The neurotrophic receptor TrkB: a drug target in anti-cancer therapy?

Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target, and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer. Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006     

Cancer and blood coagulation

In human patients, blood coagulation disorders often associate with cancer, even in its early stages. Recently, in vitro and in vivo experimental models have shown that oncogene expression, or inactivation of tumour suppressor genes, upregulate genes that control blood coagulation. These studies suggest that activation of blood clotting, leading to peritumoral fibrin deposition, is instrumental in cancer development. Fibrin can indeed build up a provisional matrix, supporting the invasive growth of neoplastic tissues and blood vessels. Interference with blood coagulation can thus be considered as part of a multifaceted therapeutic approach to cancer. Received 30 November 2005; received after revision 7 February 2005; accepted 8 February 2006     

Functional interactions of protein kinase A and C in signalling networks: a recapitulation

On the basis of evidence collected from the literature, we propose a general model by which protein kinase (PK) A and the different PKC isoforms can inversely affect cell growth. Molecular switches, which are able to direct the signal towards antiproliferative or mitogenic pathways, are the different isoforms of Raf and PKC. Conflicting data are also reported and discussed in an attempt to reconcile them. Received 10 November 2005; received after revision 28 December 2005; accepted 3 January 2006     

喜马拉雅山中段达索普粒雪芯中夏季风和尘埃信号记录研究

通过粒雪芯δ＾１８Ｏ和主要离子（Ｃａ＾２＋,Ｍｇ＾２＋,ＮＨ＾＋４,ＳＯ＾２－４和ＮＯ＾－３）的分析表明,该粒雪芯年平均积累量为０．７５ｍ水当量。粒雪芯中δ＾１８Ｏ和主要离子浓度的季节变化表明,达索普冰川中高精度的记录了现代夏季风和尘埃信号。夏季风期间降水中δ＾１８Ｏ值由“降水量效应”所控制,雪层中较低δ＾１８Ｏ值则代表了夏季风信号。亚洲中部干旱半干旱区的春季尘暴输入是造成粒雪芯中Ｃａ＾２＋,Ｍｇ     

BEM Analysis of Wave Propagation in a Water-Filled Borehole in an Anisotropic Solid

This paper describes a time-domain boundary element method developed to analyze the interactions of acoustic and elastic waves near the interfaces between water and an anisotropic elastic solid. Two models are analyzed with one being the interface between two half spaces of fluid and solid and the other being a fluid region sandwiched by half space domains of anisotropic elastic solids. Both monopole and dipole point sources are used to generate an initial pressure wave in the fluid. Some snapshots of the transient wave behavior near the fluid-solid interfaces are given. The effect of the anisotropy in the solid on the pressure waveforms in the fluid is discussed. The numerical results allow detailed arrival identification and interpretation of acoustic and elastic waves propagating along the fluid-solid interfaces.     

Studies on induction hardening of powder-metallurgy-processed Fe-Cr/Mo alloys

Induction hardening of dense Fe-Cr/Mo alloys processed via the powder-metallurgy route was studied. The Fe-3Cr-0.5Mo, Fe-1.5Cr-0.2Mo, and Fe-0.85Mo pre-alloyed powders were mixed with 0.4wt%, 0.6wt%, and 0.8wt% C and compacted at 500, 600, and 700 MPa, respectively. The compacts were sintered at 1473 K for 1 h and then cooled at 6 K/min. Ferrite with pearlite was mostly observed in the sintered alloys with 0.4wt% C, whereas a carbide network was also present in the alloys with 0.8wt% C. Graphite at prior particle boundaries led to deterioration of the mechanical properties of alloys with 0.8wt% C, whereas no significant induction hardening was achieved in alloys with 0.4wt% C. Among the investigated samples, alloys with 0.6wt% C exhibited the highest strength and ductility and were found to be suitable for induction hardening. The hardening was carried out at a frequency of 2.0 kHz for 2-3 s. A case depth of 2.5 mm was achieved while maintaining the bulk (interior) hardness of approximately HV 230. A martensitic structure was observed on the outer periphery of the samples. The hardness varied from HV 600 to HV 375 from the sample surface to the interior of the case hardened region. The best combination of properties and hardening depth was achieved in case of the Fe-1.5Cr-0.2Mo alloy with 0.6wt% C.     

On-chip natural assembly of silicon photonic bandgap crystals.

Photonic bandgap crystals can reflect light for any direction of propagation in specific wavelength ranges. This property, which can be used to confine, manipulate and guide photons, should allow the creation of all-optical integrated circuits. To achieve this goal, conventional semiconductor nanofabrication techniques have been adapted to make photonic crystals. A potentially simpler and cheaper approach for creating three-dimensional periodic structures is the natural assembly of colloidal microspheres. However, this approach yields irregular, polycrystalline photonic crystals that are difficult to incorporate into a device. More importantly, it leads to many structural defects that can destroy the photonic bandgap. Here we show that by assembling a thin layer of colloidal spheres on a silicon substrate, we can obtain planar, single-crystalline silicon photonic crystals that have defect densities sufficiently low that the bandgap survives. As expected from theory, we observe unity reflectance in two crystalline directions of our photonic crystals around a wavelength of 1.3 micrometres. We also show that additional fabrication steps, intentional doping and patterning, can be performed, so demonstrating the potential for specific device applications.     

Water capture by a desert beetle.

Some beetles in the Namib Desert collect drinking water from fog-laden wind on their backs. We show here that these large droplets form by virtue of the insect's bumpy surface, which consists of alternating hydrophobic, wax-coated and hydrophilic, non-waxy regions. The design of this fog-collecting structure can be reproduced cheaply on a commercial scale and may find application in water-trapping tent and building coverings, for example, or in water condensers and engines.     

Superconductivity in CaCuO2 as a result of field-effect doping.

Understanding the doping mechanisms in the simplest superconducting copper oxide-the infinite-layer compound ACuO2 (where A is an alkaline earth metal)-is an excellent way of investigating the pairing mechanism in high-transition-temperature (high-Tc) superconductors more generally. Gate-induced modulation of the carrier concentration to obtain superconductivity is a powerful means of achieving such understanding: it minimizes the effects of potential scattering by impurities, and of structural modifications arising from chemical dopants. Here we report the transport properties of thin films of the infinite-layer compound CaCuO2 using field-effect doping. At high hole- and electron-doping levels, superconductivity is induced in the nominally insulating material. Maximum values of Tc of 89 K and 34 K are observed respectively for hole- and electron-type doping of around 0.15 charge carriers per CuO2. We can explore the whole doping diagram of the CuO2 plane while changing only a single electric parameter, the gate voltage.     

Expanding the diversity of chemical protein modification allows post-translational mimicry

One of the most important current scientific paradoxes is the economy with which nature uses genes. In all higher animals studied, we have found many fewer genes than we would have previously expected. The functional outputs of the eventual products of genes seem to be far more complex than the more restricted blueprint. In higher organisms, the functions of many proteins are modulated by post-translational modifications (PTMs). These alterations of amino-acid side chains lead to higher structural and functional protein diversity and are, therefore, a leading contender for an explanation for this seeming incongruity. Natural protein production methods typically produce PTM mixtures within which function is difficult to dissect or control. Until now it has not been possible to access pure mimics of complex PTMs. Here we report a chemical tagging approach that enables the attachment of multiple modifications to bacterially expressed (bare) protein scaffolds: this approach allows reconstitution of functionally effective mimics of higher organism PTMs. By attaching appropriate modifications at suitable distances in the widely-used LacZ reporter enzyme scaffold, we created protein probes that included sensitive systems for detection of mammalian brain inflammation and disease. Through target synthesis of the desired modification, chemistry provides a structural precision and an ability to retool with a chosen PTM in a manner not available to other approaches. In this way, combining chemical control of PTM with readily available protein scaffolds provides a systematic platform for creating probes of protein-PTM interactions. We therefore anticipate that this ability to build model systems will allow some of this gene product complexity to be dissected, with the aim of eventually being able to completely duplicate the patterns of a particular protein's PTMs from an in vivo assay into an in vitro system.