bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for the widespread presence of liquid‐phase particles during the 1999–2000 Arctic winter
Authors: Drdla K. , Gandrud B. W. , Baumgardner D. , Wilson J. C. , Bui T. P. , Hurst D. , Schauffler S. M. , Jost H. , Greenblatt J. B. , Webster C. R.
Published: December 2002

In situ Multiangle Spectrometer Probe (MASP) particle measurements have been analyzed to determine the typical behavior of sulfate particles during the SAGE III Ozone Loss and Validation Experiment (SOLVE) campaign. The study has explored variations in the total particle concentration measured by MASP. A new analysis method has been developed in which increases of the MASP concentration can be interpreted as growth of small particles (those which are smaller than 0.2 μm in radius at midlatitudes). The method also allows all of the MASP measurements made during the SOLVE campaign to be incorporated in a single analysis. At all levels of the stratosphere, the total MASP concentration (and therefore aerosol growth) varies continuously with temperature. This behavior is well‐reproduced by assuming that the sulfate aerosols are liquid solutions, but cannot be reproduced if the aerosol is assumed to be frozen. At sufficiently cold temperatures, larger increases in the MASP concentration are consistently seen; the observed onset temperature for this growth is in good agreement with model expectations for liquid ternary solutions. Liquid‐like behavior is apparent for all measurements made in the Arctic during SOLVE, both inside and outside the vortex, and even at the coldest temperatures sampled during the campaign. At the levels with the coldest measured temperatures, which cause maximum particle sizes and thus the greatest total MASP concentrations, 90% of the particles grow as liquids. Therefore, the freezing that occurred during the 1999–2000 Arctic winter was selective, with most of the particles remaining liquid even in the presence of a small number of frozen particles.
An evaluation of the thermodynamic equilibrium assumption for fine particulate composition: Nitrate and ammonium during the 1999 Atlanta Supersite Experiment
Authors: Zhang J. , Chameides W. L. , Weber R. , Cass G. , Orsini D. , Edgerton E. , Jongejan P. , Slanina J.
Published: December 2002

Data obtained during the 1999 Atlanta Supersite Experiment are used to test the validity of the assumption of thermodynamic equilibrium between fine particulate (PM2.5) nitrate (NO3−) and ammonium (NH4+) and gas‐phase nitric acid (HNO3(g)) and ammonia (NH3(g)). Equilibrium is tested by first calculating the equilibrium concentrations of HNO3(g) and NH3(g) implied by the PM2.5 inorganic composition (i.e, Na+, NH4+, Cl−, NO3−, and SO42−), temperature, and relative humidity observed at the site. These calculated equilibrium concentrations are then compared to the corresponding observed gas‐phase concentrations. The observed PM2.5 composition is based on the 5‐min averaged measurements of the Georgia Tech PILS [Weber et al., 2001], while the observed HNO3(g) and NH3(g) concentrations are based on the measurements of Edgerton et al. [2000a] and Slanina et al. [2001], respectively. The equilibrium gas‐phase concentrations are calculated using the ISORROPIA model of Nenes et al. [1998]. Out of the entire Atlanta Supersite database, we were able to identify 272 five‐minute intervals with overlapping measurements of PM2.5 composition, HNO3(g) and NH3(g). Initial calculations using these 272 data points suggest an absence of thermodynamic equilibrium with the calculated equilibrium NH3(g) generally less than its observed concentration and predicted HNO3(g) generally greater than the observed concentration. However, relatively small downward adjustments in the measured PM2.5 SO42− (or apparent acidity) bring the calculated and measured NH3(g) and HNO3(g) into agreement. Moreover, with the exception of 31 of the 272 data points with either anomalously low observed concentrations of SO42− or NH3(g), there is a close correspondence between the SO42− (or acidity) correction needed for HNO3 and that needed for NH3 (slope of 1.04, intercept of ∼0, and r2 = 0.96). The average relative corrections required for equilibrium with HNO3 and NH3 are −14.1% and −13.7%, respectively; significantly larger than the estimated uncertainty arising from random errors in the measurement. One interpretation of our results is that thermodynamic equilibrium does in fact apply to the inorganic PM2.5 composition during the Atlanta Supersite Experiment and either (1) the PM2.5 SO42− concentration measured by the PILS was systematically overestimated by ∼15% or (2) the PM2.5 PILS systematically underestimated the concentration of the alkaline components by ∼15%; and/or 3. The ISORROPIA model systematically underestimated the pH of the PM2.5 encountered during the experiment.
Linking genetic algorithms with stochastic dynamic programming to the long‐term operation of a multireservoir system
Authors: Huang Wen‐Cheng , Yuan Lun‐Chin , Lee Chi‐Ming
Published: December 2002

The objective of this paper is to present a genetic algorithm‐based stochastic dynamic programming (GA‐based SDP) to cope with the dimensionality problem of a multiple‐reservoir system. The joint long‐term operation of a parallel reservoir system in the Feitsui and Shihmen reservoirs in northern Taiwan demonstrates the successful application of the proposed GA‐based SDP model. Within the case study system it is believed that GA is a useful technique in supporting optimization. Though the employment of GA‐based SDP may be time consuming as it proceeds through generation by generation, the model can overcome the “dimensionality curse” in searching solutions. Simulation results show Feitsui's surplus water can be utilized efficiently to fill Shihmen's deficit water without affecting Feitsui's main purpose as Taipei city's water supply. The optimal joint operation suggests that Feitsui, on average, can provide 650,000 m3/day and 920,000 m3/day to Shihmen during the wet season and dry season, respectively.
Predicting head cut erosion and migration in concentrated flows typical of upland areas
Authors: Alonso Carlos V. , Bennett Sean J. , Stein Otto R.
Published: December 2002

Soil erosion due to head cut development and migration can devastate agricultural lands, yet current prediction technology does not address this important erosion process. Here an analytical model of this erosional phenomenon is presented. Realistic, physically based approximations to the laws governing mass, momentum, and energy transfer in the neighborhood of the scour hole result in closed‐form predictive algorithms for the magnitude of the plunge pool erosion and the rate of head cut migration. The model introduces a special treatment of nonventilated overfall conditions, is limited to homogeneous, unbounded soil layers, and is validated by available experimental measurements.
Sr‐Nd‐Pb‐Hf Isotope Results from ODP Leg 187: Evidence for Mantle Dynamics of the Australian‐Antarctic Discordance and Origin of the Indian MORB Source
Authors: Kempton Pamela D. , Pearce Julian A. , Barry Tiffany L. , Fitton J. Godfrey , Langmuir Charles , Christie David M.
Published: December 2002

New high precision PIMMS Hf and Pb isotope data for 14–28 Ma basalts recovered during ODP Leg 187 are compared with zero‐age dredge samples from the Australian‐Antarctic Discordance (AAD). These new data show that combined Nd‐Hf isotope systematics can be used as an effective discriminant between Indian and Pacific MORB source mantle domains. In particular, Indian mantle is displaced to lower εNd and higher εHf ratios compared to Pacific mantle. As with Pb isotope plots, there is almost no overlap between the two mantle types in Nd‐Hf isotope space. On the basis of our new Nd‐Hf isotope data, we demonstrate that Pacific MORB‐source mantle was present near the eastern margin of the AAD from as early as 28 Ma, its boundary with Indian MORB‐source mantle coinciding with the eastern edge of a basin‐wide arcuate depth anomaly that is centered on the AAD. This observation rules out models requiring rapid migration of Pacific MORB mantle into the Indian Ocean basin since separation of Australia from Antarctica. Although temporal variations in isotopic composition can be discerned relative to the fracture zone boundary of the modern AAD at 127°E, the distribution of different compositional groups appears to have remained much the same relative to the position of the residual depth anomaly for the past 30 m.y. Thus significant lateral flow of mantle along the ridge axis toward the interface appears unlikely. Instead, the dynamics that maintain both the residual depth anomaly and the isotopic boundary between Indian and Pacific mantle are due to eastward migration of the Australian and Antarctic plates over a stagnated, but slowly upwelling, slab oriented roughly orthogonal to the ridge axis. Temporal and spatial variations in the compositions of Indian MORB basalts within the AAD can be explained by progressive displacement of shallower Indian MORB‐source mantle by deeper mantle having a higher εHf composition ascending ahead of the upwelling slab. Models for the origin of the distinctive composition of the Indian MORB‐source based on recycling of a heterogeneous enriched component that consist of ancient altered ocean crust plus<10% pelagic sediment are inconsistent with Nd‐Hf isotope systematics. Instead, the data can be explained by a model in which Indian mantle includes a significant proportion of material that was processed in the mantle wedge above a subduction zone and was subsequently mixed back into unprocessed upper mantle.
Multidecadal ocean variability and NW European ice sheet surges during the last deglaciation
Authors: Knutz Paul C. , Hall Ian R. , Zahn Rainer , Rasmussen Tine L. , Kuijpers Antoon , Moros Matthias , Shackleton Nicholas J.
Published: December 2002

A multiproxy paleoceanographic record from the Atlantic margin off the British Isles reveals in unprecedented detail discharges of icebergs and meltwater in response to sea surface temperature increases across the last deglaciation. We observe the earliest signal of deglaciation as a moderate elevation of sea surface temperatures that commenced with a weakly developed thermocline and the presence of highly ventilated intermediate waters in the Rockall Trough. This warming pulse triggered a series of multidecadal ice‐rafted debris peaks that culminated with a major meltwater discharge at 17,500 years before present related to ice sheet disintegration across the NW European region. The impact of meltwater caused a progressive reduction in deep water ventilation and a sea surface cooling phase that preceded the collapse of the Laurentide Ice Sheet during Heinrich event 1 by 500–1000 years. A similar sequence of rapid ocean‐ice sheet interaction across the European continental margin is identified during the Bølling‐Allerød to Younger Dryas transition. The strategic location of our sediment core suggests a sensitive and rapid response of ice sheets in NW Europe to transient increases in thermohaline heat transport.
Barium in the Yamuna River System in the Himalaya: Sources, fluxes, and its behavior during weathering and transport
Authors: Dalai Tarun K. , Krishnaswami S. , Sarin M. M.
Published: December 2002

Systematic measurements of Ba in waters and bed sediments of the Yamuna and many of its tributaries in the Himalaya (Yamuna River System) have been carried out. Dissolved Ba in the Yamuna River System (YRS) ranges from 17 to 871 nM. Streams near the source region draining predominantly granites/gneisses have lower abundance of Ba, <100 nM compared with those in the lower reaches. These data, coupled with those available for major ion composition of these rivers and their sediments, have been used to determine the contributions of silicates and carbonates, the two major lithologies in the drainage basin, to dissolved Ba in YRS. In YRS, dissolved Ba shows significant covariations with Na*, Si, Ca, and Mg. Using Na* as an index, it is estimated that silicates are an important source of Ba to many of the rivers; in a few streams in the lower reaches, however, they account for only <20% of measured Ba. Carbonate weathering, which dominates the major ion composition of YRS rivers, contributes on average ∼30% of dissolved Ba. Together, silicates and carbonates roughly balance measured Ba in many of the rivers, whereas in a few streams, Ba contributions from additional sources are needed to balance the budget. Prospective sources include organic matter/phosphorites. Plot of 1/Ba versus 87Sr/86Sr shows a two‐component mixing trend, one with low Ba‐high 87Sr/86Sr (silicates) and the other with high Ba‐low 87Sr/86Sr (carbonates, phosphorites). Ba also shows significant positive correlation with dissolved Re and SO4. A likely explanation for the Ba‐Re‐SO4 association is that they are supplied from organic matter/phosphorites/carbonates assemblages through H2SO4 weathering. In YRS bed sediments, Ba shows significant correlation with K and Al. Ba/Na and Ba/Sr in these sediments are higher than those in granites of the Higher Himalaya. These observations can be explained in terms of (1) differential release of these elements during weathering, Ba being less mobile because of its association with weathering resistant minerals or (2) “nonconservative” behavior of Ba in rivers resulting in its removal from dissolved to particulate phases. Either way, these results indicate that Ba is less mobile relative to Na and Sr. Dissolved Ba flux from the YRS basin is ∼5 times more than that from the Ganga headwaters, a result consistent with higher physical and chemical erosion in the YRS basin. The Yamuna and the Ganga together transport ∼5.4 × 106 mol yr−1 of Ba out of the Himalaya, which is ∼10% of the dissolved Ba flux from the Ganga at Bangladesh, roughly the same as their contribution to water discharge. The rate of Ba mobilization in the Yamuna and the Ganga basins in the Himalaya is a factor of ∼2 higher than the global average.
A five‐year variability in the modulation of the galactic cosmic radiation over epochs of low solar activity
Authors: McCracken K. G. , Beer J. , McDonald F. B.
Published: December 2002

Using cosmogenic 10Be data to study the period 1423–1980 AD, we identify a previously unrecognized 5 year modulation process that occurs during epochs of low solar activity. In this, the galactic cosmic radiation exhibits a maximum intensity near sunspot maximum, as well as the well‐known intensity maxima coincident with sunspot minimum. This demonstrates that the 5 year periodicity previously reported in the power spectra of 10Be and 14C data is not due to atmospheric processes, and allows their physical significance to be studied.
Evidence for Europa‐like tectonic resurfacing styles on Ganymede
Authors: Head James , Pappalardo Robert , Collins Geoffrey , Belton Michael J. S. , Giese Bernd , Wagner Roland , Breneman Herbert , Spaun Nicole , Nixon Brian , Neukum Gerhard , Moore Jeffrey
Published: December 2002

Very high‐resolution imaging and stereo topographic data obtained during the Galileo G28 encounter with Ganymede show 1) evidence for Europa‐like, crustal spreading and resurfacing to form portions of the bright terrain, and 2) bright terrain that appears smooth at Voyager resolution (and thus a strong candidate for cryovolcanism) but instead is tectonically deformed and lacks embayment relationships when viewed at high resolution. In contrast to previous views, these new data show that tectonism has been the dominant process in shaping some very smooth areas and that Ganymede appears to have experienced Europa‐like crustal spreading during its previous history.
Interaction of HOBr and HCl on ice surfaces in the temperature range 205–227 K
Authors: Mössinger Juliane C. , Hynes Robert G. , Cox R. Anthony
Published: December 2002

The uptake of HOBr on ice surfaces as well as the interaction of HOBr with HCl‐doped ice surfaces has been studied in a wall‐coated tubular flow reactor coupled to a quadrupole mass spectrometer. The uptake coefficient for HOBr on ice (γHOBr) was measured between 205 and 227 K and was independent of HOBr concentration over the range (2–22) × 1011 mol cm−3. A negative temperature dependence of γ was observed with γ = 0.003 ± 0.001 at 227 K increasing to γ = 0.040 ± 0.007 at 205 K. The reaction of HOBr + HCl on ice was studied over a temperature range of 205–227 K using an HCl concentration of (4.0–8.0) × 1011 mol cm−3 and an HOBr concentration of (2–22) × 1011 mol cm−3. On exposing HOBr to the HCl‐doped ice surface, BrCl was observed as a reaction product. Under conditions with the HCl concentration in excess of the HOBr concentration, the rate of the surface reaction was found to be diffusion controlled at all temperatures, with an approximate lower limit of the uptake coefficient for HOBr + HCl on ice of γ ≥ 0.1. Under conditions with the HOBr concentration in excess of the HCl concentration, a change in uptake behavior of HOBr on HCl‐doped ice was noted. Experimental evidence suggests that the reaction follows an Eley–Rideal‐type mechanism. The atmospheric implications of these results on the chemistry of the upper troposphere are discussed.
Annular variations in moisture transport mechanisms and the abundance of δ18O in Antarctic snow
Authors: Noone David , Simmonds Ian
Published: December 2002

Water isotopes are commonly used as indicators of climate state even though many biases and variations in processes affecting the polar signal have not been quantified. Results from the Melbourne University General Circulation Model suggest the annual cycle explains half of the monthly δ18O variance, and a semiannual variation contributes more than 15 in places. Eddy moisture convergence drives gross accumulation, while stationary flux allows sublimation of 25–30% of the precipitation. Part of the monthly anomaly variance is associated with a dominant annular disturbance in the circulation. This oscillatory mode alters the character of the transport processes through changes to the preferred location and strength of baroclinic cyclones. A Rayleigh model indicates that a third of the continental δ18O anomaly can be explained by temperature‐dependent fractionation, while changes to the condensation give 3 times too much depletion. The residual is explained by the migration of the zone from which midlatitude air is entrained into the polar environment by cyclonic storms. The positive phase of the annular mode is associated with an increased contribution from the near‐coastal region, which enriches the continental precipitation. Such vacillation introduces bias in reconstruction using modern analogues because the spatial temperature‐isotope slope is modified.
Seasonal and solar cycle variability of OH in the middle atmosphere
Authors: Canty T. , Minschwaner K.
Published: December 2002

The photochemistry of the hydroxyl radical (OH) in the middle atmosphere involves the action of solar ultraviolet radiation in many respects. The production of stratospheric OH is initiated through the photodissociation of ozone, and in the mesosphere, OH is produced directly from the photolysis of water vapor. We present an analysis of measurements of the vertical column abundance of OH from Fritz Peak Observatory, Colorado, for seasonal and solar cycle variability. The OH column data span over two 11‐year solar cycles and include a wide range of diurnal and seasonal conditions. Hydroxyl abundances show distinct annual and semiannual cycles, with amplitudes of 4.4% and 2.5%, respectively. About half of the seasonal variation in OH can be explained by the annual cycle of ultraviolet intensity, and by annual and semiannual cycles in ozone and water vapor in the middle atmosphere. On longer time scales, a positive correlation with the NOAA MgII solar index is observed. The amplitude of 11‐year solar cycle variations in OH is 4.2 ± 2.4%, which is consistent with photochemical model calculations that consider changes in ozone and water vapor photodissociation rates. Changes in the vertical distribution of ozone over the solar cycle are found to have a smaller effect on the OH column.
Seasonal and interannual variability of the mineral dust cycle under present and glacial climate conditions
Authors: Werner M. , Tegen I. , Harrison S. P. , Kohfeld K. E. , Prentice I. C. , Balkanski Y. , Rodhe H. , Roelandt C.
Published: December 2002

We present simulations of the dust cycle during present and glacial climate states, using a model, which explicitly simulates the control of dust emissions as a function of seasonal and interannual changes in vegetation cover. The model produces lower absolute amounts of dust emissions and deposition than previous simulations of the Last Glacial Maximum (LGM) dust cycle. However, the simulated 2‐ to 3‐fold increase in emissions and deposition at the LGM compared to today, is in agreement with marine‐ and ice‐core observations, and consistent with previous simulations. The mean changes are accompanied by a prolongation of the length of the season of dust emissions in most source regions. The increase is most pronounced in Asia, where LGM dust emissions are high throughout the winter, spring and summer rather than occurring primarily in spring as they do today. Changes in the seasonality of dust emissions, and hence atmospheric loading, interact with changes in the seasonality of precipitation, and hence of the relative importance of wet and dry deposition processes at high northern latitudes. As a result, simulated dust deposition rates in the high northern latitudes show high interannual variability. Our results suggest that the high dust concentration variability shown by the Greenland ice core records during the LGM is a consequence of changes in atmospheric circulation and precipitation locally rather than a result of changes in the variability of dust emissions.
Development of mice expressing a single D-type cyclin
Authors: Ciemerych Maria A. , Kenney Anna M. , Sicinska Ewa , Kalaszczynska Ilona , Bronson Roderick T. , Rowitch David H. , Gardner Humphrey , Sicinski Piotr
Published: December 2002

D-cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery. To directly test the ability of each D-cyclin to drive development of various lineages, we generated mice expressing only cyclin D1, or only cyclin D2, or only cyclin D3. We found that these “single-cyclin” embryos develop normally until late gestation. Our analyses revealed that in single-cyclin embryos, the tissue-specific expression pattern of D-cyclins was lost. Instead, mutant embryos ubiquitously expressed the remaining D-cyclin. These findings suggest that the functions of the three D-cyclins are largely exchangeable at this stage. Later in life, single-cyclin mice displayed focused abnormalities, resulting in premature mortality. “Cyclin D1-only” mice developed severe megaloblastic anemia, “cyclin D2-only” mice presented neurological abnormalities, and “cyclin D3-only” mice lacked normal cerebella. Analyses of the affected tissues revealed that these compartments failed to sufficiently up-regulate the remaining, intact D-cyclin. In particular, we found that in cerebellar granule neuron precursors, the N-myc transcription factor communicates with the cell cycle machinery via cyclins D1 and D2, but not D3, explaining the inability of D3-only mice to up-regulate cyclin D3 in this compartment. Hence, the requirement for a particular cyclin in a given tissue is likely caused by specific transcription factors, rather than by unique properties of cyclins.
Nob1p is required for biogenesis of the 26S proteasome and degraded upon its maturation in Saccharomyces cerevisiae
Authors: Tone Yoshiko , Toh-e Akio
Published: December 2002

Nob1p is a nuclear protein that forms a complex with the 19S regulatory particle of the 26S proteasome and with uncharacterized nuclear protein Pno1p. Overexpression of NOB1 overrode the defects in maturation of the 20S proteasome of ump1Δ cells, and temperature-sensitive nob1 and pno1 mutants exhibited defects in the processing of the β subunits and in the assembly of the 20S and the 26S proteasomes. A defect in eitherNOB1 or PNO1 caused accumulation of newly formed Pre6p in the cytoplasm, whereas Pre6p of the ump1Δ strain accumulated in the nucleus irrespective of the temperature. Here we present a model proposing that (1) Nob1p serves as a chaperone to join the 20S proteasome with the 19S regulatory particle in the nucleus and facilitates the maturation of the 20S proteasome and degradation of Ump1p, and (2) Nob1p is then internalized into the 26S proteasome and degraded to complete 26S proteasome biogenesis.
Biological functions of the ISWI chromatin remodeling complex NURF
Authors: Badenhorst Paul , Voas Matthew , Rebay Ilaria , Wu Carl
Published: December 2002

The nucleosome remodeling factor (NURF) is one of several ISWI-containing protein complexes that catalyze ATP-dependent nucleosome sliding and facilitate transcription of chromatin in vitro. To establish the physiological requirements of NURF, and to distinguish NURF genetically from other ISWI-containing complexes, we isolated mutations in the gene encoding the large NURF subunit, nurf301. We confirm that NURF is required for transcription activation in vivo. In animals lacking NURF301, heat-shock transcription factor binding to and transcription of the hsp70 and hsp26 genes are impaired. Additionally, we show that NURF is required for homeotic gene expression. Consistent with this, nurf301 mutants recapitulate the phenotypes of Enhancer of bithorax, a positive regulator of the Bithorax-Complex previously localized to the same genetic interval. Finally, mutants in NURF subunits exhibit neoplastic transformation of larval blood cells that causes melanotic tumors to form.
FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1−/− mice
Authors: Kratochwil Klaus , Galceran Juan , Tontsch Sabine , Roth Wera , Grosschedl Rudolf
Published: December 2002

Lymphoid enhancer factor (LEF1), a nuclear mediator of Wnt signaling, is required for the formation of organs that depend on inductive interactions between epithelial and mesenchymal tissues. In previous tissue recombination experiments with normal andLef1−/− tooth germs, we found that the effect of LEF1 expression in the epithelium is tissue nonautonomous and transferred to the subjacent mesenchyme. Here we examine the molecular basis for LEF1 function and find that the epithelium of the developmentally arrested Lef1−/− tooth rudiments fails to express Fgf4, Shh, andBmp4, but not Wnt10a. We identify theFgf4 gene as a direct transcriptional target for LEF1 and show that beads soaked with recombinant FGF4 protein can fully overcome the developmental arrest of Lef1−/− tooth germs. In addition, we find that FGF4 beads induce rapidly the expression of Fgf3 in dental mesenchyme and that both epithelial and mesenchymal FGF proteins induce the delayed expression of Shh in the epithelium. Taken together, these data indicate that a single target of LEF1 can account for the function of LEF1 in tooth development and for a relay of a Wnt signal reception to a cascade of FGF signaling activities, allowing for a sequential and reciprocal communication between epithelium and mesenchyme.
Assembly of the SMRT–histone deacetylase 3 repression complex requires the TCP-1 ring complex
Authors: Guenther Matthew G. , Yu Jiujiu , Kao Gary D. , Yen Tim J. , Lazar Mitchell A.
Published: December 2002

The acetylation of histone tails is a primary determinant of gene activity. Histone deacetylase 3 (HDAC3) requires the nuclear receptor corepressor SMRT for HDAC enzyme activity. Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process. SMRT displaces TRiC from HDAC3, yielding an active HDAC enzyme. The SMRT–HDAC3 repression complex thus joins the VHL–elongin BC tumor suppression complex and the cyclin E–Cdk2 cell cycle regulation complex as critical cellular machines requiring TRiC for proper assembly and function. The strict control of HDAC3 activity underscores the cellular imperative that histone deacetylation occur only in targeted regions of the genome.
Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor
Authors: Lee Changwook , Chang Jeong Ho , Lee Hyun Sook , Cho Yunje
Published: December 2002

Repression of E2F transcription activity by the retinoblastoma (Rb) tumor suppressor through its interaction with the transactivation domain of the E2F transcription factor is one of the central features of G1/S arrest in the mammalian cell cycle. Deregulation of the Rb–E2F interaction results in hyperproliferation, lack of differentiation, and apoptosis, and can lead to cancer. The 2.2-Å crystal structure of the Rb pocket complexed with an 18-residue transactivation-domain peptide of E2F-2 reveals that the boomerang-shaped peptide binds to the highly conserved interface between the A-box and the B-box of the Rb pocket in a bipartite manner. The N-terminal segment of the E2F-2 peptide in an extended β-strand-like structure interacts with helices from the conserved groove at the A–B interface, whereas the C-terminal segment, which contains one 310 helix, binds to a groove mainly formed by A-box helices. The flexibility in the middle of the E2F-2 peptide is essential for the tight association of E2F to the Rb pocket. The binding of Rb to the E2F-2 peptide conceals several conserved residues that are crucial for transcription activation of E2F. We provide the structural basis for the Rb-mediated repression of E2F transcription activity without the requirement of histone-modifying enzymes.
The NC2 α and β subunits play different roles in vivo
Authors: Creton Sandrine , Svejstrup Jesper Q. , Collart Martine A.
Published: December 2002

NC2 is a heterodimeric regulator of transcription that plays both positive and negative roles in vivo. Here we show that the α and β subunits of yeast NC2 are not always associated in a tight complex. Rather, their association is regulated, in particular by glucose depletion. Indeed, stable NC2 α/β complexes can only be purified from cells after the diauxic shift when glucose has been depleted from the growth medium. In vivo, the presence of NC2 α, but not NC2 β, at promoters generally correlates with the presence of TBP and transcriptional activity. In contrast, increased presence of NC2 β relative to TBP correlates with transcriptional repression. NC2 is regulated by phosphorylation. We found that mutation of genes encoding casein kinase II (CKII) subunits as well as potential CKII phosphorylation sites in NC2 α and β affected gene repression. Interestingly, NC2-dependent repression in the phosphorylation site mutants was only perturbed in high glucose when NC2 β and NC2 α are not associated, but not after the diauxic shift when NC2 α and β form stable complexes. Thus, the separation of NC2 α and β function indicated by these mutants also supports the existence of multiple NC2 complexes with different functions in transcription.
Receptor-mediated endoproteolytic activation of two transcription factors in yeast
Authors: Andréasson Claes , Ljungdahl Per O.
Published: December 2002

Yeast possess a plasma membrane sensor of external amino acids that functions as a ligand-activated receptor. This multimeric sensor, dubbed the SPS sensor, initiates signals that regulate the expression of genes required for proper amino acid uptake. Stp1p and Stp2p are transcription factors that bind to specific sequences within the promoters of SPS-sensor-regulated genes. These factors exhibit redundant and overlapping abilities to activate transcription. We have found that Stp1p and Stp2p are synthesized as latent cytoplasmic precursors. In response to extracellular amino acids, the SPS sensor induces the rapid endoproteolytic processing of Stp1p and Stp2p. The processing of Stp1p/Stp2p occurs independently of proteasome function and without the apparent involvement of additional components. The shorter forms of these transcription factors, lacking N-terminal inhibitory domains, are targeted to the nucleus, where they transactivate SPS-sensor target genes. These results define a completely unique and streamline metabolic control pathway that directly routes environmental signals initiated at the plasma membrane to transcriptional activation in the nucleus of yeast.
LIN-39/Hox triggers cell division and represses EFF-1/fusogen-dependent vulval cell fusion
Authors: Shemer Gidi , Podbilewicz Benjamin
Published: December 2002

General mechanisms by which Hox genes establish cell fates are known. However, a few Hox effectors mediating cell behaviors have been identified. Here we found the first effector of LIN-39/HoxD4/Dfd inCaenorhabditis elegans. In specific vulval precursor cells (VPCs), LIN-39 represses early and late expression of EFF-1, a membrane protein essential for cell fusion. Repression of eff-1 is also achieved by the activity of CEH-20/Exd/Pbx, a known cofactor of Hox proteins. Unfused VPCs in lin-39(−);eff-1(−) double mutants fail to divide but migrate, executing vulval fates. Thus,lin-39 is essential for inhibition of EFF-1-dependent cell fusion and stimulation of cell proliferation during vulva formation.

Supplemental material is available at http://www.genesdev.org.
Transcriptional Profile of theEscherichia coliResponse to the Antimicrobial Insect Peptide Cecropin A
Authors: Hong Robert W. , Shchepetov Mikhail , Weiser Jeffrey N. , Axelsen Paul H.
Published: December 2002

Cationic antimicrobial peptides are believed to exert their primary activities on anionic bacterial cell membranes; however, this model does not adequately account for several important structure-activity relationships. These relationships are likely to be influenced by the bacterial response to peptide challenge. In order to characterize the genomic aspect of this response, transcription profiles were examined forEscherichia coliisolates treated with sublethal and lethal concentrations of the cationic antimicrobial peptide cecropin A. Transcript levels for 26 genes changed significantly following treatment with sublethal peptide concentrations, and half of the transcripts corresponded to protein products with unknown function. The pattern of response is distinct from that following treatment with lethal concentrations and is also distinct from the bacterial response to nutritional, thermal, osmotic, or oxidative stress. These results demonstrate that cecropin A induces a genomic response inE. coliapart from any lethal effects on the membrane and suggest that a complete understanding of its mechanism of action may require a detailed examination of this response.
Antimicrobial Susceptibilities of
Campylobacter
Strains Isolated from Finnish Subjects Infected Domestically or from Those Infected Abroad
Authors: Rautelin Hilpi , Vierikko Antti , Hänninen Marja-Liisa , Vaara Martti
Published: December 2002

The in vitro susceptibilities of 678
Campylobacter jejuni
and
Campylobacter coli
strains isolated from stool samples of the same number of Finnish subjects were studied. A total of 523 patients, representing inhabitants from throughout Finland, had not traveled abroad within the 2 weeks prior to becoming ill, whereas 155 persons had presumably acquired their infections abroad. The antimicrobial agents studied were erythromycin, ciprofloxacin, levofloxacin, trovafloxacin, and moxifloxacin. The MICs of these antimicrobial agents were determined by the agar dilution method. The growth of all domestic isolates was inhibited by erythromycin at concentrations of 4 μg/ml, and for these isolates the fluoroquinolone MICs at which 90% of isolates are inhibited (MIC
90
s) ranged from 0.06 to 0.5 μg/ml. For the foreign isolates, the erythromycin MIC
90
was still low (4 μg/ml), but their susceptibilities to fluoroquinolones were clearly reduced (MIC
90
s, 8 to 64 μg/ml). Of the four different fluoroquinolones studied, ciprofloxacin was the least active (MIC
90
, 64 μg/ml).
Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of
Plasmodium falciparum
by Peptidyl Vinyl Sulfones
Authors: Shenai Bhaskar R. , Lee Belinda J. , Alvarez-Hernandez Alejandro , Chong Pek Y. , Emal Cory D. , Neitz R. Jeffrey , Roush William R. , Rosenthal Philip J.
Published: December 2002

The
Plasmodium falciparum
cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of
P. falciparum
in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited
P. falciparum
development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P
2
leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.
In Vitro Susceptibilities to and Bactericidal Activities of Garenoxacin (BMS-284756) and Other Antimicrobial Agents against Human Mycoplasmas and Ureaplasmas
Authors: Waites Ken B. , Crabb Donna M. , Bing Xue , Duffy Lynn B.
Published: December 2002

The in vitro susceptibilities to garenoxacin (BMS-284756), an investigational des-fluoroquinolone, and eight other agents were determined for 63
Mycoplasma pneumoniae
, 45
Mycoplasma hominis
, 15
Mycoplasma fermentans
, and 68
Ureaplasma
sp. isolates. Garenoxacin was the most active quinolone, inhibiting all isolates at ≤1 μg/ml. The garenoxacin MIC at which 90% of isolates are inhibited (MIC
90
s; ≤0.008 μg/ml) was at least 4-fold less than those of moxifloxacin and clindamycin, 8-fold less than that of sparfloxacin, and 64-fold less than those of levofloxacin and ciprofloxacin for
M. pneumoniae
. For
M. hominis
, the garenoxacin MIC
90
(≤0.008 μg/ml) was 4-fold less than those of clindamycin and moxifloxacin, 8-fold less than that of sparfloxacin, and 64-fold less than those of levofloxacin and ciprofloxacin. All 15
M. fermentans
isolates were inhibited by garenoxacin at concentrations ≤0.008 μg/ml, making it the most active drug tested against this organism. For
Ureaplasma
spp., the garenoxacin MIC
90
(0.25 μg/ml) was equivalent to those of moxifloxacin and doxycycline, 4-fold less than those of levofloxacin and sparfloxacin, 8-fold less than that of azithromycin, and 32-fold less than that of ciprofloxacin. Garenoxacin and the other fluoroquinolones tested were demonstrated to have bactericidal activities against
M. pneumoniae
and
M. hominis
by measurement of minimal bactericidal activities and by time-kill studies. Further study of garenoxacin is required, as it has great potential for use in the treatment of infections due to mycoplasmas and ureaplasmas.
The Proton Channel Is the Minimal Structure of ATP Synthase Necessary and Sufficient for Microcin H47 Antibiotic Action
Authors: Rodríguez Eliana , Laviña Magela
Published: December 2002

It had been previously determined that the presence of F
o
F
1
ATP synthase was required for microcin H47 antibiotic action. In this work, microcin-resistant
atp
mutants were genetically analyzed. Their mutations, originated by Tn
5
insertion, in all cases were found to affect determinants for the F
o
portion of ATP synthase. To discern if microcin action required the presence of the entire complex or if the F
o
proton channel would suffice, recombinant plasmids carrying different segments of the
atp
operon were constructed and introduced into an
atp
deletion strain. The phenotypic analysis of the strains thus obtained clearly indicated that the presence of the F
o
proton channel was absolutely required for microcin H47 action, while the F
1
catalytic portion was found to be dispensable. Furthermore, when any of the three components of the proton channel was missing, total resistance to the antibiotic ensued. Complementation analysis between
atp
::Tn
5
chromosomal mutations and recombinant
atp
plasmid constructions further supported the idea that the proton channel would be the minimal structure of the ATP synthase complex needed for microcin H47 antibiotic action.
Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients
Authors: Solas Caroline , Lafeuillade Alain , Halfon Philippe , Chadapaud Stéphane , Hittinger Gilles , Lacarelle Bruno
Published: December 2002

The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.
Synergistic Activity of the N-Terminal Peptide of Human Lactoferrin and Fluconazole against
Candida
Species
Authors: Lupetti Antonella , Paulusma-Annema Akke , Welling Mick M. , Dogterom-Ballering Heleen , Brouwer Carlo P. J. M. , Senesi Sonia , van Dissel Jaap T. , Nibbering Peter H.
Published: December 2002

In light of the need for new antifungal regimens, we report that at noncandidacidal concentrations, the lactoferrin-derived peptide hLF(1-11), which is highly active against fluconazole-resistant
Candida albicans
, acts synergistically with fluconazole against this yeast and a fluconazole-sensitive
C. albicans
strain as well as
C. glabrata
,
C. krusei
,
C. parapsilosis
, and
C. tropicalis
. When these yeasts were exposed to hLF(1-11) for 5 min and then incubated with fluconazole, they were killed effectively, while no candidacidal activity was observed when they were incubated first with fluconazole and then exposed to the peptide, indicating that the candidacidal activity is initiated by the peptide while fluconazole is only required during the effector phase. Investigations of the effect of azide, which inhibits mitochondrial respiration, on the activity of combinations of hLF(1-11) and fluconazole against fluconazole-resistant
C. albicans
revealed that it inhibits this activity, even when added during the effector phase only. As expected, azide inhibited the accumulation of rhodamine 123 in mitochondria and the production and release of ATP by
C. albicans
that occurred upon exposure to the combination of hLF(1-11) and fluconazole. Accordingly, oxidized ATP (oATP), an antagonist of ATP receptors, completely blocked the candidacidal activity of the hLF(1-11)-fluconazole combination, whereas oATP did not block the activity when its presence was restricted to the effector phase. The candidacidal activity of combinations of hLF(1-11) and fluconazole, which is initiated by the peptide through the involvement of energized mitochondria, renders fluconazole-resistant
C. albicans
sensitive to this azole.
Topoisomerase Targeting with and Resistance to Gemifloxacin in
Staphylococcus aureus
Authors: Ince Dilek , Zhang Xiamei , Silver L. Christine , Hooper David C.
Published: December 2002

Gemifloxacin, a novel quinolone with potent activity against
Staphylococcus aureus
, was 8- to 16-fold more active against wild-type
S. aureus
than ciprofloxacin. The two- to fourfold increase in the MIC of gemifloxacin in genetically defined
grlBA
mutants and the twofold increase in a single
gyrA
mutant, supported by the low frequency of selection of resistant mutants at twice the MIC (7.4 × 10
−11
to 1.1 × 10
−10
), suggested similar targeting of the two enzymes by gemifloxacin. Dual mutations in both gyrase and topoisomerase IV caused a 64- to 128-fold increase in the MIC of gemifloxacin, similar to that seen with ciprofloxacin. Gemifloxacin also had similar activity in vitro against topoisomerase IV and gyrase purified from
S. aureus
(50% inhibitory concentrations of 0.25 and 0.31 μg/ml, respectively). This activity was 10- to 20-fold higher than that of ciprofloxacin for topoisomerase IV and 33-fold higher than that for gyrase. In contrast to the in vitro findings, only topoisomerase IV mutants were selected in first-step mutants. Overexpression of the NorA efflux pump had a minimal effect on resistance to gemifloxacin, and a mutation in the promoter region of the gene for NorA was selected only in the sixth step of serial selection of mutants. Our data show that although gemifloxacin targets purified topoisomerase IV and gyrase similarly in vitro, topoisomerase IV is the preferred target in the bacteria. Selection of novel resistance mutations in
grlA
requires further expansion of quinolone-resistance-determining regions, and their study may provide increased insight into enzyme-quinolone interactions.
A Type II Pathway for Fatty Acid Biosynthesis Presents Drug Targets in
Plasmodium falciparum
Authors: Waller Ross F. , Ralph Stuart A. , Reed Michael B. , Su Vanessa , Douglas James D. , Minnikin David E. , Cowman Alan F. , Besra Gurdyal S. , McFadden Geoffrey I.
Published: December 2002

It has long been held that the malaria parasite,
Plasmodium
sp., is incapable of de novo fatty acid synthesis. This view has recently been overturned with the emergence of data for the presence of a fatty acid biosynthetic pathway in the relict plastid of
P. falciparum
(known as the apicoplast). This pathway represents the type II pathway common to plant chloroplasts and bacteria but distinct from the type I pathway of animals including humans. Specific inhibitors of the type II pathway, thiolactomycin and triclosan, have been reported to target this
Plasmodium
pathway. Here we report further inhibitors of the plastid-based pathway that inhibit
Plasmodium
parasites. These include several analogues of thiolactomycin, two with sixfold-greater efficacy than thiolactomycin. We also report that parasites respond very rapidly to such inhibitors and that the greatest sensitivity is seen in ring-stage parasites. This study substantiates the importance of fatty acid synthesis for blood-stage parasite survival and shows that this pathway provides scope for the development of novel antimalarial drugs.