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JCI online early table of contents: Sept. 1, 2011

EDITOR'S PICK: Activating your ABCs might help prevent AD (Alzheimer disease)

Alzheimer disease (AD) is the most common cause of dementia among older people. One of the main features of AD is the presence in the brain of abnormal clumps of the protein fragment beta-amyloid, which are known as amyloid plaques. A team of researchers, led by Jens Pahnke, at the University of Rostock, Germany, has now identified a way to reduce the amount of beta-amyloid in the brains of mice with a disease that models AD, providing hope that a similar approach might be possible in patients.

One reason that beta-amyloid accumulates in the brain of an individual with AD is that it is cleared at a much reduced rate compared with that in the brain of an individual who is healthy. The mechanistic reasons for this reduced beta-amyloid clearance are not well known. But now, Pahnke and colleagues have determined that the transport protein ABCC1 has a key role in clearing beta-amyloid from the brain of mice. Of potential clinical interest, activation of ABCC1 using a drug approved by the FDA to relieve nausea and vomiting (thiethylperazine) markedly reduced the amount of beta-amyloid in the brains of mice with a condition that models AD. The authors therefore suggest that pharmacological activation of ABC transporters could perhaps impede the formation of amyloid plaques and thereby reduce the damage to the brain that results in dementia in individuals with AD.

TITLE: Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice

Jens Pahnke
University of Rostock, Rostock, Germany.
Phone: 49.381.494.4700; Fax: 49.381.494.4702; E-mail:

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EDITOR'S PICK: Joining the dots: mutation-mechanism-disease

Individuals with an autoinflammatory syndrome experience episodes of prolonged fever and inflammation in the absence of infection. There are several different autoinflammatory syndromes identified by distinct symptoms and underlying genetic mutations. A team of researchers, led by Koji Yasutomo, at the University of Tokushima Graduate School, Japan, has now determined that a mutation of the PSMB8 gene causes Japanese autoinflammatory syndrome with lipodystrophy (JASL), a recently identified condition. The team performed a detailed analysis of how the PSMB8 mutation causes disease, providing new insight into potential therapeutic targets for this rare condition.

TITLE: A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans

Koji Yasutomo
University of Tokushima Graduate School, Tokushima, Japan.
Phone: 81.88.633.7048; Fax: 81.88.633.7114; E-mail:

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IMMUNOLOGY: A TACIt agreement to provide protection from flu

Key to ridding the body of an infecting virus, such as the one that causes flu, are immune molecules known as antibodies. Once the body has been infected by influenza virus, it maintains a population of antibody-secreting cells that enable it to respond more quickly if it is infected with the same virus a second time. A team of researchers, led by Jan Erikson, at The Wistar Institute, Philadelphia, has now gained new insight into the mechanisms governing the longevity of antibody-secreting cells in mice. Specifically, the team found that signaling via the protein TACI was important for the development and maintenance of a population of long-lived antibody-secreting cells in a mouse model of influenza virus infection. These data suggest that targeting TACI could enhance antibody responses to repeat infection with a virus and could be useful in the development of more effective antiviral vaccines.

TITLE: Protective antiviral antibody responses in a mouse model of influenza virus infection require TACI

Jan Erikson
The Wistar Institute, Philadelphia, Pennsylvania, USA.
Phone: 215.898.3823; Fax: 215.573.9053; E-mail:

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NEUROBIOLOGY: ALS-linked proteins working together to get the job done

Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is a fatal adult neurodegenerative disorder. It is similar in many ways to the early-onset neurodegenerative disorder frontotemporal dementia (FTD). Genetic mutations are the cause of disease in 5󈝶% of patients with ALS and approximately 40% of patients with FTD. Recently, mutations in the genes that carry the instructions for making two related proteins, FUS and TDP-43, have been linked to inherited forms of ALS and FTD. A team of researchers, led by Brian McCabe, at Columbia University Medical Center, New York, has now provided new insight into the functions of FUS and TDP-43 by studying them in Drosophila. The data indicate that FUS and TDP-43 work together in vivo and suggest that disruption of one or more of the pathways they jointly regulate may occur in ALS and FTD.

TITLE: The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span

Brian D. McCabe
Columbia University Medical Center, New York, New York, USA.
Phone: 212.305.3548; Fax: 212.305.5775; E-mail:

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NEPHROLOGY: Cellular powerhouses dysfunctional in sepsis-associated kidney injury

Acute kidney injury (AKI) affects approximately 50% of individuals with severe sepsis. The risk of death from a combination of sepsis and AKI is nearly double the risk of death from sepsis alone. The mechanisms underlying kidney dysfunction in individuals with sepsis-associated AKI are not well defined. It is therefore hard to develop effective therapeutics. Now, a team of researchers, led by Samir Parikh, at Beth Israel Deaconess Medical Center, Boston, has generated data in mice that suggest that dysfunction within kidney tubule cells of the cellular compartments responsible for generating energy (mitochondria) is a major contributor to the AKI that often accompanies sepsis. Moreover, Parikh and colleagues identified reduced expression of the protein PGC-1-alpha as a key factor contributing to mitochondrial dysfunction in this situation. They therefore suggest that restoring expression of PGC-1-alpha could provide a new approach to treating sepsis-associated AKI.

TITLE: PGC-1-alpha promotes recovery after acute kidney injury during systemic inflammation in mice

Samir M. Parikh
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: 617.667.5813; Fax: 617.667.2646; E-mail:

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IMMUNOLOGY: Gut microbes linked to kidney disease

Individuals with IgA nephropathy have kidneys that do not function correctly and leak blood and sometimes protein into the urine. The condition is caused by the inappropriate accumulation of IgA an immune molecule that helps rid the body of microbes in the kidneys. However, it is not known what causes IgA to accumulate in the kidneys. A team of researchers (led by Jennifer Gommerman, at the University of Toronto, Toronto; and Jeffrey Browning, at Biogen Idec, Cambridge) has now generated data in mice that suggest that IgA nephropathy could be linked to disruption of the microbial populations that normally live in the gut. These data provide a new avenue of research to further understanding of what may trigger this disease, information that is key for developing new treatments.

TITLE: Mice overexpressing BAFF develop a commensal floradependent, IgA-associated nephropathy


Jennifer Gommerman
University of Toronto, Toronto, Ontario, Canada.
Phone: 416.978.6959; Fax: 416.978.1938; E-mail:

Jeffrey Browning
Biogen Idec, Cambridge, Massachusetts, USA.
Phone: 617.679.3312; Fax: 617.679.3148; E-mail:

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ALLERGY AND ASTHMA: Protection from contact allergies

Contact allergies affect a small but significant proportion of individuals; allergic contact dermatitis is the most common occupational disease in the US and Europe. A team of researchers, led by Kerstin Steinbrink, at Johannes Gutenberg University Mainz, Germany, has now provided new insight into the cellular and molecular mechanisms that protect mice from contact allergies, information that they hope could lead to the development of new approaches for preventing contact allergies.

It is believed that an individual develops a contact allergy if their first exposure to the allergen is to a high dose of it. Conversely, repeated exposure to low doses of a contact allergen provides protection. A more detailed understanding of the molecular and cellular mechanisms underlying the protection afforded by repeated exposure to low doses of a contact allergen is needed if ways to prevent individuals from developing contact allergies are to be manufactured. In this context, Steinbrink and colleagues found that release of the immune molecule TNF by immune cells known as CD11+CD8+ DCs was required and sufficient for mice to develop protection against contact allergens. The TNF protected mice from contact allergy by killing immune cells known as effector CD8+ T cells that were destined to cause disease by reacting to the allergen. The authors hope these data can help facilitate the development of strategies to reduce the frequency of allergen-reactive effector CD8+ T cells.

TITLE: T cell killing by tolerogenic dendritic cells protects mice from allergy

Kerstin Steinbrink
University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
Phone: 49.6131.17.3792; Fax: 49.6131.17.5527; E-mail:

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TUMOR IMMUNOLOGY: Th17 immune cells promote precancerous changes in the stomach lining

Gastric cancer (cancer that originates in the stomach) is the fourth most common cancer worldwide. The development of gastric cancer is characterized by a relatively well-defined series of changes to the lining of the stomach. Proinflammatory molecules known as cytokines (in particular the cytokine IL-11) promote progression along this multistep cascade toward gastric cancer. Frank Jirik and colleagues, at the University of Calgary, Calgary, have now determined that in mice lacking the signaling molecule Smad4 in immune cells known as T cells, Th17-type T cells contribute to the development of precancerous changes in the lining of the stomach. Th17 cells are key to the body's defense against microbes and the authors therefore suggest that any chronic increase in the activity of Th17 cells in the lining of the stomach could initiate precancerous changes in the lining of the stomach.

TITLE: Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

Frank Robert Jirik
University of Calgary, Calgary, Alberta, Canada.
Phone: 403.220.8666; Fax: 403.210.8127; E-mail:

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MUSCLE BIOLOGY: Modeling muscle weakness

Hypokalemic periodic paralysis is an inherited condition that causes bouts of muscle weakness and sometimes severe paralysis. The episodes of muscle weakness are associated with low levels of potassium in the blood. Mutations in two genes one that provides the instructions for making the NaV1.4 protein and one that provides the instructions for making the CaV1.1 protein can cause hypokalemic periodic paralysis. A team of researchers, led by Stephen Cannon, at UT Southwestern Medical Center, Dallas, has now engineered mice to express the mouse equivalent of the NaV1.4-R669H variant that causes hypokalemic periodic paralysis in humans. These mice were found to have the key features of hypokalemic periodic paralysis and constitute the first mouse model of the disease.

TITLE: A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

Stephen C. Cannon
UT Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.645.6225; Fax: 214.645.6239; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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