May 7, 2010

Aliquots — research highlights from VUMC laboratories


Mutations vary in ‘power plant’ DNA

Mitochondria – cellular “power plants” – have their own DNA (mtDNA), which when mutated can cause a range of diseases. Mutation levels are known to vary significantly between a mother and her offspring (mitochondria are passed directly from mother to child). This variability limits the ability to provide genetic counseling to affected families.

Understanding mtDNA mutation inheritance requires a reliable means of measuring and comparing the variation that is passed on. David Samuels, Ph.D., and colleagues have addressed concerns about previous calculations – which used small sample sizes – by developing new equations for calculating the error in the variance. They recalculated data on mtDNA mutation level variance and found that the addition of error calculations alters the interpretation of some previous results.

In the April 9 American Journal of Human Genetics, they report that humans have a larger mtDNA mutation level variance than mice in both primary egg cells and in offspring. Their results show that more than 50 measurements are required for reliable comparisons.

Leigh MacMillan


Brain’s built-in stroke protection

Non-lethal ischemia (oxygen shortage) in the brain can spark protective mechanisms that prevent the damaging effects of a subsequent severe stroke. Understanding the pathways that initiate this phenomenon, known as “ischemic preconditioning,” could provide insight for novel stroke therapies that take advantage of the brain’s protective processes.

Wellcome Images

Wellcome Images

BethAnn McLaughlin, Ph.D., and colleagues previously established a model in cultured neurons to explore the pathways that contribute to preconditioning-induced neuroprotection. In the April 14 Journal of Neuroscience, the investigators report an essential role for the protein p66shc. They found that p66shc was activated early in preconditioned cells and moved to the mitochondria (cellular energy producers). They showed that inhibition of p66shc blocked neuroprotection, blocked the increased expression of protective proteins such as HSP70, and altered the cell’s production of energy and free radical molecules.

The findings suggest that p66shc triggers the defensive pathways that allow cells to protect themselves from stroke-related injury, suggesting new directions for stroke therapies.

Leigh MacMillan


Worm-killing natural compounds

Infections with parasitic nematodes (roundworms) can cause significant disease in humans – and substantial economic loss by infecting livestock and crops. Therefore, developing safe, effective drugs that kill these parasites (called antihelminthics) is important.

Essam Enan, Ph.D., and colleagues have found that thymol and carvacrol – ingredients of thyme and oregano essential oils – have significant antihelminthic activity against two types of roundworms. The researchers have also developed a new cell-based assay as a potential high-throughput screening platform to test new antihelminthic compounds.

The researchers expressed normal and mutant versions of the nematode tyramine receptor (TyrR) – which is implicated in the insecticidal activity of these chemicals in fruit flies – in cultured cells. Using this system, they showed that the antihelminthic activity of thymol and carvacrol may also be mediated through the nematode TyrR. These findings, published April 1 in Biochemical Pharmacology, suggest that this cell-based system might provide a good screening platform for developing new antihelminthic compounds.

Melissa Marino


Notch-ing up bile duct formation

Mutations in members of the “Notch” signaling pathway cause Alagille syndrome (AGS), a genetic disorder that affects the liver and other systems. Patients with AGS have a scarcity of intrahepatic bile ducts (IHBD) – the tubes that carry digestion-aiding bile to the small intestine.

Stacey Huppert, Ph.D., and colleagues analyzed the contribution of Notch signaling (which includes four Notch receptors and two families of ligands) to the formation and patterning of the mouse biliary system. The researchers manipulated various pathway components in mice to specifically activate and inactivate Notch signaling in the liver cells that give rise to bile ducts. They then viewed and assessed differences in the IHBD system by making resin casts of the liver architecture.

They report in the April issue of Hepatology that impairment of Notch signaling decreased – and activation of Notch signaling increased – the density of IHBDs. The findings demonstrate a dosage-sensitive Notch requirement for IHBD formation and provide explanations for the biliary pathophysiology in patients with AGS.

Leigh MacMillan


We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to:

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012