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JCI Table of Contents, January 15 2004

JCI Journals

Inhibition of Borrelia burgdorferi protein prevents invasion of tick salivary glands and may reduce Lyme disease transmission

In the January 15 issue of the Journal of Clinical Investigation researchers from Yale University demonstrate that an outer surface protein, OspC, of the organism Borrelia burgdorferi, which causes Lyme disease, is critical for the organism's ability to invade the tick salivary gland and therefore be transmitted from ticks to humans.

Lyme disease was first named in 1977, when arthritis was observed in a cluster of children in Lyme, Connecticut. The bacterium Borrelia burgdorferi is transmitted to humans by the bite of infected deer ticks and in 2002 caused more than 23,000 infections in the United States, mostly localized to California and states in the northeastern, mid-atlantic, and upper north-central regions. Symptoms include a characteristic "bulls-eye" rash at the bite site, fever, malaise, and muscle and joint aches.

When a tick harboring the bacterium engorges, initiating transmission to a new host, B. burgdorferi decreases the expression of the outer surface protein OspA that allows the bacterium to adhere to the tick gut and instead begins expressing an alternative outer surface protein, OspC. In order to determine the function of OspC, Erol Fikrig and colleagues generated a strain of the B. burgdorferi bacterium that was deficient in OspC. These bacteria were able to survive and multiply in feeding ticks; however, they were unable to invade tick salivary glands. The results agreed with their findings that OspC binds to tick salivary gland extracts and that antibody inhibition of OspC inhibits the ability of B. burgdorferi to invade tick salivary glands, and therefore inhibits transmission to a new mammalian host. These insights into pathogen transmission might offer new approaches to reducing the incidence of Lyme disease.

TITLE: OspC facilitates Borrelia burgdorferi invasion of Ixodes scapularis salivary glands

Erol Fikrig
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-2453
Fax: (203) 785-7053

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Understanding nerve degeneration in spastic paraplegia

Hereditary spastic paraplegia (HSP) encompasses a group of neurodegenerative diseases characterized by progressive weakness, spasticity, and diverse patterns of inheritance, which is caused by degeneration of nerve axons. Elena Rugarli and colleagues from the Telethon Institute of Genetics and Medicine in Naples, Italy, developed a mouse model for studying HSP due to mutations in the Spg7 gene, which encodes the enzyme paraplegin. Paraplegin-deficient mice were affected by axonal swelling from failed axon transport, and axon degeneration. Long before this swelling ocurred the authors observed abnormalities in mitochondrial shape within nerve terminals that correlated with the onset of motor skill impairment. The number of axons containing these abnormal mitochondria was far greater than the number of swollen and degenerate axons. The authors suggest that local failure of mitochondrial function may affect axonal transport and cause axonal degeneration.

In an accompanying commentary, Harris Gelbard from the University of Rochester discusses a hypothetical scheme for altered mitochondrial function that may result from the loss of paraplegin activity, which may account for the pathology observed in Spg7-/- mice. A timely therapeutic intervention may therefore prevent axonal loss.

TITLE: Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Elena Rugarli
Telethon Institute of Genetics and Medicine, Castellino, Naples, Italy.
Phone: 39-081-6132221
Fax: 39-081-5609877

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ACCOMPANYING COMMENTARY: Synapses and Sisyphus: life without paraplegin

Harris A. Gelbard
University of Rochester Medical Center, Rochester, New York, USA.
Phone: (585) 273-1473
Fax: (585) 506-1947

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Bone marrow-derived stem cells active in pulmonary fibrosis

Adult stem cells have long been thought to be restricted in their potential to differentiate and regenerate tissues in which they reside. A study by Sem Phan and colleagues from the University of Michigan, in the January 15 issue of the Journal of Clinical Investigation, suggests that the collagen overproduction and deposition in the lung causing idiopathic pulmonary fibrosis may develop from cells derived from bone marrow stems cells, rather than parenchymal lung fibroblasts.

The authors induced pulmonary fibrosis in mice that had been altered with bone marrow labeled with a fluorescent green marker protein. In these mice, cells derived from bone marrow-derived stem cells fluoresce green, while those cells that reside in the lung do not. Most of the collagen-producing fibroblasts observed in the lungs of these mice fluoresced green, indicating that they were of bone marrow origin.

In an accompanying commentary Sarah Dunsmore and Steven Shapiro from Harvard Medical School discuss this new concept in pulmonary fibrosis. They state "understanding the mechanisms of engraftment will be important as clinical applications of bone marrow stem cell therapy are explored. The clinical implications of these findings are significant; for example, we might now consider bone marrow stem cell therapy to correct structural alterations in the lung." They conclude "translation of our understanding of disease pathogenesis into clinical practice will bring us closer to our real goal - improving the lives of our patients and ultimately curing disease.

TITLE: Bone marrow-derived progenitor cells in pulmonary fibrosis

Sem H. Phan
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 763-6454
Fax: (734) 936-1938

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ACCOMPANYING COMMENTARY: The bone marrow leaves its scar: new concepts in pulmonary fibrosis

Steven D. Shapiro
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Phone: (617) 732-7599
Fax: (617) 232-4623

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Autoantibodies at large in Sandhoff disease

Sandhoff disease, a severe form of Tay-Sachs disease, is a rare, genetic, lipid storage disorder resulting in the progressive deterioration of the central nervous system. It is caused by a deficiency of the enzyme hexosaminidase, which results in the accumulation of certain fats (gangliosides) in the brain and other organs of the body. Mice deficient in the Hexb gene have provided a useful model system in which to study this human disorder. However recent studies have suggested that ganglioside accumulation in neurons alone cannot completely explain the nerve cell damage observed in Hexb-/- mice.

In the January 15 issue of the Journal of Clinical Investigation Shoji Yamanaka and colleagues from Yokohama City University report that an autoimmune response directed towards gangliosides GM2 and GA2 also plays a role in the pathology of this disease. The authors found increased levels of serum anti-ganglioside autoantibodies and IgG deposition on neurons of the central nervous system. Disruption of the Fc receptor gene, which plays a key role in immune-complex-mediated diseases, improved symptoms and increased the lifespan of Hexb-/- mice. These results support the novel concept that autoantibodies generated during the course of the disease are involved in neurodegeneration by causing apoptosis of the neuron. The data also provide a target for the development of novel therapies.

TITLE: Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses

Shoji Yamanaka
Yokohama City University School of Medicine, Yokohama, Japan.
Phone: 81-45-787-2586
Fax: 81-45-786-0191

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Impaired inhibition of TGF-beta signaling contributes to the fibrotic disorder scleroderma

Although the pathogenesis of scleroderma has not been entirely elucidated, the disease typically results from connective tissue fibrosis that disrupts the normal architecture of affected organs and ultimately leads to their dysfunction and failure. The TGF-b/Smad signaling pathway is likely to be involved in the persistent activation of the genes encoding proteins such as collagen, which underlie the thickening fibrotic process.

Hironobu Ihn and colleagues from the University of Tokyo aimed their studies at the TGF-beta1 cytokine pathway and in the January 15 issue of the Journal of Clinical Investigation show that cytokine signaling is indeed a key player in the molecular pathogenesis of this fibrotic disorder. TGF-beta1 is regulated by a negative feedback loop whereby an inhibitory molecule, Smad7, blocks activation of this pathway and promotes degradation of the TGF-beta receptor complex. Comparisons between normal and scleroderma fibroblasts reveal that Smad7 expression is elevated in diseased fibroblasts, but its ability to promote degradation of the receptor complex through recruitment of enzymes known as Smurfs, is impaired. These results further implicate autocrine TGF-beta signaling in the pathogenesis of scleroderma.

TITLE: Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts

Hironobu Ihn
University of Tokyo, Tokyo, Japan.
Phone: 81-3-3815-5411
Fax: 81-3-3814-1503

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Independent roles for insulin in metabolism and cellular growth

Insulin regulates how we store and use our food as fuel, and also controls cellular proliferation. A question that remains is does insulin promote cell growth independent of metabolism or are the two processes interdependent? In the January 15 issue of the Journal of Clinical Investigation Domenico Accili and colleagues from Columbia University in New York addressed this question by generating mice that lacked the gene encoding the insulin receptor (Insr) in a varying percentage of their body's cells. The authors characterized mouse strains with 80% (_80) and 98% (_98) reduction in Insr levels and found that both strains exhibited severely stunted growth. Interestingly, _80 mice possessed very low levels of blood sugar, whereas _98 mice had very high levels of blood sugar. The _80 mice modeled a human disorder, known as leprechaunism, caused by Insr mutations, implicating differential insulin receptor sensitivity in various tissues as a contributor to pathogenesis of the disease.

Further analyses enabled the researchers to conclude that growth was more sensitive to Insr depletion than insulin-dependent metabolism and that these two processes are regulated independently. The data also suggest that the number of insulin receptors is an important determinant of the specificity of insulin action.

TITLE: Mosaic analysis of insulin receptor function

Domenico Accili
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 851-5332
Fax: (212) 851-5331

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Cellular sodium and calcium levels are vital to skeletal muscle physiology

Intracellular calcium levels are essential to physiologic signaling processes such as the transmission of signals between synapses in nerve cells and muscle excitation and contraction. Ncx3, a sodium/calcium exchanger is able to regulate cellular calcium levels by controlling calcium import and export at the plasma membrane. In order to elucidate the physiologic role of Ncx3 in skeletal muscle, Sophie Sokolow and colleagues from Université Libre de Bruxelles, Belgium generated mice lacking the Ncx3 gene. Their report in the January 15 issue of the Journal of Clinical Investigation describes the observation in these mice of localized muscle fiber breakdown and impaired signal transmission in muscle nerves. These effects were attributed to reduced sodium and calcium exchange activity and altered calcium balance in the absence of Ncx3. These defects at the cellular level manifested as muscle weakness and ease in fatigability in Ncx3-/- mice, further emphasizing a key role for Ncx3 in skeletal muscle physiology.

TITLE: Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3

Sophie Sokolow
Université Libre de Bruxelles, Gosselies, Belgium.
Phone: 32-2-650-98-24
Fax: 32-2-650-98-20

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Vasopressin receptor V1b is crucial in times of both stress and rest

The hypothalamic-pituitary-adrenal axis (HPA axis) is the well-established neuroendocrine system that responds to stress. The pituitary gland serves as a reservoir for the most important regulators of this system: arginine-vasopressin peptide (AVP) and corticotropin-releasing hormone (CRH). AVP is involved in smooth muscle contraction and its effects are mediated through the binding of AVP to three different receptor isoforms designated V1a, V1b, and V2. V1b mediates vasopressin-stimulated adrenocorticotropic hormone (ACTH) release.

To further investigate the roles of V1b, Gozoh Tsujimoto and colleagues from Kyoto University, Japan, created mice lacking the V1b receptor gene (V1bR-/-). Under resting conditions V1bR-/- mice had lower circulating levels of ACTH and corticosterone compared to controls. Furthermore, the normal increase in ACTH levels in response to AVP administration was impaired. Under stressful conditions, ACTH levels were also blunted in V1bR-/- mice.

The data demonstrate that the V1b receptor plays a crucial role in regulating HPA axis activity under both stressful and resting conditions. Clinical implications include the possibility that drugs that regulate V1b receptor activity may have potential utility in the treatment of stress, anxiety, depression, and addiction.

TITLE: The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions

Gozoh Tsujimoto Kyoto University, Kyoto, Japan.
Phone: 81-3-3419-2476
Fax 1: 81-3-3419-1252

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Regulating folate receptors during folate deficiency

Folate, a type of B vitamin, is important in DNA synthesis and folate deficiency can lead to fetal abnormalities in spinal cord and brain development. Folate receptors (FRs) have been shown to mediate cellular folate uptake in both normal and malignant cells. In the January 15 issue of the Journal of Clinical Investigation, Asók Antony and colleagues from Indiana University demonstrate the mechanism of FR upregulation under conditions of folate deficiency. The authors had previously demonstrated that a cis-element and trans-acting protein regulate FR synthesis. In the current study they examined the expression of FRs in human cervical cancer cells after transfer from folate-rich to -poor media and found that with progressive folate deficiency the metabolite homocysteine accumulates within the cell, subsequently stimulating cis-trans regulatory interaction, which in turn results in increased folate receptor synthesis.

TITLE: Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions

Asók C. Antony
Indiana Cancer Research Institute, Indianapolis, Indiana, USA.
Phone: (317) 274-3589
Fax: (317) 274-0396

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Regulatory T cells help suppress graft rejection

CD4+CD25+ regulatory T cells (Treg cells) play a key role in regulating the immune response to both self- and foreign antigens by the suppression of aggressive T cell immune responses. As a result, they are critical in suppressing graft rejection. However it is not known whether this response is mediated by T cells that have been previously exposed to antigens (memory T cells) or by naïve T cells. In the January 15 issue of the Journal of Clinical Investigation, Zhenhua Dai and colleagues from Yale University demonstrate that this suppression of graft rejection is donor-specific and is mediated by antigen-induced, but not naïve Treg cells. The mechanism of this suppression is the apoptosis of memory T cells, which is dependent on the CD30 costimulatory molecule on Treg cells.

TITLE: CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism

Zhenhua Dai
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 737-2601
Fax: (203) 737-1801

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Distinct roles for VEGF isoforms in bone development

During bone formation, epiphyseal cartilage is avascular until secondary ossification occurs. Vascularization of this maturing tissue relies on angiogenic recruitment from surrounding vessels. The growth factor VEGF has previously been shown to be critical for metaphyseal bone vascularization and is now implicated as an angiogenic factor for epiphyseal vascularization. By generating mice that express specific splice forms of VEGF, Geert Carmeliet and colleagues from Katholike Universiteit Leuven, Belgium determined that the soluble forms of VEGF are indispensable for proper epiphyseal cartilage development, and chondrocyte development and survival. In the January 15 issue of the Journal of Clinical Investigation, Carmeliet et al. demonstrate that mice expressing only the matrix-bound form (VEGF188) but neither of the soluble forms (VEGF120 or VEGF164) had increased hypoxia and massive chondrocyte apoptosis in the epiphyseal cartilage, as well as dwarfed skeletal defects. Metaphyseal development appeared normal in these mice, demonstrating that different molecular processes requiring specific VEGF isoforms regulate epiphyseal and metaphyseal vascularization.

TITLE: Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival

Geert Carmeliet
Katholieke Universiteit Leuven, Leuven, Belgium
Phone: +32-16-345974
Fax: +32-16-345934

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Sequence motif crucial for binding adensoyl derivatives

CBS domains were originally identified as sequence motifs occurring within cystathione beta-synthase (CBS) and several other proteins, and occur in all organisms from bacteria to humans. While their functions were unknown, point mutations within these domains were known to cause several hereditary diseases including homocystinuria, Bartter syndrome, retinitis pigmentosa, and Wolff-Parkinson-White syndrome. In the January 15 issue of the Journal of Clinical Investigation, D. Grahame Hardie and colleagues from the University of Dundee, Scotland, fill in the missing link and demonstrate that pairs of CBS sequences - known as Bateman domains - derived from a number of different enzymes, bind adenosyl compounds such as AMP and ATP that act as energy sources and drive many cellular processes. The authors introduced mutations into these sequence motifs and found that they caused dramatic shifts in ligand-binding properties, underlying the loss of function of the parent proteins.

In an accompanying commentary, Bruce Kemp from St. Vincent's Institute of Medical Research in Australia discusses the impact of this report and how understanding this binding mechanism paves the way for rational drug design. He comments "There are now well over a 1000 proteins known to contain Bateman domains. For many of these proteins we can now begin to hypothesize about how they are regulated by adenosyl metabolites."

TITLE: CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

D. G. Hardie
University of Dundee, Dundee, Scotland, United Kingdom.
Phone: +44-1382-344253
Fax: +44-1382-345783

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ACCOMPANYING COMMENTARY: Bateman domains and adenosine derivatives form a binding contract

Bruce E. Kemp
St. Vincent's Institute for Medical Research, Fitzroy, Victoria, Australia.
Phone: 61-2-9288-2480
Fax: 61-3-9416-2676

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