Showing papers by "University of Tsukuba published in 2004"

The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited

Abstract: The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

Repeated temperature modulation epitaxy for p-type doping and light-emitting diode based on ZnO

Abstract: Since the successful demonstration of a blue light-emitting diode (LED)1, potential materials for making short-wavelength LEDs and diode lasers have been attracting increasing interest as the demands for display, illumination and information storage grow2,3,4. Zinc oxide has substantial advantages including large exciton binding energy, as demonstrated by efficient excitonic lasing on optical excitation5,6. Several groups have postulated the use of p-type ZnO doped with nitrogen, arsenic or phosphorus7,8,9,10, and even p–n junctions11,12,13. However, the choice of dopant and growth technique remains controversial and the reliability of p-type ZnO is still under debate14. If ZnO is ever to produce long-lasting and robust devices, the quality of epitaxial layers has to be improved as has been the protocol in other compound semiconductors15. Here we report high-quality undoped films with electron mobility exceeding that in the bulk. We have used a new technique to fabricate p-type ZnO reproducibly. Violet electroluminescence from homostructural p–i–n junctions is demonstrated at room-temperature.

Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2

Abstract: Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and antioxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system. We examined the contribution of Keap1 to the rapid turnover of Nrf2 (half-life of less than 20 min) and found that a direct association between Keap1 and Nrf2 is required for Nrf2 degradation. In a series of domain function analyses of Keap1, we found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors. Indeed, Cullin 3 (Cul3), a subunit of the E3 ligase complex, was found to interact specifically with Keap1 in vivo. Keap1 associates with the N-terminal region of Cul3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cul3-Roc1 complex. These results thus provide solid evidence that Keap1 functions as an adaptor of Cul3-based E3 ligase. To our knowledge, Nrf2 and Keap1 are the first reported mammalian substrate and adaptor, respectively, of the Cul3-based E3 ligase system.

Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers.

Abstract: Induction of a family of phase 2 genes encoding for proteins that protect against the damage of electrophiles and reactive oxygen intermediates is potentially a major strategy for reducing the risk of cancer and chronic degenerative diseases. Many phase 2 genes are regulated by upstream antioxidant response elements (ARE) that are targets of the leucine zipper transcription factor Nrf2. Under basal conditions, Nrf2 resides mainly in the cytoplasm bound to its cysteine-rich, Kelch domain-containing partner Keap1, which is itself anchored to the actin cytoskeleton and represses Nrf2 activity. Inducers disrupt the Keap1-Nrf2 complex by modifying two (C273 and C288) of the 25 cysteine residues of Keap1. The critical role of C273 and C288 was established by (i) their high reactivity when purified recombinant Keap1 was treated with dexamethasone mesylate and the dexamethasone-modified tryptic peptides were analyzed by mass spectrometry, and (ii) transfection of keap1 and nrf2 gene-deficient mouse embryonic fibroblasts with constructs expressing cysteine to alanine mutants of Keap1, and measurement of the ability of cotransfected Nrf2 to repress an ARE-luciferase reporter. Reaction of Keap1 with inducers results in formation of intermolecular disulfide bridges, probably between C273 of one Keap1 molecule and C288 of a second. Evidence for formation of such dimers was obtained by 2D PAGE of extracts of cells treated with inducers, and by the demonstration that whereas C273A and C288A mutants of Keap1 alone could not repress Nrf2 activation of the ARE-luciferase reporter, an equal mixture of these mutant constructs restored repressor activity.

Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice

Abstract: Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells--predominantly endothelial and type II epithelial cells--as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.

Ehd1, a B-type response regulator in rice, confers short-day promotion of flowering and controls FT-like gene expression independently of Hd1

Abstract: Two evolutionarily distant plant species, rice (Oryza sativa L.), a short-day (SD) plant, and Arabidopsis thaliana, a long-day plant, share a conserved genetic network controlling photoperiodic flowering. The orthologous floral regulators—rice Heading date 1 (Hd1) and Arabidopsis CONSTANS (CO)—integrate circadian clock and external light signals into mRNA expression of the FLOWERING LOCUS T (FT) group floral inducer. Here, we report that the rice Early heading date 1 (Ehd1) gene, which confers SD promotion of flowering in the absence of a functional allele of Hd1, encodes a B-type response regulator that might not have an ortholog in the Arabidopsis genome. Ehd1 mRNA was induced by 1-wk SD treatment, and Ehd1 may promote flowering by inducing FT-like gene expression only under SD conditions. Microarray analysis further revealed a few MADS box genes downstream of Ehd1. Our results indicate that a novel two-component signaling cascade is integrated into the conserved pathway in the photoperiodic control of flowering in rice.

Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1

Abstract: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitously distributed environmental chemicals. PAHs acquire carcinogenicity only after they have been activated by xenobiotic-metabolizing enzymes to highly reactive metabolites capable of attacking cellular DNA. Cytochrome P450 (CYP) enzymes are central to the metabolic activation of these PAHs to epoxide intermediates, which are converted with the aid of epoxide hydrolase to the ultimate carcinogens, diol-epoxides. Historically, CYP1A1 was believed to be the only enzyme that catalyzes activation of these procarcinogenic PAHs. However, recent studies have established that CYP1B1, a newly identified member of the CYP1 family, plays a very important role in the metabolic activation of PAHs. In CYP1B1 gene-knockout mice treated with 7,12-dimethylbenz[a]anthracene and dibenzo[a,l]pyrene, decreased rates of tumor formation were observed, when compared to wild-type mice. Significantly, gene expression of CYP1A1 and 1B1 is induced by PAHs and polyhalogenated hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin through the arylhydrocarbon receptor. Differences in the susceptibility of individuals to the adverse action of PAHs may, in part, be due to differences in the levels of expression of CYP1A1 and 1B1 and to genetic variations in the CYP1A1 and 1B1 genes.

Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II

Abstract: The angiotensin II type 1 (AT1) receptor has a crucial role in load-induced cardiac hypertrophy. Here we show that the AT1 receptor can be activated by mechanical stress through an angiotensin-II-independent mechanism. Without the involvement of angiotensin II, mechanical stress not only activates extracellular-signal-regulated kinases and increases phosphoinositide production in vitro, but also induces cardiac hypertrophy in vivo. Mechanical stretch induces association of the AT1 receptor with Janus kinase 2, and translocation of G proteins into the cytosol. All of these events are inhibited by the AT1 receptor blocker candesartan. Thus, mechanical stress activates AT1 receptor independently of angiotensin II, and this activation can be inhibited by an inverse agonist of the AT1 receptor.

Identified charged particle spectra and yields in Au + Au collisions at √sNN = 200 GeV

Abstract: The centrality dependence of transverse momentum distributions and yields for ${\ensuremath{\pi}}^{\ifmmode\pm\else\textpm\fi{}},{K}^{\ifmmode\pm\else\textpm\fi{}},p$, and $\overline{p}$ in $\text{Au}+\text{Au}$ collisions at $\sqrt{{s}_{NN}}=200\phantom{\rule{0.3em}{0ex}}\text{GeV}$ at midrapidity are measured by the PHENIX experiment at the Relativistic Heavy Ion Collider. We observe a clear particle mass dependence of the shapes of transverse momentum spectra in central collisions below $\ensuremath{\sim}2\phantom{\rule{0.3em}{0ex}}\text{GeV}∕c$ in ${p}_{T}$. Both mean transverse momenta and particle yields per participant pair increase from peripheral to midcentral and saturate at the most central collisions for all particle species. We also measure particle ratios of ${\ensuremath{\pi}}^{\ensuremath{-}}∕{\ensuremath{\pi}}^{+}$, ${K}^{\ensuremath{-}}∕{K}^{+}$, $\overline{p}∕p$, $K∕\ensuremath{\pi}$, $p∕\ensuremath{\pi}$, and $\overline{p}∕\ensuremath{\pi}$ as a function of ${p}_{T}$ and collision centrality. The ratios of equal mass particle yields are independent of ${p}_{T}$ and centrality within the experimental uncertainties. In central collisions at intermediate transverse momenta $\ensuremath{\sim}1.5--4.5\phantom{\rule{0.3em}{0ex}}\text{GeV}∕c$, proton and antiproton yields constitute a significant fraction of the charged hadron production and show a scaling behavior different from that of pions.

A plant vacuolar protease, VPE, mediates, virus-induced hypersensitive cell death

Abstract: Programmed cell death (PCD) in animals depends on caspase protease activity. Plants also exhibit PCD, for example as a response to pathogens, although a plant caspase remains elusive. Here we show that vacuolar processing enzyme (VPE) is a protease essential for a virus-induced hypersensitive response that involves PCD. VPE deficiency prevented virus-induced hypersensitive cell death in tobacco plants. VPE is structurally unrelated to caspases, although VPE has a caspase-1 activity. Thus, plants have evolved a regulated cellular suicide strategy that, unlike PCD of animals, is mediated by VPE and the cellular vacuole.

Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity

Abstract: Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of Foxo1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1 at residues acetylated by cAMP-response element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27kip1 in a deacetylase-activity-dependent manner. Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems.

Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes

Abstract: Transcription factor Nrf2 regulates basal and inducible expression of phase 2 proteins that protect animal cells against the toxic effects of electrophiles and oxidants Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1, a multidomain, cysteinerich protein that is bound to the actin cytoskeleton Keap1 acts both as a repressor of the Nrf2 transactivation and as a sensor of phase 2 inducers Electrophiles and oxidants disrupt the Keap1–Nrf2 complex, resulting in nuclear accumulation of Nrf2, where it enhances the transcription of phase 2 genes via a common upstream regulatory element, the antioxidant response element Reporter cotransfection–transactivation analyses with a series of Keap1 deletion mutants revealed that in the absence of the double glycine repeat domain Keap1 does not bind to Nrf2 In addition, deletion of either the intervening region or the C-terminal region also abolished the ability of Keap1 to sequester Nrf2, indicating that all of these domains contribute to the repressor activity of Keap1 Immunocytochemical and immunoprecipitation analyses demonstrated that Keap1 associates with actin filaments in the cytoplasm through its double glycine repeat domain Importantly, disruption of the actin cytoskeleton promotes nuclear entry of an Nrf2 reporter protein The actin cytoskeleton therefore provides scaffolding that is essential for the function of Keap1, which is the sensor for oxidative and electrophilic stress

Proof of Theorem 1.1

Abstract: This chapter is devoted to the proof of Theorem 1.1. The idea of our proof is stated as follows. First, we reduce the study of the boundary value problem $$ \left\{ \begin{array}{l} ({\rm A - }\lambda {\rm )u = f }\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,\,{\rm in D, } \\ {\rm Lu = }\mu {\rm (x')}\frac{{\partial {\rm u}}}{{\partial {\rm n}}} + \Upsilon (x')u = \varphi \,on\,\partial D \\ \end{array} \right. $$ (1.1) to that of a first-order pseudo-differential operator T(λ) = LP(λ) on the boundary ∂D, just as in Section 4.3. Then we prove that conditions (A) and (B) are sufficient for the validity of the a priori estimate $$\parallel u\parallel _{2,p} \le C(\lambda )(\parallel f\parallel _p + |\varphi| _{2 - 1/p,p} + \parallel u\parallel _p ).$$ (1.2)

A stable compound containing a silicon-silicon triple bond.

Abstract: The reaction of 2,2,3,3-tetrabromo-1,1,4,4-tetrakis[bis(trimethylsilyl)methyl]-1,4-diisopropyltetrasilane with four equivalents of potassium graphite (KC 8 ) in tetrahydrofuran produces 1,1,4,4-tetrakis[bis(trimethylsilyl)methyl]-1,4-diisopropyl-2-tetrasilyne, a stable compound with a silicon-silicon triple bond, which can be isolated as emerald green crystals stable up to 100°C in the absence of air. The SiSi triple-bond length (and its estimated standard deviation) is 2.0622(9) angstroms, which shows half the magnitude of the bond shortening of alkynes compared with that of alkenes. Unlike alkynes, the substituents at the SiSi group are not arranged in a linear fashion, but are trans-bent with a bond angle of 137.44(4)°.

Observation of the narrow state X(3872) → J/ψπ+π- in p̄p collisions at √s = 1.96 TeV

Abstract: The observation of a state consistent with X(3872) decaying into J/ψπ+π- was reported. The X(3872) mass was measured to be 3871.3±0.7(stat)±0.4(syst)MeV/c2 from a sample of 730±90 candidates. The observed width was consistent with the detector resolution. The results were found to be converging well with the measurements by the Belle Collaboration using b± decays.

Regional climate modeling: Progress, challenges, and prospects

Abstract: Regional climate modeling with regional climate models (RCMs) has matured over the past decade and allows for meaningful utilization in a broad spectrum of applications. In this paper, latest progresses in regional climate modeling studies are reviewed, including RCM development, applications of RCMs to dynamical downscaling for climate change assessment, seasonal climate predictions and climate process studies, and the study of regional climate predictability. Challenges and potential directions of future research in this important area are discussed, with the focus on those to which less attention has been given previously, such as the importance of ensemble simulations, further development and improvement of regional climate modeling approach, modeling extreme climate events and sub-daily variation of clouds and precipitation, model evaluation and diagnostics, applications of RCMs to climate process studies and seasonal predictions, and development of regional earth system models. It is believed that with both the demonstrated credibility of RCMs’ capability in reproducing not only monthly to seasonal mean climate and interannual variability but also the extreme climate events when driven by good quality reanalysis and the continuous improvements in the skill of global general circulation models (GCMs) in simulating large-scale atmospheric circulation, regional climate modeling will remain an important dynamicalmore » downscaling tool for providing the needed information for assessing climate change impacts and seasonal climate predictions, and a powerful tool for improving our understanding of regional climate processes. An internationally coordinated effort can be developed with different focuses by different groups to advance regional climate modeling studies. It is also recognized that since the final quality of the results from nested RCMs depends in part on the realism of the large-scale forcing provided by GCMs, the reduction of errors and improvement in physics parameterizations in both GCMs and RCMs remain a priority for climate modeling community.« less

Function, Intracellular Localization and the Importance in Salt Tolerance of a Vacuolar Na+/H+ Antiporter from Rice

Abstract: We examined the function and intracellular localization of the product of the Na(+)/H(+) antiporter gene (OsNHX1) cloned from rice (Oryza sativa). OsNHX1 has the ability to suppress Na(+), Li(+) and hygromycin sensitivity of yeast nhx1 mutants and sensitivity to a high K(+) concentration, a novel phenotype of the nhx1 mutants. Analysis using rice cells expressing a fusion protein of OsNHX1 and green fluorescent protein and Western blot analysis using antibodies specific for OsNHX1 confirmed the localization of OsNHX1 on the tonoplasts. These results indicate that the OsNHX1 gene encodes a vacuolar (Na(+), K(+))/H(+) antiporter. Treatment with high concentrations of NaCl and KCl increased the transcript levels of OsNHX1 in rice roots and shoots. In addition, overexpression of OsNHX1 improved the salt tolerance of transgenic rice cells and plants. These results suggest that OsNHX1 on the tonoplasts plays important roles in the compartmentation of Na(+) and K(+) highly accumulated in the cytoplasm into the vacuoles, and the amount of the antiporter is one of the most important factors determining salt tolerance in rice.

Coupling a Single-Layer Urban Canopy Model with a Simple Atmospheric Model: Impact on Urban Heat Island Simulation for an Idealized Case

Abstract: We incorporated a single-layer urban canopy model into a simple two-dimensional atmospheric model in order to describe the fundamental impact of the urban canopy model on an idealized urban heat island simulation. We found that the heat island circulation developed less strongly than when using the atmospheric model with the standard slab urban model. Additionally, the coupling with urban canopy model (i) delays the phase of surface air temperature, (ii) reduces the diurnal range of the temperature, and (iii) produces a nocturnal heat island, which results from the difference in atmospheric stability between city and its surroundings. The features from the atmospheric model coupled with the canopy model agree well with those from observation, although the atmospheric model with the slab model does not. The simulated nocturnal heat island is caused by the larger heat storage of the canopy model which releases sensible heat after sunset.

Experiment on the Synthesis of Element 113 in the Reaction 209Bi(70Zn,n)278113

Abstract: The convincing candidate event of the isotope of the 113th element, 278 113, and its daughter nuclei, 274 111 and 270 Mt, were observed, for the first time, in the 209 Bi + 70 Zn reaction at a beam energy of 349.0 MeV with a total dose of 1.7 ×10 19 . Alpha decay energies and decay times of the candidates, 278 113, 274 111, and 270 Mt, were (11.68 ±0.04 MeV, 0.344 ms), (11.15 ±0.07 MeV, 9.26 ms), and (10.03 ±0.07 MeV, 7.16 ms), respectively. The production cross section of the isotope was deduced to be 55 +150 -45 fb (10 -39 cm 2 ).

Role of Nrf2 in the Regulation of CD36 and Stress Protein Expression in Murine Macrophages Activation by Oxidatively Modified LDL and 4-Hydroxynonenal

Abstract: CD36 is an important scavenger receptor mediating uptake of oxidized low-density lipoproteins (oxLDLs) and plays a key role in foam cell formation and the pathogenesis of atherosclerosis We report

Transcription Factor Nrf2 Regulates Inflammation by Mediating the Effect of 15-Deoxy-Δ12,14-Prostaglandin J2

Abstract: Activated macrophages express high levels of Nrf2, a transcription factor that positively regulates the gene expression of antioxidant and detoxication enzymes. In this study, we examined how Nrf2 contributes to the anti-inflammatory process. As a model system of acute inflammation, we administered carrageenan to induce pleurisy and found that in Nrf2-deficient mice, tissue invasion by neutrophils persisted during inflammation and the recruitment of macrophages was delayed. Using an antibody against 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), it was observed that macrophages from pleural lavage accumulate 15d-PGJ2. We show that in mouse peritoneal macrophages 15d-PGJ2 can activate Nrf2 by forming adducts with Keap1, resulting in an Nrf2-dependent induction of heme oxygenase 1 and peroxiredoxin I (PrxI) gene expression. Administration of the cyclooxygenase 2 inhibitor NS-398 to mice with carrageenan-induced pleurisy caused persistence of neutrophil recruitment and, in macrophages, attenuated the 15d-PGJ2 accumulation and PrxI expression. Administration of 15d-PGJ2 into the pleural space of NS-398-treated wild-type mice largely counteracted both the decrease in PrxI and persistence of neutrophil recruitment. In contrast, these changes did not occur in the Nrf2-deficient mice. These results demonstrate that Nrf2 regulates the inflammation process downstream of 15d-PGJ2 by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.

Behavioral State Instability in Orexin Knock-Out Mice

Abstract: Narcolepsy is caused by a lack of orexin (hypocretin), but the physiologic process that underlies the sleepiness of narcolepsy is unknown. Using orexin knock-out (KO) mice as a model of narcolepsy, we critically tested the three leading hypotheses: poor circadian control of sleep and wakefulness, inadequate activation of arousal regions, or abnormal sleep homeostasis. Compared with wild-type (WT) littermates, orexin KO mice had essentially normal amounts of sleep and wake, but wake and non-rapid eye movement (NREM) bouts were very brief, with many more transitions between all behavioral states. In constant darkness, orexin KO mice had normal amplitude and timing of sleep-wake rhythms, providing no evidence for disordered circadian control. When placed in a new, clean cage, both groups of mice remained awake for approximately 45 min, demonstrating that, even in the absence of orexin, fundamental arousal regions can be engaged to produce sustained wakefulness. After depriving mice of sleep for 2-8 hr, orexin KO mice recovered their NREM and rapid eye movement sleep deficits at comparable rates and to the same extent as WT mice, with similar increases in EEG delta power, suggesting that their homeostatic control of sleep is normal. These experiments demonstrate that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. Instead, the fragmented behavior of orexin KO mice may be best described as behavioral state instability, with apparently low thresholds to transition between states.

Grazing intensity alters soil respiration in an alpine meadow on the Tibetan plateau

Abstract: Grazing intensity may alter the soil respiration rate in grassland ecosystems. The objectives of our study were to (1) determine the influence of grazing intensity on temporal variations in soil respiration of an alpine meadow on the northeastern Tibetan Plateau; and (2) characterise, the temperature response of soil respiration under different grazing intensities. Diurnal and seasonal soil respiration rates were measured for two alpine meadow sites with different grazing intensities. The light grazing (LG) meadow site had a grazing intensity of 2.55 sheep ha(-1), while the grazing intensity of the heavy grazing (HG) meadow site, 5.35 sheep ha(-1), was approximately twice that of the LG site. Soil respiration measurements - showed that CO2 efflux was almost twice as great at the LG site as at the HG site during the growing season, but the diurnal and seasonal patterns of soil respiration rate were similar for the two sites. Both exhibited the highest annual soil respiration rate in mid-August and the lowest in January. Soil respiration rate was highly dependent on soil temperature. The Q(10) value for annual soil respiration was lower for the HG site (2.75) than for the LG site (3.22). Estimates of net ecosystem CO2 exchange from monthly measurements of biomass and soil respiration revealed that during the period from May 1998 to April 1999, the LG site released 2040 g CO2 m(-2) y(-1) to the atmosphere, which was about one third more than the 1530g CO2 m(-2) y(-1) released at the HG site. The results suggest that (1) grazing intensity alters not only soil respiration rate, but also the temperature dependence of soil CO2 efflux; and (2) soil temperature is the major environmental factor controlling the temporal variation of soil respiration rate in the alpine meadow ecosystem. (C) 2003 Elsevier Ltd. All fights reserved.

The transcription factor NRF2 protects against pulmonary fibrosis

Abstract: The molecular mechanisms of pulmonary fibrosis are poorly understood, although reactive oxygen species are thought to have an important role. NRF2 is a transcription factor that protects cells and tissues from oxidative stress by activating protective antioxidant and detoxifying enzymes. We hypothesized that NRF2 protects lungs from injury and fibrosis induced by bleomycin, an anti-neoplastic agent that causes pulmonary fibrosis in susceptible patients. To test this hypothesis, mice with targeted deletion of Nrf2 (Nrf2-/-) and wild-type (Nrf2+/+) mice were treated with bleomycin or vehicle, and pulmonary injury and fibrotic responses were compared. Bleomycin-induced increases in lung weight, epithelial cell death, and inflammation were significantly greater in Nrf2-/- mice than in Nrf2+/+ mice. Indices of lung fibrosis (hydroxyproline content, collagen accumulation, fibrotic score, cell proliferation) were significantly greater in bleomycin-treated Nrf2-/- mice, compared with Nrf2+/+ mice. NRF2 expression and activity were elevated in Nrf2+/+ mice by bleomycin. Bleomycin caused greater up-regulation of several NRF2-inducible antioxidant enzyme genes and protein products in Nrf2+/+ mice compared with Nrf2-/- mice. Further, bleomycin-induced transcripts and protein levels of lung injury and fibrosis markers were significantly attenuated in Nrf2+/+ mice compared with Nrf2-/- mice. Results demonstrated that NRF2 has a critical role in protection against pulmonary fibrosis, presumably through enhancement of cellular antioxidant capacity. This study has important implications for the development of intervention strategies against fibrosis.