Showing papers by "University of Tsukuba published in 2001"

The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype

Abstract: Stem cells from bone marrow, skeletal muscle and possibly other tissues can be identified by the 'side-population' (SP) phenotype. Although it has been assumed that expression of ABC transporters is responsible for this phenotype, the specific molecules involved have not been defined. Here we show that expression of the Bcrp1 (also known as Abcg2 murine/ABCG2 human) gene is a conserved feature of stem cells from a wide variety of sources. Bcrp1 mRNA was expressed at high levels in primitive murine hematopoietic stem cells, and was sharply downregulated with differentiation. Enforced expression of the ABCG2 cDNA directly conferred the SP phenotype to bone-marrow cells and caused a reduction in maturing progeny both in vitro and in transplantation-based assays. These results show that expression of the Bcrp1/ABCG2 gene is an important determinant of the SP phenotype, and that it might serve as a marker for stem cells from various sources.

Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance.

Abstract: There is accumulating evidence that T-cell-mediated dominant control of self-reactive T-cells contributes to the maintenance of immunologic self-tolerance and its alteration can cause autoimmune disease. Efforts to delineate such a regulatory T-cell population have revealed that CD25+ cells in the CD4+ population in normal naive animals bear the ability to prevent autoimmune disease in vivo and, upon antigenic stimulation, suppress the activation/proliferation of other T cells in vitro. The CD25+ CD4+ regulatory T cells, which are naturally anergic and suppressive, appear to be produced by the normal thymus as a functionally distinct subpopulation of T cells. They play critical roles not only in preventing autoimmunity but also in controlling tumor immunity and transplantation tolerance.

Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor.

Abstract: Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene1, that suppresses metastases of human melanomas2 and breast carcinomas3 without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named ‘metastin’. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.

Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice.

Abstract: Induction of phase 2 enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, appears to be an effective means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part, through the antioxidant response element (ARE) found in the regulatory regions of their genes. The transcription factor Nrf2, which binds to the ARE, appears to be essential for the induction of prototypical phase 2 enzymes such as glutathione S-transferases (GSTs) and NAD(P)H:quinone oxidoreductase (NQO1). Constitutive hepatic and gastric activities of GST and NQO1 were reduced by 50-80% in nrf2-deficient mice compared with wild-type mice. Moreover, the 2- to 5-fold induction of these enzymes in wild-type mice by the chemoprotective agent oltipraz, which is currently in clinical trials, was almost completely abrogated in the nrf2-deficient mice. In parallel with the enzymatic changes, nrf2-deficient mice had a significantly higher burden of gastric neoplasia after treatment with benzo[a]pyrene than did wild-type mice. Oltipraz significantly reduced multiplicity of gastric neoplasia in wild-type mice by 55%, but had no effect on tumor burden in nrf2-deficient mice. Thus, Nrf2 plays a central role in the regulation of constitutive and inducible expression of phase 2 enzymes in vivo and dramatically influences susceptibility to carcinogenesis. Moreover, the total loss of anticarcinogenic efficacy of oltipraz in the nrf2-disrupted mice highlights the prime importance of elevated phase 2 gene expression in chemoprotection by this and similar enzyme inducers.

A simple single-layer urban canopy model for atmospheric models: Comparison with multi-layer and slab models

Abstract: We developed a simple, single-layer urban canopy model, and comparedit to both multi-layer and slab models. Our single-layer model has thefollowing features: (a) It is a column model of energy and momentumexchange between an urban surface and the atmosphere, (b) it includesthe influence of street canyons, which are parameterized to representthe urban geometry, (c) it includes shadowing from buildings andreflection of radiation, and (d) it estimates both the surfacetemperatures of, and heat fluxes from, three surface types: roof, wall,and road. In the simulation of the single-layer model, the roof washottest during the daytime, but coolest from midnight to early morning.This is consistent with output from the multi-layer model and fieldobservations at a residential area on a clear, summer day. The diurnalvariation of the energy budget from the single-layer model agrees wellwith that from the multi-layer model. Our single-layer model'sperformance is nearly that of a multi-layer model for studyingmesoscale heat islands. Nevertheless, it is simply parameterized,and thus easily included in larger-scale atmospheric models. The slabmodel has the largest nighttime cooling rate of the three models. Toovercome this, it needs more adjustments than for the canopy models.

Suppression of hadrons with large transverse momentum in central Au + Au collisions at √sNN = 130 GeV

Abstract: Transverse momentum spectra for charged hadrons and for neutral pions in the range 1 Gev/c < P-T < 5 GeV/c have been measured by the PHENIX experiment at RHIC in Au + Au collisions at rootS(NN) = 130 GeV. At high p(T) the spectra from peripheral nuclear collisions are consistent with scaling the spectra from p + p collisions by the average number of binary nucleon-nucleon collisions. The spectra from central collisions are significantly suppressed when compared to the binary-scaled p + p expectation, and also when compared to similarly binary-scaled peripheral collisions, indicating a novel nuclear-medium effect in central nuclear collisions at RHIC energies.

Functional annotation of a full-length mouse cDNA collection

Abstract: The RIKEN Mouse Gene Encyclopaedia Project, a systematic approach to determining the full coding potential of the mouse genome, involves collection and sequencing of full-length complementary DNAs and physical mapping of the corresponding genes to the mouse genome. We organized an international functional annotation meeting (FANTOM) to annotate the first 21,076 cDNAs to be analysed in this project. Here we describe the first RIKEN clone collection, which is one of the largest described for any organism. Analysis of these cDNAs extends known gene families and identifies new ones.

The Cap ‘n’ Collar Basic Leucine Zipper Transcription Factor Nrf2 (NF-E2 p45-related Factor 2) Controls Both Constitutive and Inducible Expression of Intestinal Detoxification and Glutathione Biosynthetic Enzymes

Abstract: Northern blotting has shown that mouse small intestine contains relatively large amounts of the nuclear factor-E2 p45-related factor (Nrf) 2 transcription factor but relatively little Nrf1. Regulation of intestinal antioxidant and detoxication enzymes by Nrf2 has been assessed using a mouse line bearing a targeted disruption of the gene encoding this factor. Both Nrf2-/- and Nrf2+/+ mice were fed a control diet or one supplemented with either synthetic cancer chemopreventive agents [butylated hydroxyanisole (BHA), ethoxyquin (EQ), or oltipraz] or phytochemicals [indole-3-carbinol, cafestol and kahweol palmitate, sulforaphane, coumarin (CMRN), or alpha-angelicalactone]. The constitutive level of NAD(P)H:quinone oxidoreductase (NQO) and glutathione S-transferase (GST) enzyme activities in cytosols from small intestine was typically found to be between 30% and 70% lower in samples prepared from Nrf2 mutant mice fed a control diet than in equivalent samples from Nrf2+/+ mice. Most of the chemopreventive agents included in this study induced NQO and GST enzyme activities in the small intestine of Nrf2+/+ mice. Increases of between 2.7- and 6.2-fold were observed in wild-type animals fed diets supplemented with BHA or EQ; increases of about 2-fold were observed with a mixture of cafestol and kahweol palmitate, CMRN, or alpha-angelicalactone; and increases of 1.5-fold were measured with sulforaphane. Immunoblotting confirmed that in the small intestine, the constitutive level of NQO1 is lower in the Nrf2-/- mouse, and it also showed that induction of the oxidoreductase was substantially diminished in the mutant mouse. Immunoblotting class-alpha and class-mu GST showed that constitutive expression of most transferase subunits is also reduced in the small intestine of Nrf2 mutant mice. Significantly, induction of class-alpha and class-mu GST by EQ, BHA, or CMRN is apparent in the gene knockout animal. No consistent change in the constitutive levels of the catalytic heavy subunit of gamma-glutamylcysteinyl synthetase (GCS(h)) was observed in the small intestine of Nrf2-/- mice. However, although the expression of GCS(h) was found to be increased dramatically in the small intestine of Nrf2+/+ mice by dietary BHA or EQ, this induction was essentially abolished in the knockout mice. It is apparent that Nrf2 influences both constitutive and inducible expression of intestinal antioxidant and detoxication proteins in a gene-specific fashion. Immunohistochemistry revealed that induction of NQO1, class-alpha GST, and GCS(h) occurs primarily in epithelial cells of the small intestine. This suggests that the variation in inducibility of NQO1, Gsta1/2, and GCS(h) in the mutant mouse is not attributable to the expression of the enzymes in distinct cell types but rather to differences in the dependency of these genes on Nrf2 for induction.

The Discovery of Polyacetylene Film: The Dawning of an Era of Conducting Polymers (Nobel Lecture)

Abstract: This lecture is not directly related to our discovery and development of conducting polymers to which the Nobel Prize in Chemistry 2000 was awarded. However, I would like to present my previous work that I had carried out just before we reached the discovery of chemical doping. I hope that this will be of use and deepen your understandings by learning what had happened before and how we reached the idea of chemical doping.

Identification of Liver X Receptor-Retinoid X Receptor as an Activator of the Sterol Regulatory Element-Binding Protein 1c Gene Promoter

Abstract: In an attempt to identify transcription factors which activate sterol-regulatory element-binding protein 1c (SREBP-1c) transcription, we screened an expression cDNA library from adipose tissue of SREBP-1 knockout mice using a reporter gene containing the 2.6-kb mouse SREBP-1 gene promoter. We cloned and identified the oxysterol receptors liver X receptor (LXRa) and LXRb as strong activators of the mouse SREBP-1c promoter. In the transfection studies, expression of either LXRa or -b activated the SREBP-1c promoter-luciferase gene in a dose-dependent manner. Deletion and mutation studies, as well as gel mobility shift assays, located an LXR response element complex consisting of two new LXR-binding motifs which showed high similarity to an LXR response element recently found in the ABC1 gene promoter, a reverse cholesterol transporter. Addition of an LXR ligand, 22(R)-hydroxycholesterol, increased the promoter activity. Coexpression of retinoid X receptor (RXR), a heterodimeric partner, and its ligand 9-cis-retinoic acid also synergistically activated the SREBP-1c promoter. In HepG2 cells, SREBP-1c mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR-RXR activation can induce endogenous SREBP-1c expression. The activation of SREBP-1c by LXR is associated with a slight increase in nuclear SREBP-1c, resulting in activation of the gene for fatty acid synthase, one of its downstream genes, as measured by the luciferase assay. These data demonstrate that LXR-RXR can modify the expression of genes for lipogenic enzymes by regulating SREBP-1c expression, providing a novel link between fatty acid and cholesterol metabolism.

Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia

Abstract: The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been proposed that ATP, released from different cell types, initiates the sensation of pain by acting predominantly on nociceptive ionotropic purinoceptors located on sensory nerve terminals. In this study, we examined the effects of extracellular ATP on VR1. In cells expressing VR1, ATP increased the currents evoked by capsaicin or protons through activation of metabotropic P2Y(1) receptors in a protein kinase C-dependent pathway. The involvement of G(q/11)-coupled metabotropic receptors in the potentiation of VR1 response was confirmed in cells expressing both VR1 and M1 muscarinic acetylcholine receptors. In the presence of ATP, the temperature threshold for VR1 activation was reduced from 42 degrees C to 35 degrees C, such that normally nonpainful thermal stimuli (i.e., normal body temperature) were capable of activating VR1. This represents a novel mechanism through which the large amounts of ATP released from damaged cells in response to tissue trauma might trigger the sensation of pain.

Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1.

Abstract: Heme controls expression of genes involved in the synthesis of globins and heme. The mammalian transcription factor Bach1 functions as a repressor of the Maf recognition element (MARE) by forming antagonizing hetero-oligomers with the small Maf family proteins. We show here that heme binds specifically to Bach1 and regulates its DNA-binding activity. Deletion studies demonstrated that a heme-binding region of Bach1 is confined within its C-terminal region that possesses four dipeptide cysteine–proline (CP) motifs. Mutations in all of the CP motifs of Bach1 abolished its interaction with heme. The DNA-binding activity of Bach1 as a MafK hetero-oligomer was markedly inhibited by heme in gel mobility shift assays. The repressor activity of Bach1 was lost upon addition of hemin in transfected cells. These results suggest that increased levels of heme inactivate the repressor Bach1, resulting in induction of a host of genes with MAREs.

Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation

Abstract: White adipose tissue and liver are important angiotensinogen (AGT) production sites. Until now, plasma AGT was considered to be a reflection of hepatic production. Because plasma AGT concentration has been reported to correlate with blood pressure, and to be associated with body mass index, we investigated whether adipose AGT is released locally and into the blood stream. For this purpose, we have generated transgenic mice either in which adipose AGT is overexpressed or in which AGT expression is restricted to adipose tissue. This was achieved by the use of the aP2 adipocyte-specific promoter driving the expression of rat agt cDNA in both wild-type and hypotensive AGT-deficient mice. Our results show that in both genotypes, targeted expression of AGT in adipose tissue increases fat mass. Mice whose AGT expression is restricted to adipose tissue have AGT circulating in the blood stream, are normotensive, and exhibit restored renal function compared with AGT-deficient mice. Moreover, mice that overexpress adipose AGT have increased levels of circulating AGT, compared with wild-type mice, and are hypertensive. These animal models demonstrate that AGT produced by adipose tissue plays a role in both local adipose tissue development and in the endocrine system, which supports a role of adipose AGT in hypertensive obese patients.

Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription

Abstract: Background Nrf2 belongs to the Cap-N-Collar (CNC) transcription factor family and is essential for the antioxidant responsive element (ARE)-mediated expression of a group of detoxifying and antioxidant genes. The forced expression of Nrf2 in mammalian cells activates the expression of target genes through the ARE, with Nrf2 showing the highest transactivation activity among the CNC family of transcription factors. To elucidate the molecular mechanisms generating this potent transactivation activity, we examined the functions of the domains within Nrf2. Result We found that Nrf2 contains two transcription activation domains, Neh4 and Neh5, which act synergistically to attain maximum a activation of reporter gene expression. Neh4 and Neh5 both individually and cooperatively bind to CBP (CREB (cAMP Responsive Element Binding protein) Binding Protein). In fact, the specific inhibitor of CBP, adenovirus E1A protein, significantly reduced Nrf2 activity. Importantly, the CBP-binding activity of Nrf2 deletion mutants positively correlated with their transactivation activity. Neh5 contains a motif which is commonly conserved among the CNC factors, whereas Neh4 contains the novel CBP-interacting motif recently identified in p53 and E2F. Conclusions Our results indicate that Nrf2 exploits the cooperative binding of two independent transactivation domains to CBP in the acquisition of a potent transactivation activity.

TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer.

Abstract: The existence of tumor-suppressor genes was originally demonstrated by functional complementation through whole-cell and microcell fusion1,2. Transfer of chromosome 11 into a human non-small-cell lung cancer (NSCLC) cell line, A549, suppresses tumorigenicity3. Loss of heterozygosity (LOH) on the long arm of chromosome 11 has been reported in NSCLC and other cancers4,5,6. Several independent studies indicate that multiple tumor-suppressor genes are found in this region, including the gene PPP2R1B at 11q23–24 (ref. 7). Linkage studies of NSCLC are precluded because no hereditary forms are known8,9. We previously identified a region of 700 kb on 11q23.2 that completely suppresses tumorigenicity of A549 human NSCLC cells10. Most of this tumor-suppressor activity localizes to a 100-kb segment by functional complementation. Here we report that this region contains a single confirmed gene, TSLC1, whose expression is reduced or absent in A549 and several other NSCLC, hepatocellular carcinoma (HCC) and pancreatic cancer (PaC) cell lines. TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines. Restoration of TSLC1 expression to normal or higher levels suppresses tumor formation by A549 cells in nude mice. Only 2 inactivating mutations of TSLC1 were discovered in 161 tumors and tumor cell lines, both among the 20 primary tumors with LOH for 11q23.2. Promoter methylation was observed in 15 of the other 18 primary NSCLC, HCC and PaC tumors with LOH for 11q23.2. Thus, attenuation of TSLC1 expression occurred in 85% of primary tumors with LOH. Hypermethylation of the TSLC1 promoter would seem to represent the 'second hit' in NSCLC with LOH.

Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA

Abstract: Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (DeltamtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with DeltamtDNA4696 showed normal COX activity until DeltamtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with DeltamtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.

Strenuous endurance training in humans reduces oxidative stress following exhausting exercise.

Abstract: The aim of this study was to evaluate whether high-intensity endurance training would alleviate exercise-induced oxidative stress. Nine untrained male subjects (aged 19–21 years) participated in a 12-week training programme, and performed an acute period of exhausting exercise on a cycle ergometer before and after training. The training programme consisted of running at 80% maximal exercise heart rate for 60 min · day−1, 5 days · week−1 for 12 weeks. Blood samples were collected at rest and immediately after exhausting exercise for measurements of indices of oxidative stress, and antioxidant enzyme activities [superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT)] in the erythrocytes. Maximal oxygen uptake (V˙O2max) increased significantly (P < 0.001) after training, indicating an improvement in aerobic capacity. A period of exhausting exercise caused an increase (P < 0.01) in the ability to produce neutrophil superoxide anion (O2•−) both before and after endurance training, but the magnitude of the increase was smaller after training (P < 0.05). There was a significant increase in lipid peroxidation in the erythrocyte membrane, but not in oxidative protein, after exhausting exercise, however training attenuated this effect. At rest, SOD and GPX activities were increased after training. However, there was no evidence that exhausting exercise enhanced the levels of any antioxidant enzyme activity. The CAT activity was unchanged either by training or by exhausting exercise. These results indicate that high-intensity endurance training can elevate antioxidant enzyme activities in erythrocytes, and decrease neutrophil O2•− production in response to exhausting exercise. Furthermore, this up-regulation in antioxidant defences was accompanied by a reduction in exercise-induced lipid peroxidation in erythrocyte membrane.

KNOX homeodomain protein directly suppresses the expression of a gibberellin biosynthetic gene in the tobacco shoot apical meristem

Abstract: To identify genes targeted by the tobacco KNOX homeodomain protein, Nicotiana tabacum homeobox 15 (NTH15), we have generated an inducible system using the human glucocorticoid receptor. In this system, steroid treatment strictly induced NTH15 function and immediately suppressed the expression of a gibberellin (GA) biosynthetic gene encoding GA 20-oxidase (Ntc12) and also resulted in a decrease in bioactive GA levels. The repression of Ntc12 was observed even when indirect effects were blocked by cycloheximide. NTH15 mRNA was present in corpus cells of the shoot apical meristem (SAM), whereas Ntc12 mRNA was observed in leaf primordia and rib meristem but not in the corpus. Recombinant NTH15 protein strongly bound to a 5-bp dyadsymmetric sequence, GTGAC, in the first intron of Ntc12 in vitro. Mutation of this sequence in the Ntc12 gene abolished the NTH15-dependent suppression of Ntc12 in the corpus of the SAM. Our results indicate that NTH15 directly represses Ntc12 expression in the corpus of the wild-type SAM to maintain the indeterminate state of corpus cells. The suppression of NTH15 within cells at the flanks of the SAM permits GA biosynthesis, which promotes organized cell proliferation and consequently induces the determination of cell fate.

Reversal of subjective temporal order due to arm crossing.

Abstract: How does the brain order successive events? Here we studied whether temporal order of two stimuli delivered in rapid succession, one to each hand, is determined before or after the stimuli are localized in space. When their arms were crossed, subjects could accurately report the temporal order, even when the interval between stimuli was as short as 70 ms. In most trials, subjects could also judge temporal order when their arms were crossed, but only if given adequate time (>1 s). At moderately short intervals (<300 ms), crossing the arms caused misreporting (that is, inverting) of the temporal order. Thus, at these intervals, the determining factor of temporal order was the spatial location of the hands. We suggest that it is not until the spatial locations of the hands are taken into account that the cutaneous signals from the respective hands are ordered in time.

Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria.

Abstract: Extensive complementation between fused mitochondria is indicated by recombination of 'parental' mitochondrial (mt) DNA (ref. 1,2) of yeast and plant cells. It has been difficult, however, to demonstrate the occurrence of complementation between fused mitochondria in mammalian species through the presence of recombinant mtDNA molecules, because sequence of mtDNA throughout an individual tends to be uniform owing to its strictly maternal inheritance. We isolated two types of respiration-deficient cell lines, with pathogenic mutations in mitochondrial tRNAIle or tRNALeu(UUR) genes from patients with mitochondrial diseases. The coexistence of their mitochondria within hybrids restored their normal morphology and respiratory enzyme activity by 10-14 days after fusion, indicating the presence of an extensive and continuous exchange of genetic contents between the mitochondria. This complementation between fused mitochondria may represent a defence of highly oxidative organelles against mitochondrial dysfunction caused by the accumulation of mtDNA lesions with age.

Early Metal Enrichment of the Intergalactic Medium by Pregalactic Outflows

Abstract: We assess supernova-driven pregalactic outflows as a mechanism for distributing the product of stellar nucleosynthesis over large cosmological volumes prior to the reionization epoch. Supernova (SN) ejecta will escape the grasp of halos with virial temperatures Tvir 104.3 K (corresponding to masses M 108 h-1 M☉ at redshift z = 9 when they collapse from 2 σ fluctuations) if rapid cooling can take place, and a significant fraction of their baryonic mass is converted into stars over a dynamical timescale. We study the evolution of SN-driven bubbles as they blow out from subgalactic halos and propagate into the intergalactic medium (IGM), and we show that to lift the halo gas out of the potential well, the energy injection must continue at least until blowaway occurs. If the fraction of ionizing photons that escape the dense sites of star formation into intergalactic space is greater than a few percent, pregalactic outflows will propagate into an IGM that has been prephotoionized by the same massive stars that later explode as SNe, and the expansion of the metal-enriched bubbles will be halted by the combined action of external pressure, gravity, and radiative losses. The collective explosive output of about 10,000 SNe per M 108 h-1 M☉ halo at these early epochs could pollute vast regions of intergalactic space to a mean metallicity Z = ΩZ/Ωb 0.003 (comparable to the levels observed in the Lyα forest at z ≈ 3) without hydrodynamically perturbing the IGM much, i.e., producing large variations of the baryons relative to the dark matter. Rayleigh-Taylor instabilities between the dense shell that contains pristine swept-up material and the hot, metal-enriched, low-density bubble may contribute to the mixing and diffusion of heavy elements. The volume filling factor of the ejecta is higher than 20% if the star formation efficiency is on the order of 10%. Larger filling factors (not required by current observations) may be obtained for larger efficiencies, moderately top-heavy initial mass functions, halos for which a significant fraction of the gas is in a galactic disk and does not couple to the outflow (since matter is ejected perpendicularly to the disk), or from a population of more numerous sources—which would therefore have to originate from lower amplitude peaks. When the filling factor of the ejecta becomes significant, enriched material typically will be at a higher adiabat than expected from photoionization.

Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

Abstract: Members of the muscarinic acetylcholine receptor family (M1-M5) have central roles in the regulation of many fundamental physiological functions. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult primarily because of a lack of subtype-selective ligands. Here we show that mice deficient in the M3 muscarinic receptor (M3R-/- mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3R-/- mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R-/- mice. However, M3R-/- mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system.

On the Initial Mass Function of Population III Stars

Abstract: The collapse and fragmentation of filamentary primordial gas clouds are explored using one- and two-dimensional hydrodynamical simulations coupled with the nonequilibrium processes of hydrogen molecule formation. The cloud evolution is computed from the initial central density nc = 10-106 cm-3. The simulations show that depending on the initial density, there are two occasions for the fragmentation of primordial filaments. If a filament has relatively low initial density such as nc 105 cm-3, the radial contraction is slow as a result of less effective H2 cooling and appreciably decelerates at densities higher than a critical density, where LTE populations are achieved for the rotational levels of H2 molecules and the cooling timescale becomes accordingly longer than the free-fall timescale. This filament tends to fragment into dense clumps before the central density reaches 108-109 cm-3, where H2 cooling by three-body reactions is effective and the fragment mass is more massive than some tens of M?. In contrast, if a filament is initially as dense as nc 105 cm-3, the more effective H2 cooling with the help of three-body reactions allows the filament to contract up to n ~ 1012 cm-3. After the density reaches n ~ 1012 cm-3, the filament becomes optically thick to H2 lines and the radial contraction subsequently almost stops. At this final hydrostatic stage, the fragment mass is lowered down to ?1 M? because of the high density of the filament. The dependence of the fragment mass upon the initial density could be translated into the dependence on the local amplitude of random Gaussian density fields or the epoch of the collapse of a parent cloud. Hence, it is predicted that the initial mass function of Population III stars is likely to be bimodal with peaks of ?102 and ?1 M?, where the relative heights could be a function of the collapse epoch. Implications for the metal enrichment by Population III stars at high redshifts and baryonic dark matter are briefly discussed.

Project FEELEX: adding haptic surface to graphics

Abstract: This paper presents work carried out for a project to develop a new interactive technique that combines haptic sensation with computer graphics. The project has two goals. The first is to provide users with a spatially continuous surface on which they can effectively touch an image using any part of their bare hand, including the palm. The second goal is to present visual and haptic sensation simultaneously by using a single device that doesn't oblige the user to wear any extra equipment. In order to achieve these goals, we designed a new interface device comprising of a flexible screen, an actuator array and a projector. The actuator deforms the flexible screen onto which the image is projected. The user can then touch the image directly and feel its shape and rigidity. Initially we fabricated two prototypes, and their effectiveness is examined by studying the observations made by anonymous users and a performance evaluation test for spatial resolution.

Troglitazone Inhibits Atherosclerosis in Apolipoprotein E–Knockout Mice: Pleiotropic Effects on CD36 Expression and HDL

Abstract: —Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus. Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator–activated receptor-γ (PPAR-γ), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E–knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9±2.5% vs 12.7±4.7%, P<0.05; cross-sectional lesion areas were 191 974±102 911 μm2 vs 351 738±175 597 μm2, P<0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels o...