Monovalent and divalent cation permeability and block of neuronal nicotinic receptor channels in rat parasympathetic ganglia

Acetylcholine-evoked currents mediated by activation of nicotinic receptors in rat parasympathetic neurons were examined using whole-cell voltage clamp. The relative permeability of the neuronal nicotinic acetylcholine (nACh) receptor channel to monovalent and divalent inorganic and organic cations was determined from reversal potential measurements. The channel exhibited weak selectivity among the alkali metals with a selectivity sequence of Cs+ \u3e K+ \u3e Rb+ \u3e Na+ \u3e Li+, and permeability ratios relative to Na+ (P(x)/P(Na)) ranging from 1.27 to 0.75. The selectivity of the alkaline earths was also weak, with the sequence of Mg2+ \u3e Sr2+ \u3e Ba2+ \u3e Ca2+, and relative permeabilities of 1.10 to 0.65. The relative Ca2+ permeability (P(Ca)/P(Na)) of the neuronal nACh receptor channel is ~ fivefold higher than that of the motor endplate channel (Adams, D. J., T. M. Dwyer, and B. Hille. 1980. Journal of General Physiology. 75:493-510). The transition metal cation, Mn2+ was permeant (P(x)/P(Na) = 0.67), whereas Ni2+, Zn2+, and Cd2+ blocked ACh-evoked currents with half-maximal inhibition (IC50) occurring at ~500 μM, 5 μM and 1 mM, respectively. In contrast to the muscle endplate AChR channel, that at least 56 organic cations which are permeable to (Dwyer et al. 1980), the majority of organic cations tested were found to completely inhibit ACh-evoked currents in rat parasympathetic neurons. Concentration-response curves for guanidinium, ethylammonium, diethanolammonium and arginine inhibition of ACh-evoked currents yielded IC50s of ~2.5-6.0 mM. The organic cations, hydrazinium, methylammonium, ethanolammonium and Tris, were measurably permeant, and permeability ratios varied inversely with the molecular size of the cation. Modeling suggests that the pore has a minimum diameter of 7.6 Å. Thus, there are substantial differences in ion permeation and block between the nACh receptor channels of mammalian parasympathetic neurons and amphibian skeletal muscle which represent functional consequences of differences in the primary structure of the subunits of the ACh receptor channel

Heterogeneity of Nicotinic Receptor Class and Subunit mRNA Expression among Individual Parasympathetic Neurons from Rat Intracardiac Ganglia

Neurons have the potential to form thousands of distinct neuronal nicotinic receptors from the eight alpha and three beta subunits that currently are known. In an effort to determine how much of this potential complexity is realized among individual neurons, we examined the nicotinic pharmacological and biophysical properties and receptor subunit mRNA expression patterns in individual neurons cultured from rat epicardial ganglia. Analysis of the whole-cell pharmacology of these neurons showed a diversity of responses to the agonists acetylcholine, nicotine, cytisine, and 1,1-dimethyl-4-phenylpiperazinium, suggesting that a heterogeneous population of nicotinic receptor classes, or subtypes, is expressed by individual neurons. Single-channel analysis demonstrated three distinct conductances (18, 24, and 31 pS), with patches from different neurons containing different combinations of these channel classes. We used single-cell RT-PCR to examine nicotinic acetylcholine receptor (nAChR) subunit mRNA expression by individual neurons. Although mRNAs encoding all eight neuronal nAChR subunits for which we probed (alpha 2-alpha 5, alpha 7, beta 2-beta 4) were present in multicellular cultures, we found that individual epicardial neurons express distinct subsets of these nAChR subunit mRNAs. These results suggest that individual epicardial neurons express distinct arrays of nAChR subunits and that these subunits may assemble into functional receptors with distinct and variable subunit composition. This variable receptor subunit expression provides an explanation for the diversity of pharmacological and single-channel responses we have observed in individual neurons

Comparison of prestellar core elongations and large-scale molecular cloud structures in the Lupus 1 region

Turbulence and magnetic fields are expected to be important for regulating molecular cloud formation and evolution. However, their effects on sub-parsec to 100 parsec scales, leading to the formation of starless cores, are not well understood. We investigate the prestellar core structure morphologies obtained from analysis of the Herschel-SPIRE 350 mum maps of the Lupus I cloud. This distribution is first compared on a statistical basis to the large-scale shape of the main filament. We find the distribution of the elongation position angle of the cores to be consistent with a random distribution, which means no specific orientation of the morphology of the cores is observed with respect to the mean orientation of the large-scale filament in Lupus I, nor relative to a large-scale bent filament model. This distribution is also compared to the mean orientation of the large-scale magnetic fields probed at 350 mum with the Balloon-borne Large Aperture Telescope for Polarimetry during its 2010 campaign. Here again we do not find any correlation between the core morphology distribution and the average orientation of the magnetic fields on parsec scales. Our main conclusion is that the local filament dynamics---including secondary filaments that often run orthogonally to the primary filament---and possibly small-scale variations in the local magnetic field direction, could be the dominant factors for explaining the final orientation of each core

A systematic review investigating the behaviour change strategies in interventions to prevent misuse of anabolic steroids.

We examined intervention effectiveness of strategies to prevent image- and performance-enhancing drug use. Comprehensive searches identified 14 interventions that met review inclusion criteria. Interventions were predominantly educational and delivered within school sport settings, but targeted a wide range of mediating factors. Identification of effective components was limited across studies by brief or imprecise descriptions of intervention content, lack of behavioural outcome measures and short-term follow-up times. However, studies with components in addition to information provision may be more promising. Interventions outside of sport settings are required to reflect the transition of this form of substance use to the general population

Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

[This corrects the article DOI: 10.1038/s42003-018-0226-0.]

The prestellar and protostellar population of R Coronae Australis

We present 450 and 850 um maps of R Coronae Australis. We compare the maps to previous surveys of the region, and shed new light on the previously unknown nature of the protostellar sources at the centre of the cloud. We clarify the nature of two millimetre sources previously discovered in lower resolution data. We identify one new Class 0 protostar that we label SMM 1B, and we measure the envelope masses of a number of more evolved protostars. We identify two new prestellar cores that we call SMM 1A and SMM 6.Comment: 8 page