Microwave-assisted synthesis of a MK2 inhibitor by Suzuki-Miyaura coupling for study in Werner syndrome cells

Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells

Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors

Microwave irradiation of 2-halobenzonitriles and methyl thioglycolate in the presence of triethylamine in DMSO at 130 °C provides rapid access to 3-aminobenzo[b]thiophenes in 58–96% yield. This transformation has been applied in the synthesis of the thieno[2,3-b]pyridine core motif of LIMK1 inhibitors, the benzo[4,5]thieno[3,2-e][1,4]diazepin-5(2H)-one scaffold of MK2 inhibitors and a benzo[4,5]thieno[3,2-d]pyrimidin-4-one inhibitor of the PIM kinases

The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells

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Retarding Sub- and Accelerating Super-Diffusion Governed by Distributed Order Fractional Diffusion Equations

We propose diffusion-like equations with time and space fractional derivatives of the distributed order for the kinetic description of anomalous diffusion and relaxation phenomena, whose diffusion exponent varies with time and which, correspondingly, can not be viewed as self-affine random processes possessing a unique Hurst exponent. We prove the positivity of the solutions of the proposed equations and establish the relation to the Continuous Time Random Walk theory. We show that the distributed order time fractional diffusion equation describes the sub-diffusion random process which is subordinated to the Wiener process and whose diffusion exponent diminishes in time (retarding sub-diffusion) leading to superslow diffusion, for which the square displacement grows logarithmically in time. We also demonstrate that the distributed order space fractional diffusion equation describes super-diffusion phenomena when the diffusion exponent grows in time (accelerating super-diffusion).Comment: 11 pages, LaTe

Interethnic bias in willingness to engage in casual sex versus committed relationships

Interethnic romantic relationships are widely seen as a strong indicator of a well-integrated society. However, racial bias may still be evidenced in the tendency to engage in casual sex versus committed relationships. Using a large, age-diverse sample of 3,453 White British participants, this study found a general preference for White partners over racial minority partners. Furthermore, in line with social structural theory, participants reported a relative preference for marriage (versus casual sex) with White partners, but a relative preference for casual sex (versus marriage) with racial minorities. This pattern was further modified by sex: men reported a general preference for casual sex (versus marriage) with all racial groups except White partners. Women, however, reported a general preference for marriage (versus casual sex) with all groups, but this preference was strongest for White partners. The pattern was not further modified by sexual orientation. Implications for contemporary interethnic romantic relationships are discussed

Infrared spectroscopy of phytochrome and model pigments

Fourier-transform infrared difference spectra between the red-absorbing and far-red-absorbing forms of oat phytochrome have been measured in H2O and 2H2O. The difference spectra are compared with infrared spectra of model compounds, i.e. the (5Z,10Z,15Z)- and (5Z,10Z,15E)-isomers of 2,3,7,8,12,13,17,18-octaethyl-bilindion (Et8-bilindion), 2,3-dihydro-2,3,7,8,12,13,17,18-octaethyl-bilindion (H2Et8-bilindion), and protonated H2Et8-bilindion in various solvents. The spectra of the model compounds show that only for the protonated forms can clear differences between the two isomers be detected. Since considerable differences are present between the spectra of Et8-bilindion and H2Et8-bilindion, it is concluded that only the latter compound can serve as a model system of phytochrome. The 2H2O effect on the difference spectrum of phytochrome supports the view that the chromophore in red-absorbing phytochrome is protonated and suggests, in addition, that it is also protonated in far-red-absorbing phytochrome. The spectra show that protonated carboxyl groups are influenced. The small amplitudes in the difference spectra exclude major changes of protein secondary structure

Neutrino Telescopes in the Mediterranean Sea

The observation of high energy extraterrestrial neutrinos can be an invaluable source of information about the most energetic phenomena in the Universe. Neutrinos can shed light on the processes that accelerate charge particles in an incredibly wide range of energies both within and outside our Galaxy. They can also help to investigate the nature of the dark matter that pervades the Universe. The unique properties of the neutrino make it peerless as a cosmic messenger, enabling the study of dense and distant astrophysical objects at high energy. The experimental challenge, however, is enormous. Due to the weakly interacting nature of neutrinos and the expected low fluxes very large detectors are required. In this paper we briefly review the neutrino telescopes under the Mediterranean Sea that are operating or in progress. The first line of the ANTARES telescope started to take data in March 2006 and the full 12-line detector was completed in May 2008. By January 2009 more than one thousand neutrino events had been reconstructed. Some of the results of ANTARES will be reviewed. The NESTOR and NEMO projects have made a lot of progress to demonstrate the feasibility of their proposed technological solutions. Finally, the project of a km3-scale telescope, KM3NeT, is rapidly progressing: a conceptual design report was published in 2008 and a technical design report is expected to be delivered by the end of 2009

The meaning of life in a developing universe

The evolution of life on Earth has produced an organism that is beginning to model and understand its own evolution and the possible future evolution of life in the universe. These models and associated evidence show that evolution on Earth has a trajectory. The scale over which living processes are organized cooperatively has increased progressively, as has its evolvability. Recent theoretical advances raise the possibility that this trajectory is itself part of a wider developmental process. According to these theories, the developmental process has been shaped by a larger evolutionary process that involves the reproduction of universes. This evolutionary process has tuned the key parameters of the universe to increase the likelihood that life will emerge and develop to produce outcomes that are successful in the larger process (e.g. a key outcome may be to produce life and intelligence that intentionally reproduces the universe and tunes the parameters of ‘offspring’ universes). Theory suggests that when life emerges on a planet, it moves along this trajectory of its own accord. However, at a particular point evolution will continue to advance only if organisms emerge that decide to advance the evolutionary process intentionally. The organisms must be prepared to make this commitment even though the ultimate nature and destination of the process is uncertain, and may forever remain unknown. Organisms that complete this transition to intentional evolution will drive the further development of life and intelligence in the universe. Humanity’s increasing understanding of the evolution of life in the universe is rapidly bringing it to the threshold of this major evolutionary transition

A Repeated Measures Experiment of Green Exercise to Improve Self-Esteem in UK School Children

Exercising in natural, green environments creates greater improvements in adult's self-esteem than exercise undertaken in urban or indoor settings. No comparable data are available for children. The aim of this study was to determine whether so called 'green exercise' affected changes in self-esteem; enjoyment and perceived exertion in children differently to urban exercise. We assessed cardiorespiratory fitness (20 m shuttle-run) and self-reported physical activity (PAQ-A) in 11 and 12 year olds (n = 75). Each pupil completed two 1.5 mile timed runs, one in an urban and another in a rural environment. Trials were completed one week apart during scheduled physical education lessons allocated using a repeated measures design. Self-esteem was measured before and after each trial, ratings of perceived exertion (RPE) and enjoyment were assessed after completing each trial. We found a significant main effect (F (1,74), = 12.2, p<0.001), for the increase in self-esteem following exercise but there was no condition by exercise interaction (F (1,74), = 0.13, p = 0.72). There were no significant differences in perceived exertion or enjoyment between conditions. There was a negative correlation (r = -0.26, p = 0.04) between habitual physical activity and RPE during the control condition, which was not evident in the green exercise condition (r = -0.07, p = 0.55). Contrary to previous studies in adults, green exercise did not produce significantly greater increases in self-esteem than the urban exercise condition. Green exercise was enjoyed more equally by children with differing levels of habitual physical activity and has the potential to engage less active children in exercise. © 2013 Reed et al