about whether to participate. The urgency of treatment can also mean that seeking proxy consent from a relative is impractical.

A recent editorial in USA Today highlights this area of research, called EFIC (exception from informed consent). The author, Katherine Chretien from George Washington University, cites research from Emory investigators Neal Dickert and Rebecca Pentz.

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The creeping edges of cells: lamellipodia

Lamellipodia with red box
This month’s Image feature highlights lamellipodia, the thin sheet-like regions at the leading edges of migrating cells. Lamellipodia act as tiny creeping motors that pull the cell forward.

To help visualize lamellipodia, Adriana Simionescu-Bankston, a graduate student in Grace Pavlath’s lab, provided us with this photo of muscle cells. The red box shows an example of lamellipodia. Notice the edge of the cell, where the green color is more intense.

The green color comes from FITC-phalloidin, which stains F-actin, the Ray Ban outlet filaments that make up a large part of the cells’ internal skeleton. (Phalloidin is an actin-binding toxin originally isolated from death cap mushrooms, and FITC is what makes it green.) The blue color comes from DAPI, a dye that stains the DNA in the nucleus.

Simionescu-Bankston and Pavlath recently published a paper in the journal Developmental Biology, examining the function of a protein called Bin3 in muscle development and regeneration. They found that Bin3 appears to regulate lamellipodia formation; in mice that lack Bin3, muscle cells have fewer lamellipodia and the muscle tissues regenerate slower after injury. Bin3 is also important in the eye, since the “knockout” mice develop cataracts soon after birth.

 

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