bluuebunny/crossref_metadata_2025 huggingface dataset:
Is the Bounty Trough off eastern New Zealand an aborted rift?
Authors: Grobys J. W. G. , Gohl K. , Davy B. , Uenzelmann‐Neben G. , Deen T. , Barker D.
Published: March 2007

Remarkably little is known about the Cretaceous rifting process between New Zealand and Antarctica that affected the submarine regions within the New Zealand microcontinent. Bounty Trough provides insights into these breakup processes. Here we present results from a combined gravity, multichannel seismic, and wide‐angle reflection/refraction seismic transect across the Middle Bounty Trough and interpret these results on the basis of velocity distribution and crustal composition derived from Poisson's ratio and P‐wave velocity. The lower crust exhibits a high‐velocity (vp ≅ 7 – 7.7 km/s, vs ≅ 3.9 – 4.5 km/s), high‐density (ρ = 3.02 kg/cm3) body at the location of the thinnest crust on the profile. Here the crustal thickness is reduced to about 9 km from 22–24 km beneath Chatham Rise and Campbell Plateau. We interpret the high‐velocity/density body as a magmatic intrusion into thinned continental crust. Our results show that the Cretaceous opening of Bounty Trough was very likely not the result of back‐arc extension caused by collision of the Hikurangi Plateau with the Gondwana margin, but of continental breakup processes related to the separation of New Zealand from Antarctica. Rifting ceased in the Middle Bounty Trough at the onset of seafloor spreading. Comparisons with the Oslo Rift and the Ethiopian/Kenya Rift indicate that all three rift systems show analogous extensional features. From this we derive a stretching model for the Bounty Trough that combines elements of pure shear and simple shear extension.
Measurements of vertical eddy diffusivity across the tropopause using radio acoustic sounding system (RASS)
Authors: Alexander S. P. , Tsuda T.
Published: March 2007

A four day high temporal resolution MU radar RASS data set was obtained under light wind conditions in August 1995, enabling retrieval of virtual temperatures up to 20 km. This provided a unique opportunity to study the vertical eddy diffusivity K across the tropopause using RASS Brunt‐Väisälä frequency N and radar spectral width. Co‐located six hourly radiosondes enabled calculation of K using radiosonde N and radar spectral width. RASS K decreased across the WMO tropopause, from (0.39 ± 0.05) m2s−1 in the uppermost kilometre of the troposphere to (0.27 ± 0.03) m2s−1 in the lowermost kilometre of the stratosphere. The equivalent radiosonde K were (0.43 ± 0.06) m2s−1 and (0.31 ± 0.07) m2s−1 respectively. The WMO tropopause seems to provide a better definition than the cold‐point tropopause in separating the stratosphere from the troposphere when considering the mixing of minor constituents.
Ultraviolet Io footprint short timescale dynamics
Authors: Bonfond B. , Gérard J.‐C. , Grodent D. , Saur J.
Published: March 2007

The electromagnetic interaction between Io and Jupiter's magnetic field leads to single or multiple ultraviolet spots near the feet of the Io flux tube. Variations of spot numbers and brightness and of inter‐spot distances have been observed to be linked to Io's position in its plasma torus. We have studied the evolution of the Io UV footprints with a time resolution of a few tens of seconds using the Space Telescope Imaging Spectrograph (STIS) in time‐tag mode. We present evidence of systematic strong brightness variations of the main spots (up to 50%) with a typical growth time of 1 minute. Additionally, unanticipated simultaneous fluctuations of both primary and secondary spots have also been found in the southern hemisphere. Our findings suggest that the footprint brightness is not only actively controlled by the plasma directly interacting with Io but also by the poorly constrained electron acceleration region between Io and Jupiter.
In situ monitoring of free‐phase gas accumulation and release in peatlands using ground penetrating radar (GPR)
Authors: Comas Xavier , Slater Lee , Reeve Andrew
Published: March 2007

We tested a set of surface common mid‐point (CMP) ground penetrating radar (GPR) surveys combined with elevation rods (to monitor surface deformation) and gas flux measurements to investigate in‐situ biogenic gas dynamics and ebullition events in a northern peatland (raised bog). The main findings are: (1) changes in the two‐way travel time from the surface to prominent reflectors allow estimation of average gas contents and evolution of free‐phase gas (FPG); (2) peat surface deformation and gas flux measurements are strongly consistent with GPR estimated changes in FPG content over time; (3) rapid decreases in atmospheric pressure are associated with increased gas flux; and (4) single ebullition events can induce releases of methane much larger (up to 192 g/m2) than fluxes reported by others. These results indicate that GPR is a useful tool for assessing the spatial distribution, temporal variation, and volume of biogenic gas deposits in peatlands.
Regional expression of the 1988 U.S. Midwest drought in seasonal δ13C of tree rings
Authors: Leavitt Steven W.
Published: March 2007

This study analyzes δ13C of subdivisions of the 1988 and 1989 growth rings from three conifer species (Pinus resinosa, Pinus strobus, and Picea glauca) across a network of nine sites over four states in the upper U.S. Midwest to infer seasonal and interannual environmental moisture conditions. Both years were characterized by different spatial patterns of drought (expressed through rainfall and Palmer Drought Indices), with the area of 1989 drought being smaller and shifting westward relative to 1988. Rings were subdivided into four equal segments from which holocellulose was separated. The range of δ13C variation within each ring was typically 1–2‰ for both years, and the single site where all three species co‐occurred revealed coherent seasonal δ13C patterns for the pines but no correlation of the spruce δ13C patterns with those of the pines. Various averaged combinations of monthly Palmer Drought Severity Index (PDSI) and precipitation assigned to each subdivision versus both δ13C and discrimination (Δ ≈ δ13Cair − δ13Cplant) yielded significant correlations (generally higher with PDSI) and even stronger correlations when the spruce data were removed. The fraction of average monthly cumulative precipitation (relative to 1900–2001 means) for these 2 years was more strongly related to δ13C than either monthly precipitation or monthly fraction of average precipitation, but was not as strongly related to δ13C as was PDSI. Furthermore, the pattern of increasing δ13C in 1988 observed at several sites is an indicator of the increasing moisture stress of that year, and the difference between the 1988 and 1989 average isotopic compositions of the third and fourth subdivisions matched the regional moisture shift well.
Mineral dust emission from the Bodélé Depression, northern Chad, during BoDEx 2005
Authors: Todd Martin C. , Washington Richard , Martins José Vanderlei , Dubovik Oleg , Lizcano Gil , M'Bainayel Samuel , Engelstaedter Sebastian
Published: March 2007

Mineral dust in the atmosphere is an important component of the climate system but is poorly quantified. The Bodélé Depression of northern Chad stands out as the world's greatest source region of mineral dust into the atmosphere. Frequent dust plumes are a distinguishing feature of the region's climate. There is a need for more detailed information on processes of dust emission/transport and dust optical properties to inform model simulations of this source. During the Bodélé Dust Experiment (BoDEx) in 2005, instrumentation was deployed to measure dust properties and boundary layer meteorology. Observations indicate that dust emission events are triggered when near‐surface wind speeds exceed 10 ms−1, associated with synoptic‐scale variability in the large‐scale atmospheric circulation. Dust emission pulses in phase with the diurnal cycle of near‐surface winds. Analysis of dust samples shows that the dust consists predominantly of fragments of diatomite sediment. The particle size distribution of this diatomite dust estimated from sun photometer data, using a modified Aeronet retrieval algorithm, indicates a dominant coarse mode (radius centered on 1–2 μm) similar to other Saharan dust observations. Single‐scattering albedo values are high, broadly in line with other Saharan dust even though the diatomite composition of dust from the Bodélé is likely to be unusual. The radiative impact of high dust loadings results in a reduction in surface daytime maximum temperature of around 7°C in the Bodélé region. Using optical and physical properties of dust obtained in the field, we estimate the total dust flux emitted from the Bodélé to be 1.18 ± 0.45 Tg per day during a substantial dust event. We speculate that the Bodélé Depression (∼10,800 km2) may be responsible for between 6–18% of global dust emissions, although the uncertainty in both the Bodélé and global estimates remains high.
A simple diagnostic calculation of marine stratocumulus cloud cover for use in general circulation models
Authors: Mochizuki Takashi , Miyama Toru , Awaji Toshiyuki
Published: March 2007

An improved diagnostic calculation for determining the marine stratocumulus (SCu) cloud cover has been implemented for atmospheric and coupled general circulation models (GCMs). The approach aims to improve the simulated climatological features of the lower troposphere and to reduce warm sea surface temperature (SST) biases that develop along western continental coasts in the subtropical regions of coupled GCMs. In the new diagnostic calculation introduced in the present study, the SCu cloud cover was linearly regressed to atmospheric stability, and the temporal and spatial distributions of the regression coefficients were estimated beforehand using observational data sets. The upward transport of heat, moisture and momentum in subcloud layers accompanying the SCu was also simulated by controlling the vertical diffusion coefficients. Using the new calculation, the SCu cloud cover in an atmospheric GCM become more representative in both spatial and seasonal variations. In addition, the simulation of related atmospheric structures in the lower troposphere is considerably improved. Furthermore, when the new calculation is applied to a coupled GCM, SST values to the west of continents in subtropical areas display weakened warm biases and more realistic seasonal cycles resulting from the modification of the downward shortwave radiation flux at the sea surface. The new calculation introduces both local and large‐scale improvements in model climatology over low‐latitude and midlatitude regions. In the eastern Pacific, for example, a shallow meridional circulation across the equator is excited, and the strength and location of the intertropical convergence zone and the seasonal cycle of equatorial SST become more realistic.
Northwest Pacific typhoons documented by the Philippine Jesuits, 1566–1900
Authors: García‐Herrera Ricardo , Ribera Pedro , Hernández Emiliano , Gimeno Luis
Published: March 2007

In recent years, the population and the value of properties in areas prone to tropical cyclone (TC) have increased dramatically. This has caused more attention to be placed on the characterization of TC climatologies and the identification of the role that factors such as the main teleconnection patterns may play in TC variability. Due to the timescales involved, the instrumental records have proven too short to provide a complete picture. Thus, documentary and other paleoclimatological techniques have been used to reconstruct TC occurrence. This has been done mostly for the Atlantic basin, whereas in the Pacific basin, fewer attempts have been made. The aim of this paper is to provide a high‐resolution chronology of typhoons and intense storms occurring in the Philippine Islands and their vicinity for the period 1566–1900. The chronology is based upon the writings of the Spanish Jesuit Miguel Selga, who produced the original work at the beginning of the 20th century. The sources, reliability, and completeness of the chronology are examined critically. A total of 652 events are included, 524 of which are reported as typhoons, the rest being considered as tropical storms. For each of these classes, the landfall location and the track (when sufficient information is available) have been drawn. This chronology is an indispensable step toward a final and complete typhoon record in the western Pacific basin.
Turbulent flux calculation in the polar stable boundary layer: Multiresolution flux decomposition and wavelet analysis
Authors: van den Kroonenberg Aline , Bange Jens
Published: March 2007

Airborne measurements in the Arctic stable boundary layer were performed using the helicopter‐borne turbulence measurement system Helipod. The observations were carried out during the ARK‐XII summer expedition of the research icebreaker Polarstern in the Arctic ocean. The boundary layer over closed sea ice exhibited mainly weakly stable stratification. Only flights in continuous turbulence were chosen for the analysis. The measurements of sensible heat flux H and latent heat flux λE were made 200 km away from land to reduce the influence of any captured mesoscale flux. Nevertheless, the analysis of multiresolution (MR) cospectra yield some small mesoscale flux contribution, visible at the larger timescales. A MR gap timescale τgap was defined to separate the turbulent flux from the mesoscale flux and used for the recalculation of the turbulent fluxes after high‐pass filtering. This procedure also reduced the statistical error of the fluxes significantly. For comparison, wavelet transformations were performed that led to wavelet gap scales of the fluxes in good agreement with the MR gap scale. Additionally, the wavelet covariance gave a good representation of the homogeneity of the kinematic heat flux w′θ′ and the kinematic moisture flux w′m′ in time.
Measurements of Pollution in the Troposphere (MOPITT) validation exercises during summer 2004 field campaigns over North America
Authors: Emmons L. K. , Pfister G. G. , Edwards D. P. , Gille J. C. , Sachse G. , Blake D. , Wofsy S. , Gerbig C. , Matross D. , Nédélec P.
Published: March 2007

Measurements of carbon monoxide (CO) made as part of three aircraft experiments during the summer of 2004 over North America have been used for the continued validation of the CO retrievals from the Measurements of Pollution in the Troposphere (MOPITT) instrument on board the Terra satellite. Vertical profiles measured during the NASA INTEX‐A campaign, designed to be coincident with MOPITT overpasses, as well as measurements made during the COBRA‐2004 and MOZAIC experiments, provided valuable validation comparisons. On average, the MOPITT CO retrievals are biased slightly high for these North America locations. While the mean bias differs between the different aircraft experiments (e.g., 7.0 ppbv for MOZAIC to 18.4 ppbv for COBRA at 700 hPa), the standard deviations are quite large, so the results for the three data sets can be considered consistent. On average, it is estimated that MOPITT is 7–14% high at 700 hPa and ∼3% high at 350 hPa. These results are consistent with the validation results for the Carr, Colorado, Harvard Forest, Massachusetts, and Poker Flats, Alaska, aircraft profiles for “phase 2” presented by Emmons et al. (2004) and are generally within the design criteria of 10% accuracy.
Water chemistry of the Zhujiang (Pearl River): Natural processes and anthropogenic influences
Authors: Zhang Shu‐Rong , Lu Xi Xi , Higgitt David Laurence , Chen Chen‐Tung Arthur , Sun Hui‐Guo , Han Jing‐Tai
Published: March 2007

The temporal and spatial variations of major ions in the Zhujiang (Pearl River) were analyzed using long‐term water chemistry data of major dissolved ions (Ca2+, Mg2+, the sum of Na+ and K+, HCO3−, SO42−, Cl−) and dissolved silica (SiO2) from 75 hydrological stations (1958–2002). The total dissolved solids (TDS) within the Zhujiang basin varies from 34.0 mg/l to 416.1 mg/l generally decreasing from upstream to downstream along the main stem of the Zhujiang. Rock weathering is the dominant controlling factor for the water chemistry of the Zhujiang, and more specifically, on average, 68% (22–92%) of total dissolved load comes from carbonate weathering, 22% (2–68%) from silicate weathering, and 10% (3–24%) from evaporite weathering, respectively. The flux calculations indicate that in total about 41.8 × 106 tonnes/year of TDS are transported out of the Zhujiang (excluding the Delta Region), averaged for the period 1958–2002. Changes in water chemistry can be observed from long‐term trend analysis, notably for SO42− and Cl−, as a result of anthropogenic influences, such as acid deposition, domestic and industrial wastewater discharge, and basin water resource development. An intense reforestation policy coupled with rapid reservoir development in the Zhujiang Basin would trigger more significant anthropogenic impacts on water chemistry in the future.
Signatures of the day‐night asymmetry of the Earth‐ionosphere cavity in high time resolution Schumann resonance records
Authors: Sátori Gabriella , Neska Mariusz , Williams Earle , Szendrői Judit
Published: March 2007

High time resolution Schumann resonance (SR) records are analyzed at a midlatitude (Nagycenk, 47.6°N, 16.7°E, Hungary) and a north polar (Hornsund, 77°N, 15.5°E, Spitsbergen) station from the point of view of the day‐night asymmetry of the Earth‐ionosphere cavity. The vertical electric field component, EZ, at Nagycenk in quasi‐minute time resolution exhibits jump‐like increases of SR amplitudes between the local ionospheric and surface sunrise times and sharp decreases between the local surface and ionospheric sunset times. These amplitude variations depend on frequency, increase with increasing mode number, and occur simultaneously in the three SR modes studied here. The duration of the sharp frequency‐dependent amplitude changes is generally less than 30 min. The accurate timing (“clock‐like accuracy”) of these sharp SR amplitude variations of about 12–25% in the local sunrise/sunset periods and their frequency dependence make these changes distinguishable from the amplitude variations related to the lightning source properties and strongly suggest an ionospheric origin for these sharp amplitude variations. The signature of the day‐night asymmetry of the Earth‐ionosphere cavity can also be found at Hornsund in the two short spring and autumn periods with alternating day and night periods every day, in the form of an enhanced day‐night contrast of the SR amplitudes with consistent frequency dependence for the first three SR modes.
MODIS/Terra observed seasonal variations of snow cover over the Tibetan Plateau
Authors: Pu Zhaoxia , Xu Li , Salomonson Vincent V.
Published: March 2007

Seasonal variations of snow cover fraction (SFC) over the Tibet Plateau (TP) are examined using the data acquired from the Moderate Resolution Imaging Spectroradiometer (MODIS) on the Terra spacecraft. In this study, we first evaluate the accuracy of the MODIS high‐resolution snow cover data by comparing the data with in‐situ Chinese snow observations. Results show that overall accuracy of MODIS snow data is about 90% over the TP area. Statistical analysis is then performed over the MODIS snow data during 2000–2006. It is found that the most persistent snow cover is located in the southern and western edges of the TP within large mountain ridges and western part of Yarlung Zangbo valley. The higher SCFs are mostly concentrated in the regions where the elevation is higher than 6000 m. The duration for snow persistence varies in different elevation ranges and generally becomes longer with increases in the terrain elevation.
The role of class I phosphoinositide 3-kinase in T-cell function and autoimmunity
Authors: Fruman D.A.
Published: March 2007

PI3K (phosphoinositide 3-kinase) regulates diverse cellular responses in the immune system, and members of this enzyme family are considered attractive drug targets for modulating allergy, inflammation and leukaemia. Clearly it is important to understand the function of PI3K in T-lymphocytes, cells that regulate nearly every aspect of immunity. However, the precise role of PI3K in T-cell development and function has been difficult to determine. In this review, I summarize current knowledge of PI3K function in T-cells, focusing on the class I subgroup of PI3K catalytic and regulatory isoforms. I discuss gene disruption studies in mice that reveal redundant or limited roles for individual isoforms, along with evidence for potential autoimmunity when class IA PI3K signalling is reduced.
Regulation of B-lymphocyte activation by the PH domain adaptor protein Bam32/DAPP1
Authors: Marshall A.J. , Zhang T. , Al-Alwan M.
Published: March 2007

PI3Ks (phosphoinositide 3-kinases) play critical roles in BCR (B-cell receptor) signalling via the generation of 3-phosphoinositide second messengers. Recruitment of PH domain (pleckstrin homology domain)-containing signal transduction proteins to the plasma membrane through binding to 3-phosphoinositide second messengers represents a major effector mechanism for PI3Ks. Here, we review data on the PH domain-containing adaptor protein Bam32 (B-cell adaptor molecule of 32 kDa)/DAPP1 (dual adaptor for phosphotyrosine and 3-phosphoinositides 1), focusing on its functions in B-lymphocyte activation. Present results support the view that Bam32/DAPP1 mediates multiple PI3K-dependent responses in B-cells through membrane-proximal mechanisms involving Src kinases, Rac1, F-actin and mitogen-activated protein kinases, resulting in selective effects on BCR-mediated proliferation, antigen presentation and generation of antibody responses.
T-lymphocyte navigation and migration: beyond the PI3K paradigm
Authors: Smith L. , Webb A. , Ward S.G.
Published: March 2007

The co-ordinated and directional trafficking of T-lymphocytes in lymphoid and peripheral tissues is an important process in lymphoid development, immunosurveillance and immune responses. Members of the chemokine superfamily play a key role in providing navigational cues for T-cells and chemokine receptors couple with a wide range of biochemical signals including phosphoinositide lipid metabolism, elevation of intracellular calcium levels, activation of a wide array of protein kinases as well as small GTPases. One of the most robust biochemical signals elicited by chemokines in T-lymphocytes is the activation of several members of the PI3K (phosphoinositide 3-kinase) family. In many cell systems, PI3Ks are known to contribute to several aspects of the migratory machinery, although their role in T-cell migration has been unclear and will be considered in the present paper.
Role of class II phosphoinositide 3-kinase in cell signalling
Authors: Falasca M. , Maffucci T.
Published: March 2007

Although it is now well established that PI3K (phosphoinositide 3-kinase) is a key enzyme in several intracellular processes, there are still relatively few reports that precisely identify the specific isoforms of PI3K actually involved in such events. The lack of specific inhibitors has made it particularly difficult to address the physiological roles of some isoforms, such as the members of class II. As a consequence, there is still relatively little understanding of the role of these enzymes and the question about the intracellular role of these isoforms still waits for more answers.
Non-invasive visualization of the lipid product of class I PI3K in transgenic mouse models
Authors: Sasaki T. , Sasaki J. , Watanabe K. , Suzuki A.
Published: March 2007

PI3Ks (phosphoinositide 3-kinases) regulate many critical cellular responses by producing PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate). To facilitate the spatio-temporal characterization of PI(3,4,5)P3 in living primary cells, we generated a novel strain of transgenic mice [AktPH (Akt pleckstrin homology domain)–GFP (green fluorescent protein) Tg (transgenic) mice] that express a fluorescent bioprobe for PI(3,4,5)P3/PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate). By crossing AktPH–GFP Tg mice with strains of gene-targeted ‘knockout’ mice lacking a particular phosphoinositide-metabolizing enzyme, we have been able to evaluate the contribution of each enzyme to PI(3,4,5)P3 localization in migrating neutrophils. Our results indicate that PI3Kγ and the PI(3,4,5)P3 phosphatase SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase-1] are the key regulators of PI(3,4,5)P3 dynamics during fMet-Leu-Phe (N-formylmethionyl-leucylphenylalanine; ‘chemotactic peptide’)-stimulated neutrophil migration. Our study has also validated the fluorescent transgenic strategy for studying PI(3,4,5)P3 metabolism in physiological and pathological situations.
A cascade involving p85, Cdc42 and septin 2 regulates cytokinesis
Authors: Silió V. , Marqués M. , Cortés I. , Zuluaga S. , Carrera A.C.
Published: March 2007

Mitosis, the final phase of cell division, includes the processes of nuclear division and cytosolic division (cytokinesis). Cytokinesis occurs when DNA separation terminates, and involves a number of proteins that induce furrowing at the region of cell separation, formation of new membrane, and abscission. This process is remarkably complex, and the list of proteins that regulate it is long. Our understanding is limited as to how these players are organized in space and time to ensure that the cytosol divides equally, and only after nuclear division. Class IA PI3K (phosphoinositide 3-kinase) is an enzyme activated by growth factor receptor stimulation, but it is re-activated in early mitosis and regulates mitosis entry. By the end of mitosis, PI3K activity is low; at this point, the class IA PI3K regulatory subunit p85 contributes to co-ordination of the cytoskeletal changes required for cytokinesis. The impact of these observations on current models of cytokinesis execution is discussed here.
Phosphoinositide 3-kinases and regulation of embryonic stem cell fate
Authors: Welham M.J. , Storm M.P. , Kingham E. , Bone H.K.
Published: March 2007

ES (embryonic stem) cell lines are derived from the epiblast of pre-implantation embryos and like the inner cell mass cells from which they are derived exhibit the remarkable property of pluripotency, namely the ability to differentiate into all cell lineages comprising the adult organism. ES cells and their differentiated progeny offer tremendous potential to regenerative medicine, particularly as cellular therapies for the treatment of a wide variety of chronic disorders, such as Type 1 diabetes, Parkinson's disease and retinal degeneration. In order for this potential to be realized, a detailed understanding of the molecular mechanisms regulating the fundamental properties of ES cells, i.e. pluripotency, proliferation and differentiation, is required. In the present paper, we review the evidence that PI3K (phosphoinositide 3-kinase)-dependent signalling plays a role in regulation of both ES cell pluripotency and proliferation.
Physiological roles of PKB/Akt isoforms in development and disease
Authors: Dummler B. , Hemmings B.A.
Published: March 2007

PKB (protein kinase B, also known as Akt) is a serine/threonine protein kinase that is important in various signalling cascades and acts as a major signal transducer downstream of activated phosphoinositide 3-kinase. There are three closely related isoforms of PKB in mammalian cells, PKBα (Akt1), PKBβ (Akt2) and PKBγ (Akt3), and this review discusses recent advances in our understanding of the functions of these isoforms in the regulation of adipocyte differentiation, glucose homoeostasis and tumour development.
Regulation of class IA PI3Ks
Authors: Wu H. , Yan Y. , Backer J.M.
Published: March 2007

Class IA PI3Ks (phosphoinositide 3-kinases) regulate a wide range of cellular responses through the production of PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate) in cellular membranes. They are activated by receptor tyrosine kinases, by Ras and Rho family GTPases, and in some cases by Gβγ subunits from trimeric G-proteins. Crystallographic studies on the related class IB PI3Kγ, and biochemical and structural studies on the class IA PI3Ks, have led to new insights into how these critical enzymes are regulated in normal cells and how mutations can lead to their constitutive activation in transformed cells. The present paper will discuss recent studies on the regulation of class I (p85/p110) PI3Ks, with a focus on the role of SH2 domains (Src homology 2 domains) in the p85 regulatory subunit in modulating PI3K activity.
Chemically targeting the PI3K family
Authors: Knight Z.A. , Shokat K.M.
Published: March 2007

PI3K (phosphoinositide 3-kinase) is a key regulator of cell growth, metabolism and survival. The frequent activation of the PI3K pathway in cancer has stimulated widespread interest in identifying potent and selective inhibitors of PI3K isoforms. The present paper highlights recent progress in identifying such molecules and the challenges that remain for efforts to pharmacologically target the PI3K family.
Phosphotyrosine/phosphoserine binary switches: a new paradigm for the regulation of PI3K signalling and growth factor pleiotropy?
Authors: Guthridge M.A. , Lopez A.F.
Published: March 2007

Cytokines and growth factors exert multiple biological activities through their ability to engage and activate specific receptors displayed on the surface of cells. How these receptors are able to differentially (and sometimes independently) regulate cell survival, proliferation, differentiation and activation to control quite specific and distinct cellular outcomes is unclear. Similarly, how a single growth factor or cytokine receptor can specify alternate cellular responses and control very different cellular fates is also not known. We present a new mechanism by which cytokines and growth factors are able to control these pleiotropic responses.
Exploring the potential of PI3K inhibitors for inflammation and cancer
Authors: Crabbe T.
Published: March 2007

Considerable biological evidence has accumulated in support of nominating the Class I PI3Ks (phosphoinositide 3-kinases) as excellent targets for the development of novel pharmaceuticals to treat cancer and inflammatory disease. Although it remains a goal to deliver compounds with precise PI3K isoform selectivity in order to minimize safety risks, it is not yet certain that this approach will deliver suitable benefit against disease when tested in the clinic. The UCB strategy, therefore, has been to generate a range of compounds covering a broad spectrum of PI3K isoform inhibition. Scaffold diversity has been accomplished by identifying hits using both pharmacophore search and high-throughput screening campaigns, while modulation of potency and isoform selectivity has been achieved through exploratory medicinal chemistry. Simple, high-throughput cell assays relevant to either inflammation or cancer have then been employed to establish a blueprint for defining how isoform selectivity affects biological potency. I will focus on two compounds from our collection: a pan-PI3K inhibitor and UCB1311236, a compound with significant potency against only the PI3Kγ isoform. These examples will be used to illustrate the extent to which isoform selectivity informs on compound potency against other kinases and to highlight the risks and benefits of developing compounds with limited isoform selectivity.
Single-cell time-lapse imaging of the dynamic control of NF-κB signalling
Authors: Sillitoe K. , Horton C. , Spiller D.G. , White M.R.H.
Published: March 2007

The transcription factor NF-κB (nuclear factor κB) regulates critical cellular processes including the inflammatory response, apoptosis and the cell cycle. Over the past 20 years many of the components of the NF-κB signalling pathway have been elucidated along with their functions. Recent research in this field has focused on the dynamic regulation and network control of this system. With key roles in so many important cellular processes, it is critical that NF-κB signalling is tightly regulated. Recently, single-cell imaging and mathematical modelling have identified that the timing of cellular responses may play an important role in the regulation of this pathway. p65/RelA (RelA) has been shown to translocate between the nucleus and cytoplasm with varying oscillatory patterns in different cell lines leading to differences in transcriptional outputs from NF-κB-regulated genes. Variations in the timing or persistence of these movements may control the maintenance and differential expression of NF-κB-regulated genes.
Control of the NF-κB inhibitor IκBα in pathogen infection
Authors: Naumann M.
Published: March 2007

One of the important cellular factors involved in the regulation of the host antimicrobial response is the immediate early response transcription factor NF-κB (nuclear factor κB). Human pathogenic micro-organisms trigger cellular signal transduction pathways that induce NF-κB, but pathogens have also found ways to overcome the inflammatory response through active manipulation of NF-κB regulators. Exploration of the mechanisms that influence NF-κB activity could contribute to a better understanding of the molecular pathogenesis of microbial infections and could be important for potential therapeutic intervention that may be relevant in a wide variety of inflammatory diseases.
The role of SHIP1 in T-lymphocyte life and death
Authors: Gloire G. , Erneux C. , Piette J.
Published: March 2007

SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase-1], an inositol 5-phosphatase expressed in haemopoietic cells, acts by hydrolysing the 5-phosphates from PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathway. SHIP1 plays a major role in inhibiting proliferation of myeloid cells. As a result, SHIP1−/− mice have an increased number of neutrophils and monocytes/macrophages due to enhanced survival and proliferation of their progenitors. Although SHIP1 contributes to PtdIns(3,4,5)P3 metabolism in T-lymphocytes, its exact role in this cell type is much less explored. Jurkat cells have recently emerged as an interesting tool to study SHIP1 function in T-cells because they do not express SHIP1 at the protein level, thereby allowing reintroduction experiments in a relatively easy-to-use system. Data obtained from SHIP1 reintroduction have revealed that SHIP1 not only acts as a negative player in T-cell lines proliferation, but also regulates critical pathways, such as NF-κB (nuclear factor κB) activation, and also appears to remarkably inhibit T-cell apoptosis. On the other hand, experiments using primary T-cells from SHIP1−/− mice have highlighted a new role for SHIP1 in regulatory T-cell development, but also emphasize that this protein is not required for T-cell proliferation. In support of these results, SHIP1−/− mice are lymphopenic, suggesting that SHIP1 function in T-cells differs from its role in the myeloid lineage.
Polyamines and neoplastic growth
Authors: Pegg A.E. , Feith D.J.
Published: March 2007

Studies over many years have suggested that increased polyamine synthesis may be necessary for neoplastic growth. This review summarizes recent work on the regulation of putrescine production both de novo and via the degradation of higher polyamines and provides a summary of studies using transgenic mice in which the levels of proteins that regulate these processes (L-ornithine decarboxylase, antizyme and spermidine/spermine-N1-acetyltransferase) are altered.
Metabolic enzymes regulated by the Myc oncogene are possible targets for chemotherapy or chemoprevention
Authors: Rimpi S. , Nilsson J.A.
Published: March 2007

The Myc oncogenes are dysregulated in 70% of human cancers. They encode transcription factors that bind to E-box sequences in DNA, driving the expression of a vast amount of target genes. The biological outcome is enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Based on the biological effects of Myc overexpression it was originally assumed that the important Myc target genes are those encoding components of the cell cycle machinery. Recent work has challenged this notion and indicates that Myc target genes encoding metabolic enzymes deserve attention, as they may be critical arbiters of Myc in cancer. Thus targeting metabolic enzymes encoded by Myc-target genes may provide a new means to treat cancer that have arisen in response to deregulated Myc oncogenes.
Antizyme inhibitor: a defective ornithine decarboxylase or a physiological regulator of polyamine biosynthesis and cellular proliferation
Authors: Keren-Paz A. , Bercovich Z. , Kahana C.
Published: March 2007

ODC (ornithine decarboxylase) is a central regulator of cellular polyamine synthesis. ODC is a highly regulated enzyme stimulated by a variety of growth-promoting stimuli. ODC overexpression leads to cellular transformation. Cellular ODC levels are determined at transcriptional and translational levels and by regulation of its degradation. Here we review the mechanism of ODC degradation with particular emphasis on AzI (antizyme inhibitor), an ODC homologous protein that appears as a central regulator of ODC stability, cellular polyamine homoeostasis and cellular proliferation.
Mechanisms of polyamine catabolism-induced acute pancreatitis
Authors: Hyvönen M.T. , Merentie M. , Uimari A. , Keinänen T.A. , Jänne J. , Alhonen L.
Published: March 2007

Acute pancreatitis is an autodigestive disease, in which the pancreatic tissue is damaged by the digestive enzymes produced by the acinar cells. Among the tissues in the mammalian body, pancreas has the highest concentration of the natural polyamine, spermidine. We have found that pancreas is very sensitive to acute decreases in the concentrations of the higher polyamines, spermidine and spermine. Activation of polyamine catabolism in transgenic rats overexpressing SSAT (spermidine/spermine-N1-acetyltransferase) in the pancreas leads to rapid depletion of these polyamines and to acute necrotizing pancreatitis. Replacement of the natural polyamines with methylated polyamine analogues before the induction of acute pancreatitis prevents the development of the disease. As premature trypsinogen activation is a common, early event leading to tissue injury in acute pancreatitis in human and in experimental animal models, we studied its role in polyamine catabolism-induced pancreatitis. Cathepsin B, a lysosomal hydrolase mediating trypsinogen activation, was activated just 2 h after induction of SSAT. Pre-treatment of the rats with bismethylspermine prevented pancreatic cathepsin B activation. Analysis of tissue ultrastructure by transmission electron microscopy revealed early dilatation of rough endoplasmic reticulum, probable disturbance of zymogen packaging, appearance of autophagosomes and later disruption of intracellular membranes and organelles. Based on these results, we suggest that rapid eradication of polyamines from cellular structures leads to premature zymogen activation and autodigestion of acinar cells.
Polyamines and DNA methylation in childhood leukaemia
Authors: Schipper R.G. , van den Heuvel L.P. , Verhofstad A.A.J. , De Abreu R.A.
Published: March 2007

Both polyamine metabolism and DNA methylation play an important role in normal and malignant growth. Specific enzyme inhibitors or drugs that interfere with these metabolic pathways have proven to be potential anticancer agents. Since DNA methylation and polyamine metabolism depend on a common substrate, i.e. S-adenosylmethionine, interaction between both pathways can be expected. Little is known about the relationship between these pathways but studies are available indicating that polyamines and DNA methylation are directly or indirectly interconnected, metabolically as well as physiologically with respect to the regulation of cell growth, differentiation and cancer development. These considerations give rise to the possibility that, by targeting both pathways, a more profound and effective inhibitory effect on the growth of malignant cells can be achieved. In previous studies we showed that 6-MP (6-mercaptopurine) as well as MTX (methotrexate), well-known drugs in the treatment of acute lymphoblastic leukaemia, inhibit DNA methylation and induce apoptosis in malignant blood cells. Our recent results show that combined treatment with 6-MP, MTX and drugs interfering with polyamine metabolism has additive/synergistic effects on the growth, cell viability and/or apoptotic death of leukaemic cells. Such a combination therapy could have great clinical value for patients in which therapy using inhibitors of thiopurines/purine metabolism has failed.
Polyamine-based analogues as biochemical probes and potential therapeutics
Authors: Boncher T. , Bi X. , Varghese S. , Casero R.A. , Woster P.M.
Published: March 2007

The polyamines putrescine, spermidine and spermine are ubiquitous polycationic compounds that are found in nearly every cell type, and are required to support a wide variety of cellular functions. The existence of multiple cellular effector sites for naturally occurring polyamines implies that there are numerous targets for polyamine-based therapeutic agents. Through a programme aimed at the synthesis and evaluation of biologically active polyamine analogues, our laboratory has identified three distinct structural classes of polyamine derivatives that exhibit promising biological activity in vitro. We have synthesized more than 200 symmetrically and unsymmetrically substituted alkylpolyamines that possess potent antitumour or antiparasitic activity, depending on their backbone architecture and terminal alkyl substituents. Along similar lines, we have developed novel polyamino(bis)guanidines and polyaminobiguanides that are promising antitrypanosomal agents and that interfere with biofilm formation in the pathogenic bacterium Yersinia pestis. Finally, we recently reported a series of PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) that inhibit HDACs (histone deacetylases), and in some cases are selective for individual HDAC isoforms. These studies support the hypothesis that polyamine-based small molecules can be developed for use as biochemical probes and as potential therapies for multiple diseases.
Nuclear and membrane receptor-mediated signalling pathways modulate polyamine biosynthesis and interconversion
Authors: Grzelakowska-Sztabert B. , Dudkowska M. , Manteuffel-Cymborowska M.
Published: March 2007

Polyamines play an important role in cell growth and differentiation, while their overproduction has potentially oncogenic consequences. Polyamine homoeostasis, a critical determinant of cell fate, is precisely tuned at the level of biosynthesis, degradation and transport. The enzymes ODC (ornithine decarboxylase), AdoMetDC (S-adenosylmethionine decarboxylase) and SSAT (spermidine/spermine N1-acetyltransferase) are critical for polyamine pool maintenance. Our experiments were designed to examine the expression of these enzymes in testosterone-induced hypertrophic and antifolate-induced hyperplastic mouse kidney, characterized by activation of AR (androgen receptor) and HGF (hepatocyte growth factor) membrane receptor c-Met respectively. The expression of these key enzymes was up-regulated by antifolate CB 3717 injury-evoked activation of HGF/c-Met signalling. In contrast, activation of the testosterone/AR pathway remarkably induced a selective increase in ODC expression without affecting other enzymes. Studies in catecholamine-depleted kidneys point to a synergistic interaction between the signalling pathways activated via cell membrane catecholamine receptors and AR, as well as c-Met. We found that this cross-talk modulated the expression of ODC and AdoMetDC, enzymes limiting polyamine biosynthesis, but not SSAT. This is in contrast with the antagonistic cross-talk between AR- and c-Met-mediated signalling which negatively regulated the expression of ODC, but affected neither AdoMetDC nor SSAT.
Inhibition of cell proliferation and induction of apoptosis by N1,N11-diethylnorspermine-induced polyamine pool reduction
Authors: Oredsson S.M. , Alm K. , Dahlberg E. , Holst C.M. , Johansson V.M. , Myhre L. , Söderstjerna E.
Published: March 2007

Reduction of cellular polyamine pools results in inhibition of cell proliferation and sometimes in induction of cell death. Reduction of cellular polyamine pools can be achieved by several strategies involving all the mechanisms of polyamine homoeostasis, i.e. biosynthesis, catabolism and transport across the cell membrane. In the present paper, we concentrate on results achieved using the polyamine analogue DENSPM (N1,N11-diethylnorspermine) on different cell lines. We discuss polyamine levels in DENSPM-treated cells in relation to effects on cell cycle kinetics and induction of apoptosis. To really understand the role of polyamines in cell cycle regulation and apoptosis, we believe it is now time to go through the vast polyamine literature in a meta-analysis-based manner. This short review does not claim to be such a study, but it is our hope to stimulate such studies in the polyamine field. Such work is especially important from the viewpoint of introducing drugs that affect polyamine homoeostasis in the treatment of various diseases such as cancer.
Emerging use of non-viral RNA interference in the brain
Authors: Cryan J.F. , Thakker D.R. , Hoyer D.
Published: March 2007

Psychiatric and neurological disorders are among the most complex, poorly understood and debilitating diseases in medicine. Abrogating gene function using knockout animals is one of the primary means of examining the pathophysiological significance of a given gene product and has been used successfully in models of neuropsychiatric disorders. However, the developmental compensations that may potentially arise from such approaches are problematic and difficult to assess. The recent discovery of RNAi (RNA interference), as a highly efficient method for gene knockdown, has opened up the possibility for its application in examining the potential role of genes in adult brain function and/or disorders. Recent efforts have focused on applying RNAi-based knockdown to understand the genes implicated in neuropsychiatric disorders. We have developed a method of gene knockdown involving chronic infusion of siRNA (short interfering RNA) using osmotic minipumps. We have silenced a number of genes including those for the serotonin and dopamine transporter. Such tailoring of tools that deliver RNAi in the brain will significantly aid in our understanding of the complex pathophysiology of neuropsychiatric disorders where there is an immensely unmet medical need.
Movement without dopamine: striatal dopamine is required to maintain but not to perform learned actions
Authors: Dowd E. , Dunnett S.B.
Published: March 2007

The different populations of dopaminergic neurons located in the ventral mesencephalon have long been associated with distinct functional roles. The nigrostriatal projection is considered necessary for efficient motor performance, while the mesolimbocortical projection is usually associated with reward signalling. However, a number of recent studies in our laboratory suggest that the divergence between these two functions of dopamine is not as delineated as it may once have seemed. In these experiments, we have been developing improved behavioural methods for assessing the nature of the deficit in rats with unilateral dopamine lesions, as well as the efficacy of various experimental cell and gene therapies for Parkinson's disease. The behavioural task we selected is a lateralized nose-poking task in which rats are trained to respond to stimulus lights on either side of their heads. This task not only allows us to accurately measure aspects of motor performance, but, because it requires extensive training, it also allows us to assess aspects of motor learning. The concurrence of motor performance parameters (which are considered to be dependent on striatal dopamine) and motor learning parameters (which are thought to be dependent on mesolimbocortical reward signalling) within the same task has revealed some surprising consequences of dopamine lesions and neuroprotective/neuroreparative approaches to repair in rat models of Parkinson's disease. The data generated using this task suggest that the motor deficits that occur as a consequence of dopamine lesions may be downstream of a deficit in reward signalling. If so, this could redefine our perception of the role of dopamine in controlling motor function.