HITTING THE BOTTLE WITH THE GENETIC BASIS FOR ALCOHOLISM
Alcoholism is a major health concern and genetic factors play an important role in the development and maintenance of alcohol drinking behaviors. In a new study appearing on October 3 in The Journal of Clinical Investigation, Subhash Pandey and colleagues from The University of Illinois show that decreased function of the CREB gene transcription factor in an area of the brain called the central amygdala is involved in anxiety and excessive alcohol drinking behavior.
The authors use rats that either prefer or do not prefer alcohol, and they measured the levels of CREB, phosphorylated CREB, and other proteins in the central amygdala, the part of the brain involved in assigning emotional significance to sensory input. They show that decreased CREB function in this area is important for maintaining high anxiety and excessive alcohol drinking. This genetic determinant for alcoholism creates a vulnerable neural substrate that interacts with alcohol to create abuse potential.
In a related commentary, Gary Wand writes, "these provocative data suggest that a CREB-depedent neuromechanism underlies high anxiety-like and excessive alcohol-drinking behavior."
TITLE: Deficits in Amygdaloid cAMP Responsive-Element Binding Protein Signaling play a role in Genetic Predisposition to Anxiety and Alcoholism
University of Illinois, Chicago, IL USA
Phone: 312-569-7418; Fax: 312-569-8114; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=24381
TITLE: The anxious amygdala: CREB signaling and predisposition to anxiety and alcoholism
Johns Hopkins University School of Medicine, Baltimore, MD USA
Phone: 410-955-7225; Fax: 410-955-0841; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=26436
MITOCHONDRIAL BIOLOGY GETS A NEW CHAPERONE
Mitochondrial complex I deficiency is one of the most common defects in patients with mitochondrial disease. The deficiency results from a failure to assemble the enzyme properly, but the nature of the molecular chaperones that are necessary for this process in mammals have remained obscure.
In a new study appearing on October 3 in The Journal of Clinical Investigation, Eric Shoubridge and colleagues McGill University identify candidate proteins involved in complex I assembly, and show that one of the candidates, B17.2L, is an assembly factor.
The authors identify a null mutation in a patient with a progressive encephalopathy, and show that the defect can be functionally complemented by expression of the wild-type cDNA in patient cells. They also show that an antibody against the B17.2L protein recognizes a subassembly of complex I in several additional patients with complex I assembly defects, but not the whole enzyme complex itself, consistent with a role as a molecular chaperone.
This is the first molecular chaperone to be characterized for mammalian complex I, and is the first identification of the genetic basis of disease in a patient with a complex I assembly defect.
In a related commentary, Robert Nussbaum writes, "The research described here combines clever model organism genomics and bioinformatics to identify the first mammalian protein required for the normal assembly of complex I."
TITLE: A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy
Montreal Neurological Institute, Montreal, Canada
Phone: 514-398-1997; Fax: 514-398-1509; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26020
TITLE: Mining yeast in silico unearths a golden nugget for mitochondrial biology
National Human Genome Research Institute, Bethesda, MD USA
Phone: 301-402-2039; Fax: 301 402-2170; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=26625
NATURE AND NURTURE NEEDED TO NUDGE INDUCTION OF THROMBOTIC THROMBOCYTOPENIC PURPURA
Thrombotic thrombocytopenic purpura (TTP) is an important illness affecting many organ systems, whose cause remained unknown until the cloning in of the gene responsible for this disorder, called ADAMTS13. TTP is a life-threatening disease that is characterized by anemia, fever, neurological problems and kidney dysfunction.
In a new study appearing on October 3 in The Journal of Clinical Investigation, David Ginsburg and colleagues from the University of Michigan report detailed analysis of ADAMTS13-deficient mice generated by gene targeting.
The authors find that ADAMTS13 deficiency is necessary, but not sufficient to trigger the symptoms that are characteristic of TTP. They demonstrate that the microbial toxin, Shigatoxin triggers a syndrome in susceptible mice that is remarkably similar to human TTP. The authors identify genetic susceptibility factors required for TTP that differ among mouse strains. Thus, loss of ADAMTS13 alone cannot induce clinical TTP and other key factors or environmental triggers are needed.
These results may explain the variation in age of onset and disease severity among TTP patients, which has become a topic of considerable interest. These findings provide a major advance in understanding the pathophysiology of TTP.
TITLE: Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice
University of Michigan, Ann Arbor, MI USA
Phone: 734-647-4808; Fax: 734-936-2888; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26007
PUTTING CHRONIC PULMONARY HYPERTENSION ON HOLD
Therapies for pulmonary arterial hypertension are often effective in acute situations, but in chronic pulmonary hypertension current therapies have had limited success. In a new study appearing on October 3 in The Journal of Clinical Investigation, Ralph Schermuly and colleagues describes the successful therapeutic use of STI571, a clinically available PDGF inhibitor, in a well-established animal model of severe pulmonary hypertension.
This approach does not just prevent or arrest pulmonary hypertension – it reverses it. PDGF is a protein produced by platelets and other cells that stimulates cell growth and division and is involved in normal wound healing.
The authors provide data, which demonstrate that treatment with STI571 not only improved hemodynamic, and morphometric parameters but also increased survival. The PDGF receptor (PDGF-R) and PDGF is upregulated in the course of disease. STI571 treatment normalized PDGF-R expression and downstream signaling events to mediate therapeutic effects.
In a related commentary, write, "These studies provide preclinical proof of concept for the clinical development of a PDGF inhibitor as a targeted therapy for pulmonary arterial hypertension patients."
TITLE: Reversal of experimental pulmonary hypertension by platelet derived growth factor inhibition
Justus-Liebig-Universitat Giessen, Giessen, Germany
Phone: 49 641 99 42420; Fax: 49 641 99 42419; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24838
TITLE: PDGF signaling in pulmonary arterial hypertension
Columbia University, New York, NY USA
Phone: (212) 305-4436; Fax: (212) 342-1443; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26593
BREAKING DOWN FATS WITH APOA5
APOA5 is a newly identified apolipoprotein that helps regulate plasma triglyceride levels. In a new study appearing on October 3 in The Journal of Clinical Investigation, Christophe Marcais and colleagues from Hospice Civil de Lyon report the first mutation of the apolipoprotein A5 gene, Q139X, causing a unusual form of late onset familial hyperchylomicronemia, is a rare hereditary enzyme deficiency that results in abnormal breakdown of fats in the body. In a related commentary, Martin Merkel and Joerg Heeren write that this discovery consolidates the role of APOA5 as one of the key players in human triglyceride metabolism.
TITLE: ApoAV Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment
Hospice Civil de LYON, Cedex, France
Phone: 33 4 78 86 15 99; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24471
TITLE: Give me A-five for lipoprotein hydrolysis!
University Hospital Hamburg-Eppendorf, Hamburg, Germany
Phone: 49 40 42803-5542; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26712
NEW WAYS TO TRANSPORT CHOLESTEROL AND DECREASE ATHEROSCLEROSIS
High plasma levels of the "good cholesterol" HDL decrease the risk of atherosclerosis and vascular disease. Expression of a receptor in the liver, called SR-BI takes up HDL cholesterol and transports cholesterol from macrophage cells eventually to the feces, a process known as reverse cholesterol transport (RCT)
In a new study appearing on October 3 in The Journal of Clinical Investigation, Daniel Rader and colleagues from the University of Pennsylvania describe studies using a new method they developed for tracing macrophage to feces RCT to address the question of whether liver expression SR-BI regulates the rate of RCT.
The authors show that liver SR-BI expression is a positive regulator of macrophage RCT. Mice overexpressing SR-BI efficiently clear cholesterol to the feces while mice lacking the receptor have decreased cholesterol clearance. This shows that hepatic SR-BI affects physiological processes that are critical to atherogenesis. It also suggests that upregulation of SR-BI expression in the liver could be a novel approach to increasing RCT.
In a related commentary, Astrid van der Velde and Albert Groen write that this method "may be a first step in the development of an assay to determine RCT in humans."
TITLE: Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo
Daniel J. Rader
University of Pennsylvania Medical Center, Philadelphia, PA USA
Phone: 215-573-4176; Fax: 215-573-8606; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25327
TITLE: Shifting gears: Liver SR-BI drives reverse cholesterol transport in macrophages
Albert K. Groen
Academic Medical Center Liver Center, Amsterdam, Netherlands
Phone: 3120-566-4174; Fax: 3120-566-9190; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26241
SENDING THE CELLULAR SIGNALS THAT SAVE THE HEART
Atrial natriuretic peptide (ANP) is an agent that regulates fluid balance and blood pressure, and has been shown to protect the heart. In a new study appearing on October 3 in The Journal of Clinical Investigation, Mark Sussman and colleagues from San Diego State University examine the cardioprotective signaling mediated by ANP.
The authors show that ANP stimulation leads to elevation of cGMP and nuclear accumulation of Akt, a cell survival protein. The accumulation of activated Akt in the nucleus correlates with translocation of zyxin, a cytoskeletal signaling molecule known to shuttle through the nucleus. The linking of cardioprotective stimuli with a molecular mechanism to account for nuclear accumulation of Akt kinase establishes a new paradigm for antiapoptotic signaling and opens new possibilities for interventional approaches to influence cell survival.
Cardioprotective effects ANP are being examined in a clinical setting for treatment of heart failure. These findings clarify the signal transduction downstream from these stimuli and also answer questions regarding the molecular mechanism for Akt nuclear translocation that has until now remained unknown.
TITLE: Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt
AUTHOR CONTACT: Mark Sussman
San Diego State University, San Diego, CA USA
Phone: 619 594-2983; Fax: 619 594-2610; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24280
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.
The probability that we may fail in the struggle ought not to deter us from the support of a cause we believe to be just.
~ Abraham Lincoln