Analysis of natural product regulation of cannabinoid receptors in the treatment of human disease

The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB2 selective affinity; the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from commercial markets for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules

The diet and feeding ecology of Conger conger (L. 1758) in the deep waters of the Eastern Ionian Sea

The diet of the European conger eel Conger conger was investigated for the first time in the Eastern Mediterranean. Fish dominated the European conger eel diet in the deep waters of E. Ionian Sea. All other prey taxa were identified as accidental preys. However, intestine analysis showed that Natantia, Brachyura and Cephalopoda might have a more important contribution in the diet of the species. C. conger exhibited a benthopelagic feeding behavior as it preyed upon both demersal and mesopelagic taxa. The high vacuity index and the low stomach and intestine fullness indicated that the feeding intensity of the species in the deep waters of Eastern Ionian Sea was quite low. C. conger feeding strategy was characterised by specialisation in various resource items. A between-phenotype contribution to niche width was observed for some prey categories. European Conger eel feeding specialisation seemed to be an adaptation to a food-scarce environment, as typified in deep-water habitat

Current cosmological bounds on neutrino masses and relativistic relics

We combine the most recent observations of large-scale structure (2dF and SDSS galaxy surveys) and cosmic microwave anisotropies (WMAP and ACBAR) to put constraints on flat cosmological models where the number of massive neutrinos and of massless relativistic relics are both left arbitrary. We discuss the impact of each dataset and of various priors on our bounds. For the standard case of three thermalized neutrinos, we find an upper bound on the total neutrino mass sum m_nu < 1.0 (resp. 0.6) eV (at 2sigma), using only CMB and LSS data (resp. including priors from supernovae data and the HST Key Project), a bound that is quite insensitive to the splitting of the total mass between the three species. When the total number of neutrinos or relativistic relics N_eff is left free, the upper bound on sum m_nu (at 2sigma, including all priors) ranges from 1.0 to 1.5 eV depending on the mass splitting. We provide an explanation of the parameter degeneracy that allows larger values of the masses when N_eff increases. Finally, we show that the limit on the total neutrino mass is not significantly modified in the presence of primordial gravitational waves, because current data provide a clear distinction between the corresponding effects.Comment: 13 pages, 6 figure

Multimodal long noncoding RNA interaction networks: Control panels for cell fate specification

Lineage specification in early development is the basis for the exquisitely precise body plan of multicellular organisms. It is therefore critical to understand cell fate decisions in early development. Moreover, for regenerative medicine, the accurate specification of cell types to replace damaged/diseased tissue is strongly dependent on identifying determinants of cell identity. Long noncoding RNAs (lncRNAs) have been shown to regulate cellular plasticity, including pluripotency establishment and maintenance, differentiation and development, yet broad phenotypic analysis and the mechanistic basis of their function remains lacking. As components of molecular condensates, lncRNAs interact with almost all classes of cellular biomolecules, including proteins, DNA, mRNAs, and microRNAs. With functions ranging from controlling alternative splicing of mRNAs, to providing scaffolding upon which chromatin modifiers are assembled, it is clear that at least a subset of lncRNAs are far from the transcriptional noise they were once deemed. This review highlights the diversity of lncRNA interactions in the context of cell fate specification, and provides examples of each type of interaction in relevant developmental contexts. Also highlighted are experimental and computational approaches to study lncRNAs

New Constraints from Electric Dipole Moments on Parameters of the Supersymmetric SO(10) Model

We calculate the chromoelectric dipole moment (CEDM) of d- and s-quark in the supersymmetric SO(10) model. CEDM is more efficient than quark electric dipole moment (EDM), in inducing the neutron EDM. New, strict constraints on parameters of the supersymmetric SO(10) model follow in this way from the neutron dipole moment experiments. As strict bounds are derived from the upper limits on the dipole moment of odd isotope of mercury.Comment: 9 pages, latex, 3 figures available at reques

Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events

Abstract Background In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point. Patients and methods Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form. Results Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66–0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65–0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE. Conclusion In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE

SWI/SNF remains localized to chromatin in the presence of SCHLAP1

SCHLAP1 is a long noncoding RNA that is reported to function by depleting the SWI/SNF complex from the genome. We investigated the hypothesis that SCHLAP1 affects only specific compositions of SWI/SNF. Using several assays, we found that SWI/SNF is not depleted from the genome by SCHLAP1 and that SWI/SNF is associated with many coding and noncoding RNAs, suggesting that SCHLAP1 may function in a SWI/SNF-independent manner

Economics of preceding crops and nitrogen application rates for canola and barley production in western Canada

Non-Peer ReviewedThe objective of this study was to evaluate the economic effects of a range of legume and non-legume preceding crops and N rates on costs and net revenue (NR) of canola (Brassica napus L.), barley (Hordeum vulgare L.) and canola-barley rotation under various environmental conditions. Legumes such as field pea (Pisum sativum L.) and lentil (Lens culinaris Medik.) as preceding crop generated higher net revenues for the following crops canola and barley than when wheat (Triticum aestivum L.) and canola were the preceding crops. Although faba bean (Vicia faba L.) grown as a green manure produced the highest annual net revenues for the following crops canola and barley, this contribution was not enough to compensate for the loss of income during the green manure production year. Therefore, growing faba bean as a green manure was not economical. Response of net revenue to N rates was mainly linear or quadratic, and N was optimal at 60 to 90 kg ha-1 at most sites. The results indicate that growing legumes for seed prior to canola can increase net revenues of canola and subsequent barley

Contribution of legume preceding crops to improve economic and non-renewable energy use efficiency of canola production

Non-Peer Reviewe