Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity

The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan-histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk-benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6-selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea-based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea-based hydroxamic acids. Herein, we report highly potent N-alkoxyurea-based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti-proliferative properties compared to nexturastat A.     

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications

Prolactinoma has the highest incidence rate among patients with functional pituitary tumours. Although mostly benign, there is a subgroup that can be aggressive. Some clinical, radiological and pathology features have been associated with a poor prognostic. Therefore, it can be considered as a group of heterogeneous tumours. The aim of this paper is to give an overview of the molecular pathways involved in the behaviour of prolactinoma in order to improve our approach and gain deeper insight into the better understanding of tumour development and its management. This is essential for identifying patients harbouring aggressive prolactinoma and to establish personalised therapeutics options.     

Data reconciliation: Development of an object-oriented software tool

Object-oriented modeling methodology is used for encapsulating different methods and attributes of data reconciliation (DR) in classes. Classes which are defined for DR, cover steady-state, dynamic, linear and nonlinear DR problems. Two main classes are Constraints and DR and defined for manipulating constraints and general DR problem. The remaining classes are derived from these two classes. A class namely DDRMethod is developed for encapsulating all common attributes and methods needed for any DDR method. Developed DR software and the method of performing dynamic DR are discussed in this paper. Two illustrative examples of Extended Kalman Filtering and artificial neural networks are used for DDR and two classes of DDRByKalman and NetDDRMethod developed by inheritance from DDRMethod class for these two methods. Performance of the proposed method is investigated by DDR of temperature measurements of a distillation column.     

Is it really possible to compensate for colour blindness with a filter?

In the last 2 decades, there has been a resurgence of the idea that passive aids such as colour filters can be an effective solution to compensate colour vision deficiency (CVD) or improve colour vision for subjects with CVD. We examine briefly the scientific evidence that has to date been gathered to study the reliability of these aids. In the light of our experience working in this field, we reflect on several related issues: why this question has not been elucidated before, how a filter would have to be designed for a specific task, and the importance of developing a personalised colour space for subjects with CVD to gain some insight into the effect of aids.     

Determination of number-average and weight-average molecular weights of polymer sample from diffusion and sedimentation velocity measurements in theta solvent

Several methods to determine number-average molecular weight M_n and weight-average molecular weight M_w, of a polymer sample are proposed from diffusion and sedimentation velocity measurements at the θ point. According to these methods, M_n and M_w are determined from the diffusion constant vs. molecular weight relationship, and also from the equations of Svedberg and Flory–Mandelkern, using the 2nd-order and the –2nd-order diffusion constants. These methods have been applied to four samples of polydisperse polystyrene in the θ solvent, cyclohexane at 35°C. It was experimentally ascertained that M_n and M_w of each sample determined by the present methods were in good agreement with the results of column fractionation, light scattering, and calculated values from molecular weight distribution curve within experimental errors. It is concluded that the present methods are useful for determining M_n and M_w, since the reliabilities of M_n and M_w values, which are fundamental quantities of polymer characterization, can be raised by comparing the experimental data observed by conventional methods such as osmotic pressure, light scattering, and the Archibald method with those observed by the present methods.     

Estimation of critical properties with group contribution methods

Currently available group-contribution methods for T_c, P_c, and V_c were evaluated using the Ambrose (1980) critical property data compilation. The Ambrose estimation methods were found to be the most accurate. Linear regression methods were also employed to develop alternate estimation methods which were found to have an accuracy comparable to those of Ambrose.     

Thermal degradation kinetics of a commercial epoxy resin—Comparative analysis of parameter estimation methods

The thermal degradation behavior of a commercial epoxy resin, EpoFix® (Struers), has been investigated by thermogravimetry (TG), differential thermal gravimetry (DTG), and differential thermal analysis (DTA) under nonisothermal conditions in an argon atmosphere. Different methods (Kissinger, Flynn–Wall–Ozawa (FWO), Friedman isoconversion methods, and nonlinear least‐squares (NLSQ) estimation method) have been used to analyze the thermal degradation process and determine the apparent kinetic parameters. The methods produce similar results in terms of activation energy estimations. Nevertheless, the NLSQ method has several advantages over the other methods in terms of both characterizing the activation energy and modeling the thermal degradation—i.e., including this model in a resin degradation process simulation. However, it is interesting to combine the NLSQ method with other isoconversion methods: they can reflect the dependence and variability of the activation energies during pyrolysis processes, while providing a good starting point for a nonlinear procedure, especially with respect to the activation energy E. This work is the first step (apparent kinetic reaction) of complete simulation of experimental oven of degradation of epoxy resin coating of impregnate nuclear fuel sample. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42201.     

Fracture toughness, strength, and other characteristics of yttria-stabilized zirconium ceramics

The mechanical behavior of zirconium ceramics with different porosities (456 and 1330 MPa) is studied with an accent on the fracture toughness (the study of other characteristics in a wide temperature range plays an auxiliary role) The tests are predominantly performed with the use of a Vickers pyramid (theIF andIS methods) and under flexure (theSEVNB andSENB methods) The results of the indentation and subsequent bending of the specimens are used to plot aR-curve that turns out to be plane It is shown that despite the substantial difference in the strength of the studied variants of ceramics their crack resistance differs inconsiderably The values of the critical coefficients of stress intensity determined by various methods for the same ceramics are shown to differ The results obtained are analyzed using the data of a micro-Raman analysis The tests for crack resistance by the method ofSEVNB (bending of a beam with a polishedV-notch) show that the specimens do not undergo a tetragonal-monoclinic phase transformation during the deposition of a stress concentrator Transleted from Ogneupory i Technicheskaya Keramika, No. 8, pp. 7 – 13, August, 2000.     

A Systematic Chemometric Approach to Identify the Geographical Origin of Olive Oils

The verification of the geographical origin of olive oils by analytical techniques is still a challenge. The goal of this work is to explore the application and accuracy of different chemometric tools combined with near infrared spectroscopy (NIR) based analytical methods in the field of geographical authenticity of olive oils. As olive oils associated with different geographical origins are mainly characterized by different fatty acid (FA) and triacylglycerol (TAG) compositions, NIR methods for the fast and reliable determination of these parameters are developed. Next, these NIR methods are used to characterize a comprehensive set of olive oils (n > 5000) derived from 19 different countries. This set of data is used to build a statistical workflow, which allows the determination of the geographical origin of unknown olive oil samples. First of all, the untreated data set is pretreated by k‐means clustering and the selection of the relevant analytical variables by principal component analysis (PCA) and linear discriminant analysis (LDA) and min/max normalization of all parameters. Subsequently, classification is performed with a reduced sample set of the 200 most similar samples identified by k‐nearest neighbor tool (kNN). For classification purpose kNN, LDA, naïve Bayes classifier, and logit regression are applied. Practical Applications: The established statistical workflow can be used to verify the geographical origin of olive oils. The application and usage of up to four different statistical models for classification purpose results in a superior probability of the predicted origin in comparison to the application of only one single statistical classification test. As standardized methods are used as reference methods for building the NIR methods, the FA and TAG composition and the iodine value can be either determined by the standard methods or by the described NIR method. The presented statistical approach will help to build up a system for the verification of the geographical origin of olive oils.     

Evaluation of emu oil extraction methods and their effects on physical and rheological behavior

In this study we evaluated the efficiency of six extraction methods for emu fat based on the quantification of yield, color, density, refraction index, and rheological behavior. Both physical methods (Bain Marie, rotary evaporator, fusion, ultrasound, and microwave) and chemical methods (solvents) were evaluated. Oil properties were compared with commercial emu oil as a reference. Solvent‐based extraction produced the greatest yield (72.8%). Among the physical methods, the greatest yield was produced by the ultrasound method (42.8%). In general, properties were similar to those reported for vegetable oils. The rotary evaporator method showed the greatest difference in total color (ΔE) in comparison with a commercially‐produced reference, while the fusion method showed the smallest ΔE. No statistically significant differences were found between the density and refraction index of the treated samples and those of the reference. Kinematic viscosity increased significantly in samples extracted via microwave method. All samples displayed pseudoplastic behavior. The data showed a good fit to the power law model (R² > 0.90). The consistency coefficient and flow behavior index were determined for all methods. Practical applications: Therapeutic applications for oil have been posited for emu oil. In pharmaceutical products, oils are used as emollients and as carriers for medicinal substances. The practical importance of an oil depends on its physical properties, thus a thorough understanding of those physical properties is very important for identifying potential applications. These properties are affected by the extraction method employed; the present paper evaluates the effects of a range of extraction methods on yield efficiency, as well as physical and rheological properties. Novel extraction methods such as ultrasound and microwave are also evaluated in this study.     

Detection of Pathological Markers of Neurodegenerative Diseases following Microfluidic Direct Conversion of Patient Fibroblasts into Neurons

Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are clinically diagnosed using neuropsychological and cognitive tests, expensive neuroimaging-based approaches (MRI and PET) and invasive and time-consuming lumbar puncture for cerebrospinal fluid (CSF) sample collection to detect biomarkers. Thus, a rapid, simple and cost-effective approach to more easily access fluids and tissues is in great need. Here, we exploit the chemical direct reprogramming of patient skin fibroblasts into neurons (chemically induced neurons, ciNs) as a novel strategy for the rapid detection of different pathological markers of neurodegenerative diseases. We found that FAD fibroblasts have a reduced efficiency of reprogramming, and converted ciNs show a less complex neuronal network. In addition, ciNs from patients show misfolded protein accumulation and mitochondria ultrastructural abnormalities, biomarkers commonly associated with neurodegeneration. Moreover, for the first time, we show that microfluidic technology, in combination with chemical reprogramming, enables on-chip examination of disease pathological processes and may have important applications in diagnosis. In conclusion, ciNs on microfluidic devices represent a small-scale, non-invasive and cost-effective high-throughput tool for protein misfolding disease diagnosis and may be useful for new biomarker discovery, disease mechanism studies and design of personalised therapies.     

Chemosensory responses of cowpea weevil,Callosobruchus chinensis to an aquatic weed,water hyacinth,Eichhornia crassipes (Mart) Solms

The behavioral responses of cowpea weevil,Callosobruchus chinensis to the leaf extracts of the aquatic weed, water hyacinth,Eichhornia crassipes (Mart) Solms. was evaluated by three different methods. The petroleum ether-soluble fraction ofE. crassipes induced high weevil attraction in all methods employed. The olfactometer assay provided a reading on weevil chemosensory responses, whereas the free-choice tests measured response and preference of weevils to the untreated or extract-treated food grain of their choice over a longer period. The extracts were also presented under no choice test conditions to assay them for the presence of oviposition stimulants. In all these methods the extracts of water hyacinth evoked a quick directional response. Another interesting feature is that the extract, besides producing attraction, also caused mortality of the insects.     

Weekly Weather Generation for a Nitrogen Turnover Model

Three methods of deriving weather for use in a nitrogen decision support system with a weekly time-step are described and evaluated. The simplest of these is simply the mean (M) of the three weather variables: Rainfall (R), evapotranspiration (ET) and temperature (T). To represent the variability of weather, many sets of generated data are needed but this is not possible with mean values. Two methods of generating rainfall are described: a fully stochastic simulator (FS) and a method based on partitioning the distribution into sections (SM). Temperature, T, and evapotranspiration ET are represented in both generators by sinusoidal functions. The amount of R is modelled as an empirical distribution, rain persistence as a Markov chain. All three means of deriving weather were compared directly with actual weather from the historical record and in use with the SUNDIAL DSS. The mean values of R, ET and T were reproduced satisfactorily (r > 0.99) by both FS and SM, but variability less accurately (r > 0.80 for the standard deviations of T, r > 0.97 for R and ET). The mean values of several components of the nitrogen cycle sim ulated with SUNDIAL were generally reproduced well for both methods of weather generation, but less accurately for mean weather. For leaching, the root mean square errors were 2.6, 2.3 and 11.4 kg/ha for FS, SM and M, respectively. The sectioning method generally gave a poor estimate of variation, which was significantly underestimated for the majority of variables, in the case of leaching by a factor of three. Where variance is important, FS is preferred; weather data generated by this method may be used with confidence for risk assessments of denitrification and crop N uptake.     

Scaling-up of process for production of antibiotic of Myxococcus xanthus TA

A process for the production of Myxococcus xanthus TA (M. xanthus TA) antibiotic was scaled-up to bench and pilot plant scales. The process includes the following steps: (a) propagation of M. xanthus TA in cultures of up to 750 litres. After 4 days of growth the maximum antibiotic yield achieved was 24 units/ml supernatant, and the highest titres were obtained at a low oxygen absorption rate of 0.2; (b) processing of the clarified culture supernatant. Two methods were successfully piloted: the chloroform extraction method and the kaolin adsorption method. Both methods were followed by elution with 20% methanol in chloroform. The recoveries of antibiotic activity were 90% and 85% respectively by the two methods. The process described could be used for the large-scale preparation of the novel antibiotic of M. xanthus TA.     

Analysis of several methods to determine the activity of water in solutions of strong electrolytes

The methods of Zdanovskii-Stokes-Robinson (ZSR), Reilly-Wood-Robinson (RWR), Pitzer and Correa, to determine water activity in ternary solutions of electrolytes from data for water activity in binary solutions, were analysed. In addition, the first two methods were used to estimate the activity of water in supersaturated binary solutions using data from ternary solutions. Also, the equation of Correa for binary solutions was extrapolated to calculate the activity of water at supersaturation. The methods were tested using the experimental data (at 25°C) for nine ternary systems, with a common ion, involving the following ions: Li⁺, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺, Cl^? and NO₃^?. Zdanovskii's method gave the best estimations of water activity in ternary systems. The method of Correa gave smaller standard deviations than the methods of Pitzer and RWR with the advantage that its application is simpler. For binary solutions at supersaturation, Correa's method gave better results than the method of ZSR and this, in turn, yielded smaller deviations than the RWR method.