Thiol-reactive analogues of galanthamine, codeine and morphine as potential probes to interrogate allosteric binding within nAChRs

Alkaloids including galanthamine (1) and codeine (2) are reported to be positive allosteric modulators of nicotinic acetylcholine receptors (nAChRs) but the binding sites responsible for this activity are not known with certainty. Analogues of galanthamine (1), codeine (2) and morphine (3) with reactivity towards cysteine thiols were synthesised including conjugated enone derivatives of the three alkaloids 4-6 and two chloro-alkane derivatives of codeine 7 and 8. The stability of the enones was deemed sufficient for use in buffered aqueous solutions and their reactivity towards thiols was assessed by determining the kinetics of reaction with a cysteine derivative. All three enone derivatives were of sufficient reactivity and stability to be used in covalent trapping, an extension of the substituted cysteine accessibility method (SCAM), to elucidate the allosteric binding sites of galanthamine and codeine at nAChRs

Alpha9 nicotinic acetylcholine receptors and the treatment of pain

Chronic pain is a vexing worldwide problem that causes substantial disability and consumes significant medical resources. Although there are numerous analgesic medications, these work through a small set of molecular mechanisms. Even when these medications are used in combination, substantial amounts of pain often remain. It is therefore highly desirable to develop treatments that work through distinct mechanisms of action. While agonists of nicotinic acetylcholine receptors (nAChRs) have been intensively studied, new data suggest a role for selective antagonists of nAChRs. α-Conotoxins are small peptides used offensively by carnivorous marine snails known as Conus. A subset of these peptides known as α-conotoxins RgIA and Vc1.1 produces both acute and long lasting analgesia. In addition, these peptides appear to accelerate the recovery of function after nerve injury, possibly through immune mediated mechanisms. Pharmacological analysis indicates that RgIA and Vc1.1 are selective antagonists of α9α10 nAChRs. A recent study also reported that these α9α10 antagonists are also potent GABA-B agonists. In the current study, we were unable to detect RgIA or Vc1.1 binding to or action on cloned GABA-B receptors expressed in HEK cells or Xenopus oocytes. We review the background, findings and implications of use of compounds that act on α9* nAChRs.11* indicates the possible presence of additional subunits.Fil: McIntosh, J. Michael. University of Utah; Estados UnidosFil: Absalom, Nathan. The University of Sydney; AustraliaFil: Chebib, Mary. The University of Sydney; AustraliaFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Vincler, Michelle. Wake Forest University Health Sciences; Estados Unido

The relative impact of evolving pleiotropy and mutational correlation on trait divergence

Both pleiotropic connectivity and mutational correlations can restrict the decoupling of traits under divergent selection, but it is unknown which is more important in trait evolution. To address this question, we create a model that permits within-population variation in both pleiotropic connectivity and mutational correlation, and compare their relative importance to trait evolution. Specifically, we developed an individual-based stochastic model where mutations can affect whether a locus affects a trait and the extent of mutational correlations in a population. We find that traits can decouple whether there is evolution in pleiotropic connectivity or mutational correlation, but when both can evolve, then evolution in pleiotropic connectivity is more likely to allow for decoupling to occur. The most common genotype found in this case is characterized by having one locus that maintains connectivity to all traits and another that loses connectivity to the traits under stabilizing selection (subfunctionalization). This genotype is favored because it allows the subfunctionalized locus to accumulate greater effect size alleles, contributing to increasingly divergent trait values in the traits under divergent selection without changing the trait values of the other traits (genetic modularization). These results provide evidence that partial subfunctionalization of pleiotropic loci may be a common mechanism of trait decoupling under regimes of corridor selection.Peer reviewe

Domestication syndrome via indirect selection in simulated cereal grains

Domestication syndrome in cereal grains is commonly thought to be the product of domestication through a combination of direct artificial selection and indirect natural selection by humans. We propose an agent-based model of grain domestication. We simulate cereal grains with four genes that impact their reproductive cycle undergoing harvesting and selective planting by simulated humans. When direct artificial selection is applied to one gene domestication syndrome emerges in the other genes as a result of indirect natural selection. In the absence of direct artificial selection no domestication syndrome emerged, consistent with periods of predomestication cultivation in human history. Domesticated variants are strongest when humans select for traits inconsistent with the wild type traits, and weakest when humans select for traits consistent with the wild type

Political Preferences and Individual Choice: A Latin American’s Countries Perspective

Analyzing the “left” and “right” political positions of individuals is challenging because personal attributes may influence political decisions without directly causing them. This issue may be even more pronounced in Latin America, where young democracies encounter the challenge of stabilizing political choices over time. This study contributes to the literature by analyzing the influence of personal attributes on political choices, focusing on the early 2000s, when the “left” turn occurred. The present study relies on the World Values Survey’s fifth wave (2005-2008) to fulfil this objective. This dataset is composed of data that have been collected globally, and the questions are related to diverse subjects associated with the quality of life of individuals. From the available sample, we included all of the Latin American countries that participated in this wave: Argentina, Brazil, Chile, Colombia, Mexico, Peru, and Uruguay. In this study, the aim is to directly understand the impact of these individuals own attributes on their declared self-positioning about the political leaning. To this aim, an ordered logit model was used to analyse how each variable exerts influence on the political leaning of the respondents. Our results found that political cleavages depend on demographic factors, economic factors, and individual opinions in agreement with previous studies. Increased age, religious service attendance, and satisfaction with one’s financial life increase the tendency of individuals for self-positioning to the right of the political spectrum. The possession of a university degree and residence in a large city increases the likelihood of individuals of self-identifying with a leftist political position. This study contributes to the literature by analysing the influence of personal attributes on political choices. Although this research represents an important step toward understanding political leanings in Latin American countries, a significant amount of future research remains. The definitions of “left” and “right” continue to be unclear as they relate to dimensions that include democracy, autocracy, and political reform. Understanding the ways individuals set up their choices would increase the responsibility of political parties and authorities for the hidden claim the population has about their deliverables. At the same time, studies like ours may enhance the awareness of the general impression over political party choices of candidates. Finally, even with so many confounding aspects in this antagonist position, the left and the right continue to be a simple way to characterize veiled assumptions. Therefore, it may be an ambiguous form of defining choices, but this seemingly binary choice is still very significant for voters in Latin America.

Identification of GABA receptors in chick cornea

Purpose: The cornea has an important role in vision, is highly innervated and many neurotransmitter receptors are present, e.g., muscarine, melatonin, and dopamine receptors. γ-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the retina and central nervous system, but it is unknown whether GABA receptors are present in cornea. The aim of this study was to determine if GABA receptors are located in chick cornea. Methods: Corneal tissues were collected from 25, 12-day-old chicks. Real time PCR, western blot, and immunohistochemistry were used to determine whether alpha1 GABAA, GABAB, and rho1 GABAC receptors were expressed and located in chick cornea. Results: Corneal tissue was positive for alpha1 GABAA and rho1 GABAC receptor mRNA (PCR) and protein (western blot) expression but was negative for GABAB receptor mRNA and protein. Alpha1 GABAA and rho1 GABAC receptor protein labeling was observed in the corneal epithelium using immunohistochemistry. Conclusions: These investigations clearly show that chick cornea possesses alpha1 GABAA, and rho1 GABAC receptors, but not GABAB receptors. The purpose of the alpha1 GABAA and rho1 GABAC receptors in cornea is a fascinating unexplored question