bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of bisoprolol treatment for chronic heart failure initiated and followed up by primary care physicians
Authors: Schuchert A. ,   On behalf of the BISEX Investigators (Appendix A)
Published: June 2004

Primary care physicians prescribe beta‐blockers for chronic heart failure infrequently. The aims of the study were to assess the effects of beta‐blocker treatment in out‐clinic patients with regard to NYHA class and frequency of adverse events. Beta‐blocker treatment was initiated and followed up by primary care physicians.

Methods:

Chronic heart failure patients already treated with ACE‐inhibitors and diuretics were included. The 24‐week follow‐up consisted of a titration phase followed by a maintenance phase. The patients received the beta‐blocker bisoprolol with an initial dose of 1.25 mg and a maximal dose of 10 mg.

Results:

NYHA class II, III and IV had 174, 146, and one patient, respectively. Treatment duration lasted 189±73 days with a maximal bisoprolol dose of 7.2±3.2 mg. Sixty‐one percent of the patients tolerated at least 7.5 mg bisoprolol. The NYHA class improved from 2.4±0.5 at baseline to 1.8±0.6 at week 24 (P<0.001). At final assessment, 74% of the patients showed an improvement. The number of permanent treatment withdrawals was 57 (17%). Death occurred in six patients and hospitalisation in 38 patients.

Conclusions:

Bisoprolol treatment in patients with chronic heart failure was effectively and safely carried out by primary care physicians.
VIGR – a novel inducible adhesion family G‐protein coupled receptor in endothelial cells
Authors: Stehlik Christian , Kroismayr Renate , Dorfleutner Andrea , Binder Bernd R. , Lipp Joachim
Published: June 2004

Using a signal sequence trap for selection of differentially expressed secretory and membrane proteins, we identified a novel member of the adhesion family of G‐protein coupled receptors (GPCRs), termed vascular inducible GPCR (VIGR). VIGR contains C1r‐C1s, Uegf and Bmp1 (CUB) and pentraxin (PTX)‐like modules and a mucin‐like spacer, followed by seven transmembrane domains. By surface biotinylation as well as by immunofluorescence analysis we demonstrate that endogenous, highly glycosylated VIGR is expressed on the cell surface of endothelial cells (ECs) upon LPS or thrombin treatment, and inducible expression is mediated by MAP kinases, but not NF‐κB. We show that VIGR is selectively expressed in ECs derived from larger vessels, but not from microvessels. In summary, VIGR represents a novel GPCR of the adhesion family, which is unique in its long extra‐cellular domain comprising CUB and PTX‐like modules and in its inducibility by LPS and thrombin in a subset of ECs, suggesting an important function in cell‐adhesion and potentially links inflammation and coagulation.
The mitochondrial ABC transporter Atm1p functions as a homodimer
Authors: Chloupková Maja , Reaves Scott K , LeBard Linda M , Koeller David M
Published: June 2004

The ATP‐binding cassette (ABC) transporters constitute one of the largest families of proteins in evolution. The ATM1 gene of the yeast Saccharomyces cerevisiae encodes an ABC protein, which is localized to the mitochondrial inner membrane. A deletion of ATM1 results in the accumulation of up to a 30‐fold excess of mitochondrial iron, loss of mitochondrial cytochromes and abnormalities of cytosolic iron metabolism. In this study, we have evaluated the role of conserved sequence elements in Atm1p in its function and dimerization in vivo. We report that conserved residues in the Walker A and B motifs of the nucleotide binding domain, which are required for ATP binding and hydrolysis, are essential for Atm1p function. In addition, we provide evidence that ATP binding is important for Atm1p dimerization.
Crystal structure of the biologically active form of class Ib ribonucleotide reductase small subunit from Mycobacterium tuberculosis
Authors: Uppsten Malin , Davis Jamaine , Rubin Harvey , Uhlin Ulla
Published: June 2004

Two nrdF genes of Mycobacterium tuberculosis code for different R2 subunits of the class Ib ribonucleotide reductase (RNR). The proteins are denoted R2F‐1 and R2F‐2 having 71% sequence identity. The R2F‐2 subunit forms the biologically active RNR complex with the catalytic R1E‐subunit. We present the structure of the reduced R2F‐2 subunit to 2.2 Å resolution. Comparison of the R2F‐2 structure with a model of R2F‐1 suggests that the important differences are located at the C‐terminus. We found that within class Ib, the E‐helix close to the iron diiron centre has two preferred conformations, which cannot be explained by the redox‐state of the diiron centre. In the R2F‐2 structure, we also could see a mobility of αE in between the two conformations.
The unprecedented nos gene cluster of Wolinella succinogenes encodes a novel respiratory electron transfer pathway to cytochrome c nitrous oxide reductase
Authors: Simon Jörg , Einsle Oliver , Kroneck Peter M.H , Zumft Walter G
Published: June 2004

The ε‐proteobacterium Wolinella succinogenes grows anaerobically by respiratory nitrite ammonification but not by denitrification. Nevertheless, it is capable of N2O reduction to N2. Recently, the genome sequence of W. succinogenes revealed a nos gene cluster with intriguing features encoding a new type of N2O reductase. The predicted enzyme is similar to other N2O reductases exhibiting conservation of all residues ligating the two multinuclear copper centers but carries an unprecedented C‐terminal monoheme cytochrome c domain. Notably, the N2O reductase pre‐protein is synthesized with a Sec‐dependent signal peptide, rather than the usually observed twin‐arginine signal sequence, implying that the copper and heme cofactors are both incorporated in the periplasm. The nos gene cluster further consists of four adjacent open reading frames which are predicted to encode two monoheme c‐type cytochromes as well as homologs of NapG and NapH. The latter proteins are thought to function in quinol oxidation coupled to cytochrome c reduction in electron transport to periplasmic nitrate reductase. While the accessory genes nosD, ‐F, ‐Y and ‐L are present in W. succinogenes, homologs of nosR and nosX are absent from the genome. We hypothesize that the nos gene cluster of W. succinogenes encodes a complete electron transport chain catalyzing N2O reduction by menaquinol, a pathway which might also be relevant to other bacteria.
Serine protease inhibitor 2A inhibits caspase‐independent cell death
Authors: Liu Ni , Wang Yue , Ashton-Rickardt Philip G
Published: June 2004

The release of cysteine cathepsins from the lysosome into the cytoplasm can trigger programs of cell death (PCD) that do not require caspase executioner proteases but instead are mediated by toxic reactive oxygen species (ROS). Here, we show that a cytoplasmic inhibitor of papain‐like cathepsins – Serine protease inhibitor 2A (Spi2A) – is required for the protection of cells from caspase‐independent PCD triggered by tumor necrosis factor‐α. In the absence of caspase activity, Spi2A suppressed PCD by inhibiting cathepsin B after it was released into the cytoplasm. Spi2A also directly protected against ROS‐mediated PCD, which is consistent with a role in suppressing caspase‐independent pathways of PCD. We conclude that inhibition of lysosomal executioner proteases by Spi2A is a physiological mechanism by which cells are protected from caspase‐independent programmed cell death.
Activation of Ca2+/calmodulin‐dependent protein kinase II is involved in hyperosmotic induction of the human taurine transporter
Authors: Satsu Hideo , Manabe Mariko , Shimizu Makoto
Published: June 2004

We investigated the signaling pathways participating in hyperosmotic regulation of the human taurine transporter (TAUT) by using specific inhibitors of various intracellular signaling molecules. Among them, the specific inhibitor of calcium/calmodulin‐dependent protein kinase II (Ca2+/CaM kinase II) completely repressed the hyperosmotic regulation of TAUT. The osmosensitive upregulation of TAUT was also significantly inhibited by calmodulin antagonists and calcium‐chelators. The increased expression level of TAUT mRNA by hypertonicity was repressed by the specific Ca2+/CaM kinase II inhibitor. The activated form of Ca2+/CaM kinase II protein could only be detected in Caco‐2 cells under hypertonic conditions.
Hyaline cartilage degenerates after autologous osteochondral transplantation
Authors: Tibesku C. O. , Szuwart T. , Kleffner T. O. , Schlegel P. M. , Jahn U. R. , Van Aken H. , Fuchs S.
Published: June 2004

Objectives: Autologous osteochondral grafting is a well‐established clinical procedure to treat focal cartilage defects in patients, although basic research on this topic remains sparse. The aim of the current study was to evaluate (1) histological changes of transplanted hyaline cartilage of osteochondral grafts and (2) the tissue that connects the transplanted cartilage with the adjacent cartilage in a sheep model.

Method: Both knee joints of four sheep were opened surgically and osteochondral grafts were harvested and simultaneously transplanted to the contralateral femoral condyle. The animals were sacrificed after three months and the received knee joints were evaluated histologically.

Results: Histological evaluation showed a complete ingrowth of the osseous part of the osteochondral grafts. A healing or ingrowth at the level of the cartilage could not be observed. Histological evaluation of the transplanted grafts according to Mankin revealed significantly more and more severe signs of degeneration than the adjacent cartilage, such as cloning of chondrocytes and irregularities of the articular surface.

Conclusion: We found no connecting tissue between the transplanted and the adjacent cartilage and histological signs of degeneration of the transplanted hyaline cartilage. In the light of these findings, long‐term results of autologous osteochondral grafts in human beings have to be followed critically. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Lead isotope composition of Central American volcanoes: Influence of the Galapagos plume
Authors: Feigenson Mark D. , Carr Michael J. , Maharaj Susan V. , Juliano Scott , Bolge Louise L.
Published: June 2004

Lead isotopic analyses of lavas from Central America, both along and behind the volcanic arc, help to clarify source components in the mantle wedge. Analysis of previous Pb isotopic data had implied that little or no marine sediment lead was added to the Central American source region, as all samples fell within the MORB field, in contrast to other information (e.g., Ba/La, 10Be, 87Sr/86Sr) that indicated a high subduction component. The data presented here include several analyses of local marine sediment, showing it to be exceptionally unradiogenic in Pb and thus permitting high sediment contributions to the mantle source region without significant changes in Pb isotopes. Combined Pb‐Nd and Pb‐Sr isotopic diagrams clearly illustrate the influence of crustal contamination for samples from Guatemala and Honduras, and of subducted sediment for all lavas of the volcanic front. Samples collected behind the volcanic front are derived from mixing between enriched and depleted mantle sources, and in central Costa Rica (extending to the back arc) overlap Pb, Sr and Nd isotope values for both Cocos Island and some components of the Galapagos hot spot. The restricted geographical occurrence of the enriched mantle signature in Central America, coupled with the persistence of the signal well into the back arc region, imply that these lavas are sampling Galapagos plume‐influenced mantle. The presence of this plume component beneath southern Central America and extending to the northeast beneath the Caribbean confirms a Galapagos hot spot origin for this part of Caribbean Plate.
Variability in flow and temperatures within mantle subduction zones
Authors: Kincaid C. , Griffiths R. W.
Published: June 2004

A series of laboratory experiments is used to model three‐dimensional aspects of flow in subduction zones, and the consequent temperature variations in the slab and overlying mantle wedge. The effects of longitudinal, rollback and slab‐steepening components of motions are considered, along with different thicknesses of the over‐riding lithosphere. The results show that the style of plate sinking influences the evolution of subduction zones, both in terms of the speed, orientation and temperature of flow in the overlying wedge and in terms of the temperatures at the surface of the descending slab. In the simplest case of longitudinal sinking, without rollback motion, velocities in the mantle wedge are 30–40% of the downdip plate speed. Return flow paths in the shallow mantle wedge are nearly horizontal for slow slab speeds and steepen with higher slab speeds, and there is no mass flux around the edges of a slab segment (of finite width). Rollback subduction leads to flow both around and beneath the sinking slab, with larger velocities in the wedge (up to 150% of the slab speed) and flow focused toward the center of the plate segment. Rollback subduction, in which either the trench migrates or the plate steepens with time, induces shallow and steep wedge return flow trajectories, respectively. The thermal evolution of the plate is strongly influenced by sinking style and rate: highest temperatures are along the edges of the slab for longitudinal sinking, but along the centerline of the slab segment for rollback motion. Slab surface temperatures, when scaled to the mantle, are higher than those given by previous two‐dimensional numerical models, and are consistent with recent observational and experimental data on melt compositions.
Role of the Polar‐night Jet Oscillation on the formation of the Arctic Oscillation in the Northern Hemisphere winter
Authors: Kuroda Yuhji , Kodera Kunihiko
Published: June 2004

The coupling between the Polar‐night Jet Oscillation (PJO) and the Arctic Oscillation (AO) was examined using observational data. Positive and negative AO indices tended to appear within a specific phase of the time evolution of the PJO, and the lifetime of the AO tended to be longer when the AO was coupled with the PJO. We performed lagged regression analyses for Eulerian mean wave forcing to examine how the AO signal appears with the time evolution of the PJO. We found that the AO signal at the surface is created through meridional circulation driven by the combined effect of mechanical and thermal eddy forcing at some stage of the PJO. The effect of these wave forcings on sea level pressure (SLP) changes was investigated using a zonal‐mean quasi‐geostrophic model on the sphere. Approximately 40% of the polar SLP change was found to come from thermal forcing when the AO‐like signal appeared and two thirds from the stratosphere, whereas 60% of the polar SLP change was a result of mechanical forcing that originated almost in the troposphere. The contribution from the wave of the zonal wave number 1 component was very important in both forcings, particularly for SLP in the polar cap region. Waves of zonal wave number 2 and 3 components also contributed significantly to tropospheric forcing.
Observations of diurnal and spatial variability of radiative forcing by equatorial deep convective clouds
Authors: Nowicki Sophie M. J. , Merchant Christopher J.
Published: June 2004

From geostationary satellite observations of equatorial Africa and the equatorial east Atlantic during May and June 2000 we explore the radiative forcing by deep convective cloud systems in these regions. Deep convective clouds (DCCs) are associated with a mean radiative forcing relative to non–deep convective areas of −39 W m−2 over the Atlantic Ocean and of +13 W m−2 over equatorial Africa (±10 W m−2 in both cases). We show that over land the timing of the daily cycle of convection relative to the daily cycle in solar illumination and surface temperature significantly affects the mean radiative forcing by DCCs. Displacement of the daily cycle of DCC coverage by 2 hours changes their overall radiative effect by ∼10 W m−2, with implications for the simulation of the radiative balance in this region. The timing of the minimum DCC cover over land, close to noon local time, means that the mean radiative forcing is nearly maximized.
Evidence for drift waves in ionospheric heating experiments
Authors: Kelley Michael C.
Published: June 2004

Universal Drift Wave instabilities commonly occur in laboratory plasmas and yet have not been detected in space experiments. Meter‐scale waves occurring in convective ionospheric storms, also known as equatorial spread F conditions, were long thought, erroneously, to be caused by drift waves, even though laboratory simulations of the Rayleigh‐Taylor instability seem to result in drift modes. Most space‐based instabilities occur at such large scales that the gradients required to support drift waves are simply too weak. The results of a laboratory‐like experiment, performed in space using high power radiowaves, are then revisited. Such experiments produce modest density depletions having very short scales across the magnetic field. Here, wavelets are used to parse the signal into a deterministic structure—the needle‐like irregularities—and a noise‐like signal corresponding to waves trapped in the depletions, which are very likely lower hybrid drift waves. Recent space experiments have revealed natural phenomena with similar characteristics.
Can climate trends be calculated from reanalysis data?
Authors: Bengtsson Lennart , Hagemann Stefan , Hodges Kevin I.
Published: June 2004

Several global quantities are computed from the ERA40 reanalysis for the period 1958–2001 and explored for trends. These are discussed in the context of changes to the global observing system. Temperature, integrated water vapor (IWV), and kinetic energy are considered. The ERA40 global mean temperature in the lower troposphere has a trend of +0.11 K per decade over the period of 1979–2001, which is slightly higher than the MSU measurements, but within the estimated error limit. For the period 1958–2001 the warming trend is 0.14 K per decade but this is likely to be an artifact of changes in the observing system. When this is corrected for, the warming trend is reduced to 0.10 K per decade. The global trend in IWV for the period 1979–2001 is +0.36 mm per decade. This is about twice as high as the trend determined from the Clausius‐Clapeyron relation assuming conservation of relative humidity. It is also larger than results from free climate model integrations driven by the same observed sea surface temperature as used in ERA40. It is suggested that the large trend in IWV does not represent a genuine climate trend but an artifact caused by changes in the global observing system such as the use of SSM/I and more satellite soundings in later years. Recent results are in good agreement with GPS measurements. The IWV trend for the period 1958–2001 is still higher but reduced to +0.16 mm per decade when corrected for changes in the observing systems. Total kinetic energy shows an increasing global trend. Results from data assimilation experiments strongly suggest that this trend is also incorrect and mainly caused by the huge changes in the global observing system in 1979. When this is corrected for, no significant change in global kinetic energy from 1958 onward can be found.
Spectroscopic Studies of Diatomic Indium Halides
Authors: Mishra S. K. , Yadav Raj K. S. , Singh V. B. , Rai S. B.
Published: June 2004

A critical review of the available spectroscopic information about diatomic indium halides has been performed. The literature was surveyed till early 2002 and the data on the molecular constants for the ground state, as well as excited states of these molecules has been presented. A brief discussion on the dissociation energies, ionization potentials, and the nature of the bonding in the ground state is given. The energy level diagram and Rydberg–Klein–Rees potential curves for the different electronic states of these molecules are also presented. Mechanism of laser emission/fluorescence due to atomic indium in the ultraviolet photodissociation of indium monohalides has also been discussed.
Atomic Spectral Tables for the Chandra X-Ray Observatory. Part III. Mg V–Mg X
Authors: Podobedova L. I. , Kelleher D. E. , Reader J. , Wiese W. L.
Published: June 2004

Tables of critically compiled wavelengths, energy levels, line classifications, and transition probabilities are given for spectra of ionized magnesium (Mg V–Mg X) in the region 35–170 Å. These tables provide data of interest for the Emission Line Project in support of analyses of astronomical data from the Chandra X-Ray Observatory. They will also be useful for the diagnostics of plasmas encountered in fusion energy research. The transition probabilities were obtained mainly from recent sophisticated calculations carried out with complex computer codes.
Atomic Spectral Tables for the Chandra X-ray Observatory. Part IV. Ne V–Ne VIII
Authors: Podobedova L. I. , Fuhr J. R. , Reader J. , Wiese W. L.
Published: June 2004

Tables of critically compiled wavelengths, energy levels, line classifications, and transition probabilities are given for spectra of ionized neon (Ne V–Ne VIII) in the region 55–170 Å. These tables provide data of interest for the Emission Line Project in support of analysis of astronomical data from the Chandra X-Ray Observatory. They will also be useful for the diagnostics of plasma encountered in fusion energy research. The transition probabilities were obtained mainly from recent sophisticated calculations carried out with complex computer codes.
Equations of State for Mixtures of R-32, R-125, R-134a, R-143a, and R-152a
Authors: Lemmon Eric W. , Jacobsen Richard T
Published: June 2004

Mixture models explicit in Helmholtz energy have been developed to calculate the thermodynamic properties of refrigerant mixtures containing R-32, R-125, R-134a, R143a, and R-152a. The Helmholtz energy of the mixture is the sum of the ideal gas contribution, the compressibility (or real fluid) contribution, and the contribution from mixing. The independent variables are the density, temperature, and composition. The model may be used to calculate the thermodynamic properties of mixtures, including dew and bubble point properties, within the experimental uncertainties of the available measured properties. It incorporates the most accurate equations of state available for each pure fluid. The estimated uncertainties of calculated properties are 0.1% in density and 0.5% in heat capacities and in the speed of sound. Calculated bubble point pressures have typical uncertainties of 0.5%.
Gentrification, Segregation, and Discrimination in the American Urban System
Authors: Wyly Elvin K , Hammel Daniel J
Published: June 2004

Recent discussions of the ‘geography of gentrification’ highlight the need for comparative analysis of the nature and consequences of inner-city transformation. In this paper, the authors map the effects of housing-market and policy changes in the 1990s, focusing on 23 large cities in the USA. Using evidence from field surveys and a mortgage-lending database, they measure the class selectivity of gentrification and its relation to processes of racial and ethnic discrimination. They find a strong resurgence of capital investment in the urban core, along with magnified class segregation. The boom of the 1990s and policies targeted towards ‘new markets' narrowed certain types of racial and ethnic disparities in urban credit markets, but there is evidence of intensified discrimination and exclusion in gentrified neighborhoods.
Gentrification and the Nature of Work: Exploring the Links in Williamsburg, Brooklyn
Authors: Curran Winifred
Published: June 2004

This paper looks at the linkages between gentrification and the displacement of small-scale manufacturing and blue-collar work in the Williamsburg neighborhood of Brooklyn, New York. Although the link between global economic change and gentrification has been made for the upper classes who are the consumers of the gentrified landscape, very little work has been done on the blue-collar work and workers that remain in the central city despite the assumption by policymakers that deindustrialization is complete. I argue that manufacturing is still a viable sector of the urban economy that is increasingly at risk of displacement because of the conversion of industrial space to residential use and speculative real-estate pressure. In this way, gentrification is encouraging industrial displacement, which in turn is leading to the degradation of the blue-collar work that remains and to the increasing informalization of work.
North American Gentrification? Revanchist and Emancipatory Perspectives Explored
Authors: Slater Tom
Published: June 2004

By offering a response to recent calls for a ‘geography of gentrification’, the author attempts to move on from the intractable theoretical divisions and overgeneralizations that continue to pervade the gentrification literature. The research described in this paper takes the form of a comparative assessment of the gentrifying neighbourhoods of South Parkdale, Toronto, Canada, and Lower Park Slope, New York City, USA. A central part of this research has been an engagement with two contrasting academic discourses on gentrification, the ‘emancipatory city’ (a Canadian construct) and the ‘revanchist city’ (a US construct), to examine how gentrification may or may not have changed since these discourses were produced and articulated. The author combines narratives from in-depth interviews (with a particular focus on displaced tenants) with supplementary data from secondary sources and demonstrates that gentrification is neither emancipatory nor revanchist in either case. This has important implications for how gentrification is understood and evaluated in Canada and the USA. Although one can see crucial broad similarities both in the causes and in the effects of gentrification in each neighbourhood (which would appear to endorse casual references to ‘North American gentrification’), the process is also differentiated according to contextual factors, and the nuances of the gentrification process are illuminated and clarified by international comparison. In sum, the author points to the need to exercise caution in referring to ‘North American gentrification’, especially as a geography of gentrification is only in its infancy.
Litoria gracilenta (Anura : Hylidae) and related species in New Guinea
Authors: Menzies J. I. , Tyler M. J.
Published: June 2004

We examined a large collection (n = 132) of tree frogs, hitherto identified as Litoria gracilenta, from various localities in New Guinea and compared them with Litoria gracilenta from Queensland and with the recently described Litoria elkeae from far west New Guinea. We found that the frogs in question were neither L. gracilenta nor L. elkeae but comprised two distinct taxa described herein as new species.We call attention to the problems of performing statistical analysis on measurements of soft-bodied organisms and consider that the conclusions reached in this analysis are both conservative and realistic.
Seasonal reproductive dynamics in a tropical Australian rodent, Rattus tunneyi tunneyi (Rodentia : Muridae)
Authors: Taylor J. Mary , Calaby John H.
Published: June 2004

Histological and gross assessments and measurements of gonads and related organs are used to analyse the pattern of reproduction in the native murid rodent, Rattus tunneyi tunneyi. This is the first study to confirm by histological analysis the breeding dynamics of this rat in all seasons of the year. It was found to breed between the latter part of the wet season and the middle of the dry period, at which time seasonal suppression of breeding occurred in both adults and maturing individuals.
Using conservation of pattern to estimate spatial parameters from a single snapshot
Authors: Keeling Matt J. , Brooks Stephen P. , Gilligan Christopher A.
Published: June 2004

Rapid reaction in the face of an epidemic is a key element in effective and efficient control; this is especially important when the disease has severe public health or economic consequences. Determining an appropriate level of response requires rapid estimation of the rate of spread of infection from limited disease distribution data. Generally, the techniques used to estimate such spatial parameters require detailed spatial data at multiple time points; such data are often time-consuming and expensive to collect. Here we present an alternative approach that is computationally efficient and only requires spatial data from a single time point, hence saving valuable time at the start of the epidemic. By assuming that fundamental spatial statistics are near equilibrium, parameters can be estimated by minimizing the expected rate of change of these statistics, hence conserving the general spatial pattern. Although applicable to both ecological and epidemiological data, here we focus on disease data from computer simulations and real epidemics to show that this method produces reliable results that could be used in practical situations.
Functional organization of sensory input to the olfactory bulb glomerulus analyzed by two-photon calcium imaging
Authors: Wachowiak Matt , Denk Winfried , Friedrich Rainer W.
Published: June 2004

Glomeruli in the olfactory bulb are anatomically discrete modules receiving input from idiotypic olfactory sensory neurons. To examine the functional organization of sensory inputs to individual glomeruli, we loaded olfactory sensory neurons with a Ca
2+
indicator and measured odorant-evoked presynaptic Ca
2+
signals within single glomeruli by using two-photon microscopy in anaesthetized mice. Odorants evoked patterns of discrete Ca
2+
signals throughout the neuropil of a glomerulus. Across glomeruli, Ca
2+
signals occurred with equal probability in all glomerular regions. Within single glomeruli, the pattern of intraglomerular Ca
2+
signals was indistinguishable for stimuli of different duration, identity, and concentration. Moreover, the response time course of the signals was similar throughout the glomerulus. Hence, sensory inputs to individual glomeruli are spatially heterogeneous but seem to be functionally indiscriminate. These results support the view of olfactory glomeruli as functional units in representing sensory information.
RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: A mechanism for diabetes-associated erectile dysfunction
Authors: Bivalacqua Trinity J. , Champion Hunter C. , Usta Mustafa F. , Cellek Selim , Chitaley Kanchan , Webb R. Clinton , Lewis Ronald L. , Mills Thomas M. , Hellstrom Wayne J. G. , Kadowitz Philip J.
Published: June 2004

Significant impairment in endothelial-derived nitric oxide is present in the diabetic corpus cavernosum. RhoA/Rho-kinase may suppress endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that RhoA/Rho-kinase contributes to diabetes-related erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis. Colocalization of Rho-kinase and eNOS protein was present in the endothelium of the corpus cavernosum. RhoA/Rho-kinase protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZ-diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess the functional role of RhoA/Rho-kinase in the penis, we evaluated the effects of an adeno-associated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) on RhoA/Rho-kinase and eNOS and erectile function
in vivo
in the STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in the control rats. There was a significant decrease in erectile response to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene transfer improved erectile responses in the STZ-diabetic rat to values similar to control. These data demonstrate a previously undescribed mechanism for the down-regulation of penile eNOS in diabetes mediated by activation of the RhoA/Rho-kinase pathway. Importantly, these data imply that inhibition of RhoA/Rho-kinase improves eNOS protein content and activity thus restoring erectile function in diabetes.
Nitric oxide represses inhibitory κB kinase through S-nitrosylation
Authors: Reynaert Niki L. , Ckless Karina , Korn Solange H. , Vos Nanda , Guala Amy S. , Wouters Emiel F. M. , van der Vliet Albert , Janssen-Heininger Yvonne M. W.
Published: June 2004

Nitric oxide (NO) possesses antiinflammatory effects, which may be exerted via its ability to inhibit the transcription factor, NF-κB. A commonly proposed mode of action for inhibition of NF-κBbyNO involves interference with NF-κB binding to DNA. Because activation of inhibitory κB kinase (IKK), the prerequisite enzyme complex necessary to induce NF-κB, is subject to redox regulation, we assessed whether IKK could present a more proximal target for NO to inhibit NF-κB activation. We demonstrate here that
S
-nitrosothiols (SNO) caused a dose-dependent inhibition of the enzymatic activity of IKK, in lung epithelial cells and in Jurkat T cells, which was associated with S-nitrosylation of the IKK complex. Using biotin derivatization of SNO, we revealed that IKKβ, the catalytic subunit required for NF-κB activation, was a direct target for S-nitrosylation. A mutant version of IKKβ containing a Cys-179-to-Ala mutation was refractory to inhibition by SNO or to increases in S-nitrosylation, in contrast to wild-type IKKβ, demonstrating that Cys-179 is the main target for attack by SNO. Importantly, inhibition of NO synthase activity in Jurkat T cells resulted in activation of IKK, in association with its denitrosylation. Moreover, NO synthase inhibition enhanced the ability of tumor necrosis factor α to activate IKK, illustrating the importance of endogenous NO in regulating the extent of NF-κB activation by cytokines. Collectively, our findings demonstrate that IKKβ is an important target for the redox regulation of NF-κB by endogenous or exogenous NO, providing an additional mechanism for its antiinflammatory properties.
AtNAP7 is a plastidic SufC-like ATP-binding cassette/ATPase essential for
Arabidopsis
embryogenesis
Authors: Xu Xiang Ming , Møller Simon Geir
Published: June 2004

In bacteria, yeast, and mammals, iron-sulfur (Fe-S) cluster-containing proteins are involved in numerous processes including electron transfer, metabolic reactions, sensing, signaling, and regulation of gene expression. In humans, iron-storage diseases such as X-linked sideroblastic anemia and ataxia are caused by defects in Fe-S cluster availability. The biogenesis of Fe-S clusters involves several pathways, and in bacteria, the
SufABCDSE
operon has been shown to play a vital role in Fe-S biogenesis and repair during oxidative stress. Although Fe-S proteins play vital roles in plants, Fe-S cluster biogenesis and maintenance and physiological consequences of dysfunctional Fe-S cluster assembly remains obscure. Here we report that
Arabidopsis
plants deficient for the SufC homolog AtNAP7 show lethality at the globular stage of embryogenesis.
AtNAP7
is expressed in developing embryos and in apical, root, and floral meristems and encodes an ATP-binding cassette/ATPase that can partially rescue growth defects in an
Escherichia coli SufC
mutant during oxidative stress. AtNAP7 is plastid-localized, and mutant embryos contain abnormal developing plastids with disorganized thylakoid structures. We found that AtNAP7 can interact with AtNAP6, a plastidic
Arabidopsis
SufD homolog, and because
Arabidopsis
plastids also harbor SufA, SufB, SufS, and SufE homologs, plastids probably contain a complete SUF system. Our results imply that AtNAP7 represents a conserved SufC protein involved in the biogenesis and/or repair of oxidatively damaged Fe-S clusters and suggest an important role for plastidic Fe-S cluster maintenance and repair during
Arabidopsis
embryogenesis.
Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand
Authors: Willy Patricia J. , Murray Ian R. , Qian Jing , Busch Brett B. , Stevens William C. , Martin Richard , Mohan Raju , Zhou Sihong , Ordentlich Peter , Wei Ping , Sapp Douglas W. , Horlick Robert A. , Heyman Richard A. , Schulman Ira G.
Published: June 2004

Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1α as a strong coactivator of the orphan nuclear receptor estrogen-related receptor α (ERRα), implicating ERRα as a potential mediator of PGC-1α action. To understand the role of ERRα in PGC-1α signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERRα small-molecule regulators and target genes. We report here the identification of a potent and selective ERRα inverse agonist that interferes effectively with PGC-1α/ERRα-dependent signaling. This inverse agonist inhibits the constitutive activity of ERRα in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERRα target gene whose expression is regulated by PGC-1α and ERRα and inhibited by the ERRα inverse agonist. The discovery of potent and selective ERRα modulators and their effect on PGC-1α signaling provides mechanistic insight into gene regulation by PGC-1α. These findings validate ERRα as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.
Preferential states in soil moisture and climate dynamics
Authors: D'Odorico Paolo , Porporato Amilcare
Published: June 2004

Summer precipitation in continental midlatitude regions is significantly contributed by local recycling, i.e., by moisture returning to the atmosphere through evapotranspiration from the same region. On the other hand, reduced soil moisture availability may limit evapotranspiration rates with effects on the planetary boundary layer dynamics through the partitioning between sensible and latent heat fluxes. Thus, a dependence may exist between precipitation and antecedent soil moisture conditions. Here we provide theoretical and experimental evidence in support of the hypothesis that in continental regions summer soil moisture anomalies affect the probability of occurrence of subsequent precipitation. Owing to these feedbacks, two preferential states may arise in summer soil moisture dynamics, which thus tend to remain locked either in a “dry” or a “wet” state, whereas intermediate conditions have low probability of occurrence. In this manner, such land–atmosphere interactions would explain the possible persistence of summer droughts sustained by positive feedbacks in response to initial (spring) surface moisture anomalies.
Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression
Authors: Rhodes Daniel R. , Yu Jianjun , Shanker K. , Deshpande Nandan , Varambally Radhika , Ghosh Debashis , Barrette Terrence , Pandey Akhilesh , Chinnaiyan Arul M.
Published: June 2004

Many studies have used DNA microarrays to identify the gene expression signatures of human cancer, yet the critical features of these often unmanageably large signatures remain elusive. To address this, we developed a statistical method, comparative metaprofiling, which identifies and assesses the intersection of multiple gene expression signatures from a diverse collection of microarray data sets. We collected and analyzed 40 published cancer microarray data sets, comprising 38 million gene expression measurements from >3,700 cancer samples. From this, we characterized a common transcriptional profile that is universally activated in most cancer types relative to the normal tissues from which they arose, likely reflecting essential transcriptional features of neoplastic transformation. In addition, we characterized a transcriptional profile that is commonly activated in various types of undifferentiated cancer, suggesting common molecular mechanisms by which cancer cells progress and avoid differentiation. Finally, we validated these transcriptional profiles on independent data sets.
Critical roles of interferon regulatory factor 4 in CD11bhighCD8α–dendritic cell development
Authors: Suzuki Shoichi , Honma Kiri , Matsuyama Toshifumi , Suzuki Kazuo , Toriyama Kan , Akitoyo Ichinose , Yamamoto Kazuo , Suematsu Takashi , Nakamura Michio , Yui Katsuyuki , Kumatori Atsushi
Published: June 2004

IFN regulatory factors (IRFs) are a family of transcription factors that play an essential role in the homeostasis and function of immune systems. Recent studies indicated that IRF-8 is critical for the development of CD11blowCD8α+conventional dendritic cells (DCs) and plasmacytoid DCs. Here we show that IRF-4 is important for CD11bhighCD8α–conventional DCs. The development of CD11bhighDCs from bone marrow of IRF-4–/–mice was severely impaired in two culture systems supplemented with either GM-CSF or Flt3-ligand. In the IRF-4–/–spleen, the number of CD4+CD8α–DCs, a major subset of CD11bhighDCs, was severely reduced. IRF-4 and IRF-8 were expressed in the majority of CD11bhighCD4+CD8α–DCs and CD11blowCD8α+DCs, respectively, in a mutually exclusive manner. These results imply that IRF-4 and IRF-8 selectively play critical roles in the development of the DC subsets that express them.
Chemoattractant-induced phosphatidylinositol 3,4,5-trisphosphate accumulation is spatially amplified and adapts, independent of the actin cytoskeleton
Authors: Janetopoulos Chris , Ma Lan , Devreotes Peter N. , Iglesias Pablo A.
Published: June 2004

Experiments in amoebae and neutrophils have shown that local accumulations of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] mediate the ability of cells to migrate during gradient sensing. To define the nature of this response, we subjectedDictyostelium discoideumcells to measurable temporal and spatial chemotactic inputs and analyzed the accumulation of PI(3,4,5)P3on the membrane, as well as the recruitment of the enzymes phosphoinositide 3-kinase and PTEN. In latrunculin-treated cells, spatial gradients elicited a PI(3,4,5)P3response only on the front portion of the cell where the response increased more steeply than the gradient and did not depend on its absolute concentration. Phosphoinositide 3-kinase bound to the membrane only at the front, although it was less sharply localized than PI(3,4,5)P3. Membrane-bound PTEN was highest at the rear and varied inversely with receptor occupancy. The localization of PI(3,4,5)P3was enhanced further in untreated polarized cells containing an intact cytoskeleton. Interestingly, the treated cells could respond to two independent gradients simultaneously, demonstrating that a response at the front does not necessarily inhibit the back. Combinations of temporal and spatial stimuli provided evidence of an inhibitory process and showed that a gradient generates a persistent steady-state response independent of a previous history of exposure to chemoattractant. These results support a local excitation/global inhibition model and argue against other schemes proposed to explain directional sensing.
Activation of NF-κB and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis
Authors: Stoffel Archontoula , Chaurushiya Mira , Singh Bhuvanesh , Levine Arnold J.
Published: June 2004

Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common extranodal lymphoid cell neoplasia; it frequently follows chronic bacteria-induced inflammation in various tissues. MALT lymphomas are characterized genetically by the t(11;18)(q21;q21) translocation, which yields chimeric transcripts encoding structurally distinct API2/MALT1 fusion proteins. In this study, we provide functional evidence for the contribution of API2/MALT1 fusion proteins to transformation of cells in culture by activating the NF-κB pathway through a RelB/p50 dimer. Using microchip gene expression analysis, we demonstrate that different forms of the API2/MALT1 proteins activate both unique and overlapping gene programs in cells. In addition to this genome reprogramming, expression of distinct API2/MALT1 fusion products inhibits DNA damage-induced, p53-mediated apoptosis in an NF-κB-dependent manner. Collectively, these data reveal previously unknown functional diversity among API2/MALT1 fusion products and their function in NF-κB signaling as it connects to the apoptotic program, a pathway with strong relevance to cancer. Furthermore, they provide evidence underlying the emerging role of the NF-κB signaling pathway in the inhibition of apoptosis.
Genetic diversity enhances the resistance of a seagrass ecosystem to disturbance
Authors: Hughes A. Randall , Stachowicz John J.
Published: June 2004

Motivated by recent global reductions in biodiversity, empirical and theoretical research suggests that more species-rich systems exhibit enhanced productivity, nutrient cycling, or resistance to disturbance or invasion relative to systems with fewer species. In contrast, few data are available to assess the potential ecosystem-level importance of genetic diversity within species known to play a major functional role. Using a manipulative field experiment, we show that increasing genotypic diversity in a habitat-forming species (the seagrass
Zostera marina
) enhances community resistance to disturbance by grazing geese. The time required for recovery to near predisturbance densities also decreases with increasing eelgrass genotypic diversity. However, there is no effect of diversity on resilience, measured as the rate of shoot recovery after the disturbance, suggesting that more rapid recovery in diverse plots is due solely to differences in disturbance resistance. Genotypic diversity did not affect ecosystem processes in the absence of disturbance. Thus, our results suggest that genetic diversity, like species diversity, may be most important for enhancing the consistency and reliability of ecosystems by providing biological insurance against environmental change.
Crystal structures of the DsbG disulfide isomerase reveal an unstable disulfide
Authors: Heras Begoña , Edeling Melissa A. , Schirra Horst J. , Raina Satish , Martin Jennifer L.
Published: June 2004

Dsb proteins control the formation and rearrangement of disulfide bonds during the folding of secreted and membrane proteins in bacteria. DsbG, a member of this family, has disulfide bond isomerase and chaperone activity. Here, we present two crystal structures of DsbG at 1.7and 2.0-Å resolution that are meant to represent the reduced and oxidized forms, respectively. The oxidized structure, however, reveals a mixture of both redox forms, suggesting that oxidized DsbG is less stable than the reduced form. This trait would contribute to DsbG isomerase activity, which requires that the active-site Cys residues are kept reduced, regardless of the highly oxidative environment of the periplasm. We propose that a Thr residue that is conserved in the
cis
-Pro loop of DsbG and DsbC but not found in other Dsb proteins could play a role in this process. Also, the structure of DsbG reveals an unanticipated and surprising feature that may help define its specific role in oxidative protein folding. Thus, the dimensions and surface features of DsbG show a very large and charged binding surface that is consistent with interaction with globular protein substrates having charged surfaces. This finding suggests that, rather than catalyzing disulfide rearrangement in unfolded substrates, DsbG may preferentially act later in the folding process to catalyze disulfide rearrangement in folded or partially folded proteins.