JCI table of contents: April 26, 2010

EDITOR'S PICK: Understanding how folic acid might help heal brain and spinal cord injuries Babies born to women who do not consume enough folic acid (sometimes referred to as folate or vitamin B9) are at high risk of developing neural tube defects (i.e., defects in the development of the spinal cord or brain). This is the reason underlying the recommendation that women who are pregnant take a folic acid supplement. A team of researchers, led by Bermans Iskandar, at the University of Wisconsin, Madison, has now generated data in rodents suggesting that folic acid might also help promote healing in injured brain and spinal cord. Specifically, the team was able to uncover a molecular pathway by which folate can promote nerve cell regeneration following injury in rodents.

In an accompanying commentary, Matthias Endres and Golo Kronenberg, at Charité – Universitätsmedizin Berlin, Germany, discuss how these data, together with the safety and simplicity of folate supplementation, provide a rationale for testing whether folate supplementation is beneficial for patients with spinal cord and brain trauma.

TITLE: Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

AUTHOR CONTACT:
Bermans J. Iskandar
University of Wisconsin, Madison, Wisconsin, USA.
Phone: 608.263.9651; Fax: 608.263.1728; E-mail: iskandar@neurosurg.wisc.edu.

View this article at: http://www.jci.org/articles/view/40000?key=7699cee3397c28e321ac

ACCOMPANYING COMMENTARY
TITLE: Neuronal injury: folate to the rescue?

AUTHOR CONTACT:
Matthias Endres
Charité – Universitätsmedizin Berlin, Berlin, Germany.
Phone: 49.30.450.560.102; Fax: 49.30.450.560.932; E-mail: matthias.endres@charite.de.

View this article at: http://www.jci.org/articles/view/40764?key=TpndN64MezO2HHZ2NCmW

EDITOR'S PICK: New requirements for male fertility

Two independent groups of researchers have identified distinct roles for two proteins in a family of proteins known as PLA2s as crucial for sperm function and fertility in mice. These data identify proteins that could underlie causes of infertility and provide potential targets for the development of new contraceptive agents and new approaches to treating infertility. In addition, these data provide a caution to those developing drugs that target members of this closely related group of proteins to treat hardening of the arteries (atherosclerosis) and inflammation.

The team of researchers led by Makoto Murakami, at The Tokyo Metropolitan Institute of Medical Science, Japan, found that sPLA2-III was expressed in a region of the testis known as the proximal epididymal epithelium. Mice lacking this protein had substantially decreased fertility because their sperm did not mature properly. Specifically, the defects in maturation meant that the sperm showed decreased motility and decreased ability to fertilize eggs in vitro.

In the second study, Christophe Arnoult and colleagues, at Grenoble Institute of Neuroscience, France, found in mice that group X secreted PLA2 (also known as mGX) was a predominant constituent of a compartment in sperm known as the acrosome. This compartment has a key role in breaking down the coat that surrounds an egg so that the sperm can elicit fertilization. Consistent with this, male mice lacking mGX produced smaller litters than did normal male mice and sperm from the mGX-deficient mice were not efficient at fertilizing eggs in vitro. Further, molecules that inhibited mGX and molecules that more broadly inhibited secreted PLA2s each reduced the efficiency of in vitro fertilization (IVF). By contrast, the presence of additional mGX improved the efficiency of IVF.

TITLE: Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice

AUTHOR CONTACT:
Makoto Murakami
The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Phone: 81.3.5316.3228; Fax: 81.3.5316.3125; E-mail: murakami-mk@igakuken.or.jp.

View this article at: http://www.jci.org/articles/view/40493?key=97a554ce7a008712aa57

ACCOMPANYING ARTICLE
TITLE: Group X phospholipase A2 is released during sperm acrosome reaction and controls fertility outcome in mice

AUTHOR CONTACT:
Christophe Arnoult
Grenoble Institute of Neuroscience, INSERM U836, Grenoble, France.
Phone: 33.4.56.52.05.64; Fax: 33.4.56.52.05.72; E-mail: christophe.arnoult@ujf-grenoble.fr.

View this article at: http://www.jci.org/articles/view/40494?key=ec2760d5fdcfa04f0042

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

AUTHOR CONTACT:
Kenneth M. Hargreaves
University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Phone: 210.567.3381; Fax: 210.567.3389; E-mail: hargreaves@uthscsa.edu.

View this article at: http://www.jci.org/articles/view/41678?key=9c726bad5dba215ac93d

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

AUTHOR CONTACT:
David A. Brown
University College London, London, United Kingdom.
Phone: 44.207.679.7297; Fax: 44.207.679.4496; E-mail: d.a.brown@ucl.ac.uk.

View this article at: http://www.jci.org/articles/view/42143?key=f8703aab7c6870b75570

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

AUTHOR CONTACT:
Jill Dixon
University of Manchester, Manchester, United Kingdom.
Phone: 44.161.275.5217; Fax: 44.161.275.5082; E-mail: jill.dixon@manchester.ac.uk.

Hans van Bokhoven
Radboud University Nijmegen Medical Centrum, Nijmegen, The Netherlands.
Phone: 31.24.3616696; Fax: 31.24.3668752;
E-mail: H.vanBokhoven@antrg.umcn.nl.

View this article at: http://www.jci.org/articles/view/40266?key=7175150f0837ad5aaceb

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

AUTHOR CONTACT:
Antonio Costanzo
University of Rome "Tor Vergata," Rome, Italy.
Phone: 39.0672596177; Fax: 39.0620902742; E-mail: antonio.costanzo@uniroma2.it.

View this article at: http://www.jci.org/articles/view/40267?key=a26999ef3e17a52b1cab

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

AUTHOR CONTACT:
Amel Gritli-Linde
Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
Phone: 46.31.786.3386; Fax: 46.31.418122; E-mail: amel@odontologi.gu.se.

View this article at: http://www.jci.org/articles/view/42821?key=264f9d394fa5ca5ad803

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

AUTHOR CONTACT:
Peter B. Crino
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
Phone: 215.349.5312; Fax: 215.573.2029; E-mail: peter.crino@uphs.upenn.edu.

MEDIA CONTACT:
Karen Kreeger
Senior Science Communications Manager
University of Pennsylvania School of Medicine &
Health System, Philadelphia, Pennsylvania, USA.
Phone: 215.349.5658 (land); 215.459.0544 (cell); Fax: 215.349.8312; E-mail: karen.kreeger@uphs.upenn.edu.

View this article at: http://www.jci.org/articles/view/41592?key=8a7e97802b4129478550

ACCOMPANYING COMMENTARY
TITLE: Caveat mTOR: aberrant signaling disrupts corticogenesis

AUTHOR CONTACT:
Lucy R. Osborne
University of Toronto, Toronto, Ontario, Canada.
Phone: 416.946.5804; Fax: 416.978.8765; E-mail: lucy.osborne@utoronto.ca.

View this article at: http://www.jci.org/articles/view/43030?key=4c663ac93e89286a887c

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

AUTHOR CONTACT:
Christopher H. Mody
University of Calgary, Calgary, Alberta, Canada.
Phone: 403.220.8479; Fax: 403.210.8463; E-mail: cmody@ucalgary.ca.

View this article at: http://www.jci.org/articles/view/41963?key=93ff4bbc0967d32624b5

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

AUTHOR CONTACT:
Arturo Casadevall
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718.430.3665; Fax: 718.430.8711; E-mail: Arturo.casadevall@einstein.yu.edu.

View this article at: http://www.jci.org/articles/view/42949?key=6e99cf49f7699acede3e

Source: Journal of Clinical Investigation