Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases

There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist ‘Eve’ designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax.     

Two distinct events, section compression and loss of particles ("lost caps"), contribute to z-axis distortion and bias in optical disector counting

Deformation of tissue sections in the z-axis can bias optical disector counting. When samples of particle densities are not representative for the entire tissue section, significant bias of estimated numbers can result. To assess the occurrence, prevalence, extent, sequence of events, and causes of z-axis distortion, the distribution of neuronal nucleoli in thick paraffin and vibratome sections was determined in chicken, rodent, and human brain tissues. When positions of neuronal nucleoli were measured in the z-axis, nucleoli were more frequent at the surfaces (bottom and top) of tissue sections than in the core. This nonlinear z-axis distribution was not lab-, equipment-, or investigator-specific, and was independent of age, fixation quality, coverslipping medium, or paraffin melting temperature, but in paraffin sections, was highly correlated with the tilt of the knife (cutting) angle. Manipulation of subsequent tissue processing steps revealed that two events contribute to z-axis distortion. Initially, a higher density of particles results at surfaces after sectioning, apparently due to section compression. Subsequently, particles can be lost to varying degrees from surfaces during floating or staining and dehydration, resulting in "lost caps." These results may explain different degrees of z-axis distortion between different types of sections and different labs, and reinforce the importance of checking z-axis distributions as a "quality control" prior to selection of guard zones in optical disector counting. Indirect approaches to assess section quality, such as resectioning in a perpendicular plane, yield additional artifacts, and should be replaced by a direct quantitative measurement of z-axis distribution of particles.     

Effect of time on the hydration and temperature-induced phase separation in aqueous polymer solutions. H NMR study

Dehydration during temperature-induced phase separation in D₂O solutions of poly(vinyl methyl ether) (PVME), poly(N-isopropylmethacrylamide) (PIPMAm) and poly(N-isopropylacrylamide) (PIPAAm) was followed from time dependences of NMR spin-spin relaxation times T₂ of HDO. Both the time characterizing the exclusion of the water from mesoglobules (manifested by the increase in T₂ values) and the induction period which precedes the increase in T₂ values, increased in the order PVME < PIPMAm < PIPAAm. For D₂O solutions of PIPMAm/PVME (or PIPMAm/PIPAAm) mixtures a direct connection between the state of the mesoglobules (hydrated or dehydrated) formed by the component with lower LCST (PVME, PIPAAm) and the temperatures of the phase transition of the PIPMAm component was established by NMR spectroscopy.     

High-Temperature Oxidation Resistance of Ceramic Matrix Composites Si3N4 – Cf

We have studied the behavior of ceramic matrix composites in the system Si₃N₄ – C_f, reinforced with different types of carbon fibers, at moderate (1100°C) and maximum (1500°C) service temperatures. We have studied the effect of the composition of ceramic matrix composites and the oxidation temperature conditions on their strength properties and microstructure.     

Stimuli‐sensitive behaviour of novel betaine‐type polyampholytes

Novel linear and crosslinked polyampholytes of betaine structure based on acrylic acid and ethyl 3‐aminocrotonate (ethyl ester of 3‐amino‐2‐butenoic acid) have been synthesized by Michael addition reaction followed by radical copolymerization. The mechanism of formation of monomer and polymer betaines is discussed. The linear polyampholyte has been characterized by potentiometric titration, IR, NMR and GPC. Crosslinked polymeric betaines were synthesized in the presence of N,N′‐methylenebisacrylamide. The stimuli‐sensitive properties of amphoteric gels have been studied as a function of pH, ionic strength, water–organic mixture composition, electric, and combined electric and magnetic fields. The isoelectric points of linear and crosslinked polymeric betaines correspond to pH 2.0–2.1. The effect of ionic strength on the solution and gel properties of polybetaine has been interpreted on the basis of destruction of inter‐chain, intra‐chain and intra‐group salt bonds. Water–acetone, water–ethanol or water–DMF mixtures cause the shrinking of amphoteric gel due to change of the dielectric constant of the medium and decrease of the osmotic pressure. Electrocollapse is observed under the action of DC electric field. Simultaneously cross action of electric and magnetic fields enhances the collapsing rate. Appearance of pH gradient within the volume of polyampholyte gel under the externally imposed DC electric field has been observed. Copyright © 2003 Society of Chemical Industry     

A regular,hydrophobically modified polyampholyte as novel pour point depressant

A new regular polyampholyte, namely poly(N,N‐diallyl‐N‐octadecylamine‐alt‐(maleic acid)), was studied as an additive to crude oil. The amphiphilic polyampholyte proved to be an efficient pour point depressant, to inhibit the deposition of wax, and to improve the viscosity of waxy crude oil from the Akshabulak oilfield (Western Kazakhstan). On optimizing the concentration of the polymer, both the kinematical viscosity and the pour point of waxy crude oils were found to be strongly decreased. The morphology of the paraffin aggregates formed was compared before and after heat treatment of the waxy crude oils, in the presence and the absence of the polymer. The rheological characteristics of the waxy crude oil were markedly improved, in particular, by decreasing the plastic viscosity and the yield stress values upon addition the polymer. The inhibition of wax deposits in the presence of the amphiphilic polyampholyte was interpreted in terms of its interference with the wax crystallization process because of the formation of inverse micellar structures. Although the interaction of the cationic and the anionic groups on the polymer backbone stabilizes the smaller size of the aggregates, the hydrophobic side chains of the polymer provide nucleation sites and cocrystallize with the paraffins, thus modifying the paraffin crystal structure. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 2101–2108, 2005     

Characteristics of undernourished older medical patients and the identification of predictors for undernutrition status

Background  

Undernutrition among older people is a continuing source of concern, particularly among acutely hospitalized patients. The purpose of the current study is to compare malnourished elderly patients with those at nutritional risk and identify factors contributing to the variability between the groups.     

Impact of Ba2+ on Structure and Piezoelectric Properties of PMN–PZN–PNN–PT Ceramics Near the Morphotropic Phase Boundary

The effect of using Ba²⁺ to modify the structure and dielectric and piezoelectric properties of Pb_(1?x)Ba_x(Mg_1/3Nb_2/3)_m(Zn_1/3Nb_2/3)_y(Ni_1/3Nb_2/3)_nTi_zO₃(x = 0–0.15) ceramics near the morphotropic phase boundary has been investigated. It is found that increasing the content of Ba²⁺ leads to a sequence of structural transformations from heterophase state (tetragonal and pseudocubic phases) to a cubic state via an intermediate pseudocubic phase. The evolution of the dielectric and piezoelectric properties (sequences of transformations: normal ferroelectric →relaxor ferroelectric → paraelectric) is shown. It is stated that ceramics with x = 0.025–0.050 possess the optimal combination of functional parameters for use in low‐frequency receivers and actuators. They are characterized by high values of small‐signal and large‐signal piezoelectric coefficients d₃₃ of 621 pC/N and ~1500 m/V (at E = 5 kV/cm), respectively, and also by increased values of dielectric permittivity ε/ε₀ and tunability coefficient (К = [(ε/ε₀(E = 0) ? ε/ε₀(E≠0))/ε/ε₀(E = 0)]·100%), equal to ~7000 and ~80%, respectively (at E = 20 kV/cm). It is shown that for the creation of high‐power piezoelectric transducers it is necessary to use ceramics with x = 0.125, which differs with high values of the mechanical quality factor Q_m and ε/ε₀ (1406 and 10 890, respectively).     

Sonochemical Synthesis and Magnetism in Co-doped ZnO Nanoparticles

The understanding and control of ferromagnetism in diluted magnetic semiconducting oxides (DMO) is a special challenge in solid-state physics and materials science due to its impact in magneto-optical devices and spintronics. Several studies and mechanisms have been proposed to explain intrinsic ferromagnetism in DMO compounds since the theoretical prediction of room-temperature ferromagnetism. However, genuine and intrinsic ferromagnetism in 3d-transition metal-doped n-type ZnO semiconductors is still a controversial issue. Furthermore, for DMO nanoparticles, some special physical and chemical effects may also play a role. In this contribution, structural and magnetic properties of sonochemically prepared cobalt-doped ZnO nanoparticles were investigated. A set of ZnO samples was prepared varying cobalt molar concentration and time of ultrasonic exposure. The obtained results showed that single phase samples can be obtained by the sonochemical method. However, cobalt nanoclusters can be detected depending on synthesis conditions. Magnetic measurements indicated a possible ferromagnetic response, associated to defects and cobalt substitutions at the zinc site by cobalt. However, ferromagnetism is depleted at higher magnetic fields. Also, an antiferromagnetic response is detected due to cobalt oxide cluster at high cobalt molar concentrations.     

Poly(imide-amide)-poly(ethylene glycol) hybrid networks: nanostructure,molecular dynamics and membrane properties

Summary Nanometer-scale structure, molecular dynamics (at 100-580 K) and membrane properties were studied in two series of poly(imide-amide) (PIA)-poly(ethylene glycol) (PEG) hybrid networks with regularly varied composition and different lengths of PEG crosslinks (M_n= 1000 or 3400). Combined WAXD/SAXS/polarized microscopy/DSC/DRS/TSDC/creep rate spectroscopy (CRS) analysis of these hybrids was performed. Depending on their composition, semicrystalline or mesomorphous, or amorphous state, and nanostructural heterogeneity were observed for these networks. They could be subdivided into (a) the PIA-rich hybrids with spatially isolated PEG domains, “suppressed” dynamics in the PEG glass transition, and PIA domains with T_g=520–570 K (group 1), and (b) the other hybrids with a continuous PEG phase and low-temperature glass transition only (group 2). Heterogeneity in segmental dynamics was revealed by CRS over the temperature range from T_g^PEG to T_g^PIA. In the second group of hybrids, the permeability coefficients were higher, by two or three orders of magnitude, for organic vapors than those for air gases.