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WHEN INEOS Team UK's Britannia II was finished, boatbuilder Jason Carrington fully grasped the achievement of building not one, but two AC75s--easily the most complex sailboats he and his craftsmen [...]

Bulk crystals of undoped and In-doped (on the order of 1%) SnSe2were synthesized using a solid-state temperature-gradient method and characterized by diffuse reflection, Raman scattering, ARPES and STM studies. An n-to-p crossover was observed as a function of the indium concentration in Hall measurements at 300 K, but the Seebeck coefficient is n-type at that temperature for all studied indium concentrations. The measured resistivity at 300 K reaches a maximum at the minimum carrier concentration. Our results suggest a multiband semiconducting nature for doped SnSe2, which provides insight into the exploration of enhanced thermoelectric performance and exotic electric behavior.

The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4-d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22was initially identified and profiled in vivo, before further modifications led to the discovery of 44(UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivoprofile of 44positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.

Background: Immunosuppressive drugs are widely used to prevent and treat allograft rejection and autoimmune diseases. Mycophenolic acid (MPA) and its derivatives are currently one of the most prescribed immunosuppressive drugs; however, metabolic drawbacks and variable interand intrapatient responses limit their use. Objective: In order to find out new safe and effective immunosuppressive compounds, we report here the synthesis and pharmacological evaluation of hybrid MPA derivatives containing the thalidomide/ phthalimide subunits. Results: All compounds 3a-d exhibited an enhanced ability to reduce the levels of pro-inflammatory cytokines compared to the parental drugs MPA and thalidomide. The mixed lymphocyte reaction assay has demonstrated that compound 3d - (E)-(3-(1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1- yl)methyl-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enoate – has superior activity compared to that of MPA. In addition, compound 3d was less cytotoxic against Jurkat cells than MPA and did not demonstrate in vivo genotoxic effect. Conclusion: All these data have shown that compound 3d is a promising lead compound useful in the immunosuppressive therapy.

•Satellite imagery (LULC) reveals impact of a long-term research project on land-use.•Population growth triggers increase of deforestation in remote villages.•Cash income triggers expansion of subsistence agronomy to cash-crops.•Cash-crops such as corn are used for local alcohol production generating additional income.•SyncroSim predicts a 78% fold increase in deforestation over the upcoming 50 years.

A new design of High Temperature Steam Electrolyzer (HTSE) based on metallic seals, associated to an insulating cell support and a flexible interconnect system has been proposed. In this work, complete simulations of this 3D design have been performed with ANSYS®‐FLUENT® software. The temperature repartition is determined by taking into account thermal exchanges, fluids movements, and electrochemical reactions. Moreover, due to stress relaxation mechanism, the flexible interconnect loading decreases during time, which may impact the contact resistance and the electrochemical solution. A possible degradation of the contact resistance with time is predicted by the simulation and its effect will be discussed according to some design parameters. Steam electrolysis tests have been conducted at 800 °C on this new design. The comparisons to the simulations are also presented. All these results obtained in this study lead to propose some recommendations for such a design.

Both clinical and experimental evidence illustrate that p190 and p210 BCR/ABL oncogenic tyrosine kinases induce resistance to DNA damage and confer an intrinsic genetic instability. Here, we investigated whether BCR/ABL expression could modulate nucleotide excision repair (NER). We found that ectopic expression of p210 BCR/ABL in murine lymphoid BaF3 cell line inhibited NER activity in vitro, promoting hypersensitivity of these cells to ultraviolet (UV) treatment and facilitating a mutator phenotype. However, expression of p210 BCR/ABL in human and murine myeloid cell lines and primary bone marrow cells resulted in the increased NER activity and resistance to UV irradiation. The ABL tyrosine kinase inhibitor STI571 reversed these effects, showing that p210 BCR/ABL tyrosine kinase activity is responsible for deregulation of NER. Hypoactivity of NER in p210 BCR/ABL-positive lymphoid cells was accompanied by the decreased interaction between proliferating cell nuclear antigen (PCNA) and xeroderma pigmentosum group B (XPB); conversely, this interaction was enhanced in p210 BCR/ABL-positive myeloid cells. p190 BCR/ABL did not affect NER in lymphoid and myeloid cells. In summary, our study suggests that p210 BCR/ABL reduced NER activity in lymphoid cells, leading to hypersensitivity to UV and mutagenesis. In contrast, p210 BCR/ABL expression in myeloid cells facilitated NER and induced resistance to UV. (Blood. 2003;102:2632-2637)

Induction of apoptosis by chemotherapeutic drugs involves the sphingomyelin-ceramide (SM-CER) pathway. This signaling is critically dependent on reactive oxygen species (ROS) generation and p53/p56 Lyn activation. In this study, we have investigated the influence of protein kinase C (PKC) ζ overexpression on the SM-CER pathway in U937 human leukemia cell line. We show that PKCζ overexpression resulted in delayed apoptosis and significant resistance to both 1-β-d-arabinofuranosylcytosine (ara-C) and daunorubicin (DNR), but there was no significant protection against cell-permeant C6-CER. Moreover, PKCζ overexpression abrogated drug-induced neutral sphingomyelinase stimulation and CER generation by inhibiting ROS production. We further investigated p53/p56 Lyn activation in PKCζ-overexpressing U937 cells treated with ara-C or DNR. We demonstrate that PKCζ inhibited p53/p56 Lyn phosphorylation and stimulation in drug- or H2O2-treated cells, suggesting that p53/p56 Lyn redox regulation is altered in PKCζ-overexpressing cells. Finally, we show that PKCζ-overexpressing U937 cells displayed accelerated H2O2detoxification. Altogether, our study provides evidence for the role of PKCζ in the negative regulation of drug-induced SM-CER pathway.

Induction of apoptosis by chemotherapeutic drugs involves the sphingomyelin-ceramide (SM-CER) pathway. This signaling is critically dependent on reactive oxygen species (ROS) generation and p53/p56 Lyn activation. In this study, we have investigated the influence of protein kinase C (PKC) zeta overexpression on the SM-CER pathway in U937 human leukemia cell line. We show that PKCzeta overexpression resulted in delayed apoptosis and significant resistance to both 1-beta-D-arabinofuranosylcytosine (ara-C) and daunorubicin (DNR), but there was no significant protection against cell-permeant C(6)-CER. Moreover, PKCzeta overexpression abrogated drug-induced neutral sphingomyelinase stimulation and CER generation by inhibiting ROS production. We further investigated p53/p56 Lyn activation in PKCzeta-overexpressing U937 cells treated with ara-C or DNR. We demonstrate that PKCzeta inhibited p53/p56 Lyn phosphorylation and stimulation in drug- or H(2)O(2)-treated cells, suggesting that p53/p56 Lyn redox regulation is altered in PKCzeta-overexpressing cells. Finally, we show that PKCzeta-overexpressing U937 cells displayed accelerated H(2)O(2) detoxification. Altogether, our study provides evidence for the role of PKCzeta in the negative regulation of drug-induced SM-CER pathway.

DNA polymerase β(Pol β), an error-prone DNA-synthesizing enzyme tightly down-regulated in healthy somatic cells, has been shown to be overexpressed in many human tumors. In this study, we show that treatment with the 2′,3′-dideoxycytidine (ddC) nucleoside analog inhibited in vitro and in vivo the proliferation of Pol β-transfected B16 melanoma cells, which up-regulate Pol βcompared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol β-overexpressing B16 melanoma. When the phosphorylated form of ddC was electrotransfered into Pol β-transfected melanoma, the cell growth inhibition was strengthened, strongly suggesting that the cytotoxic effect results from incorporation of the chain terminator into DNA. Using in vitro single- and double-stranded DNA synthesis assays, we demonstrated that excess Pol βperturbs the replicative machinery, favors ddC-TP incorporation into DNA, and consequently promotes chain termination. Therefore, the use of chain terminator anticancer agents could be suitable for the treatment of tumors with a high level of Pol β.

DNA polymerase beta (Pol beta), an error-prone DNA-synthesizing enzyme tightly down-regulated in healthy somatic cells, has been shown to be overexpressed in many human tumors. In this study, we show that treatment with the 2',3'-dideoxycytidine (ddC) nucleoside analog inhibited in vitro and in vivo the proliferation of Pol beta-transfected B16 melanoma cells, which up-regulate Pol beta compared with control isogenic cells. The administration of ddC also increased specifically the survival of mice bearing Pol beta-overexpressing B16 melanoma. When the phosphorylated form of ddC was electrotransfered into Pol beta-transfected melanoma, the cell growth inhibition was strengthened, strongly suggesting that the cytotoxic effect results from incorporation of the chain terminator into DNA. Using in vitro single- and double-stranded DNA synthesis assays, we demonstrated that excess Pol beta perturbs the replicative machinery, favors ddC-TP incorporation into DNA, and consequently promotes chain termination. Therefore, the use of chain terminator anticancer agents could be suitable for the treatment of tumors with a high level of Pol beta.

Abstract: A study of the loss of coherency suffered by gamma-prime precipitates after aging or through plastic deformation was carried out in a superalloy, IN 713C* Selected aging treatments were employed so as to observe different stages of coherency loss. Examination using transmission electron microscopy reveals that itinerant or matrix dislocations, generated either by internal stresses (carbides,etc.) or through the usual processes of general plastic deformation, rearrange themselves by cross-slip and climb around gamma-prime precipitates to produce misfit dislocation networks. Along with the network formation, the precipitate morphology changes to maximize the misfit accommodation. The final dislocation and precipitate configurations are consistent with the Lasalmonie and Strudel model.

An updated compilation of shallow seismicity in the Tonga-Kermadec arc and back-arc region, including especially 304 focal mechanisms from centroid moment tensor solutions files, provides new insights on the present-day tectonics and allows the relative motions between the Pacific, Indo-Australian and Tonga-Kermadec plates to be quantified.

A new and improved method for the treatment of dislocations in continuum numerical models, in the mesoscale range of lengths 1-1000 nm, is introduced. The dislocation representation, based on splined parametric polynomials, is described. The necessary numerical procedures are presented and justified in detail. Application of the method is illustrated by three examples. Firstly, the passage of perfect dislocations through a composite containing passive voids is studied; it is shown that in this case the resistance to dislocation motion can approach closely to the ideal of impenetrable obstacles. Secondly, the interaction of dissociated superdislocations with impenetrable obstacles is considered, for superpartial separations as small as two Burgers vectors; a smooth transition between known analytic limits is shown, demonstrating the utility of the method. Thirdly, the behaviour of Heidenreich-Shockley dissociated dislocations of varying character at coherent dispersoids is investigated; it is suggested that the probability of bypass by cross-slip is highest for dislocations of near-60d`character.

Materials of reduced density and increased strength can be achieved by the creation of dispersed voids. A procedure for the manufacture of such materials is described and their characteristic strength estimated.

On the basis that a crack may be represented by a dislocation continuum it is shown that a crack extension force (G) cannot occur in the absence of a dislocation-free zone (D.F.Z.). Given such a zone it is shown that Gis apt to be sensitive to the variation of flow stress in the plastic zone and hence to work hardening.

The stresses which occur in the vicinity of a dislocation are modified by the presence of an atmosphere of solute atoms. This modification can result in a marked change in the calculated distribution of the atmosphere and a commensurate reduction in the total solute population. In the case of relatively dense atmospheres this reduction can be by a factor of four.

The resistance to grain-boundary motion provided by a dispersion of spherical particles has been calculated for primary and secondary recrystallization (normal grain growth). Specific account has been taken of grain-boundary flexibility, and of those forces, which aid and those which hinder motion.When neither the intrinsic surface energy of particles nor that of grain boundaries is changed by the presence of the other, the resistance decreases markedly with increasing volume fraction of the particulate phase. Where there is interaction this resistance can be markedly larger, particularly at the highest volume fractions.

It is suggested that, independent of the specific mechanism involved, diffusion-induced grain boundary motion can be attributed to a solute-induced variation in grain boundary energy which exhibits a minimum at some particular concentration. Some of the basic consequences of this are given in outline.

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Abstract: We have reconfigured the Texas digital ocean bottom seismograph (OBS) to operate in a triggered mode and record regional earthquake signals. This paper reports the results of a deployment program designed to test these digital OBS, by moni toring earthquake activity in and near the trench in southern Vanuatu (formerly, the New Hebrides). We successfully recorded hundreds of earthquakes, including 133 located regional earth quakes recorded by three or more stations. We also report J-B residuals for 21 earthquakes reported and located by the ISC. Fourier analysis of seismograms from regional earthquakes suggest that the frequencies of spectral peaks at any station were nearly the same for large, small, nearby, and distant events. However, we obtained very disparate frequencies when we analyzed seismograms for the same earthquake recorded at different stations. The most plausible interpretation is that spectral peaks do not depend on the characteristics of the earthquake source, but instead on site characteristics, or, more specifically, on the coupling of the instrument to the seafloor. To record reliable spectral data, we need to overcome this problem.

Relative motions between the Pacific plate (P), Indo-Australian plate (IA), New Hebrides (NH) arc microplate and the North Fiji Basin (NFB) microplate are estimated using shallow seismicity, 276 focal mechanism solutions, bathymetry, magnetism and the RM-2 plate model of Minster and Jordan (1978).

The theory of normal grain growth that invokes random walk is further extended by allowing for biases in step direction. It is concluded that the predictions of this theory are in overall quantitative accord with experiment. However, the degree of agreement between theory and experiment as to the exact form of the grain size distribution function remains in doubt because of a lack of precision in the definition and measurement of grain size. Possibly, this difficulty may be surmounted by replacing measurements of grain size by those of the lengths of grain boundary edges as found in planar sections of polycrystals.

The stresses developed by misfitting spheres close to a planar free surface have been calculated. It is found that the mean stresses in the neighbourhood of such particles can be large enough to indicate significant increases in the rate of substitutional diffusion. Also, interactions can be so large that the formation of a crater is energetically favourable.

In a polycrystal consisting of a matrix and a uniform dispersion of particles or bubbles with a grain size determined by critical Zener pinning it is known that the yield stress is controlled not so much by direct particle - dislocation interactions as by indirect particle-grain-boundary-dislocation interactions. After yield, dislocations accumulate in the matrix, at hard particles (but not at bubbles) and at grain boundaries. These accumulations cause work hardening. In the case of hard particles the particle (direct) work hardening and the grain-boundary (indirect) work hardening are equal. In the case of bubbles the direct work hardening is approximately zero. At low strains, therefore, indirect hardening dominates the flow stress. Only at high strains is the matrix work hardening significant and in strong alloys, with a high volume fraction of small particles, it is never significant

We propose a novel and rapid method of measuring the total area of a rough surface using a scanning electron microscope. We show, under certain circumstances, that this area is almost exactly proportional to the secondary electron yield from the surface. The relationship of this measurement to fractal characterization is discussed.

Premature crack closure has been considered an important factor affecting the applied driving force under cyclic load. Among several factors that induce crack closure, plasticity and oxidation or corrosion have been recognized as the most significant. An analytical estimation of both is made using dislocation theory. The analysis indicates that (a) plasticity originating from crack tip does not induce crack closure and (b) closure arising from asperity ridges due to oxides, corrosion products or surface roughness is small and insignificant unless crack is completely packed with asperities.

Recent data (bathymetric map and petrological investigations) as well as reappraisal of local seismological events for more than 20 years allow us to present a new geodynamic interpretation of the southern New Hebrides subduction zone. A multidisciplinary approach to this complex area, where transform movements relay subduction process, clearly shows the interrelationships between intermediate seismicity, lithospheric plates tectonics and volcanic activity. According to our model, two hinge zones, tearing the downgoing slab along directions which parallel the convergence vector (N70°E), reasonably account for most seismological and petrological data from the region. The approach of the Loyalty islands ridge towards the trench and its increasing influence on the subduction regime is beginning to complicate this scheme.

Recent experiments on high strength steel having a very fine microstructure have been interpreted in terms of the Petch relationship with the apparent dislocation pile-up lengths as small as 85 Å. For this reason, the behaviour of such small dislocation pile-ups has been examined theoretically. The results indicate that the Petch relation can be extended in a modified way to these extremely small grain sizes, e.g. < 50 Å. The main point is that for a small number of straight dislocations, the discontinuous nature of the Petch relation is important because each dislocation has a significant influence upon the stress concentrating character of the pile-up.

Approximate distributions for dislocations in linear arrays have previously been found by a method in which discrete dislocations are replaced by a continuous distribution of elementary dislocations. This method is now extended to cases where screw-type arrays are stacked one above the other in infinite sequences.When the ratio of the separation to the length of an array is small the number of dislocations in each is determined by the stress and separation and the associated strain by the applied stress alone.

The paper describes metallographic observations of the development of fatigue cracks in copper. The specimens (polycrystal and single crystals) were tested in push-pull at 1000 c.p.s. It was shown that the fatigue crack started in a slip band inside a single grain. An electropolishing technique showed changes in the character of the slip band after 5% of the life had expired. Cracks more than one grain long were present when half the life had expired. It was confirmed that the fatigue life could be increased by preventing access of oxygen to the surface. The bearing of these observations on the problem of the origin of a fatigue crack is discussed.

Evidence for the existence of a mechanical equation of state of limited applicability in a Cu-Sb (1.8%) alloy is presented. It is found that the yielding behaviour of this alloy is similar to that of iron-carbon alloys and concluded that the equation of state observed in both materials arises probably as a consequence of the presence of the solute locking of dislocations.

Results obtained from a network of five short-period seismograph stations operated for 2 months on the island of Santo in the central region of the New Hebrides provide evidence for the anomalous propagation of seismic waves through the zone of shearing contact between the converging plates of the New Hebrides Island Arc.

THIS method replaces direct solutions of the Airy relation by, in effect, linear combinations of solutions of this equation for the edge dislocation. So far its use has been investigated only in connexion with the stress fields of dislocations in finite bodies; it may well be that it is useful in other connexions as well.

Detailed surveys (bathymetry, magnetism, seismicity and focal mechanism solutions) recorded on the junction between the southern New Hebrides Arc and the North Fiji Basin enlighten the geodynamic complexity of the area.