bluuebunny/crossref_metadata_2025 huggingface dataset:
Reaction of γ‐Tocopherol with Hypochlorous Acid
Authors: Nguyen Quyen , Southwell‐Keely Peter T.
Published: January 2007

In addition to being a very good antioxidant, γ‐tocopherol is also an excellent electrophile trap. This is a study of the reactivity of γ‐tocopherol with hypochlorous acid/hypochlorite, a potential biological foe that is both an oxidant and an electrophile. Aqueous sodium hypochlorite (1.72 mmol; pH 7.4) was stirred with γ‐tocopherol (0.12 mmol) in hexane for 2 min at room temperature. The following products were isolated: γ‐tocopheryl quinone (0.6%), tocored (10%), 3‐chloro‐γ‐tocopheryl quinone (14%), an ether dimer of 3‐chloro‐γ‐tocopheryl quinone (0.4%), two isomers of 5‐(5‐γ‐tocopheryl)‐γ‐tocopherol (3 and 2% respectively), 5‐chloro‐γ‐tocopherol (14%) and two chlorinated dimers (14 and 24% respectively) which were identified as diastereomers of (3R,10R)‐11a‐chloro‐2,3,9,10‐tetrahydro‐3,5,6,10,12,13‐hexamethyl‐3,10‐bis[(4R,8R)‐4,8,12‐trimethyltridecyl]‐1H‐pyrano(3,2a)‐8H‐pyrano(3,2g)‐dibenzofuran‐14(7aH)(14aH)‐one. The chlorinated dimers, 5‐chloro‐γ‐tocopherol, 3‐chloro‐γ‐tocopheryl quinone and its ether dimer are new compounds.
Butters Varying in trans 18:1 and cis‐9,trans‐11 Conjugated Linoleic Acid Modify Plasma Lipoproteins in the Hypercholesterolemic Rabbit
Authors: Bauchart Dominique , Roy Alexandre , Lorenz Stephanie , Chardigny Jean‐Michel , Ferlay Anne , Gruffat Dominique , Sébédio Jean‐Louis , Chilliard Yves , Durand Denys
Published: January 2007

The experiment was designed to study the effects of butters differing in conjugated linoleic acid (CLA) and trans 18:1 contents on lipoproteins associated with the risk of atherogenesis. New Zealand White male rabbits (9.6 weeks; 2.1 kg) were assigned for 6 or 12 weeks to three diets (n = 6 per diet) made of conventional pellets with 0.2% cholesterol and with 12% fat provided from a butter poor in trans‐10 and trans‐11 18:1 and in CLA (standard group), or rich in trans‐10 18:1 (trans‐10 18:1 group) or rich in trans‐11 18:1 and in cis‐9,trans‐11 CLA (trans‐11 18:1/CLA group). Blood samples were collected at the end of dietary treatments. Lipoproteins were separated by gradient‐density ultracentrifugation. Lipid classes were determined enzymatically and apolipoproteins A‐I and B by radial immunodiffusion. Mainly in the 12‐week rabbits, higher plasma triglycerides and apolipoprotein B levels shown in the standard and trans‐10 18:1 groups compared with those in the trans‐11 18:1/CLA group are associated with higher plasma levels of very low density lipoproteins (VLDL) and low density lipoproteins (LDL) also shown in these two groups. In the 12‐week rabbits, a shift towards denser LDL, considered as more atherogenic, was shown only in the trans‐10 18:1 group. In these animals, the VLDL + LDL to HDL ratio was 1.7–2.3 times higher in the trans‐10 18:1 group than in the other groups (P = 0.076). These results suggest a rather neutral effect of trans‐11 18:1/CLA butter towards the risk of atherogenesis, whereas trans‐10 18:1 butter would tend to be detrimental.
Trauma to erythrocytes induced by long term in vitro pumping using a roller pump
Authors: Ding M.J. , Xu S.W. , Zhang J. , Wang Q. , Chang Y. , Chen F. , Zeng Y.J.
Published: January 2007

The objective of this study is to investigate the impact of trauma on erythrocyte caused by long term in vitro pumping using roller pump. Ten bags of human blood (400 ml each) were provided by a local blood bank and they were divided into two groups with five bags in each group. Each blood bag was subject to pumping in a closed circuit, which was composed of silica gel tubes and a roller pump. Polystan and COBE pumps were used for the two groups, respectively. The blood was pumped for 16 h in vitro. Free hemoglobin (FHb), platelets (PLT), erythrocyte fragility (EF), and morphological analysis of erythrocytes observed under scanning electron microscope were measured to evaluate the impact of trauma on erythrocytes. A small amount of blood was collected for analysis before pumping, at the end of the 4th hour and then every 2 h till the end of the 16th hour. Some blood samples were also collected for electron microscope scanning before pumping and every 4 h during pumping. It was found that FHb and PLT linearly increased with the pumping time. There was a significant correlation between the two parameters (r= 0.7745, p< 0.001). The hemolysis indexes of the two groups were 0.296 and 0.3993 mg/L/h, respectively, with no significant difference. During the pumping process, EF changed slightly. The observation of scanning electron microscopy showed various deformed erythrocytes after pumping, including the distortion of cell membrane and the appearance of echinocytes, which increased with pumping time. This study demonstrated that long term pumping using roller pump not only caused the immediate rupture of red blood cells, i.e. the immediate hemolysis, but also caused sub‐trauma to a large number of erythrocytes, which led to the delayed hemolysis. The change of erythrocyte morphology was the basis of the delayed hemolysis.
CD14 is a ligand for the integrin α4β1
Authors: Humphries Jonathan D. , Humphries Martin J.
Published: January 2007

Cell adhesion mediated by the integrin α4β1 plays a key role in many biological processes reflecting both the number and functional significance of α4β1 ligands. The lipopolysaccharide (LPS) receptor, CD14, is a GPI‐linked cell surface glycoprotein with a wide range of reported functions and associations, some of which overlap with that of α4β1. This overlap led us to test the specific hypothesis that α4β1 and CD14 interact directly. Jurkat T cells (α4β1+) were found to adhere to a recombinant CD14‐Fc protein via α4β1, whilst K562 cells (α4β1−) did not. However, stable reexpression of the α4‐subunit conferred this ability. The adhesion of both cell types to CD14 displayed activation state‐dependent binding very similar to the interaction of α4β1 with its prototypic ligand, VCAM‐1. In solid‐phase assays, CD14‐Fc bound to affinity‐purified α4β1 in a dose‐dependent manner that was induced by activating anti‐β1 mAbs. Finally, in related experiments, JY cells (α4β7+) were also found to attach to CD14‐Fc in an α4‐dependent manner. In summary, CD14 is a novel ligand for α4β1, exhibiting similar activation‐state dependent binding characteristics as other α4β1 ligands. The biological relevance of this interaction will be the subject of further studies.
Ceramide kinase regulates growth and survival of A549 human lung adenocarcinoma cells
Authors: Mitra Poulami , Maceyka Michael , Payne Shawn G. , Lamour Nadia , Milstien Sheldon , Chalfant Charles E. , Spiegel Sarah
Published: January 2007

Ceramide‐1‐phosphate (C1P) is emerging as a new addition to the family of bioactive sphingolipid metabolites. At low concentrations, C1P enhanced survival of NIH 3T3 fibroblasts and A549 lung cancer cells, while at high concentrations, it reduced survival and induced apoptosis. Apoptosis correlated with degradation of C1P to pro‐apoptotic ceramide. To examine the role of endogenous C1P, expression of ceramide kinase, the enzyme that produces C1P, was downregulated, which reduced cellular proliferation, progression into S phase and enhanced apoptosis induced by serum starvation. Our results suggest that ceramide kinase determines the balance between pro‐apoptotic ceramide and anti‐apoptotic C1P to regulate cell fate, reminiscent of its function in plants.
Bioinformatic tools uncover the C‐terminal strand of Rubisco's large subunit as hot‐spot for specificity‐enhancing mutations
Authors: Burisch C. , Wildner G.F. , Schlitter J.
Published: January 2007

Here, we (a) present an analysis of sequences of the large subunit which reliably finds specificity‐enhancing mutations and ranks them according to the probability of success. For mutations near the C‐terminus, we (b) show by simulations that the positive influence they have on specificity can be explained by the time‐window hypothesis.
Climate variability in the Aral Sea basin (Central Asia) during the late Holocene based on vegetation changes
Authors: Sorrel Philippe , Popescu Speranta-Maria , Klotz Stefan , Suc Jean-Pierre , Oberhänsli Hedi
Published: January 2007

High-resolution pollen analyses (∼ 50 yr) from sediment cores retrieved at Chernyshov Bay in the NW Large Aral Sea record shifts in vegetational development from subdesertic to steppe vegetation in the Aral Sea basin during the late Holocene. Using pollen data to quantify climatic parameters, we reconstruct and date for the first time significant changes in moisture conditions in Central Asia during the past 2000 yr. Cold and arid conditions prevailed between ca. AD 0 and 400, AD 900 and 1150, and AD 1500 and 1650 with the extension of xeric vegetation dominated by steppe elements. These intervals are characterized by low winter and summer mean temperatures and low mean annual precipitation (Pmm< 250 mm/yr). Conversely, the most suitable climate conditions occurred between ca. AD 400 and 900, and AD 1150 and 1450, when steppe vegetation was enriched by plants requiring moister conditions (Pmm∼ 250–500 mm/yr) and some trees developed. Our results are fairly consistent with other late Holocene records from the eastern Mediterranean region and the Middle East, showing that regional rainfall in Central Asia is predominantly controlled by the eastern Mediterranean cyclonic system when the North Atlantic Oscillation (NAO) is in a negative phase.
An assessment of human versus climatic impacts on Holocene soil erosion in NE Peloponnese, Greece
Authors: Fuchs M.
Published: January 2007

Soil erosion is a natural geomorphological process, which can be triggered by both natural (climate, tectonics, or both) and anthropogenic (e.g., agriculture) perturbation of the ecosystem. Evidence has accrued that the Holocene climate experienced large fluctuations in amplitude and suggestions of human impact on the ecosystem provided by the Neolithic revolution dating back to the early Holocene have been made. The question of whether man or climate was the dominant factor responsible for Holocene soil erosion remains unresolved. To resolve the reasons for Holocene sediment redistribution, high-resolution chronometric data on sediments derived from colluvial and alluvial archives from southern Greece were obtained and combined with available archaeological and paleoclimatic data from the eastern Mediterranean. These data show a significant correlation between sedimentation rates and settlement history. Climatic fluctuations are only weakly correlated with sedimentation history. The results show high sedimentation rates during the Early Neolithic (7th millennium BC) in southern Greece, suggesting that Holocene soil erosion was triggered by human activity and then amplified by enhanced precipitation. This would explain the high sedimentation rates during the Early Neolithic in connection with enhanced precipitation in the eastern Mediterranean, which continued until the mid-Holocene.
Negotiating difference/negotiating rights: the challenges and opportunities of women’s human rights
Authors: GUERRINA ROBERTA , ZALEWSKI MARYSIA
Published: January 2007

The year 2004 marked the 25th anniversary of the signing of the Convention on the Elimination of All Forms of Discrimination Against Women. A significant landmark in the development of a coherent strategy for the promotion and protection of women’s human rights, it established the principle that for women to enjoy equal rights, they needed an extra layer of ‘protection’. More importantly, it detailed states’ legal obligations in the area of women’s rights. Since then, the development of women’s human rights has continued to challenge the boundaries between the public, the private and the international. It was in this context that the Beijing women’s conference (1995) created a climate of expectation among women’s groups and non-governmental organisations (NGOs) that the project to advance women’s human rights in practice might gather and sustain momentum. Yet, it is evident that there remains an enormous gap between the rhetoric and realities of women’s human rights, whereby women’s rights continue to be contested in countries across the world and governments are often unwilling to fulfil their international obligations.
Debating women’s human rights as a universal feminist project: defending women’s human rights as a political tool
Authors: STEANS JILL
Published: January 2007

The central aims of this article are twofold: first to debate whether or not women’s human rights can underpin a universal feminist project; second to defend women’s human rights as a useful political tool that can be used to challenge injustice and discrimination against women. The first section of the article briefly sets out the universality/particularity debate in both human rights theory and in feminist theory. This serves as a point of departure for the subsequent discussion of universality and particularity in relation to women’s human rights specifically. Section one of the article is entitled ‘debating’ women’s human rights as a universal feminist project, because this is, indeed, a matter of dispute (as evidenced by the contributions to this forum). That women’s human rights are universal is contested by some feminists although the reasons for their scepticism are quite different from those advanced by ultra-conservatives and religious fundamentalists.
Wartime sexual violence: women’s human rights and questions of masculinity
Authors: ALISON MIRANDA
Published: January 2007

This article examines wartime sexual violence, one of the most recurring wartime human rights abuses. It asserts that our theorisations need further development, particularly in regard to the way that masculinities and the intersections with constructions of ethnicity feature in wartime sexual violence. The article also argues that although women and girls are the predominant victims of sexual violence and men and boys the predominant agents, we must also be able to account for the presence of male victims and female agents. This, however, engenders a problem; much of the women’s human rights discourse and existing international mechanisms for addressing wartime sexual violence tend to reify the male-perpetrator/female-victim paradigm. This is a problem which feminist human rights theorists and activists need to address.
A wall, water and power: the Israeli ‘separation fence’
Authors: TROTTIER JULIE
Published: January 2007

The ‘separation fence’ ‘constructed by Israel to isolate itself from the Palestinians’ raises many questions. Why was the construction of a fence perceived by the Israelis as a solution and as the only solution? What determined the specific, serpentine path of the fence and what impact does it have on both Palestinian and Israeli societies? A resulting reconfiguration of the power structure within Palestinian society is clearly unfolding and deserves analysis.
Strategic regionalism in East Asia
Authors: GILSON JULIE
Published: January 2007

The US, China and Japan are often portrayed as three giant states dominating the region of East Asia in perpetual potential conflict. This article proposes that such assessments should be tempered in the light of changing regional and global dynamics and, in particular, in view of the growing centrality of the region of East Asia itself for foreign policy agendas. Adopting a framework underpinned by the concept of strategic regionalism, this article focuses upon the developing collective identification of region, and assesses the possibility for joint leadership in East Asia.
Constructing communities: the curious case of East Asian regionalism
Authors: JONES DAVID MARTIN , SMITH MICHAEL L. R.
Published: January 2007

The prevailing scholarly orthodoxy regarding recent diplomatic initiatives in the Asia-Pacific assumes that East Asia is evolving into a distinctive regional community. The orthodoxy attributes this development to the growing influence of the diplomatic practices espoused by the Association of Southeast Asian States (ASEAN) and its related institutions. However, a paradox remains, namely: despite the failure of ASEAN’s distinctive practice to fulfil its rhetorical promise in Southeast Asia both immediately prior to and in the aftermath of the Asian financial crisis in 1997, it is nevertheless considered sufficient to validate the projection of ASEAN defined norms onto a wider Pacific canvas. This study analyses how an academic preference for constructivism has misinterpreted the growth in official rhetoric extolling East Asian regionalism since 1997 in a way that has helped produce and reinforce this paradox. By contrast, we contend that government declarations of a developing East Asian identity actually serve to obscure the continuation of traditional interstate relations and do not herald any wider, let alone inexorable, movement towards an integrated regional community.
Inconsistent objectives – reflections on some selective health care policy developments in Europe
Authors: Oliver Adam
Published: January 2007

Over the last two decades, there has been an increased focus among the health policy and research communities upon improving efficiency, in terms of activity levels and health outcomes, in the health care systems of the EU member states. In this article, some of these developments are described and to some extent assessed, and an attempt is made to highlight how they may serve to undermine more fundamental aspects of these systems: namely, that access to health care be universal and affordable at the point of use.
Regionalization versus competition in complex cancer surgery
Authors: Ho Vivian , Town Robert J. , Heslin Martin J.
Published: January 2007

The empirical association between high hospital procedure volume and lower mortality rates has led to recommendations for the regionalization of complex surgical procedures. While regionalization may improve outcomes, it also reduces market competition, which has been found to lower prices and improve health care quality. This study estimates the potential net benefits of regionalizing the Whipple surgery for pancreatic cancer patients. We confirm that increased hospital volume and surgeon volume are associated with lower inpatient mortality rates. We then predict the price and outcome consequences of concentrating Whipple surgery at hospitals that perform at least two, four, and six procedures respectively per year. Our consumer surplus calculations suggest that regionalization can increase consumer surplus, but potential price increases extract over half of the value of reduced deaths from regionalization. We reach three conclusions. First, regionalization can increase consumer surplus, but the benefits may be substantially less than implied by examining only the outcome side of the equation. Second, modest changes in outcomes due to regionalization may lead to decreases in consumer surplus. Third, before any regionalization policy is implemented, a deep and precise understanding of the nature of both outcome/volume and price/competition relationships is needed.
A new approach to the comparative analysis of health systems: invasive treatment for heart disease in the US, France, and their two world cities
Authors: Gusmano Michael K. , Rodwin Victor G. , Weisz Daniel , Das Dhiman
Published: January 2007

Cross-national comparisons that assess dimensions of health system performance indicate that the US provides higher rates of revascularization procedures than France and other developed nations, but we believe these findings are misleading. In this paper, we compare the use of these procedures in the US, France and their two world cities, Manhattan and Paris. In doing so, we address a number of limitations associated with existing cross-national comparisons of heart disease treatment. After adjusting for the prevalence of disease in these nations and cities, we found that residents of France aged 45–64 years receive more revascularization procedures than residents of the US and that Parisians receive more revascularizations than residents of Manhattan. Older residents 65 years and over (65+) in the US receive more of these procedures than their French counterparts, but the differences are not nearly as great as previous studies suggest. Moreover, our data on Manhattan and Paris where the population and level of health resources are more comparable, indicate that older Parisians obtain more revascularization procedures than older Manhattanites. Finally, we found that the use of revascularization procedures is significantly lower in Manhattan among persons without private health insurance and among racial and ethnic minorities.
Effects of mineral spatial distribution on reaction rates in porous media
Authors: Li L. , Peters C. A. , Celia M. A.
Published: January 2007

This study examined the effects of variations in mineral spatial distributions on reaction rates in porous media. Pore‐scale network models were constructed to represent sandstones with anorthite and kaolinite present in various amounts and in different spatial patterns. Simulation conditions corresponded to geological sequestration of carbon dioxide. To examine scaling effects arising from pore‐scale heterogeneities, reaction rates from network models were compared to rates from continuum models that use uniform concentrations. With small percentages of reactive minerals the scaling effects are large, and the effect of spatial distribution is significant. Scaling effects are largest when reactive minerals are closely clustered and oriented parallel to flow. Conversely, spatial distributions that enhance mass transport to and from reactive minerals, such as small mineral clusters or elongated clusters oriented transverse to flow, result in reaction rates that are well represented by the continuum model.
Are geomagnetic field reversals controlled by turbulence within the Earth's core?
Authors: Ryan David A. , Sarson Graeme R.
Published: January 2007

We consider geomagnetic field reversal sequences from the last 160 Ma, and find the inter‐reversal times to be well fit by a lognormal distribution. Such a distribution could arise from ‘multiplicative noise’ in the underlying geodynamo; and turbulent fluctuations within the core may be expected to provide such noise via theα‐effect of dynamo theory. We investigate this mechanism by coupling a low orderαω‐type dynamo to a shell model of turbulence. This model reproduces field reversals varying in duration from subchrons to superchrons; these are reasonably fit by a lognormal distribution, consistent with the multiplicative noise mechanism proposed.
Tomographic filtering of geodynamic models: Implications for model interpretation and large‐scale mantle structure
Authors: Ritsema Jeroen , McNamara Allen K. , Bull Abigail L.
Published: January 2007

The resolution operator is a critical accompaniment to tomographic models of the mantle. facilitates the comparison between conceptual three‐dimensional velocity models and tomographic models because it can filter these theoretical models to the spatial resolution of the tomographic model. We compute for the tomographic model S20RTS (Ritsema et al., 1999, 2004) and two companion models that are based on the same data but derived with different norm damping values. The three models explain (within measurement uncertainty) S‐SKS and S‐SKKS travel times equally well. To demonstrate how artifacts distort tomographic images and complicate model interpretation, we apply to (1) a thermochemical and (2) an isochemical model of convection in the mantle that feature different patterns of shear velocity heterogeneity in the deep mantle if we assume that shear velocity heterogeneity is caused by temperature variations only. suppresses short‐wavelength structures, removes strong velocity gradients, and introduces artificial stretching and tilting of velocity anomalies. Temperature anomalies in the thermochemical model resemble the spatial extent of low seismic velocity anomalies and the shear velocity spectrum in the D” region better than the isochemical model. However, the thermochemical model overpredicts the amplitude of shear velocity variation and places the African and Pacific anomalies imperfectly. We suspect that inaccurate velocity scaling laws and uncertain initial conditions control these mismatches. Extensive hypothesis testing is required to identify successful models.
Modes of mesoscale sea surface height and temperature variability in the East Australian Current
Authors: Wilkin John L. , Zhang Weifeng G.
Published: January 2007

Mesoscale variability where the East Australian Current (EAC) separates from the coast is studied using sea surface temperature and surface velocity streamfunction observed by satellite and a regional numerical model. The mean circulation simulated by the model (the Regional Ocean Modeling System (ROMS)) is compared to a high‐resolution regional climatology, and the realism of the simulated mesoscale variability is tested by comparison to statistical analyses of the satellite data. Both ROMS and data show spectral peaks in the mesoscale energy band at periods between 90 and 180 days. Complex Empirical Orthogonal Function (EOF) analysis identifies two significant modes of mesoscale variability in the data; an Eddy Mode, for which the variability propagates southwestward along the coast, and a Wave Mode, for which phase propagation is predominantly onshore. The regional model open boundary conditions include only annual and semiannual harmonics of variability so remote mesoscale forcing is absent. The Eddy Mode is represented well in the model indicating this aspect of the circulation results from local instabilities of the flow and that its underlying dynamical process is simulated well. While the observed and modeled Wave Modes have some similarities, their differences suggest the model is deficient in representing westward propagation of mesoscale period variability in the region. Whatever the source of this energy, the orthogonality property of the EOF analysis indicates the Wave Mode does not interact significantly with eddy processes in the EAC separation.
Hydration of aircraft engine soot particles under plume conditions: Effect of sulfuric and nitric acid processing
Authors: Shonija N. K. , Popovicheva O. B. , Persiantseva N. M. , Savel'ev A. M. , Starik A. M.
Published: January 2007

Hydration properties of original engine soot produced by burning TC1 aviation kerosene in aircraft engine combustor are studied under simulated plume conditions. Engine‐generated soot demonstrates a high level of water uptake due to the existence of fraction of impurities originating within an engine. It contains 13.5 wt% water soluble compounds including 3.5 wt% organic and inorganic sulfates. Total amount of water vapor absorbed by engine soot particles increases with the temperature decrease in the exhaust plume and reaches 18 wt% at threshold contrail formation conditions. Chemical processing of soot particles in the young plume through the coagulation with sulfate aerosols and H2SO4/H2O heterogeneous nucleation leads to 0.2 wt% of H2SO4 accumulating at high fuel sulfur content. Such a small amount of additional H2SO4 cannot result in the increase of water uptake by the fraction of impurities of engine‐generated soot particles but may activate the hydrophobic fraction that originally contains a negligible amount of water soluble compounds. HNO3 processing may compete with H2SO4 in respect to increase of water uptake. It is inferred that the fraction of impurities of engine‐generated soot plays a key role in the CCN formation in the aircraft plume.
Bayesian Monte Carlo analysis applied to regional‐scale inverse emission modeling for reactive trace gases
Authors: Deguillaume L. , Beekmann M. , Menut L.
Published: January 2007

The purpose of this article is inverse modeling of emissions at regional scale for photochemical applications. The study is performed for the Ile‐de‐France region over a two summers (1998 and 1999) period. This area represents an ideal framework since concentrated anthropogenic emissions in the Paris region frequently lead to the formation of urban plumes. The inversion method is based on Bayesian Monte Carlo analysis applied to a regional‐scale chemistry transport model, CHIMERE. This method consists in performing a large number of successive simulations with the same model but with a distinct set of model input parameters at each time. Then a posteriori weights are attributed to individual Monte Carlo simulations by comparing them with observations from the AIRPARIF network: urban NO and O3 concentrations and rural O3 concentrations around the Paris area. For both NO and O3 measurements, observations used for constraining Monte Carlo simulations are additionally averaged over the time period considered for analysis. The observational constraints strongly reduce the a priori uncertainties in anthropogenic NOx and volatile organic compounds (VOC) emissions: (1) The a posteriori probability density function (pdf) for NOx emissions is not modified in its average, but the standard deviation is decreased to around 20% (40% for the a priori one). (2) VOC emissions are enhanced (+16%) in the a posteriori pdf's with a standard deviation around 30% (40% for the a priori one). Uncertainties in the simulated urban NO, urban O3, and O3 production within the plume are reduced by a factor of 3.2, 2.4, and 1.7, respectively.
Experimental observations on fungal diagenesis of carbonate substrates
Authors: Kolo Kamal , Keppens Eddy , Préat Alain , Claeys Philippe
Published: January 2007

Carbonate substrates (dolomites and limestones) are susceptible to fungal attack that results in significant microbial diagenesis of these substrates. In a 15‐day experimental study, fungi growing in Petri dishes from airborne spores attacked petrographic thin sections and chips prepared from the dolomites of Terwagne Formation (Viséan, Bocahut quarry at Avesnes‐sur‐Helpe, northern France) and limestones of the Morrone di Pacentro Formation (Lower Cretaceous, Italy). The analyses of the fungal material (samples of mycelia), thin sections and chips under optical microscopy, scanning electron microscope (SEM), energy dispersive X‐ray (EDX), X‐ray diffraction (XRD), Raman spectroscopy and stable isotopes (C and O) revealed an extensive fungally induced diagenesis. The results indicate strong diagenesis and biomineral neomorphism: neo‐dolomite, glushinskite, weddellite, whewellite and possibly struvite, as well as intense substrate “de‐micritization” and “micritization” with oxalates, grain bridging and cementation, open space filling, formation of intergranular and intragranular porosity, and permeability enhancement. Advanced stages of diagenesis were characterized by dissolution and replacement of original minerals by new substrates produced by fungal biomineralization. The formation of new substrates on the original attacked surfaces produced microscale stratification. Stable isotope analysis of fungal biomineralized material and of attacked and unattacked chip surfaces revealed marked differences in their isotopic signatures. The C and O isotopes of biomineralized material within the fungal mass were fractionated differently as compared to the signature measured in the original and unattacked surfaces. In sedimentary cycles, such microbially modified isotopic signature of carbonate substrates may be used to define microbial events, and consequently whether certain types of diagenesis were produced by microbial interaction. The finding of neo‐dolomite formed during fungi‐dolomite substrate interaction suggests the possibility of sedimentary dolomite recycling in a fungal microenvironment. The results of this experimental study confirm the significant role of fungi in reshaping carbonate substrates and forming new biominerals in the natural environment.
Challenges in non-viral ocular gene transfer
Authors: Peeters L. , Sanders N.N. , Demeester J. , De Smedt S.C.
Published: January 2007

Nowadays, there is no effective treatment for many retinal disorders. Knowledge of the genetic basis of many severe ocular diseases may allow for alternative treatments by gene therapy. Non-viral gene complexes, such as lipo- and poly-plexes, can be delivered to the posterior segment, most often the target tissue, by intravitreal or subretinal injection. Since subretinal injections are very invasive, intravitreal injection is a promising alternative route to deliver gene complexes into the eye. However, the drawback of this technique is the relative long distance the complexes have to travel through the vitreous gel before they reach the retina. This mini-review reports on how non-viral gene complexes behave in vitreous. It especially focuses on how the coating of lipoplexes with poly(ethylene glycol) influences their behaviour in vitreous and the transfection of retinal pigment epithelium.
Peptide-based delivery of nucleic acids: design, mechanism of uptake and applications to splice-correcting oligonucleotides
Authors: Abes S. , Moulton H. , Turner J. , Clair P. , Richard J.P. , Iversen P. , Gait M.J. , Lebleu B.
Published: January 2007

CPPs (cell-penetrating peptides) have given rise to much interest for the delivery of biomolecules such as peptides, proteins or ONs (oligonucleotides). CPPs and their conjugates were initially thought to translocate through the cell membrane by a non-endocytotic mechanism which has recently been re-evaluated. Basic-amino-acid-rich CPPs first interact with cell-surface proteoglycans before being internalized by endocytosis. Sequestration and degradation in endocytotic vesicles severely limits the cytoplasmic and nuclear delivery of the conjugated biomolecules. Accordingly, splicing correction by CPP-conjugated steric-block ON analogues is inefficient in the absence of endosomolytic agents. New arginine-rich CPPs allowing efficient splicing correction by conjugated PNAs (peptide nucleic acids) or PMO (phosphorodiamidate morpholino oligomer) steric blockers in the absence of endosomolytic agents have recently been defined in our group and are currently being characterized. They offer promising leads for the development of efficient cellular delivery vectors for therapeutic steric-block ON analogues.
Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging
Authors: Tomalia D.A. , Reyna L.A. , Svenson S.
Published: January 2007

Dendrimers are routinely synthesized as tuneable nanostructures that may be designed and regulated as a function of their size, shape, surface chemistry and interior void space. They are obtained with structural control approaching that of traditional biomacromolecules such as DNA/RNA or proteins and are distinguished by their precise nanoscale scaffolding and nanocontainer properties. As such, these important properties are expected to play an important role in the emerging field of nanomedicine. This review will describe progress on the use of these features for both targeted diagnostic imaging and drug-delivery applications. Recent efforts have focused on the synthesis and pre-clinical evaluation of a multipurpose STARBURST® PAMAM (polyamidoamine) dendrimer prototype that exhibits properties suitable for use as: (i) targeted, diagnostic MRI (magnetic resonance imaging)/NIR (near-IR) contrast agents, (ii) and/or for controlled delivery of cancer therapies. Special emphasis will be placed on the lead candidate, namely [core: 1,4-diaminobutane; G (generation)=4.5], [dendri-PAMAM(CO2Na)64]. This dendritic nanostructure (i.e. ∼5.0 nm diameter) was selected on the basis of a very favourable biocompatibility profile [The Nanotechnology Characterization Laboratory (NCL), an affiliate of the National Cancer Institute (NCI), has completed extensive in vitro studies on the lead compound and have found it to be very benign, non-immunogenic and highly biocompatible], the expectation that it will exhibit desirable mammalian kidney excretion properties and demonstrated targeting features.
Gene delivery by cationic lipids: in and out of an endosome
Authors: Hoekstra D. , Rejman J. , Wasungu L. , Shi F. , Zuhorn I.
Published: January 2007

Cationic lipids are exploited as vectors (‘lipoplexes’) for delivering nucleic acids, including genes, into cells for both therapeutic and cell biological purposes. However, to meet therapeutic requirements, their efficacy needs major improvement, and better defining the mechanism of entry in relation to eventual transfection efficiency could be part of such a strategy. Endocytosis is the major pathway of entry, but the relative contribution of distinct endocytic pathways, including clathrin- and caveolae-mediated endocytosis and/or macropinocytosis is as yet poorly defined. Escape of DNA/RNA from endosomal compartments is thought to represent a major obstacle. Evidence is accumulating that non-lamellar phase changes of the lipoplexes, facilitated by intracellular lipids, which allow DNA to dissociate from the vector and destabilize endosomal membranes, are instrumental in plasmid translocation into the cytosol, a prerequisite for nuclear delivery. To further clarify molecular mechanisms and to appreciate and overcome intracellular hurdles in lipoplex-mediated gene delivery, quantification of distinct steps in overall transfection and proper model systems are required.
Receptor-mediated internalization of chelator–PNA–peptide hybridization probes for radioimaging or magnetic resonance imaging of oncogene mRNAs in tumours
Authors: Tian X. , Chakrabarti A. , Amirkhanov N. , Aruva M.R. , Zhang K. , Cardi C.A. , Lai S. , Thakur M.L. , Wickstrom E.
Published: January 2007

Early external detection of cancer gene activity might enable early treatment of cancer and might reduce cancer mortality. We hypothesized that oncogene mRNA overexpressed at thousands of copies per malignant cell in a zone of transformed cells could be imaged externally by scintigraphic imaging, PET (positron emission tomography) or MRI (magnetic resonance imaging) with PNA (peptide nucleic acid) hybridization probes that include chelators for metal cations and a cyclized peptide analogue of IGF-1 (insulin-like growth factor 1), D(Cys-Ser-Lys-Cys), to mediate internalization by IGF1R (IGF-1 receptor) overexpressed on cancer cells. We observed that human MCF7 breast cancer cells that overexpress IGF1R efficiently internalized fluorescein–chelator–PNA–D(Cys-Ser-Lys-Cys) to the cytoplasm, but not with D(Cys-Ala-Ala-Cys). Scintigraphic imaging of MCF7 xenografts in immunocompromised mice revealed that CCND1 and MYC [99mTc]chelator–PNA–D(Cys-Ser-Lys-Cys) probes yielded xenograft. PET imaging with [64Cu]chelator–PNA–D(Cys-Ser-Lys-Cys) yielded stronger signals. Scintigraphic imaging of human AsPC1 pancreas cancer xenografts with [99mTc]chelator–KRAS PNA–D(Cys-Ser-Lys-Cys) yielded strong xenograft signals. Stronger xenograft image intensities were obtained by PET imaging of [64Cu]chelator–KRAS PNA–D(Cys-Ser-Lys-Cys). MRI required extension of chelator–polydiamidopropanoate dendrimers from the N-termini of the PNA probes to increase the number of contrast paramagnetic gadolinium (III) cations per probe. These results provide a basis for detection of oncogene activity in tissues from outside the body by hybridization with metal–chelator–PNA–peptides that are selectively internalized by cancer cells.
Molecular determinants of TRP channel assembly
Authors: Lepage P.K. , Boulay G.
Published: January 2007

Calcium channels play important roles in cellular signalling. TRP (transient receptor potential) channels form a superfamily of calcium channels through which Ca2+ enters the cell. TRPs have six transmembrane segments with a putative pore between the fifth and the sixth segments, and assemble in tetrameric complexes to form functional Ca2+ channels. They are thus similar to KV (voltage-gated potassium channel) channels in terms of structure and molecular determinants that promote subunit assembly. In this review, the molecular determinants mediating the assembly of Drosophila TRP, TRPC (TRP canonical), TRPV (TRP vanilloid) and KV channels are described.
Assembly domains in TRP channels
Authors: Schindl R. , Romanin C.
Published: January 2007

The large family of mammalian TRP (transient receptor potential) ion channels encompasses diverse sensory functions. TRP proteins consist of six transmembrane domains, with a pore–loop motif between the fifth and sixth domains and cytosolic N- and C-termini. The intracellular strands not only interact with various proteins and lipids, but also include essential multimerization regions. This review summarizes the current knowledge of the intrinsic assembly domains that assure tetrameric TRP channel formation.
TRPM3, a biophysical enigma?
Authors: Oberwinkler J.
Published: January 2007

TRPM3 [TRP (transient receptor potential) melastatin 3] is one of the least investigated proteins of the TRP family of ion channels. Heterologously expressed TRPM3 channels are constitutively active, have an outwardly rectifying current–voltage relationship and are inhibited by intracellular Mg2+ ions. Besides these rather common features, in which TRPM3 channels resemble the closely related channels TRPM6 and TRPM7, TRPM3 channels have several unique characteristics. The TRPM3 gene encodes a plethora of different proteins owing to alternative splicing and alternative exon usage. One site of alternative splicing affects the ion-conducting pore region and profoundly alters the pore properties of the encoded channels. The channels having the longer pore region efficiently conduct univalent cations, but are only poorly permeated by bivalent cations. Conversely, the channels with the shorter pore region are highly permeable to bivalent cations. Unusually, the short-pore TRPM3 channels are inhibited by extracellular Na+ ions. At physiological sodium concentration, this block is very strong, making it difficult to envision a physiological function for these ion channels. Recently, pharmacological investigations have been initiated in order to identify substances that influence TRPM3 channel activity. With the use of such substances, it might be possible to identify TRPM3 channels in their native environment and to elucidate some of their physiological roles. Hopefully, TRPM3 channels will then no longer appear to be as enigmatic as they do right now.
TRPC1: a core component of store-operated calcium channels
Authors: Ambudkar I.S.
Published: January 2007

The TRPC (transient receptor potential canonical) proteins are activated in response to agonist-stimulated PIP2 (phosphatidylinositol 4,5-bisphosphate) hydrolysis and have been suggested as candidate components of the elusive SOC (store-operated calcium channel). TRPC1 is currently the strongest candidate component of SOC. Endogenous TRPC1 has been shown to contribute to SOCE (store-operated calcium entry) in several different cell types. However, the mechanisms involved in the regulation of TRPC1 and its exact physiological function have yet to be established. Studies from our laboratory and several others have demonstrated that TRPC1 is assembled in a signalling complex with key calcium signalling proteins in functionally specific plasma membrane microdomains. Furthermore, critical interactions between TRPC1 monomers as well as interactions between TRPC1 and other proteins determine the surface expression and function of TRPC1-containing channels. Recent studies have revealed novel regulators of TRPC1-containing SOCs and have demonstrated a common molecular basis for the regulation of CRAC (calcium-release-activated calcium) and SOC channels. In the present paper, we will revisit the role of TRPC1 in SOCE and discuss how studies with TRPC1 provide an experimental basis for validating the mechanism of SOCE.
Regulation of TRP channels: a voltage–lipid connection
Authors: Nilius B. , Mahieu F. , Karashima Y. , Voets T.
Published: January 2007

TRP (transient receptor potential) channels respond to a plethora of stimuli in a fine-tuned manner. We show here that both membrane potential and the level of PI (phosphatidylinositol) phosphates are efficient regulators of TRP channel gating. Recent work has shown that this regulation applies to several members of the TRPV (TRP vanilloid) subfamily (TRPV1 and TRPV5) and the TRPM (TRP melastatin) subfamily (TRPM4/TRPM5/TRPM7/TRPM8), whereas regulation of members of the TRPC subfamily is still disputed. The mechanism whereby PIP2 (PI 4,5-bisphosphate) acts on TRPM4, a Ca2+- and voltage-activated channel, is shown in detail in this paper: (i) PIP2 may bind directly to the channel, (ii) PIP2 induces sensitization to activation by Ca2+, and (iii) PIP2 shifts the voltage dependence towards negative and physiologically more meaningful potentials. A PIP2-binding pocket seems to comprise a part of the TRP domain and especially pleckstrin homology domains in the C-terminus.
Regulation of calcium signalling by adenine-based second messengers
Authors: Fliegert R. , Gasser A. , Guse A.H.
Published: January 2007

cADPR [cyclic ADPR (ADP-ribose)], NAADP (nicotinic acid–adenine dinucleotide phosphate) and ADPR belong to the family of adenine-containing second messengers. They are metabolically related and are all involved in the regulation of cellular Ca2+ homoeostasis. Activation of specific plasma membrane receptors is connected to cADPR formation in many cell types and tissues. In contrast receptor-mediated formation of NAADP and ADPR has been shown only in a few selected cellular systems. The intracellular Ca2+ channel triggered by cADPR is the RyR (ryanodine receptor); in the case of NAADP, both activation of RyR and a novel Ca2+ channel have been proposed. In contrast, ADPR opens the non-specific cation channel TRPM2 [TRP (transient receptor potential) melastatin 2] that belongs to the TRP family of ion channels.
Biological functions of TRPs unravelled by spontaneous mutations and transgenic animals
Authors: Freichel M. , Flockerzi V.
Published: January 2007

The identification of the biological functions of TRP (transient receptor potential) proteins requires genetic approaches because a selective TRP channel pharmacology to unravel the roles of TRPs is not available so far for most TRPs. A survey is therefore presented of transgenic animal models carrying mutations in TRP genes, as well as of those TRP genes that when mutated result in human disease; the chromosomal locations of TRP channel genes in the human and mouse are also presented.
TRP channels and kidney disease: lessons from polycystic kidney disease
Authors: Qamar S. , Vadivelu M. , Sandford R.
Published: January 2007

Important insights in to the function of members of the TRP (transient receptor potential) channel superfamily have been gained from the identification of disease-related mutations. In particular the identification of mutations in the PKD2 gene in autosomal dominant polycystic kidney disease has revealed a link between TRP channel function, mechanosensation and the role of the primary cilium in renal cyst formation. The PKD2 gene encodes TRPP2 (transient receptor potential polycystin 2) that has significant homology to voltage-activated calcium and sodium TRP channels. It interacts with polycystin-1 to form a large membrane-associated complex that is localized to the renal primary cilium. Functional characterization of this polycystin complex reveals that it can respond to mechanical stimuli such as flow, resulting in influx of extracellular calcium and release of calcium from intracellular stores. TRPP2 is expressed in the endoplasmic reticulum/sarcoplasmic reticulum where it also regulates intracellular calcium signalling. Therefore TRPP2 modulates many cellular processes via intracellular calcium-dependent signalling pathways.