NEUROBIOLOGY: Too hot to handle: how heat causes pain

Our body detects heat above 43 degrees Celsius as painful. The main detector of noxious heat is the protein TRPV1 on pain-sensing sensory nerve cells. Exactly how TRPV1 sensitivity to heat is regulated has not been clearly determined. However, Kenneth Hargreaves and colleagues, at the University of Texas Health Science Center at San Antonio, have now identified in rodents two molecules known as 9-HODE and 13-HODE, which are generated by the breakdown of the omega-6 fat linoleic acid, as activators of TRPV1 and inducers of the feeling of pain in response to heat. As products of linoleic acid breakdown, such as 9-HODE and 13-HODE, are produced by injured cells, the authors suggest that agents blocking either the production or action of these substances could lead to therapeutic interventions for pain disorders.

In an accompanying commentary, David Brown and Gayle Passmore, at University College London, United Kingdom, discuss how the concept of a "heat messenger" released from damaged tissue provides new food for thought for those developing approaches to pain therapy.

TITLE: Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

ACCOMPANYING COMMENTARY TITLE: Some new insights into the molecular mechanisms of pain perception

DEVELOPMENT: Mechanisms underlying 2 genetically distinct forms of cleft palate linked

Cleft lip and cleft palate are frequent and debilitating congenital malformations. Mutations in the genes p63 and IRF6 have each been shown to cause cleft lip and cleft palate, but the molecular and cellular mechanisms underlying this have not been clearly determined. However, two independent teams of researchers - one led by Jill Dixon, at the University of Manchester, United Kingdom, and Hans van Bokhoven, at Radboud University Nijmegen Medical Centrum, The Netherlands, and the other led by Antonio Costanzo, at the University of Rome "Tor Vergata," Italy - have now found that in mice p63 and IRF6 operate within a regulatory loop to coordinate key events in the normal development of the palate (the structure that separates the nasal cavity from the oral cavity, allowing simultaneous breathing and eating); disruption of this loop as a result of mutations in p63 and IRF6 causes cleft lip and cleft palate. Amel Gritli-Linde, at the University of Gothenburg, Sweden, highlights the importance of these studies in an accompanying commentary.

TITLE: Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice

ACCOMPANYING ARTICLE TITLE: A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias

ACCOMPANYING COMMENTARY TITLE: p63 and IRF6: brothers in arms against cleft palate

DEVELOPMENT: Understanding how a rare genetic mutation causes a severe brain disorder

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare genetic disorder that was identified in an Old Order Mennonite pediatric population. It is characterized by abnormal brain development, an abnormally large brain, cognitive disability, and severe, therapy-resistant epilepsy. PMSE is caused by mutations in the gene STRADA. A team of researchers, led by Peter Crino, at the University of Pennsylvania, Philadelphia, has now provided insight into how mutations in STRADA cause PMSE by analyzing a human PMSE brain and mice. Specifically, their data indicate that the lack of STRAD-alpha protein caused by the STRADA gene mutations results in the protein LKB1 being abnormally localized, and that this leads to activation of the mTOR signaling pathway, thereby promoting abnormal cell growth and brain development. The authors suggest that early treatment with the mTOR inhibitor rapamycin, which is used in the clinic to prevent rejection of organ transplants, and other mTOR inhibitors may prevent the devastating neurological features of PMSE.

In an accompanying commentary, Lucy Osborne, at the University of Toronto, Canada, discusses how the data generated by Crino and colleagues adds PMSE to a group of disorders caused by uncontrolled mTOR pathway activation and characterized by benign tumors and malformations of the brain.

TITLE: STRAD-alpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice

ACCOMPANYING COMMENTARY TITLE: Caveat mTOR: aberrant signaling disrupts corticogenesis

MYCOLOGY: Visualizing brain invasion by a fungus

Infection with the fungus Cryptococcus neoformans can cause meningitis (inflammation of the membranes surrounding the brain) and encephalitis (inflammation of the brain itself), conditions that are often lethal. To elicit these effects, the fungus must somehow leave the blood stream and enter the brain, but little is known about how it does this. A team of researchers, at the University of Calgary, Canada, has now used a form of microscopy known as intravital microscopy, which enables researchers to observe events in real-time in live animals, to visualize in mice the process of brain invasion by Cryptococcus neoformans.

A key observation of the team, led by Christopher Mody, was that Cryptococcus neoformans stops suddenly in mouse brain capillaries that are similar or smaller in diameter than it is. Only after stopping abruptly was the fungus seen to cross the wall of the blood vessel and enter the brain. Interestingly, the protein urease was required for Cryptococcus neoformans to invade the brain, and treatment with a urease inhibitor reduced brain infection. The authors therefore suggest that therapeutics that inhibit urease might help prevent meningitis and encephalitis caused by infection with Cryptococcus neoformans.

In an accompanying commentary, Arturo Casadevall, at Albert Einstein College of Medicine, New York, suggests that such inhibitors might not be applicable in the clinic, because most patients already have substantial brain infection when they first seek medical help. However, he highlights that the study opens up numerous new avenues of research that could be exploited in the clinic in the future.

TITLE: Real-time imaging of trapping and urease-dependent transmigration of Cryptococcus neoformans in mouse brain

ACCOMPANYING COMMENTARY TITLE: Cryptococci at the brain gate: break and enter or use a Trojan horse?

Karen Honey
Journal of Clinical Investigation