Showing papers by "Kyushu University published in 2007"

SOCS proteins, cytokine signalling and immune regulation.

Abstract: Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the immune system. In this Review we bring together data from recent studies on SOCS proteins and their role in immunity, and propose a cohesive model of how cytokine signalling regulates immune-cell function.

An Asian emission inventory of anthropogenic emission sources for the period 1980-2020

Abstract: . We developed a new emission inventory for Asia (Regional Emission inventory in ASia (REAS) Version 1.1) for the period 1980–2020. REAS is the first inventory to integrate historical, present, and future emissions in Asia on the basis of a consistent methodology. We present here emissions in 2000, historical emissions for 1980–2003, and projected emissions for 2010 and 2020 of SO2, NOx, CO, NMVOC, black carbon (BC), and organic carbon (OC) from fuel combustion and industrial sources. Total energy consumption in Asia more than doubled between 1980 and 2003, causing a rapid growth in Asian emissions, by 28% for BC, 30% for OC, 64% for CO, 108% for NMVOC, 119% for SO2, and 176% for NOx. In particular, Chinese NOx emissions showed a marked increase of 280% over 1980 levels, and growth in emissions since 2000 has been extremely high. These increases in China were mainly caused by increases in coal combustion in the power plants and industrial sectors. NMVOC emissions also rapidly increased because of growth in the use of automobiles, solvents, and paints. By contrast, BC, OC, and CO emissions in China showed decreasing trends from 1996 to 2000 because of a reduction in the use of biofuels and coal in the domestic and industry sectors. However, since 2000, Chinese emissions of these species have begun to increase. Thus, the emissions of air pollutants in Asian countries (especially China) showed large temporal variations from 1980–2003. Future emissions in 2010 and 2020 in Asian countries were projected by emission scenarios and from emissions in 2000. For China, we developed three emission scenarios: PSC (policy success case), REF (reference case), and PFC (policy failure case). In the 2020 REF scenario, Asian total emissions of SO2, NOx, and NMVOC were projected to increase substantially by 22%, 44%, and 99%, respectively, over 2000 levels. The 2020 REF scenario showed a modest increase in CO (12%), a lesser increase in BC (1%), and a slight decrease in OC (−5%) compared with 2000 levels. However, it should be noted that Asian total emissions are strongly influenced by the emission scenarios for China.

62.2: Invited Paper: Fast Electro‐Optical Switching in Polymer‐Stabilized Liquid Crystalline Blue Phases for Display Application

Abstract: Blue phases have two major advantages over commonly used nematic phases:1) the response is much faster, 2) the zero-electric field state is optically isotropic. We demonstrate the sufficiently large electric field-induced birefringence and the micro-second response of the polymer-stabilized blue phases and the induced-isotropic phases without any surface treatment.

Rapid and reversible shape changes of molecular crystals on photoirradiation

Abstract: The development of actuators based on materials that reversibly change shape and/or size in response to external stimuli has attracted interest for some time. A particularly intriguing possibility is offered by light-responsive materials, which allow remote operation without the need for direct contact to the actuator. The photo-response of these materials is based on the photoisomerization of constituent molecules (typically trans-cis isomerization of azobenzene chromophores), which gives rise to molecular motions and thereby deforms the bulk material. This effect has been used to create light-deformable polymer films and gels, but the response of these systems is relatively slow. Here we report that molecular crystals based on diarylethene chromophores and with sizes ranging from 10 to 100 micrometres exhibit rapid and reversible macroscopic changes in shape and size induced by ultraviolet and visible light. We find that on exposure to ultraviolet light, a single crystal of 1,2-bis(2-ethyl-5-phenyl-3-thienyl)perfluorocyclopentene changes from a square shape to a lozenge shape, whereas a rectangular single crystal of 1,2-bis(5-methyl-2-phenyl-4-thiazolyl)perfluorocyclopentene contracts by about 5-7 per cent. The deformed crystals are thermally stable, and switch back to their original state on irradiation with visible light. We find that our crystals respond in about 25 microseconds (that is, about five orders of magnitude faster than the response time of the azobenzene-based polymer systems) and that they can move microscopic objects, making them promising materials for possible light-driven actuator applications.

Control of magnetic properties through external stimuli.

Abstract: The magnetic properties of many magnetic materials can be controlled by external stimuli. The principal focus here is on the thermal, photochemical, electrochemical, and chemical control of phase transitions that involve changes in magnetization. The molecular compounds described herein range from metal complexes, through pure organic compounds to composite materials. Most of the Review is devoted to the properties of valence-tautomeric compounds, molecular magnets, and spin-crossover complexes, which could find future application in memory devices or optical switches.

Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region.

Abstract: Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.

Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome

Abstract: Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.

Light Regulation of Stomatal Movement

Abstract: Stomatal pores, each surrounded by a pair of guard cells, regulate CO2 uptake and water loss from leaves. Stomatal opening is driven by the accumulation of K+ salts and sugars in guard cells, which is mediated by electrogenic proton pumps in the plasma membrane and/or metabolic activity. Opening responses are achieved by coordination of light signaling, light-energy conversion, membrane ion transport, and metabolic activity in guard cells. In this review, we focus on recent progress in blue- and red-light-dependent stomatal opening. Because the blue-light response of stomata appears to be strongly affected by red light, we discuss underlying mechanisms in the interaction between blue-light signaling and guard cell chloroplasts.

A flexible interpenetrating coordination framework with a bimodal porous functionality.

Abstract: Introducing a functional part into open-framework materials that tunes the pore size/shape and overall porous activity will open new routes in framework engineering and in the fabrication of new materials. We have designed and synthesized a bimodal microporous twofold interpenetrating network {[Ni(bpe)2(N(CN)2)](N(CN)2)(5H2O)}n (1), with two types of channel for anionic N(CN)2- (dicyanamide) and neutral water molecules, respectively. The dehydrated framework provides a dual function of specific anion exchange of free N(CN)2- for the smaller N3- anions and selective gas sorption. The N3-exchanged framework leads to a dislocation of the mutual positions of the two interpenetrating frameworks, resulting in an increase in the effective pore size in one of the counterparts of the channels and a higher accommodation of adsorbate than in the as-synthesized framework (1), showing the first case of controlled sorption properties in flexible porous frameworks.

UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis

Abstract: Microglia, brain immune cells, engage in the clearance of dead cells or dangerous debris, which is crucial to the maintenance of brain functions. When a neighbouring cell is injured, microglia move rapidly towards it or extend a process to engulf the injured cell. Because cells release or leak ATP when they are stimulated or injured, extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro and in vivo, a previously unrecognized mechanism underlying microglial chemotaxis; in contrast, microglial phagocytosis has received only limited attention. Here we show that microglia express the metabotropic P2Y6 receptor whose activation by endogenous agonist UDP triggers microglial phagocytosis. UDP facilitated the uptake of microspheres in a P2Y6-receptor-dependent manner, which was mimicked by the leakage of endogenous UDP when hippocampal neurons were damaged by kainic acid in vivo and in vitro. In addition, systemic administration of kainic acid in rats resulted in neuronal cell death in the hippocampal CA1 and CA3 regions, where increases in messenger RNA encoding P2Y6 receptors that colocalized with activated microglia were observed. Thus, the P2Y6 receptor is upregulated when neurons are damaged, and could function as a sensor for phagocytosis by sensing diffusible UDP signals, which is a previously unknown pathophysiological function of P2 receptors in microglia.

CD38 is critical for social behaviour by regulating oxytocin secretion

Abstract: CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.

Recent advancements in surface plasmon resonance immunosensors for detection of small molecules of biomedical, food and environmental interest

Abstract: Interest in the development of surface plasmon resonance (SPR) based immunosensors for detection and monitoring of low-molecular-weight analytes of biomedical, food and environmental fields has been rapidly increasing over the last 10 years. By combining the advantages of the specific antigen–antibody immunoreaction and the high sensitivity and reliability of SPR signal transduction, SPR immunoassays offer exceptional performance capabilities with respect to sensitivity, specificity, speed and multianalyte detection in complex analytical matrices. Advancements in the technology of antibody production and the signal transduction provide a promising scope for SPR immunosensors to lead in the next generation biosensors. This review highlights the current state-of-the-art in SPR immunosensors and outlines briefly the important issues with regard to the development of SPR immmunosensors, such as preparation of the biomolecules, sensor fabrication, non-specific adsorption, surface regeneration and detection principles. Particular emphasis is given to the indirect competitive immunoassay principle which is compatible and highly promising for detection of small analytes with enhanced sensitivity. In addition, recent advancements and trends in the application of SPR immunosensors in biomedical, environmental and food-related analyses are discussed.

Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease

Abstract: Background Accurate estimation of the glomerular filtration rate (GFR) is crucial for the detection of chronic kidney disease (CKD). In clinical practice, GFR is estimated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) study equation or the Cockcroft-Gault (CG) equation instead of the time-consuming method of measured clearance for exogenous markers such as inulin. In the present study, the equations originally developed for a Caucasian population were tested in Japanese CKD patients, and modified with the Japanese coefficient determined by the data.

Cyclic Electron Transport Around Photosystem I: Genetic Approaches

Abstract: The light reactions in photosynthesis convert light energy into chemical energy in the form of ATP and drive the production of NADPH from NADP+. The reactions involve two types of electron flow in the chloroplast. While linear electron transport generates both ATP and NADPH, photosystem I cyclic electron transport is exclusively involved in ATP synthesis. The physiological significance of photosystem I cyclic electron transport has been underestimated, and our knowledge of the machineries involved remains very limited. However, recent genetic approaches using Arabidopsis thaliana have clarified the essential functions of this electron flow in both photoprotection and photosynthesis. Based on several lines of evidence presented here, it is necessary to reconsider the fundamental mechanisms of chloroplast energetics.

Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease

Abstract: Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction, and its prevalence has markedly increased. We previously evaluated the expression of fatty acid metabolism-related genes in NAFLD and reported changes in expression that could contribute to increased fatty acid synthesis. In the present study, we evaluated the expression of additional fatty acid metabolism-related genes in larger groups of NAFLD (n=26) and normal liver (n=10) samples. The target genes for real-time PCR analysis were as follows: acetyl-CoA carboxylase (ACC) 1, ACC2, fatty acid synthase (FAS), sterol regulatory element-binding protein 1c (SREBP-1c), and adipose differentiation-related protein (ADRP) for evaluation of de novo synthesis and uptake of fatty acids; carnitine palmitoyltransferase 1a; (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), long-chain L-3-hydroxyacylcoenzyme A dehydrogenase alpha (HADHalpha), uncoupling protein 2 (UCP2), straight-chain acyl-CoA oxidase (ACOX), branched-chain acyl-CoA oxidase (BOX), cytochrome P450 2E1 (CYP2E1), CYP4A11, and peroxisome proliferator-activated receptor (PPAR)alpha for oxidation in the mitochondria, peroxisomes and microsomes; superoxide dismutase (SOD), catalase, and glutathione synthetase (GSS) for antioxidant pathways; and diacylglycerol O-acyltransferase 1 (DGAT1), PPARgamma, and hormone-sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, although fatty acids accumulated in hepatocytes, their de novo synthesis and uptake were up-regulated in association with increased expression of ACC1, FAS, SREBP-1c, and ADRP. Fatty acid oxidation-related genes, LCAD, HADHalpha, UCP2, ACOX, BOX, CYP2E1, and CYP4A11, were all overexpressed, indicating that oxidation was enhanced in NAFLD, whereas the expression of CTP1a and PPARalpha was decreased. Furthermore, SOD and catalase were also overexpressed, indicating that antioxidant pathways are activated to neutralize reactive oxygen species (ROS), which are overproduced during oxidative processes. The expression of DGAT1 was up-regulated without increased PPARgamma expression, whereas the expression of HSL was decreased. Our data indicated the following regarding NAFLD: i) increased de novo synthesis and uptake of fatty acids lead to further fatty acid accumulation in hepatocytes; ii) mitochondrial fatty acid oxidation is decreased or fully activated; iii) in order to complement the function of mitochondria (beta-oxidation), peroxisomal (beta-oxidation) and microsomal (omega-oxidation) oxidation is up-regulated to decrease fatty acid accumulation; iv) antioxidant pathways including SOD and catalase are enhanced to neutralize ROS overproduced during mitochondrial, peroxisomal, and microsomal oxidation; and v) lipid droplet formation is enhanced due to increased DGAT expression and decreased HSL expression. Further studies will be needed to clarify how fatty acid synthesis is increased by SREBP-1c, which is under the control of insulin and AMP-activated protein kinase.

Resident Vδ1+ γδ T Cells Control Early Infiltration of Neutrophils after Escherichia coli Infection via IL-17 Production

Abstract: Neutrophils infiltrate the site of infection and play critical roles in host defense, especially against extracellular bacteria. In the present study, we found a rapid and transient production of IL-17 after i.p. infection with Escherichia coli, preceding the influx of neutrophils. Neutralization of IL-17 resulted in a reduced infiltration of neutrophils and an impaired bacterial clearance. Ex vivo intracellular cytokine flow cytometric analysis revealed that γδ T cell population was the major source of IL-17. Mice depleted of γδ T cells by mAb treatment or mice genetically lacking Vδ1 showed diminished IL-17 production and reduced neutrophil infiltration after E. coli infection, indicating an importance of Vδ1+ γδ T cells as the source of IL-17. It was further revealed that γδ T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23, which was induced rapidly after E. coli infection in a TLR4 signaling-dependent manner. Thus, although γδ T cells are generally regarded as a part of early induced immune responses, which bridge innate and adaptive immune responses, our study demonstrated a novel role of γδ T cells as a first line of host defense controlling neutrophil-mediated innate immune responses.

NOx emission trends for China, 1995–2004: The view from the ground and the view from space

Abstract: [1] A rapid increase of NO2 columns over China has been observed by satellite instruments in recent years. We present a 10-a regional trend of NOx emissions in China from 1995 to 2004 using a bottom-up methodology and compare the emission trends with the NO2 column trends observed from GOME and SCIAMACHY, the two spaceborne instruments. We use a dynamic methodology to reflect the dramatic change in China's NOx emissions caused by energy growth and technology renewal. We use a scenario analysis approach to identify the possible sources of uncertainties in the current bottom-up inventory, in comparison with the satellite observation data. Our best estimates for China's NOx emissions are 10.9 Tg in 1995 and 18.6 Tg in 2004, increasing by 70% during the period considered. NOx emissions and satellite-based NO2 columns show broad agreement in temporal evolution and spatial distribution. Both the emission inventory data and the satellite observations indicate a continuous and accelerating growth rate between 1996 and 2004 over east central China. However, the growth rate from the emission inventory is lower than that from the satellite observations. From 1996 to 2004, NOx emissions over the region increased by 61% according to the inventory, while a 95% increase in the NO2 columns measured by satellite was observed during the same period. We found good agreement during summertime but a large discrepancy during wintertime. The consistency between the summertime trends suggests that the bias cannot be due to systematic error of activity data or emission factors. The reasons for the discrepancy cannot yet be fully identified, but possible explanations include an underestimation in seasonal emission variations, variability of meteorology, NOx injection height, and the increasing trend of sulfate aerosols.

Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers.

Abstract: Purpose The programmed death-1 (PD-1)/B7-H1 (also called PD-L1) pathway negatively regulates T cell activation and has been suggested to play an important role in regulating antitumor host immunity. To investigate the clinical significance of B7-H1 expression to the tumor grade and postoperative prognosis of patients with urothelial cancer, we analyzed the relationship between B7-H1 expression and various clinicopathological features and postoperative prognosis.

Catalytic decomposition of N2O over CeO2 promoted CO3O4 spinel catalyst

Abstract: A series of CeO2 promoted cobalt spinel catalysts were prepared by the co-precipitation method and tested for the decomposition of nitrous oxide (N2O). Addition of CeO2 to Co3O4 led to an improvement in the catalytic activity for N2O decomposition. The catalyst was most active when the molar ratio of Ce/Co was around 0.05. Complete N2O conversion could be attained over the CoCeO.05 catalyst below 400 degrees C even in the presence of O-2, H2O or NO. Methods of XRD, FE-SEM, BET, XPS, H-2-TPR and O-2-TPD were used to characterize these catalysts. The analytical results indicated that the addition of CeO2 could increase the surface area Of Co3O4, and then improve the reduction of Co3+ to Co2+ by facilitating the desorption of adsorbed oxygen species, which is the rate-determining step of the N2O decomposition over cobalt spinel catalyst. We conclude that these effects, caused by the addition of CeO2, are responsible for the enhancement of catalytic activity Of Co3O4. (c) 2007 Elsevier B.V. All rights reserved.

Germline gain-of-function mutations in RAF1 cause Noonan syndrome

Abstract: Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects1,2. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause ∼60% of cases of Noonan syndrome3,4,5,6,7,8,9. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not. Cells transfected with constructs containing Noonan syndrome–associated RAF1 mutations showed increased in vitro kinase and ERK activation, and zebrafish embryos with morpholino knockdown of raf1 demonstrated the need for raf1 for the development of normal myocardial structure and function. Thus, our findings implicate RAF1 gain-of-function mutations as a causative agent of a human developmental disorder, representing a new genetic mechanism for the activation of the MAPK pathway.

Early human atherosclerosis : Accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration

Abstract: Objective— The present study was designed to clarify the morphological features of early human atherosclerosis and to determine whether specific extracellular matrix proteoglycans play a role in early atherogenesis. Methods and Results— Step and serial sections were obtained from right coronary arteries with no or early atherosclerosis. Atherosclerosis was classified into 4 grades according to the amount of lipid deposition. Coronary arteries with Grade 0 showed diffuse intimal thickening (DIT) with no lipid deposits. The extracellular matrix proteoglycans, biglycan and decorin, were localized in the outer layer of DIT. Most cases of Grade 1 and Grade 2 exhibited fatty streaks with extracellular lipids colocalizing with biglycan and decorin in the outer layer of the intima. As lipid grades increased, macrophages increased in number and were present in the deeper layers. Most cases of Grade 3 exhibited pathologic intimal thickening (PIT) with extracellular lipids underneath a layer of foam cell macrophages. Conclusions— In early human coronary atherosclerosis, fatty streaks develop via extracellular deposition of lipids associated with specific types of proteoglycans in the outer layer of preexisting DIT. As the amount of the lipid increases in fatty streaks, macrophages infiltrate toward the deposited lipid to form PIT with foam cells.

Direct Evidence Revealing Structural Elements Essential for the High Binding Ability of Bisphenol A to Human Estrogen-Related Receptor-γ

Abstract: Background Various lines of evidence have shown that bisphenol A [BPA; HO-C6H4-C(CH3)2-C6H4-OH] acts as an endocrine disruptor when present in very low doses We have recently demonstrated that BPA binds strongly to human estrogen-related receptor-γ (ERR-γ ) in a binding assay using [3H]4-hydroxytamoxifen ([3H]4-OHT) We also demonstrated that BPA inhibits the deactivation activity of 4-OHT

A giant outburst two years before the core-collapse of a massive star

Abstract: The death of massive stars produces a variety of supernovae, which are linked to the structure of the exploding stars. The detection of several precursor stars of type II supernovae has been reported (see, for example, ref. 3), but we do not yet have direct information on the progenitors of the hydrogen-deficient type Ib and Ic supernovae. Here we report that the peculiar type Ib supernova SN 2006jc is spatially coincident with a bright optical transient that occurred in 2004. Spectroscopic and photometric monitoring of the supernova leads us to suggest that the progenitor was a carbon-oxygen Wolf-Rayet star embedded within a helium-rich circumstellar medium. There are different possible explanations for this pre-explosion transient. It appears similar to the giant outbursts of luminous blue variable stars (LBVs) of 60-100 solar masses, but the progenitor of SN 2006jc was helium- and hydrogen-deficient (unlike LBVs). An LBV-like outburst of a Wolf-Rayet star could be invoked, but this would be the first observational evidence of such a phenomenon. Alternatively, a massive binary system composed of an LBV that erupted in 2004, and a Wolf-Rayet star exploding as SN 2006jc, could explain the observations.

Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.

Abstract: We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family1 of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling2. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple cafe-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a cafe-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a cafe-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway3,4. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.