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JCI online early table of contents: July 12, 2010

EDITOR'S PICK: Why Parkinson disease patients aren't walking talls

Many of the symptoms of Parkinson disease can be alleviated with drugs that target dompamine, a chemical in the brain that is involved in nerve cell communication and therefore known as a neurotransmitter. However, such drugs do not improve the gait disorders and falls that commonly affect individuals with severe and advanced forms of Parkinson disease. Understanding which nerve cells in the brain are involved in these symptoms of Parkinson disease might provide researchers with new therapeutic targets. In this context, a team of researchers, led by Chantal Franois and Etienne Hirsch, at Universit Pierre et Marie Curie Paris 6, France, has now determined that the presence of gait disorders in patients with Parkinson disease and in aged monkeys with Parkinson-like disease was associated with loss of nerve cells that produce the neurotransmitter acetylcholine in a region of the brain known as the pedunculopontine nucleus (PPN). Consistent with this, disrupting these nerve cells induced gait and postural deficits in monkeys. The authors therefore suggest that targeting acetylcholine-producing nerve cells in the PPN might provide a way to alleviate the gait disorders and falls experienced by individuals with Parkinson disease.

TITLE: Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease

Chantal Franois
Universit Pierre et Marie Curie Paris 6, CR-ICM, UMR-S975, Paris, France.
Phone:; Fax:; E-mail:

Etienne C. Hirsch
Universit Pierre et Marie Curie Paris 6, CR-ICM, UMR-S975, Paris, France.
Phone:; Fax:; E-mail:

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EDITOR'S PICK: TIMely intervention for asthma

Asthma can be a severely debilitating disease. Its increasing prevalence and the fact that most treatments do not control severe asthma well has stimulated intensive research into genetic susceptibility to asthma in the hope that the information gleaned will lead to new therapeutics. One gene identified as a asthma susceptibility gene is TIM1 and now, a team of researchers, led by Paul Rennert, at Biogen Idec Inc., Cambridge, has generated data in a humanized mouse model of asthma that suggest that targeting TIM-1 protein might have therapeutic benefit in the treatment of patients with asthma. Specifically, the team found that an antibody that bound to a defined region of the TIM-1 protein (a cleft formed within the IgV domain) had therapeutic activity in the humanized mouse model of experimental asthma, ameliorating inflammation and airway hyperresponsiveness.

TITLE: Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma

Paul D. Rennert
Biogen Idec Inc., Cambridge, Massachusetts, USA.
Phone: 617.679.2986; Fax: 617.679.2304; E-mail:

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EDITOR'S PICK: The hormone IGF-1: a trigger of puberty

The onset of puberty is triggered by pulsatile release of the hormone GnRH from nerve cells in a region of the brain known as the hypothalamus. Exactly what signals tell these nerve cells to release GnRH in this manner has not been determined, although it has been suggested that hormones associated with good nutritional status (such as insulin and IGF-1) have a role. A team of researchers, led by Sara DiVall, at Johns Hopkins University, Baltimore, has now confirmed that in mice IGF-1 does indeed have a key role in coordinating the timing of puberty onset.

To study the issue, the team generated mice lacking either the receptor for insulin or the receptor for IGF-1 in GnRH-producing nerve cells. Male and female mice in which the receptor for insulin had been deleted displayed normal timing of puberty and fertility, but male and female mice with the receptor for IGF-1 deleted showed delayed pubertal development but normal fertility. Furthermore, administration of IGF-1 to normal female mice triggered the onset of puberty. The authors therefore conclude that IGF-1 signaling is necessary for timely triggering of pulsatile GnRH production at puberty and that it helps coordinate puberty with a specific stage of body development.

TITLE: Divergent roles of growth factors in the GnRH regulation of puberty in mice

Sara A. DiVall
Johns Hopkins University, Baltimore, Maryland, USA.
Phone: 410.502.7573; Fax: 410.502.7580; E-mail:

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IMMUNOLOGY: Drugs for high blood pressure of benefit in multiple sclerosis?

The hormone angiotensin II (Ang II) is a key regulator of blood pressure. Drugs that block the molecules to which Ang II binds to mediate its effects (AT1Rs) are used to treat high blood pressure. Now, a team of researchers, led by Lawrence Steinman, at Stanford University School of Medicine, Stanford, has identified Ang II as a molecule that sustains inflammation in the brain in mice with a disease that models multiple sclerosis. The effects of Ang II were a result of its ability to promote production of the soluble immune factor TGF-beta in the brain. Importantly, a molecule that blocks AT1Rs reduced the severity of disease in the model of multiple sclerosis by reducing TGF-beta production. The authors therefore suggest that the AT1R-blocking drugs used to treat high blood pressure might be of benefit to individuals with multiple sclerosis.

TITLE: Angiotensin II sustains brain inflammation in mice via TGF-beta

Lawrence Steinman
Stanford University School of Medicine, Stanford, California, USA.
Phone: 650.725.6401; Fax: 650.725.0627; E-mail:

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VACCINE DESIGN: Targeting malaria-causing parasites in the blood

There is currently no vaccine against malaria. The vaccine that is in late-stage clinical trails is designed to target the malaria-causing parasites in the skin and liver, and it reduces the risk of disease by approximately 30-50%. A vaccine that targets the malaria-causing parasite while it is in the blood is likely to provide even more benefit, but such vaccines have been hard to design and develop. However, a team of researchers, led by Michael Good, at the Queensland Institute of Medical Research, Australia, has generated data in mice that suggest that it might now be possible to develop such vaccines. Specifically, they found that administering low doses of killed malaria-causing parasite together with molecules known as CpG-ODN triggered in mice an immune response that targeted malaria-causing parasites in the blood and provided durable and cross-strain protection against disease. The authors hope that their approach might be applicable in humans.

TITLE: Low doses of killed parasite in CpG elicit vigorous CD4+ T cell responses against blood-stage malaria in mice

Michael F. Good
Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Phone: 61.7.3362.0203; Fax: 61.7.3362.0110; E-mail:

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NEUROBIOLOGY: Protein mislocalization gets nerve cells all excited

Individuals with the childhood epilepsy syndrome genetic epilepsy with febrile seizures plus (GEFS+) suffer generalized epilepsies of variable severity and febrile seizures, which are convulsions brought on by a fever. GEFS+ is often associated with genetic mutations that alter the function of proteins known as sodium channels. To investigate how such mutations cause the symptoms of GEFS+, a team of researchers, led by Steven Petrou, at The University of Melbourne, Australia, generated mice expressing one copy of a mutated gene associated with GEFS+ in humans. This gene made a C121W mutant version of the beta-1 sodium channel accessory subunit protein. Detailed analysis of the mice led the team to conclude that the beta-1 sodium channel accessory subunit protein normally modulates the excitability of regions of pyramidal nerve cells known as the axon initial segments and that the C121W mutant protein was excluded from such regions, thereby disrupting the regulation of axon initial segment excitability and causing epilepsy.

TITLE: Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

Steven Petrou
The University of Melbourne, Parkville, Victoria, Australia.
Phone: 61.3.83441957; Fax: 61.3.93470446; E-mail:

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ONCOLOGY: Pathways to cancer: follow the protein Gankyrin

Mutations that activate Ras proteins drive cancer onset and progression and are found in approximately 30% of human cancers. Despite their key role in human disease, the tumorigenic pathways downstream of activated Ras have yet to be completely defined. Data generated by Xue-Min Zhang, Hui-Yan Li, and colleagues, at the National Center of Biomedical Analysis, China, has identified a new molecular pathway with an essential role in Ras-initiated tumorigenesis in mouse and human cells.

Specifically, Zhang, Li, and colleagues found that the protein Gankyrin increases interaction between two proteins known as RhoA and RhoGDI; this decreases RhoA activity, which leads to inhibition of the protein ROCK; this in turn prolongs activation of the protein Akt, an event known to be critical in activated Rasinduced tumor onset and progression. As the authors find that Gankyrin is a critical mediator of Ras-induced tumorigenesis, they suggest it could be a therapeutic target for the treatment of cancers caused by activating Ras mutations.

TITLE: Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells

Xue-Min Zhang
Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
Phone: 86.10.86538178; Fax: 8610.68246161; E-mail:

Hui-Yan Li
Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China.
Phone: 86.10.86538473; Fax: 8610.68246161; E-mail:

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BONE BIOLOGY: Generation of bone-destroying cells promoted by the protein ATF4

Maintaining healthy bone density requires that the number of bone-forming cells (osteoblasts) is balanced by the number of bone-destroying cells (osteoclasts). Increased numbers and/or function of osteoclasts is a feature of diseases such as osteoporosis, Paget disease of bone, and rheumatoid arthritis. A team of researchers, led by Guozhi Xiao, at the University of Pittsburgh, Pittsburgh, has now generated several lines of evidence that indicate that the gene regulatory protein ATF4 has an important role in promoting the generation of osteoclasts in mice. For example, the generation of osteoclasts in ATF4-deficient bones was dramatically reduced when compared with the generation of such cells in normal bones. The authors therefore suggest that targeting ATF4 might provide a way to treat diseases associated with increased osteoclast numbers and/or activity.

TITLE: Activating transcription factor 4 regulates osteoclast differentiation in mice

Guozhi Xiao
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Phone: 412.360.3036; Fax: 412.360.6960; E-mail:

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HEPATOLOGY: Integrating death-inducing and survival signals in liver disease

Acute (fulminant) hepatitis is a major cause of drug-induced liver failure. The protein Fas plays a role in the establishment of fulminant hepatitis because its activation elicits signals to surrounding cells that induce their death and others that protect them. The mechanisms by which these signals are integrated during disease are unknown. Insight into this has now been provided by a team of researchers, led by Rama Khokha, at the Ontario Cancer Institute, Toronto, through their analysis of several strains of genetically engineered mice. Specifically, the team found that the proteins TIMP3 and ADAM17 cooperate to integrate the survival and death-inducing signals triggered by Fas activition during the acute liver stresses that can lead to fulminant hepatitis.

TITLE: Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

Rama Khokha
Ontario Cancer Institute, Toronto, Ontario, Canada.
Phone: 416.946.2051; Fax: 416.946.2984; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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