Mutations build better flu antibody
In 2008, James Crowe, Jr., M.D., and colleagues isolated antibodies to the 1918 flu from the immune cells of survivors of that pandemic. They later showed that these antibodies also bound to and neutralized the 2009 H1N1 influenza strain. But what makes these antibodies so potent remains under investigation.
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Crowe and colleagues recently reported in the journal mBio that the antibody, called 2D1, has an extra 3 amino acids inserted in a section known as the heavy-chain variable region. They found that this insertion caused a structural change to the antibody that removes a “steric conflict” and allows a more favorable binding interaction between the antibody and virus. The researchers also proposed a sequence of events that may account for the evolution of this more potent antibody.
The findings suggest that this type of structural change can dramatically impact antibody potency – and that this mechanism may be an important part of antibody diversification in humans.
— Melissa Marino
Variable vulnerability to oncogene
Mutations that activate the Kras oncogene are common in many epithelial tumors, including cancers of the pancreas, colon and lung, but Kras mutations are rare in cancers of the oral cavity and stomach. Why some tissues are vulnerable to Kras mutations, and some are not, is unclear.
To explore the susceptibility of different epithelial tissues to Kras mutations, Anna Means, Ph.D., and colleagues introduced one of the most common Kras mutations broadly in adult epithelial tissues of the mouse. They report in the journal PLoS ONE that the Kras mutation caused neoplastic changes in some, but not all, tissues. They observed hyperplasias, metaplasias and adenomas in the oral cavity, stomach, colon, and lungs; there were no changes in the small intestines. Metaplasias with characteristics of early stage pancreatic cancer also developed in the pancreas, supporting the hypothesis that pancreatic ducts can give rise to cancer.
The mouse model will be useful for probing the environmental factors and tissue-intrinsic mechanisms that make some tissues more vulnerable than others to Kras activation.
— Leigh MacMillan
Mutant mice have appetite for fats
The most common genetic cause of severe obesity in children is a condition called “MC4R haploinsufficiency” in which the child has one defective copy of the melanocortin 4 receptor (MC4R) gene, which is involved in food intake and metabolism.
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Roger Cone, Ph.D., and colleagues are examining how dietary fat content affects feeding behavior in mice in which one or both copies of MC4R are deleted (MC4R+/- and MC4R-/- respectively). They found that diets high in either saturated or monounsaturated fats cause MC4R-/- mice and MC4R+/- mice to eat more fatty food at a much faster rate than normal (wild type) mice – suggesting that fatty food is more rewarding yet less satisfying to the melanocortin receptor deficient mice. They also identified alterations in lipid signaling molecules that may play a role in the increased feeding behavior.
The findings, reported in the March issue of Endocrinology, suggest that early nutritional interventions might slow the rate of weight gain in children with this condition.
— Melissa Marino
Dialing down the mercury
Methylmercury – the organic form of mercury found in fish – is a potent neurotoxin that accumulates in astrocytes, brain cells that surround and support neurons. How methylmercury exerts its toxic effects is not fully understood.
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Michael Aschner, Ph.D., and colleagues explored mechanisms of methylmercury neurotoxicity, with a focus on oxidative stress pathways. They exposed cultured rat neonatal astrocytes to methylmercury, with or without pretreatment with the antioxidant compound ebselen.
They report in the journal NeuroToxicology that methylmercury inhibited astrocyte uptake of glutamine, an energy substrate, and depleted the mitochondrial inner membrane potential, an indicator of cell viability. Methylmercury also increased activation of the proteins ERK and caspase-3, signaling molecules that participate in the process of cell death. The selenium-containing compound ebselen blocked each of these methylmercury-induced effects. The findings suggest that selenium-containing compounds may represent promising pharmacological options for treating methylmercury poisoning.
— 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: aliquots@vanderbilt.edu.
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