Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity

Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells

Youth citizenship, national unity and poverty alleviation: East and West African approaches to the education of a new generation

Youth citizenship is now on the international agenda. This paper explores what that concept might mean in the context of two African nations: Kenya and Ghana. Post independence, both countries focused on rethinking the colonial concept of citizenship in line with their political-cultural traditions, providing education for all youth and to encouraging new notions of national citizenship. Programmes for civic education were established that have been reshaped over the last fifty years. These citizenship education programmes display the tension between different political goals of national unity, economic progress and the promotion of human rights, working with diversity, and encouraging collective responsibility and individual development. The aim is to use the education of the citizen to encourage civic engagement although there is evidence that these programmes might not, for a variety of reasons, engage all young people into the nation building project. The paper considers evidence from a wide range of documentary and social scientific sources to open debate about how to encourage young people's citizenship within the project of poverty alleviation

Synthesis and in vitro Bioactivity of Polyunsaturated Fatty Acid Conjugates of Combretastatin A-4

Combretastatin A-4 (CA-4) (1) is a plant-derived anticancer agent binding to the tubulin colchicine site. Polyunsaturated fatty acids (PUFA) are readily taken up by cancer cells and have been used to improve cell targeting. In the present study, four CA-4-PUFA conjugates were synthesized by coupling combretastatin A-4 (1) with several polyunsaturated fatty acids. The conjugates (2a-d) were characterized using spectroscopic methods. Their cytotoxicity was evaluated against human breast cancer cells (MCF-7) and the inhibition of tubulin polymerization was determined in vitro. All conjugates influenced tubulin polymerization with the arachidonic acid conjugate (2c) displaying cytotoxicity similar in potency to the natural product CA-4 (1)

Long-Range A-Site Cation Disorder in NaA(MO4)2 (M = Mo, W) Double Scheelite Oxides

Synchrotron X-ray and neutron powder diffraction methods have been used to obtain accurate long-range average structures of some double scheelite compounds of the type NaA(BO4)2 (A = La, Pr, Nd, Sm, Lu, and Bi; B = Mo, W) at room temperature. Phase pure samples were synthesized using standard solid-state methods. Rietveld refinements using combined synchrotron X-ray diffraction (SXRD) and neutron diffraction (NPD) revealed a random distribution of the Na and A-type cations regardless of the presence of 6s2 lone pairs (such as Bi3+) and the difference in oxidation states and ionic radii between the cations. The NaA(BO4)2 (A = La, Pr, Nd, Sm, Lu, and Bi) series displayed linear trends in lattice parameters and AO8 polyhedra volume with the ionic radius of the A-type cation for the lanthanoids, but a deviation from the trend was observed for A = Bi3+. The NaBi(BO4)2 structure has a smaller than expected unit cell volume than based on extrapolation from the corresponding NaLn(BO4)2 series, possibly due to short-range ordering of the 6s2 lone pair electrons

Crossover between liquid-like and gas-like behaviour in CH4 at 400 K

We report experimental evidence for a crossover between a liquid-like state and a gas-like state in fluid methane (CH4). This crossover is observed in all of our experiments, up to 397 K temperature; 2.1 times the critical temperature of methane. The crossover has been characterized with both Raman spectroscopy and X-ray diffraction in a number of separate experiments, and confirmed to be reversible. We associate this crossover with the Frenkel line - a recently hypothesized crossover in dynamic properties of fluids extending to arbitrarily high pressure and temperature, dividing the phase diagram into separate regions where the fluid possesses liquid-like and gas-like properties. On the liquid-like side the Raman-active vibration increases in frequency linearly as pressure is increased, as expected due to the repulsive interaction between adjacent molecules. On the gas-like side this competes with the attractive Van der Waal’s potential leading the vibration frequency to decrease as pressure is increased

Cation and lone pair order-disorder in the polymorphic mixed metal bismuth scheelite Bi3FeMo2O12

The Bi3FeMo2O12 system is examined as a rare example of a transition metal oxide which, upon heating, undergoes a symmetry lowering and 2:1 ordering of the transition metal cations. The compound was synthesised in the tetragonal scheelite structure (S.G. #88: I41/a) by a sol-gel method and converted into the monoclinic polymorph (S.G. #15: C2/c) by calcination above 500 °C. The structure of both polymorphs was analysed using a combination of X-ray and neutron diffraction data, and the temperature-dependent phase transition between these was investigated in situ using variable temperature neutron powder diffraction and scanning transmission electron microscopy. The results show that the structural phase transition takes place at low temperature (~500 °C) and is 1st order in nature, as evident from the coexistence of both structures. The transition from tetragonal to monoclinic results in reduction of the equivalent unit cell volume. The role of the Bi3+ 6s lone pairs in the temperature-driven phase transition has been studied using neutron pair distribution function analysis. Local structure analysis via neutron total scattering revealed the Bi3+ 6s lone pairs to be stereochemically active in both structures, with short correlation lengths in the tetragonal structure and long correlation lengths in the monoclinic structure, leading to the facile phase conversion and to a more efficient packing density with highly correlated lone pairs in the monoclinic structure. Magnetization isotherms of the tetragonal structure collected at 1.8 K exhibit ferromagnetic behavior, suggesting that the interplay between the observed short-range monoclinic order, defects and surface-to-bulk effects alters the magnetic interaction, leading to short range ferromagnetic interactions, which is highly unexpected given the low temperature antiferromagnetic order observed in the monoclinic structure

Solar System Physics for Exoplanet Research

Over the past three decades, we have witnessed one of the great revolutions in our understanding of the cosmos-the dawn of the Exoplanet Era. Where once we knew of just one planetary system (the solar system), we now know of thousands, with new systems being announced on a weekly basis. Of the thousands of planetary systems we have found to date, however, there is only one that we can study up-close and personal-the solar system. In this review, we describe our current understanding of the solar system for the exoplanetary science community-with a focus on the processes thought to have shaped the system we see today. In section one, we introduce the solar system as a single well studied example of the many planetary systems now observed. In section two, we describe the solar system's small body populations as we know them today-from the two hundred and five known planetary satellites to the various populations of small bodies that serve as a reminder of the system's formation and early evolution. In section three, we consider our current knowledge of the solar system's planets, as physical bodies. In section four we discuss the research that has been carried out into the solar system's formation and evolution, with a focus on the information gleaned as a result of detailed studies of the system's small body populations. In section five, we discuss our current knowledge of planetary systems beyond our own-both in terms of the planets they host, and in terms of the debris that we observe orbiting their host stars. As we learn ever more about the diversity and ubiquity of other planetary systems, our solar system will remain the key touchstone that facilitates our understanding and modeling of those newly found systems, and we finish section five with a discussion of the future surveys that will further expand that knowledge

Bdellovibrio bacteriovorus Inhibits Staphylococcus aureus Biofilm Formation and Invasion into Human Epithelial Cells

Bdellovibrio bacteriovorus HD100 is a predatory bacterium that attacks many Gram-negative human pathogens. A serious drawback of this strain, however, is its ineffectiveness against Gram-positive strains, such as the human pathogen Staphylococcus aureus. Here we demonstrate that the extracellular proteases produced by a host-independent B. bacteriovorus (HIB) effectively degrade/inhibit the formation of S. aureus biofilms and reduce its virulence. A 10% addition of HIB supernatant caused a 75% or greater reduction in S. aureus biofilm formation as well as 75% dispersal of pre-formed biofilms. LC-MS-MS analyses identified various B. bacteriovorus proteases within the supernatant, including the serine proteases Bd2269 and Bd2321. Tests with AEBSF confirmed that serine proteases were active in the supernatant and that they impacted S. aureus biofilm formation. The supernatant also possessed a slight DNAse activity. Furthermore, treatment of planktonic S. aureus with the supernatant diminished its ability to invade MCF-10a epithelial cells by 5-fold but did not affect the MCF-10a viability. In conclusion, this study illustrates the hitherto unknown ability of B. bacteriovorus to disperse Gram-positive pathogenic biofilms and mitigate their virulence.open6