To explain cancer biology, use metaphors

An expert on doctor-patient communication says: let the explanatory metaphors Read more

Enhanced verbal abilities in the congenitally blind

Congenitally blind study participants displayed superior verbal, but not spatial abilities. Possibly reflects their greater reliance on verbal information, and the recruitment of the visual cortex for verbal Read more

Three remarkable Emory case reports from #ACC17

Three remarkable case reports being presented at the American College of Cardiology meeting, including cardiac electrical storm, reverse Takotsubo and congenital heart Read more

Uncategorized

The very first cells

Please welcome cell biologist Dorothy Lerit to Emory.

Dorothy Lerit, PhD

She was the lead author on a recent Cell Reports paper on primordial germ cell formation in Drosophila, along with colleagues from NHLBI, where she was a postdoc, as well as Princeton, UVA and Columbia. Primordial germ cells are the cells that are destined to become sperm or eggs.

Germ cells are the very first cells that form out of the embryo, Lerit says. Lab Land is reminded of Lewis Wolpert’s claim that gastrulation – the separation of an apparently uniform group of embryonic cells into three germ layers — is “truly the most important time in your life.” Germ cell specification, certainly important from the viewpoint of future generations, occurs even before gastrulation.

In the Cell Reports paper, Lerit was examining the function of a particular gene called Germ cell-less; remember that Drosophila genes are often named after the effects of a mutation in the gene.

Drosophila development is superficially quite different from that of mammals. In particular, for a while the early embryo becomes a bag full of cell nuclei — without membranes separating them — known as a syncytium. This is the time when Germ cell-less function is important.

Amazing picture of germ cell formation from HHMI/Nature Cell Biology/Ruth Lehmann’s lab https://www.hhmi.org/node/16760/devel

Lerit’s background is in studying the centrosome, the place in the cell where microtubules meet, and critical for orderly cell division and for ensuring that “germline fate determinants” are sequestered to the right primordial cells.

Despite the differences between insect and mammalian embryo development, the function of Germ cell-less seems to have been conserved in evolution since problems with the human version of the gene are linked to sterility in men.

Posted on by Quinn Eastman in Uncategorized Leave a comment

Provocative prions may protect yeast cells from stress

Prions have a notorious reputation. They cause neurodegenerative disease, namely mad cow/Creutzfeld-Jakob disease. And the way these protein particles propagate – getting other proteins to join the pile – can seem insidious.

Yet prion formation could represent a protective response to stress, research from Emory University School of Medicine and Georgia Tech suggests.

A yeast protein called Lsb2, which can trigger prion formation by other proteins, actually forms a “metastable” prion itself in response to elevated temperatures, the scientists report.

The results were published this week in Cell Reports.

Higher temperatures cause proteins to unfold; this is a major stress for yeast cells as well as animal cells, and triggers a “heat shock” response. Prion formation could be an attempt by cells to impose order upon an otherwise chaotic jumble of misfolded proteins, the scientists propose.

A glowing red clump can be detected in yeast cells containing a Lsb2 prion (left), because Lsb2 is hooked up to a red fluorescent protein. In other cells lacking prion activity (right), the Lsb2 fusion protein is diffuse.

“What we found suggests that Lsb2 could be the regulator of a broader prion-forming response to stress,” says Keith Wilkinson, PhD, professor of biochemistry at Emory University School of Medicine.

The scientists call the Lsb2 prion metastable because it is maintained in a fraction of cells after they return to normal conditions but is lost in other cells. Lsb2 is a short-lived, unstable protein, and mutations that keep it around longer increase the stability of the prions.

The Cell Reports paper was the result of collaboration between Wilkinson, Emory colleague Tatiana Chernova, PhD, assistant professor of biochemistry, and the laboratory of Yury Chernoff, PhD in Georgia Tech’s School of Biological Sciences.

“It’s fascinating that stress treatment may trigger a cascade of prion-like changes, and that the molecular memory of that stress can persist for a number of cell generations in a prion-like form,” Chernoff says.”Our further work is going to check if other proteins can respond to environmental stresses in a manner similar to Lsb2.” Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Unlocking a liver receptor puzzle

Imagine a key that opens a pin tumbler lock.  A very similar key can also fit into the lock, but upside down in comparison to the first key.

Biochemist Eric Ortlund and colleagues have obtained analogous results in their study of how potential diabetes drugs interact with their target, the protein LRH-1. Their research, published in Journal of Biological Chemistry, shows that making small changes to LRH-1-targeted compounds makes a huge difference in how they fit into the protein’s binding pocket.

First author Suzanne Mays, a graduate student in Emory's MSP program

First author Suzanne Mays, a graduate student in Emory’s MSP program

This research was selected as “Paper of the Week” by JBC and is featured on the cover of the December 2 issue.

LRH-1 (liver receptor homolog-1) is a nuclear receptor, a type of protein that turns on genes in response to small molecules like hormones or vitamins.  LRH-1 acts in the liver to regulate metabolism of fat and sugar.

Previous research has shown that activating LRH-1 decreases liver fat and improves insulin sensitivity in mice. Because of this, many research teams have been trying to design synthetic compounds that activate this protein, which could have potential to treat diabetes and nonalcoholic fatty liver disease. This has been a difficult task, because not much is known about how synthetic compounds interact with LRH-1 and switch it into the active state. Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Retaining the resistance: MCR-1, colistin + lysozyme

If you’ve been following the news about antibiotic resistant bacteria, you may have heard about a particularly alarming plasmid: MCR-1. A plasmid is a circle of DNA that is relatively small and mobile – an easy way for genetic information to spread between bacteria. MCR-1 raises concern because it provides bacteria resistance against the last-resort antibiotic colistin. The CDC reports MCR-1 was found in both patients and livestock in the United States this summer.
David Weiss, director of Emory’s Antibiotic Resistance Center, and colleagues have a short letter in The Lancet Infectious Diseases showing that MCR-1 also confers resistance to an antimicrobial enzyme produced by our bodies called lysozyme. MCR-1-containing strains were 5 to 20 times less susceptible to lysozyme, they report.
This suggests that the pressure of fighting the host immune system may select for MCR-1 to stick around, even in the absence of colistin use, the authors say.
While the findings are straightforward in bacterial culture, Weiss cautions that there is not yet evidence showing that this mechanism occurs in live hosts. For those that really want to get alarmed, he also calls attention to a recent Nature Microbiology paper describing a hybrid plasmid with both MCR-1 and resistance to carbapenem, another antibiotic.

Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Gestational age estimated via DNA methylation

Researchers have developed a method for estimating developmental maturity of newborns. It is based on tracking DNA methylation, a structural modification of DNA, whose patterns change as development progresses before birth.

The new method could help doctors assess developmental maturity in preterm newborns and make decisions about their care, or estimate the time since conception for a woman who does not receive prenatal care during pregnancy. As a research tool, the method could help scientists study connections between the prenatal environment and health in early childhood and adulthood.

How advanced is the development of a newborn, possibly preterm baby? Geneticists have developed a method for estimating gestational age by looking at DNA methylation.

The study, led by Alicia Smith, PhD and Karen Conneely, PhD, used blood samples from more than 1,200 newborns in 15 cohorts from around the world. The results are published in Genome Biology.

Smith is an associate professor and vice chair of research for the Department of Gynecology and Obstetrics in the School of Medicine, and Conneely is an assistant professor in the Department of Human Genetics. The first author, Anna Knight, is a graduate student in the Genetics and Molecular Biology Program.

Gestational age, is normally estimated by obstetricians using ultrasound during the first trimester, by asking a pregnant woman about her last menstrual period, or by examining the baby at birth. Ultrasound is considered to be the most precise estimate of gestational age. This work extends upon earlier studies of DNA methylation patterns that change over development and predict age and age-related health conditions in children and adults.

The Emory team gathered DNA methylation data from previous studies examining live births and health outcomes, and used an unbiased statistical learning approach to select 148 DNA methylation sites out of many thousands in the genome. By examining methylation at those sites, gestational age could be accurately estimated between 24 and 44 weeks, the authors report. The median difference between age determined by DNA methylation and age determined by an obstetrician estimate was approximately 1 week.

The researchers also found that the difference between a newborn’s age predicted by DNA methylation and by an obstetrician may be another indicator of developmental maturity, and is correlated with birthweight, commonly used as an indicator of perinatal health. Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Strength tests for platelets

Bleeding disorders could one day be diagnosed by putting platelets through strength tests, researchers have proposed.

Biomedical engineers from Emory and Georgia Tech have devised a microfluidic testing ground where platelets can demonstrate their strength by squeezing two protein dots together. Imagine rows and rows of strength testing machines from a carnival, but very tiny. Platelets are capable of exerting forces that are several times larger, in relation to their size, in comparison with muscle cells.

After a blood clot forms, it contracts, promoting wound closure and restoration of normal blood flow. This process can be deficient in a variety of blood clotting disorders. Previously, it was difficult to measure individual platelet’s contributions to contraction, because clots’ various components got in the way.

The prototype diagnostic tools are described in Nature Materials.

platelet_strength_test

Top: platelets exert their strength. Bottom left: red = platelets, green = fibrinogen dots. Bottom right: size of actual device.

“We discovered that platelets from some patients with bleeding disorders are ‘wimpier’ than platelets from healthy people,” says Wilbur Lam, MD, PhD, assistant professor in the Department of Pediatrics at Emory University School of Medicine and in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “Our device may function as a new physics-based method to test for bleeding disorders, complementary to current methods.”

The first author of the paper is instructor David Myers, PhD. Lam is also a physician in the Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta. Collaborators at North Carolina State University led by Ashley Brown, PhD, contributed to testing the device.

The scientists infer how strong or wimpy someone’s platelets are by measuring how far the protein dots move, taking a picture of the rows of dots, and then analyzing the picture on a computer. The dots are made of fibrinogen, a sticky protein that is the precursor for fibrin, which forms a mesh of insoluble strands in a blood clot.

In addition to detecting problems with platelet contraction in patients with known inherited disorders such as Wiskott Aldrich syndrome, Myers, Lam and colleagues could also see differences in some patients who had bleeding symptoms, but who performed normally on standard diagnostic tests. Read more

Posted on by Quinn Eastman in Heart, Uncategorized Leave a comment

Tapping evolution to improve biotech products

Scientists can improve protein-based drugs by reaching into the evolutionary past, a paper published this week in Nature Biotechnology proposes.

As a proof of concept for this approach, the research team from Emory, Children’s Healthcare of Atlanta and Georgia Tech showed how “ancestral sequence reconstruction” or ASR can guide engineering of the blood clotting protein known as factor VIII, which is deficient in the inherited disorder hemophilia A.

fviii_2r7e

Structure of Factor VIII

Other common protein-based drugs include monoclonal antibodies, insulin, human growth hormone and white blood cell stimulating factors given to cancer patients. The authors say that ASR-based engineering could be applied to other recombinant proteins produced outside the human body, as well as gene therapy.

It has been possible to produce human factor VIII in recombinant form since the early 1990s. However, current factor VIII products still have problems: they don’t last long in the blood, they frequently stimulate immune responses in the recipient, and they are difficult and costly to manufacture.

Experimental hematologist and gene therapist Chris Doering, PhD and his colleagues already had some success in addressing these challenges by filling in some of the sequence of human factor VIII with the same protein from pigs.

“We hypothesized that human factor VIII has evolved to be short lived in the blood to reduce the risk of thrombosis,” Doering says. “And we reasoned that by going even farther back in evolutionary history, it should be possible to find more stable, potent relatives.”

Doering is associate professor of pediatrics at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. The first author of the paper is former Molecular and Systems Pharmacology graduate student Philip Zakas, PhD.

Doering’s lab teamed up with Trent Spencer, PhD, director of cell and gene therapy for the Aflac Cancer and Blood Disorders Center, and Eric Gaucher, PhD, associate professor of biological sciences at Georgia Tech, who specializes in ASR. (Gaucher has also worked with Emory biochemist Eric Ortlund – related item on ASR from Gaucher)

ASR involves reaping the recent harvest of genome sequences from animals as varied as mice, cows, goats, whales, dogs, cats, horses, bats and elephants. Using this information, scientists reconstruct a plausible ancestral sequence for a protein in early mammals. They then tweak the human protein, one amino acid building block at a time, toward the ancestral sequence to see what kinds of effects the changes could have. Read more

Posted on by Quinn Eastman in Immunology, Uncategorized Leave a comment

Bile acid uptake inhibitor prevents NASH/fatty liver in mice

Drugs that interfere with bile acid recycling can prevent several aspects of NASH (nonalcoholic steatohepatitis) in mice fed a high-fat diet, scientists from Emory University School of Medicine and Children’s Healthcare of Atlanta have shown.

The findings suggest that these drugs, known as ASBT inhibitors, could be a viable clinical strategy to address NASH, an increasingly common liver disease. The results were published in Science Translational Medicine on September 21, 2016.

“By targeting a process that takes place in the intestine, we can improve liver function and reduce insulin resistance in a mouse model of NASH,” says senior author Saul Karpen, MD, PhD. “We can even get fat levels in the liver down to what we see in mice fed a regular diet. These are promising results that need additional confirmation in human clinical trials.”

Karpen is Raymond F. Schinazi distinguished professor of pediatrics at Emory University School of Medicine and chief of the Division of Pediatric Gastroenterology, Hepatology and Nutrition at Children’s Healthcare of Atlanta. He and Paul Dawson, PhD, Emory professor of pediatrics, jointly run a lab that investigates the role of bile acids in liver disease.

Saul Karpen, MD, PhD

Saul Karpen, MD, PhD

Many people in developed countries have non-alcoholic fatty liver disease, an accumulation of fat in the liver that is linked to diet and obesity. Fatty liver disease confers an elevated risk of type II diabetes and heart disease. NASH is a more severe inflammation of the liver that can progress to cirrhosis, and is a rising indication for liver transplant. Besides diet and exercise, there are no medical treatments for NASH, which affects an estimated 2 to 5 percent of Americans. Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Leaky gut plus diet together drive liver disease

 

Frank Anania, MD

Lots of people in the United States consume a diet that is high in sugar and fat, and many develop non-alcoholic fatty liver disease, a relatively innocuous condition. NASH (non-alcoholic steatohepatitis) is the more unruly version, linked to elevated risk of cardiovascular and metabolic diseases, and can progress to cirrhosis. NASH is expected to become the leading indication for liver transplant. But only a fraction of people with non-alcoholic fatty liver disease go on to develop NASH.

Thus, many researchers are trying to solve this equation:

High-sugar, high-fat diet plus X results in NASH.

Emory hepatologist Frank Anania and colleagues make the case in a recent Gastroenterology paper that a “leaky gut”, allowing intestinal microbes to promote liver inflammation, could be a missing X factor.

Anania’s lab started off with mice fed a diet high in saturated fat, fructose and cholesterol (in the figure, PrintHFCD). This combination gives the mice moderate fatty liver disease and metabolic syndrome (see this 2015 paper, and we can expect to hear more about this model soon from Saul Karpen). Leaky gut, brought about by removing a junction protein from intestinal cells, sped up and intensified the development of NASH.

The authors say that this model could be useful for the study of NASH, which has been difficult to reproduce in mice.

The researchers could attenuate liver disease in the mice by treatment with antibiotics or sevelamer, a phosphate binding polymer that soaks up inflammatory toxins from bacteria. Sevelamer is now used to treat excess phosphate in patients with chronic kidney disease, and is being studied clinically in connection with insulin resistance.
Read more

Posted on by Quinn Eastman in Uncategorized Leave a comment

Challenging long-held dogmas in cardiology

IGF1_heart

The growth factor IGF-1 (red) peaks roughly two days after an artificial heart attack in mice. But its levels are limited by an enzyme called chymase produced by mast cells. What if the influence of chymase could be curtailed?

Alert to science journalists looking for active debate: Emory cardiology researchers Nawazish Naqvi and Ahsan Husain are not afraid of controversy in their field.

In a 2014 Cell paper, they challenged the long-held assumption that after birth, cardiac muscle cells do not divide, showing a dramatic burst of thyroid hormone-driven cell division in the hearts of preadolescent mice. This finding has implications for regenerative medicine if it can be harnessed, but also stimulated a cluster of papers aiming to refute their findings in Cell the following year (and more are coming).

A second assumption that they’ve challenged more recently is that hours after a heart attack, endangered cardiac muscle cells can’t be rescued. Husain and Naqvi’s paper, published this week in PNAS, shows that the enzyme chymase — produced by a type of immune cell called mast cells — limits the heart’s ability to heal itself. Critically, differences in the extent of damage seen in mice lacking chymase and controls show up days after an artificial heart attack. More here.

Posted on by Quinn Eastman in Uncategorized Leave a comment
1 2 3 4 5 6 7 8 9 10 ... 19 20   Next »