Non-steroidal aromatase inhibitors based on a biphenyl scaffold: synthesis, in vitro SAR, and molecular modelling

The synthesis and in vitro biological evaluation (JEG-3 cells) of a series of novel and potent aromatase inhibitors, prepared by microwave-enhanced Suzuki cross-coupling methodology, are reported. These compounds possess a biphenyl template incorporated with the haem-ligating triazolylmethyl moiety, either on its own or in combination with other substituent(s) at various positions on the phenyl rings. The most potent aromatase inhibitor reported herein has an IC(50) value of 0.12 nM, although seven of its congeners are also highly potent (IC(50)相似文献   

Synthesis and characterization of cytidine derivatives that inhibit the kinase IspE of the non-mevalonate pathway for isoprenoid biosynthesis

The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are attractive targets for the development of novel drugs against malaria and tuberculosis. This pathway is used exclusively by the corresponding pathogens, but not by humans. A series of water-soluble, cytidine-based inhibitors that were originally designed for the fourth enzyme in the pathway, IspD, were shown to inhibit the subsequent enzyme, the kinase IspE (from Escherichia coli). The binding mode of the inhibitors was verified by co-crystal structure analysis, using Aquifex aeolicus IspE. The crystal structures represent the first reported example of a co-crystal structure of IspE with a synthetic ligand and confirmed that ligand binding affinity originates mainly from the interactions of the nucleobase moiety in the cytidine binding pocket of the enzyme. In contrast, the appended benzimidazole moieties of the ligands adopt various orientations in the active site and establish only poor intermolecular contacts with the protein. Defined binding sites for sulfate ions and glycerol molecules, components in the crystallization buffer, near the well-conserved ATP-binding Gly-rich loop of IspE were observed. The crystal structures of A. aeolicus IspE nicely complement the one from E. coli IspE for use in structure-based design, namely by providing invaluable structural information for the design of inhibitors targeting IspE from Mycobacterium tuberculosis and Plasmodium falciparum. Similar to the enzymes from these pathogens, A. aeolicus IspE directs the OH group of a tyrosine residue into a pocket in the active site. In the E. coli enzyme, on the other hand, this pocket is lined by phenylalanine and has a more pronounced hydrophobic character.     

Combined experimental and numerical study on the effective grain growth dynamics in highly anisotropic systems: Application to barium titanate

Abnormal grain growth is a commonly observed phenomenon in barium titanate. It is usually associated with grain boundaries of different mobility and energy present in the microstructure. The influence of interfaces with variable mobility and energy on grain growth is investigated by a combined experimental and numerical approach in a transition region where growth behaviour strongly deviates from Arrhenius behaviour. Abnormal growth occurs between 1275 and 1325 °C, with normal grain growth occurring above and below this temperature range. The overall grain growth rate of the small matrix grains in the transition region is found to increase nonlinearly with inverse temperature between the high- and low-temperature states. A similar behaviour is found in simulations using a 3-D mesoscale grain growth model under the assumption of fractions of grain boundaries being in the high- or low-temperature state. The transition at the grain boundary is in agreement with the complexion model. Additionally, the simulation is used to map the nucleation probability for abnormal grains in the transition region as a function of combined energy and mobility advantages. The energy advantage of the grain boundaries is found to be of greater importance for the nucleation of abnormal grains compared to results from mean field models.     

Immune Aging and Immunotherapy in Cancer

Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.     

Development of Covalent Chitosan-Polyethylenimine Derivatives as Gene Delivery Vehicle: Synthesis,Characterization, and Evaluation

There is an increasing interest in cationic polymers as important constituents of non-viral gene delivery vectors. In the present study, we developed a versatile synthetic route for the production of covalent polymeric conjugates consisting of water-soluble depolymerized chitosan (dCS; M_W 6–9 kDa) and low molecular weight polyethylenimine (PEI; 2.5 kDa linear, 1.8 kDa branched). dCS-PEI derivatives were evaluated based on their physicochemical properties, including purity, covalent bonding, solubility in aqueous media, ability for DNA condensation, and colloidal stability of the resulting polyplexes. They were complexed with non-integrating DNA vectors coding for reporter genes by simple admixing and assessed in vitro using liver-derived HuH-7 cells for their transfection efficiency and cytotoxicity. Using a rational screening cascade, a lead compound was selected (dCS-Suc-LPEI-14) displaying the best balance of biocompatibility, cytotoxicity, and transfection efficiency. Scale-up and in vivo evaluation in wild-type mice allowed for a direct comparison with a commercially available non-viral delivery vector (in vivo-jetPEI). Hepatic expression of the reporter gene luciferase resulted in liver-specific bioluminescence, upon intrabiliary infusion of the chitosan-based polyplexes, which exceeded the signal of the in vivo jetPEI reference formulation by a factor of 10. We conclude that the novel chitosan-derivative dCS-Suc-LPEI-14 shows promise and potential as an efficient polymeric conjugate for non-viral in vivo gene therapy.     

Assessing the Role of Developmental and Environmental Factors in Chemical Defence Variation in Heliconiini Butterflies

Journal of Chemical Ecology - Chemical defences in animals are both incredibly widespread and highly diverse. Yet despite the important role they play in mediating interactions between predators...     

Optimized state estimation by application of machine learning

The requirements concerning the technical availability as part of the overall equipment effectiveness increase constantly in production nowadays. Unplanned downtimes have to be prevented via efficient methods. Predictive, condition-based maintenance represents a valuable approach for fulfilling these demands, but precise models for state estimation are missing. From the manufacturers’ point of view the challenge consists in wear models with the capability of specifying the correct component’s state as well as providing reliable failure forecasts. Unfortunately, nowadays creation of wear models is based on specific stress tests or design of experiments from the manufacturer. The integration of the production phase or even data feedback and user knowledge does not take place. New potential is promised by cross-cutting technologies from ICT like cloud technologies—in general virtual platform concepts—or approaches of machine learning as enabling technologies. The objective of this paper is to adopt existing algorithms to the new application of condition monitoring in order to evaluate the applicability for automated training of robust wear models. In that context the most commonly used algorithms are described and the reader gets an impression what challenges have to be met when dealing with machine learning. A selection of about ten algorithms with 45 variants is evaluated for four different features within a packaging machine. In the outlook the embedding of the trained model in a cloud architecture is presented.     

Processing and analytical characterisation of pulp-enriched cloudy apple juices

Pulp-enriched cloudy apple juices were manufactured from two apple varieties by blending of apple puree with natural cloudy apple juice in order to enrich bioactive secondary plant substances. Finishing of the puree with a 0.6-mm mesh screen and final product homogenisation revealed as the optimum processing technology for the novel 100% fruit beverage. The presence of large particles originating from the puree prevented long-term cloud stability, but due to the proportion of cloud-stable juice a complete phase separation did not occur. Optimal drinkability was achieved at a viscosity of 11.5 mPa s. Polyphenol compositions and concentrations were determined by means of RP-HPLC/PDA. The results ranged from 109 to 610 mg/l. All samples showed the typical polyphenol pattern of apples with dominating hydroxycinnamic acids followed by flavanols and flavonols. The puree addition to the cloudy apple juices increased the polyphenol concentrations by average 100%. Relatively, the highest increase could be observed for dimeric procyanidins. Different technological variants did not affect significantly the polyphenol concentrations. The dietary fibre contents of the pulp-enriched cloudy apple juices ranged from 5.8 to 9.4 g/l.     

Polymeric solar cells based on P3HT:PCBM: Role of the casting solvent

Polymeric photovoltaic (PV) solar cells have been fabricated using six solvents: chloroform (CHCl₃), toluene (T), chlorobenzene (CB), orthodichlorobenzene (ODCB), 1,2,3,4-tetrahydronaphthalene (THN) and 1,2,4-trichlorobenzene (TCB). The active layers were composed of poly(3-hexyl)thiophene (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM). Special care has been taken to keep all experimental parameters constant (thickness of the active layers, donor/acceptor weight ratio, area of active surface and electrodes) in order to avoid artefacts and truly study the effect of solvents. Studies using atomic force microscopy (AFM) and optical absorption (UV-vis) showed the relationship between the photovoltaic performance and the evaporation rate of solvents. The use of solvents with high boiling point results in a higher degree of organization in the structure of P3HT. A direct comparison with devices processed with thermal treatment has also been performed. As often reported thermal annealing increases photo-conversion efficiency of devices created from common solvents, due to better separation of phase between the two materials of the blend. In the case of solvents with high boiling point such as THN and TCB, neither phase separation nor modification of P3HT crystallization induced by thermal annealing has been observed. However thermal treatment appears to enhance performance, ensuing the evaporation of remaining solvent in the active layers. An overview of the effect of solvent on the electrical properties of films containing pure P3HT and P3HT:PCBM blend reported in the literature has been completed for the discussion.