In silico interaction analysis of cannabinoid receptor interacting protein 1b (CRIP1b) � CB1 cannabinoid receptor

Cannabinoid Receptor Interacting Protein isoform 1b (CRIP1b) is known to interact with the CB1 receptor. Alternative splicing of the CNRIP1 gene produces CRIP1a and CRIP1b with a difference in the third exon only. Exons 1 and 2 encode for a functional domain in both proteins. CRIP1a is involved in regulating CB1 receptor internalization, but the function of CRIP1b is not very well characterized. Since there are significant identities in functional domains of these proteins, CRIP1b is a potential target for drug discovery. We report here predicted structure of CRIP1b followed by its interaction analysis with CB1 receptor by in-silico methods A number of complementary computational techniques, including, homology modeling, ab-initio and protein threading, were applied to generate three-dimensional molecular models for CRIP1b. The computed model of CRIP1b was refined, followed by docking with C terminus of CB1 receptor to generate a model for the CRIP1b- CB1 receptor interaction. The structure of CRIP1b obtained by homology modelling using RHOGDI-2 as template is a sandwich fold structure having beta sheets connected by loops, similar to predicted CRIP1a structure. The best scoring refined model of CRIP1b in complex with the CB1 receptor C terminus peptide showed favourable polar interactions. The overall binding pocket of CRIP1b was found to be overlapping to that of CRIP1a. The Arg82 and Cys126 of CRIP1b are involved in the majority of hydrogen bond interactions with the CB1 receptor and are possible key residues required for interactions between the CB1 receptor and CRIP1b. © 2017 Elsevier Inc

Loop-Generated Bounds on Changes to the Graviton Dispersion Relation

We identify the effective theory appropriate to the propagation of massless bulk fields in brane-world scenarios, to show that the dominant low-energy effect of asymmetric warping in the bulk is to modify the dispersion relation of the effective 4-dimensional modes. We show how such changes to the graviton dispersion relation may be bounded through the effects they imply, through loops, for the propagation of standard model particles. We compute these bounds and show that they provide, in some cases, the strongest constraints on nonstandard gravitational dispersions. The bounds obtained in this way are the strongest for the fewest extra dimensions and when the extra-dimensional Planck mass is the smallest. Although the best bounds come for warped 5-D scenarios, for which the 5D Planck Mass is O(TeV), even in 4 dimensions the graviton loop can lead to a bound on the graviton speed which is comparable with other constraints.Comment: 18 pages, LaTeX, 4 figures, uses revte

Lepton Masses and Mixing in a Left-Right Symmetric Model with a TeV-scale Gravity

We construct a left-right symmetric (LRS) model in five dimensions which accounts naturally for the lepton flavor parameters. The fifth dimension is described by an orbifold, S_1/Z_2 times Z'_2, with a typical size of order TeV^{-1}. The fundamental scale is of order 25 TeV which implies that the gauge hierarchy problem is ameliorated. In addition the LRS breaking scale is of order few TeV which implies that interactions beyond those of the standard model are accessible to near future experiments. Leptons of different representations are localized around different orbifold fixed points. This explains, through the Arkani-Hamed-Schmaltz mechanism, the smallness of the tau mass compared to the electroweak breaking scale. An additional U(1) horizontal symmetry, broken by small parameters, yields the hierarchy in the charged lepton masses, strong suppression of the light neutrino masses and accounts for the mixing parameters. The model yields several unique predictions. In particular, the branching ratio for the lepton flavor violating process mu^- --> e^+ e^- e^- is comparable with its present experimental sensitivity.Comment: 21 pages, 1 figure, references added, discussion on the predictiveness of the model in the generic non-universal case added, to appear in PR

Relic Neutrino Absorption Spectroscopy

Resonant annihilation of extremely high-energy cosmic neutrinos on big-bang relic anti-neutrinos (and vice versa) into Z-bosons leads to sizable absorption dips in the neutrino flux to be observed at Earth. The high-energy edges of these dips are fixed, via the resonance energies, by the neutrino masses alone. Their depths are determined by the cosmic neutrino background density, by the cosmological parameters determining the expansion rate of the universe, and by the large redshift history of the cosmic neutrino sources. We investigate the possibility of determining the existence of the cosmic neutrino background within the next decade from a measurement of these absorption dips in the neutrino flux. As a by-product, we study the prospects to infer the absolute neutrino mass scale. We find that, with the presently planned neutrino detectors (ANITA, Auger, EUSO, OWL, RICE, and SalSA) operating in the relevant energy regime above 10^{21} eV, relic neutrino absorption spectroscopy becomes a realistic possibility. It requires, however, the existence of extremely powerful neutrino sources, which should be opaque to nucleons and high-energy photons to evade present constraints. Furthermore, the neutrino mass spectrum must be quasi-degenerate to optimize the dip, which implies m_{nu} >~ 0.1 eV for the lightest neutrino. With a second generation of neutrino detectors, these demanding requirements can be relaxed considerably.Comment: 19 pages, 26 figures, REVTeX

Phenomenology of Neutrino Oscillations

This review is focused on neutrino mixing and neutrino oscillations in the light of the recent experimental developments. After discussing possible types of neutrino mixing for Dirac and Majorana neutrinos and considering in detail the phenomenology of neutrino oscillations in vacuum and matter, we review all existing evidence and indications in favour of neutrino oscillations that have been obtained in the atmospheric, solar and LSND experiments. We present the results of the analyses of the neutrino oscillation data in the framework of mixing of three and four massive neutrinos and investigate possibilities to test the different neutrino mass and mixing schemes obtained in this way. We also discuss briefly future neutrino oscillation experiments.Comment: 109 pages. Final version to be published in Progress in Particle and Nuclear Physics, Volume 43. Typos correcte

Molecular Interaction between Distal C-Terminal Domain of the CB₁ Cannabinoid Receptor and Cannabinoid Receptor Interacting Proteins (CRIP1a/CRIP1b)

We have investigated the structure of the distal C-terminal domain of the of the CB1 cannabinoid receptor (CB1R) to study its interactions with CRIP1a and CRIP1b using computational techniques. The amino acid sequence from the distal C-terminal domain of CB1R (G417-L472) was found to be unique, as it does not share sequence similarity with other protein structures, so the structure was predicted using ab initio modeling. The computed model of the distal C-terminal region of CB1R has a helical region between positions 441 and 455. The CRIP1a and CRIP1b were modeled using Rho-GDI 2 as a template. The three-dimensional model of the distal C-terminal domain of the CB1R was docked with both CRIP1a as well as CRIP1b to study the crucial interactions between CB1R and CRIP1a/b. The last nine residues of CB1R (S464TDTSAEAL4722) are known to be a CRIP1a/b binding site. The majority of the key interactions were identified in this region, but notable interactions were also observed beyond theses nine residues. The multiple interactions between Thr418 (CB1R) and Asn61 (CRIP1a) as well as Asp430 (CB1R) and Lys76 (CRIP1a) indicate their importance in the CB1R-CRIP1a interaction. In the case of CRIP1b, multiple hydrogen bond interactions between Asn437 (CB1R) and Glu77 (CRIP1b) were observed. These interactions can be critical for CB1R's interaction with CRIP1a/b, and targeting them for further experimental studies can advance information about CRIP1a/b functionality. © 2019 American Chemical Society

Nucleosynthesis in Supernovae

We present the status and open problems of nucleosynthesis in supernova explosions of both types, responsible for the production of the intermediate mass, Fe-group and heavier elements (with the exception of the main s-process). Constraints from observations can be provided through individual supernovae (SNe) or their remnants (e.g. via spectra and gamma-rays of decaying unstable isotopes) and through surface abundances of stars which witness the composition of the interstellar gas at their formation. With a changing fraction of elements heavier than He in these stars (known as metallicity) the evolution of the nucleosynthesis in galaxies over time can be determined. A complementary way, related to gamma-rays from radioactive decays, is the observation of positrons released in beta(+)-decays, as e.g. from Al-26, Ti-44, Ni-56,Ni-57 and possibly further isotopes of their decay chains (in competition with the production of e(+)e(-) pairs in acceleration shocks from SN remnants, pulsars, magnetars or even of particle physics origin). We discuss (a) the role of the core-collapse supernova explosion mechanism for the composition of intermediate mass, Fe-group (and heavier?) ejecta, (b) the transition from neutron stars to black holes as the final result of the collapse of massive stars, and the relation of the latter to supernovae, faint supernovae, and gamma-ray bursts/hypernovae, (c) Type Ia supernovae and their nucleosynthesis (e.g. addressing the Mn-55 puzzle), plus (d) further constraints from galactic evolution, gamma-ray and positron observations. This is complemented by the role of rare magneto-rotational supernovae (related to magnetars) in comparison with the nucleosynthesis of compact binary mergers, especially with respect to forming the heaviest r-process elements in galactic evolution