Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Inwardly rectifying K+ (Kir) channels allow K+ to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. There are ...

Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles

Calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different int...

https://www.physiology.org/doi/pdf/10.1152/physrev.00004.2005

Microdomains of intracellular Ca2+: molecular determinants and functional consequences.

Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological al...

Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal

Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca2+ versus voltage dependent inactivation of L-type Ca2+ current (ICaL); kinetics for the transient outward, rapid delayed rectifier (IKr), Na+/Ca2+ exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by IKr block during slow pacing, and AP and Ca2+ alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling. INaCa linked Ca2+ alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na+]i, via its modulation of the electrogenic Na+/K+ ATPase current. At fast pacing rates, late Na+ current and ICaL were also contributors. APD shortening during restitution was primarily dependent on reduced late Na+ and ICaL currents due to inactivation at short diastolic intervals, with additional contribution from elevated IKr due to incomplete deactivation.

/pdf/simulation-of-the-undiseased-human-cardiac-ventricular-2ji8omiuzi.pdf

Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation

The relative contributions of voltage- and Ca2+-dependent mechanisms of inactivation to the decay of L-type Ca2+ channel currents (ICaL) is an old story to which recent results have given an unexpected twist. In cardiac myocytes voltage-dependent inactivation (VDI) was thought to be slow and Ca2+-dependent inactivation (CDI) resulting from Ca2+ influx and Ca2+-induced Ca2+-release (CICR) from the sarcoplasmic reticulum provided an automatic negative feedback mechanism to limit Ca2+ entry and the contribution of ICaL to the cardiac action potential. Physiological modulation of ICaL by β-adrenergic and muscarinic agonists then involved essentially more or less of the same by enhancing or reducing Ca2+ channel activity, Ca2+ influx, sarcoplasmic reticulum load and thus CDI. Recent results on the other hand place VDI at the centre of the regulation of ICaL. Under basal conditions it has been found that depolarization increases the probability that an ion channel will show rapid VDI. This is prevented by β-adrenergic stimulation. Evidence also suggests that a channel which shows rapid VDI inactivates before CDI can become effective. Therefore the contributions of VDI and CDI to the decay of ICaL are determined by the turning on, by depolarization, and the turning off, by phosphorylation, of the mechanism of rapid VDI. The physiological implications of these ideas are that under basal conditions the contribution of ICaL to the action potential will be determined largely by voltage and by Ca2+ following β-adrenergic stimulation.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2003.047902

Physiological modulation of inactivation in L-type Ca2+ channels: one switch.

Dualistic behavior of ATP-sensitive K+ channels toward intracellular nucleoside diphosphates

Real-time recording of the kinetics of systemically administered drugs in in vivo microenvironments may accelerate the development of effective medical therapies. However, conventional methods require considerable analyte quantities, have low sampling rates and do not address how drug kinetics correlate with target function over time. Here, we describe the development and application of a drug-sensing system consisting of a glass microelectrode and a microsensor composed of boron-doped diamond with a tip of around 40 μm in diameter. We show that, in the guinea pig cochlea, the system can measure—simultaneously and in real time—changes in the concentration of bumetanide (a diuretic that is ototoxic but applicable to epilepsy treatment) and the endocochlear potential underlying hearing. In the rat brain, we tracked the kinetics of the drug and the local field potentials representing neuronal activity. We also show that the actions of the antiepileptic drug lamotrigine and the anticancer reagent doxorubicin can be monitored in vivo. Our microsensing system offers the potential to detect pharmacological and physiological responses that might otherwise remain undetected. A system consisting of a glass microelectrode and a boron-doped diamond microsensor can simultaneously track, in rat brains and in the guinea pig cochlea, the local real-time kinetics of injected drugs and the resulting electrophysiological activity.

A microsensing system for the in vivo real-time detection of local drug kinetics

1. The effects of intracellular redox couples were investigated on the activation by voltage, Ca2+ and NS 1619 of maxi-K channels in enzymatically isolated smooth muscle cells from large pulmonary arteries of rabbits. 2. In inside-out membrane patches, maxi-K channels were characterized by a single-channel conductance of 266 pS in symmetrical 140 mM KCl solutions. The relationship between the open-state probability (Po) and the membrane potential could be fitted to the Boltzmann equation. The activating action of intracellular Ca2+ was reversible, concentration dependent, and was manifested as the reduction in the voltage necessary to half-activate the channel (V1/2) with no change in the slope factor. NS 1619 also predisposed the maxi-K channel to open at more hyperpolarized membrane potentials. 3. The oxidizing agent 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, 1 mM) activated maxi-K channels by inducing a negative shift of the activity-voltage curve, while the reducing agent 2-hydroxy-1-ethanethiol (beta-mercaptoethanol) (BME, 1 mM) had no effect. DTNB increased the efficacy of Ca2+ in activating maxi-K channels. The action of DTNB was not reversible upon wash-out, but could be counteracted by BME. 4. Maxi-K channel activity was unaffected by other oxidizing agents, such as NAD (2 mM) and glutathione disulphide (GSSG, 5 mM), or by their reduced forms (NADH and GSH). Mg-ATP (0.1 and 1 mM) increased the channel activity in a dose-dependent manner, while guanine nucleotides (100 microM GTP gamma S, 500 microM GDP and 200 microM GDP beta S) had no effect. 5. Our data suggest that a change in the intracellular redox state, which would be expected during acute hypoxia, does not alter the activity of maxi-K channels of large pulmonary artery smooth muscle cells. The sulfhydryl-specific redox reagents (DTNB and BME) must act through another regulatory mechanism.

Ian Findlay

Papers

Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles

Physiological modulation of inactivation in L-type Ca2+ channels: one switch.

Dualistic behavior of ATP-sensitive K+ channels toward intracellular nucleoside diphosphates

A microsensing system for the in vivo real-time detection of local drug kinetics

Contrasting effects of intracellular redox couples on the regulation of maxi-K channels in isolated myocytes from rabbit pulmonary artery.