Fragile X: preclinical portfolio for PI3k drug strategy

An alternative drug strategy for fragile X is gathering strength. Lots of data on behavior and biochemistry from mouse Read more

Stem cells driven into selective suicide

The term “stem cell” is increasingly stretchy. This is one way to get rid of a particular Read more

The blue spot: where seeds of destruction begin

Learn more about the locus coeruleus, a "canary in the coal Read more

Department of Medicine

There will be microparticles (in stored blood)

More than 9 million people donate blood in the United States every year, according to the American Red Cross. Current guidelines say that blood can be stored for up to six weeks before use.

What happens to red blood cells while they are in storage, which transfusion experts call the “storage lesion”? Multiple studies have shown that older blood may have sub-optimal benefits for patients receiving a transfusion. The reasons include: depletion of the messenger molecule nitric oxide, lysis of red blood cells and alterations in the remaining cells’ stiffness.

To that list, we could add the accumulation of microparticles, tiny membrane-clothed bags that contain proteins and RNA, which have effects on blood vessels and the immune system upon transfusion. Note: microparticles are similar to exosomes but larger – the dividing line for size is about 100 nanometers. Both are much smaller than red blood cells.

EUH blood bank director John Roback recently gave a talk on the blood storage issue, and afterwards, cardiologist Charles Searles and research fellow Adam Mitchell were discussing their work on microparticles that come from red blood cells (RBCs). They have been examining the effects RBC-derived microparticles have on endothelial cells, which line blood vessels, and on immune cells’ stickiness.Red blood cell microparticles280

Mitchell mentioned that he had some striking electron microscope images of microparticles and some of the particles looked like worms. With the aim of maintaining Lab Land’s “Cool Image” feature, I resolved to obtain a few of his photos, and Mitchell generously provided several.

“Those worms definitely had me mesmerized for a while,” he says.

In his talk, Roback described some of the metabolomics research he has been pursuing with Dean Jones. Instead of focusing only on how long blood should be stored, Roback’s team is examining how much differences between donors may affect donated blood’s capacity to retain its freshness. Read more

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Decoding lupus using DNA clues

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

A team of Emory scientists has been investigating some fundamental questions about lupus: where do the cells that produce the self-reactive antibodies come from? Are they all the same?

In the accompanying video, Kelli Williams, who helps study the disease and has lupus herself, describes what a flare feels like. In addition, Emory researchers Iñaki Sanz, MD and Chris Tipton, PhD explain their findings, which were published this summer in Nature Immunology.

Judging by the number and breadth of abstracts on lupus at the Department of Medicine Research Day (where Tipton won 1st place for basic science poster), more intriguing findings are in the pipeline. Goofy Star Wars metaphors and more explanations of the science here.

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Low-level cadmium toxicity and fatty liver disease

A recent study concluded that it’s more difficult for adults today to maintain the same weight as those a few decades ago, even with the same levels of food intake and exercise. On one level, this news is comforting to anyone in middle age, who may have been athletic as a teenager in the 1980s but isn’t anymore. It’s just harder nowadays!

However, the study authors also suggested, in an interview with The Atlantic’s Olga Khazan, an array of factors that might be contributing to the rise in obesity: exposure to chemicals such as pesticides and flame retardants, prescription drugs such as antidepressants, and altered microbiomes linked with antibiotic use in livestock.

The heavy metal cadmium may belong on that list of chemicals, not primarily as a booster of obesity, but instead in connection with the increase in prevalence in NAFLD (non-alcoholic fatty liver disease) over the last few decades.

Researchers led by Young-Mi Go and Dean Jones exposed mice to low levels of cadmium, so that the amounts of cadmium in their livers were comparable to those present in average middle age Americans, without tobacco or occupational exposure. They observed that cadmium-treated mice had more fat accumulation in the liver and elevated liver enzymes in their blood, compared with control mice with 10 times less cadmium.

Cadmium accumulates in the body over time. Tobacco smoke and the industrial workplace can be routes for cadmium exposure, but food is the major source for most non-smokers. Until the 1990s, most batteries were made with cadmium, and much cadmium production still goes into batteries. It is also found in paint and in corrosion-resistant steel. Read more

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Anti-aging tricks from dietary supplement seen in mice

Our recent news item on a Cell Reports paper from ShiQin Xiong and Wayne Alexander describes a connection between two important biological molecules: the exercise-induced transcription coactivator PGC1-alpha and the enzyme telomerase, sometimes described as a “fountain of youth” because telomeres protect the ends of chromosomes.

While the Emory researchers did not directly assess the effects of exercise in their experiments, their findings provide molecular clues to how exercise might slow the effects of aging or chronic disease in some cell types.

Xiong and Alexander found that the dietary supplement alpha lipoic acid (ALA) can stimulate telomerase, with positive effects in a mouse model of atherosclerosis. ALA is a sulfur-containing fatty acid used to treat diabetic neuropathy in Germany, and has previously been shown to combat atherosclerosis in animal models. The Emory authors’ main focus was on vascular smooth muscle cells and note that more study of ALA’s effects on other cell types is needed.

Below are four key references that may help you put the Cell Reports paper in context: Read more

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How white blood cells limit muscle regeneration

A paper from cardiologist Aloke Finn and colleagues (published Wednesday, Aug. 5 in Nature Communications) describes how the protein CD163, produced by macrophages, puts the brakes on muscle repair after ischemic injury in mice. Here’s why we think this paper is interesting.

*Speculatively, there are connections to the recent wave of “young blood cures old body” parabiosis research. Increased CD163 is a marker of aging in humans. Maybe low levels of CD163 are part of how young blood is restorative.

*Translational potential — it wouldn’t be too hard to make an antibody against human CD163. Something that blocks CD163 could possibly be used to treat muscle breakdown, which occurs in response to injury, inactivity and in diseases such as cancer and diabetes.

*Finn says his team was surprised to find that mice lacking CD163, tested in experiments where blood flow is restricted in one leg, showed increased blood vessel and muscle growth in the other leg. It looks like part of CD163’s role is to limit muscle regeneration to the site of injury. Read more

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Following lupus troublemaker cells, via DNA barcodes

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

The immune system can produce many types of antibodies, directed against infectious viruses (good) or against human proteins as in lupus (harmful). Each antibody-secreting cell carries a DNA rearrangement that reflects the makeup of its antibody product. Scientists can use the DNA to identify and track that cell, like reading a bar code on an item in a supermarket.

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Iñaki Sanz, MD is a Georgia Research Alliance Eminent Scholar, director of the Lowance Center for Human Immunology and head of the Rheumatology division in the Department of Medicine.

Postdoc Chris Tipton, GRA Eminent Scholar Iñaki Sanz and colleagues at Emory have been using these DNA bar codes to investigate some fundamental questions about lupus: where do the autoantibody-producing cells come from? Are they all the same?

Their findings were published in Nature Immunology in May, and a News and Views commentary on the paper calls it “a quantum advance in the understanding of the origin of the autoreactive B cells.” It’s an example of how next-generation sequencing technology is deepening our understanding of autoimmune diseases.

The Emory team obtained blood samples from eight patients experiencing lupus flares and compared them to eight healthy people who had recently been vaccinated against influenza or tetanus.

When the immune system is responding to something it’s seen before, like when someone receives a booster vaccine, the bar codes of the antibody-producing cells look quite similar to each other. A set of just a few antibody-producing cells multiply and expand, making what looks like clones. In contrast, the researchers found that in lupus, many different cells are producing antibodies. Some of the expanded sets of cells are producing antibodies against infectious agents.

“We expected to see an expansion of the cells that produce autoantibodies, but instead we saw a very broad expansion of cells with all types of specificities,” Tipton says.

To use a Star Wars analogy: a booster vaccine response looks like the Clone Wars (oligoclonal — only a few kinds of monsters), but a lupus flare looks like a visit to Mos Eisley cantina (polyclonal — many monsters). Read more

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Subset of plasma cells display immune ‘historical record’

You may have read about recent research, published in Science, describing a technique for revealing which viruses have infected someone by scanning antiviral antibodies in the blood.

Emory immunologists have identified corresponding cells in which long-lived antibody production resides. A subset of plasma cells keep a catalog of how an adult’s immune system responded to infections decades ago, in childhood encounters with measles or mumps viruses.

The results, published Tuesday, July 14 in Immunity, could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

“If you’re developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen,” says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare’s Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Lee says that her team’s research on plasma cells in humans provided insights unavailable from mice, since mice don’t live as long and their plasma cells also have a different pattern of protein markers. More here.

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Reversing liver fibrosis via adiponectin

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver conditions in the United States, affecting 30 percent of the population, and increasing — and likely to catch up in prevalence with obesity and diabetes. In NAFLD, fat content of the liver is elevated to 6 percent or more in people who drink in moderation or not at all. Patients will first present with elevated liver enzyme values in blood tests, but then an imaging test or tissue biopsy may be ordered to evaluate the extent of the damage. NAFLD is mostly asymptomatic and is variable in severity; a majority of those afflicted do not need drug treatments. However, NAFLD is thought to be a preliminary condition that can eventually progress to severe manifestations, such as cirrhosis, hepatocellular carcinoma, and end stage liver failure.

Progression of liver disease, from NIDDK.  This article is a guest post from Kristina Bargeron Clark, a graduate student at Emory and communications chair for Women in Bio-Atlanta. Her website is www.inkcetera.org.

Progression of liver disease, from NIDDK.
This is a guest post from Kristina Bargeron Clark, a MMG graduate student at Emory and communications chair for Women in Bio-Atlanta. Her website is www.inkcetera.org.

At Emory, Frank Anania, director of the Department of Medicine’s Division of Digestive Diseases, and his colleagues are developing a tool to treat liver disease. A recent publication in the FASEB Journal describes their investigation into the potential for the hormone adiponectin to modulate liver fibrosis.

Adiponectin is produced by adipose tissue, but is known to decrease in overweight people with metabolic disease. Research by others indicates that it may prevent heart and kidney fibrosis. The Emory team’s studies were conducted to determine if adiponectin could also reduce liver fibrosis.

Read more

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Bone-strengthening particles stimulate autophagy

Neale Weitzmann and George Beck have been publishing a series of papers describing how silica nanoparticles can increase bone mineral density in animals. Their findings could someday form the basis for a treatment for osteoporosis.

In 2012, we posted an article and video on this topic. We wanted to call attention to a few of the team’s recent papers, one of which probes the mechanism for a remarkable phenomenon: how can very fine silica particles stimulate bone formation?

The particles’ properties seem to depend on their size: 50 nanometers wide – smaller than a HIV or influenza vision. In a 2014 ACS Nano paper, Beck, Weitzmann and postdoc Shin-Woo Ha show that the particles interact with particular proteins involved in the process of autophagy, a process of “self digestion” induced by stress.

“These studies suggest that it is not the material per se that stimulates autophagy but rather size or shape,” they write. Read more

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Pre-hospital recognition of severe sepsis

 

Severe sepsis, a consequence of the body’s response to infection, is a major cause of death in hospitals. The earlier that doctors recognize that a patient has sepsis, the earlier the patient can be treated with antibiotics, fluids and other measures, and the better the chance of survival.

That’s why critical care and emergency medicine researchers have been looking for ways to spot whether someone coming to the hospital might have sepsis, even before arrival.

At Emory, Carmen Polito, Jonathan Sevransky and colleagues recently published a paper in the American Journal of Emergency Medicine on an emergency medical services screening tool for severe sepsis. Polito and Sevransky are in the division of pulmonary, allergy, critical care and sleep medicine in the Department of Medicine. The tool was evaluated based on Grady emergency medical services data from 2011 and 2012.

“Sepsis is largely a face without a name in the EMS setting, “ Polito says. “The goal of our study was to create a tool to assist EMS providers in naming this deadly condition at the point of first medical contact. Similar to other life-threatening, time-sensitive conditions like stroke and heart attack, naming sepsis is the first step in developing coordinated care pathways that focus on delivering rapid, life-saving treatment once the patient arrives at the hospital.”

Read more

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