International Union of Basic and Clinical Pharmacology. CXII: adenosine receptors: a further update

Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011.Significance Statement-Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists ("biased" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A2A and A2BAR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A2AAR antagonist (istradefylline) has been approved as an anti-Parkinson agent.Medicinal Chemistr

Abrupt episode of mid-Cretaceous ocean acidification triggered by massive volcanism

Large igneous province volcanic activity during the mid-Cretaceous approximately 94.5 million years ago triggered a global-scale episode of reduced marine oxygen levels known as Oceanic Anoxic Event 2. It has been hypothesized that this geologically rapid degassing of volcanic carbon dioxide altered seawater carbonate chemistry, affecting marine ecosystems, geochemical cycles, and sedimentation. Here, we report on two sites drilled by the International Ocean Discovery Program offshore of southwest Australia that exhibit clear evidence for suppressed pelagic carbonate sedimentation in the form of a stratigraphic interval barren of carbonate, recording ocean acidification during the event. We then use the osmium isotopic composition of bulk sediments to directly link this protracted ~600- kiloyear shoaling of the marine calcite compensation depth to the onset of volcanic activity. This decrease in marine pH was prolonged by biogeochemical feedbacks in highly productive regions that elevated heterotrophic respiration of carbon dioxide to the water column. A compilation of mid- Cretaceous marine stratigraphic records reveals a contemporaneous decrease of sedimentary carbonate content at continental slope sites globally. Thus, we contend that changes in marine carbonate chemistry are a primary ecological stress and important consequence of rapid emission of carbon dioxide during many large igneous province eruptions in the geologic past

Development of Bicyclo[3.1.0]hexane-based A3 receptor ligands: closing the gaps in the structure–affinity relationships

The adenosine A3 receptor is a promising target for treating and diagnosing inflammation and cancer. In this paper, a series of bicyclo[3.1.0]hexane-based nucleosides was synthesized and evaluated for their P1 receptor affinities in radioligand binding studies. The study focused on modifications at 1-, 2-, and 6-positions of the purine ring and variations of the 5'-position at the bicyclo[3.1.0]hexane moiety, closing existing gaps in the structure-affinity relationships. The most potent derivative 30 displayed moderate A3AR affinity (Ki of 0.38 μM) and high A3R selectivity. A subset of compounds varied at 5'-position was further evaluated in functional P2Y1R assays, displaying no off-target activity.Medicinal Chemistr

Super-resolution imaging of C-type lectin spatial rearrangement within the dendritic cell plasma membrane at fungal microbe contact sites

Dendritic cells express DC-SIGN and CD206, C-type lectins (CTLs) that bind a variety of pathogens and may facilitate pathogen uptake for subsequent antigen presentation. Both proteins form punctate membrane nanodomains (~80 nm) on naïve cells. We analyzed the spatiotemporal distribution of CTLs following host-fungal particle contact using confocal microscopy and three distinct methods of cluster identification and measurement of receptor clusters in super-resolution datasets: DBSCAN, Pair Correlation and a custom implementation of the Getis spatial statistic. Quantitative analysis of confocal and super-resolution images demonstrated that CTL nanodomains become concentrated in the contact site relative to non-contact membrane after the first hour of exposure and established that this recruitment is sustained out to 4 h. DC-SIGN nanodomains in fungal contact sites exhibit a 70% area increase and a 38% decrease in interdomain separation. Contact site CD206 nanodomains possess 90% greater area and 42% lower interdomain separation relative to non-contact regions. Contact site CTL clusters appear as disk-shaped domains of approximately 150–175 nm in diameter. The increase in length scale of CTL nanostructure in contact sites suggests that the smaller nanodomains on resting membranes may merge during fungal recognition, or that they become packed closely enough to achieve sub-resolution inter-domain edge separations of <30 nm. This study provides evidence of local receptor spatial rearrangements on the nanoscale that occur in the plasma membrane upon pathogen binding and may direct important signaling interactions required to recognize and respond to the presence of a relatively large pathogen

The generalized second law of thermodynamics of the universe bounded by the event horizon and modified gravity theories

In this paper, we investigate the validity of the generalized second law of thermodynamics of the universe bounded by the event horizon. Here we consider homogeneous and isotropic model of the universe filled with perfect fluid in one case and in another case holographic model of the universe has been considered. In the third case the matter in the universe is taken in the form of non-interacting two fluid system as holographic dark energy and dust. Here we study the above cases in the Modified gravity, f(R) gravity.Comment: 9 page

Inherited dysfunctional platelet P2Y12 receptor mutations associated with bleeding disorders

The platelet adenosine 5'-diphosphate (ADP) receptor P2Y12 (P2Y12R) plays a critical role in platelet aggregation. The present report illustrates an update of dysfunctional platelet P2Y12R mutations diagnosed with congenital lifelong bleeding problems. Described patients with heterozygous or homozygous substitution in the P2Y12R gene and qualitative abnormalities of the platelet P2Y12R are summarized. Recently, a further dysfunctional variant of P2Y12R has been identified in two brothers who presented with a lifelong severe bleeding disorder. During in vitro aggregation studies, the patient's platelets show a markedly reduced and rapid reversible ADP-promoted aggregation. A homozygous c.561T > A substitution that changes the codon for His187 to Gln (p.His187Gln) in the P2Y12R gene has been identified. This mutation causes no change in receptor expression but decreases the affinity of the ligand for the receptor, even at high concentrations. Structure modelling studies indicated that the p.His187Gln mutation, located in the fifth transmembrane spanning domain (TM5), impairs conformational changes of the receptor. Structural integrity of the TM5 region is necessary for agonist and antagonist binding and for correct receptor function

Cosmological equations and Thermodynamics on Apparent Horizon in Thick Braneworld

We derive the generalized Friedmann equation governing the cosmological evolution inside the thick brane model in the presence of two curvature correction terms: a four-dimensional scalar curvature from induced gravity on the brane, and a five-dimensional Gauss-Bonnet curvature term. We find two effective four-dimensional reductions of the Friedmann equation in some limits and demonstrate that they can be rewritten as the first law of thermodynamics on the apparent horizon of thick braneworld.Comment: 25 pages, no figure, a definition corrected, several references added, more motivation and discussio

Entropic Corrections to Coulomb's Law

Two well-known quantum corrections to the area law have been introduced in the literatures, namely, logarithmic and power-law corrections. Logarithmic corrections, arises from loop quantum gravity due to thermal equilibrium fluctuations and quantum fluctuations, while, power-law correction appears in dealing with the entanglement of quantum fields in and out the horizon. Inspired by Verlinde's argument on the entropic force, and assuming the quantum corrected relation for the entropy, we propose the entropic origin for the Coulomb's law in this note. Also we investigate the Uehling potential as a radiative correction to Coulomb potential in 1-loop order and show that for some value of distance the entropic corrections of the Coulomb's law is compatible with the vacuum-polarization correction in QED. So, we derive modified Coulomb's law as well as the entropy corrected Poisson's equation which governing the evolution of the scalar potential $\phi$. Our study further supports the unification of gravity and electromagnetic interactions based on the holographic principle.Comment: 17 pages, 5 figures, accepted in IJT

Minimum Energy Configurations in the NN-Body Problem and the Celestial Mechanics of Granular Systems

Minimum energy configurations in celestial mechanics are investigated. It is shown that this is not a well defined problem for point-mass celestial mechanics but well-posed for finite density distributions. This naturally leads to a granular mechanics extension of usual celestial mechanics questions such as relative equilibria and stability. This paper specifically studies and finds all relative equilibria and minimum energy configurations for $N=1,2,3$ and develops hypotheses on the relative equilibria and minimum energy configurations for $N\gg 1$ bodies.Comment: Accepted for publication in Celestial Mechanics and Dynamical Astronom

Kinetic profiling and functional characterization of 8-phenylxanthine derivatives as A2B adenosine receptor antagonists

A2B adenosine receptor (A2BAR) antagonists have therapeutic potential in inflammation-related diseases such as asthma, chronic obstructive pulmonary disease and cancer. However, no drug is currently clinically approved, creating a demand for research on novel antagonists. Over the last decade, the study of target binding kinetics, along with affinity and potency, has been proven valuable in early drug discovery stages, as it is associated with improved in vivo drug efficacy and safety. In this study, we report the synthesis and biological evaluation of a series of xanthine derivatives as A2BAR antagonists, including an isothiocyanate derivative designed to bind covalently to the receptor. All 28 final compounds were assessed in radioligand binding experiments, to evaluate their affinity and for those qualifying, kinetic binding parameters. Both structure-affinity and structure-kinetic relationships were derived, providing a clear relationship between affinity and dissociation rate constants. Two structurally similar compounds, 17 and 18, were further evaluated in a label-free assay due to their divergent kinetic profiles. An extended cellular response was associated with long A2BAR residence times. This link between a ligand's A2BAR residence time and its functional effect highlights the importance of binding kinetics as a selection parameter in the early stages of drug discovery.Medicinal Chemistr