Role of phosphoproteomics in the development of personalized cancer therapies

Cell signalling pathways driven by protein and lipid kinases contribute to the onset and progression of virtually all cancer types. Consequently, several inhibitors against these enzymes have clinical utility for the treatment of different forms of cancer. A problem that hampers further development is that not all patients respond equally well to kinase inhibitors and a significant proportion of those that initially respond eventually develop resistance. This review considers how an integrative analysis of kinase signalling may be used to address this issue. Advances in the biophysics of mass spectrometry, in biochemical procedures for phosphopeptide enrichment, and in computational approaches for label-free quantification have contributed to the development of phosphoproteomics workflows compatible with the analysis of clinical material. These developments, together with new bioinformatics tools to derive information on signalling circuitry from phosphoproteomics data, allow investigating kinase networks with unprecedented depth. Phosphoproteomics technology is starting to be used in translational research and, with further developments, such methods may also be able to measure the circuitry of cancer signalling networks in routine clinical assays. This review reflects on how this information could be used to accurately predict the best kinase inhibitor for each individual cancer patient.     

Improving the performance of Invertible Bloom Lookup Tables

Invertible Bloom Lookup Tables (IBLTs) have been recently introduced as an extension of traditional Bloom filters. IBLTs store key-value pairs. Unlike traditional Bloom filters, IBLTs support both a lookup operation (given a key, return a value) and an operation that lists out all the key-value pairs stored. One issue with IBLTs is that there is a probability that a lookup operation will return “not found” for a key. In this paper, a technique to reduce this probability without affecting the storage requirement and only moderately increasing the search time is presented and evaluated. The results show that it can significantly reduce the probability of not returning a value that is actually stored in the IBLT. The overhead of the modified search procedure, compared to the standard IBLT search procedure, is small and has little impact on the average search time.     

In-situ Mössbauer spectroscopic study of the behaviour of tin(II) chloride during coal hydrogenation

In-situ Mössbauer spectroscopy has been used to study the catalytic role of SnCl₂ and its interaction with the IL6 coal during hydrogenation. The measurements have been recorded under three different atmospheres of nitrogen, hydrogen, and hydrogen in the presence of a heavy distillate solvent SRC-II. The study has shown that both tin and chlorine can enter the coal structure at an early stage of hydrogenation. The presence of chlorine has been shown to cause the cleavage of ether-oxygen linkages in the coal. Tin (II) sulphide is the predominant form of the catalyst after the hydrogenation and is the product of the scavenging of coal sulphur by tin. The study has also shown the formation of FeCl₂ · xH₂0 (x = 1, 2) as a result of the reaction between pyrrhotites (Fe_(1?x)S, formed by the decomposition of FeS₂) and hydrochloric acid in the nitrogen and the hydrogen atmospheres.     

Effects of dietary n−3/n−6 ratio on lipid metabolism of gilthead seabream (Sparus aurata)

The current study was conducted to evaluate the effects of various dietary n?3/n?6 ratio on growth and lipid metabolism in gilthead seabream (Sparus aurata) juveniles. The fish were fed ad libitum on three isoproteic (52%), isolipidic (14%), and isoenergetic diets (21 MJ/kg), formulated to contain three different n?3/n?6 ratios: a high (3.8), medium (2.5), or low (0.9) ratio. Fish grew from 9.5 ± 0.1 g to 54.2 ± 0.7 g in 12 weeks. Growth rate (2.2% BW/day), voluntary feed intake (2.4 ± 0.1% BM/day), feed conversion ratio (1.38 ± 0.05), and net protein utilization (27.5 ± 1.0%) did not vary among treatments. In contrast, body lipid content and lipid deposition efficiency were significantly reduced in fish fed low n?3/n?6 ratio. Fish fed the highest n?3/n?6 ratio showed the lowest hepatic glucose‐6‐phosphate dehydrogenase (G6PD) activity (p = 0.02). The n?3/n?6 ratio decreased, while DHA/eicosapentaenoic acid (EPA) ratio increased significantly with decreasing dietary n?3/n?6 content. Among n?3 PUFA, the DHA and, particularly, the docosapentaenoic acid (DPA) showed the highest deposition rate both in muscle and liver. The lower deposition rate (<1) of linoleic acid (LA) and linolenic acid (LNA) suggests that a reduction in dietary n?3/n?6 ratio may stimulate their transport to the intermediary metabolism for energy production.     

Zinc oxide/carboxylic acid lamellar structures

Hybrid organic–inorganic semiconductor nanocomposites of layered zinc oxide/carboxylic acids were fabricated. Products are pure phases with structures constituted by double-layer sheets of the inorganic component sandwiched between self-assembled surfactant layers. The optical properties of the nanocomposites are found to be qualitatively similar to those of bulk zinc oxide. However, blue shifted absorption band edges and enhanced band-gap energies are observed. The photocatalytic activity of the products in the degradation of methylene blue indicates that the efficiency of the nanocomposites is comparable or even better than that of bulk oxide.     

Superhard Nanobuttons: Constraining Crystal Plasticity and Dealing with Extrinsic Effects at the Nanoscale

The compressive plastic strength of nanosized single‐crystal metallic pillars is known to depend on their diameter D. Herein, the role of pillar height h is analyzed instead, and the suppression of the generalized crystal plasticity below a critical value h_CR is observed. Novel in situ compression tests on regular pillars as well as nanobuttons, that is, pillars with h < h_CR, show that the latter are much harder, withstanding stresses >2 GPa. A statistical model that holds for both pillars and buttons is formulated. Owing to their superhard nature, the nanobuttons examined here underline with unprecedented resolution the extrinsic effects—often overlooked—that naturally arise during testing when the Saint‐Venant assumption ceases to be accurate. The bias related to such effects is identified in the test data and removed when possible. Finally, continuous hardening is observed to occur under increasing stress level, in analogy to reports on nanoparticles. From a metrological standpoint the results expose some difficulties in nanoscale testing related to current methodology and technology. The implications of the analysis of extrinsic effects go beyond nanobuttons and extend to nano‐/microelectromechanical system design and nanomechanics in general.     

Quantifying Linearization Error When Modeling Fluid Pipeline Transients Using the Frequency Response Method

The unsteady mass and momentum equations for pipe flow can be solved in the frequency domain and provides additional insight into the behavior of fluid transients. Additionally, this approach has significant computational advantages compared to the method of characteristics because it is not based on a rigid time-space grid. Despite its advantages, the frequency domain approach must be used with care as it uses linearized forms of the steady friction and orifice equations—which can deviate significantly from the true nonlinear solution. The conditions in which the frequency response method can be accurately used are currently unknown. This paper investigates and quantifies the error in the frequency-domain method, via comparison to a highly discretized time-domain model that uses the method of characteristics, and describes situations where the frequency response method can be used with accurate results. A reservoir-pipe-valve system was used in this study with transients generated by perturbation of the valve. The error consists of errors from two sources: the linear approximations of the steady friction and the steady orifice equations. The frequency response method was shown to produce identical results to the method of characteristics when these two sources of error are minimized. The error in the frequency-domain model was quantified as functions of the perturbation magnitude, frequency, and system parameters. The results indicate that errors are significant when the perturbation size is more than 25% of the steady-state condition and this error is frequency dependent with the largest errors occurring at the harmonic peaks of the system.     

Effect of wall velocities on the determination of optimal separation times in electrical field flow fractionation (EFFF)

Electrical field flow fractionation (EFFF) has two perpendicular driving forces that help to produce an optimal separation of solute in a mixture [Giddings, Science 1993; 260:1456–1465]. For Couette flow based devices, the ratio of the velocity of the capillary walls offers an extra parameter that can be exploited to enhance the efficiency of EFFF applications. The analysis of the effects of this parameter on optimal times of separation is the subject matter of this contribution. The use of this additional parameter increases flexibility in the design of new devices for the improvement of the separation of solutes, such as proteins, DNA, and pharmaceuticals, as it will be illustrated with the results of this analysis (Jaroszeski et al., 2000 ; Trinh et al., 1999 ). The analysis has been illustrated by selecting parameter values that represent a number of potential useful applications. A set of five parameters (i.e., z, the valence; µ, electrophoretic mobility; Pe, Peclet number; Ω, the orthogonal applied electrical field; and R, the ratio of channel wall velocities) has been combined to obtain the best operating conditions for optimal separation of solutes. Results indicate that R, the ratio of the channel wall velocities, is actually the most important driving parameter.