Variables associated with owner perceptions of the health of their dog: Further analysis of data from a large international survey.

In a recent study (doi: 10.1371/journal.pone.0265662), associations were identified between owner-reported dog health status and diet, whereby those fed a vegan diet were perceived to be healthier. However, the study was limited because it did not consider possible confounding from variables not included in the analysis. The aim of the current study was to extend these earlier findings, using different modelling techniques and including multiple variables, to identify the most important predictors of owner perceptions of dog health. From the original dataset, two binary outcome variables were created: the 'any health problem' distinguished dogs that owners perceived to be healthy ("no") from those perceived to have illness of any severity; the 'significant illness' variable distinguished dogs that owners perceived to be either healthy or having mild illness ("no") from those perceived to have significant or serious illness ("yes"). Associations between these health outcomes and both owner-animal metadata and healthcare variables were assessed using logistic regression and machine learning predictive modelling using XGBoost. For the any health problem outcome, best-fit models for both logistic regression (area under curve [AUC] 0.842) and XGBoost (AUC 0.836) contained the variables dog age, veterinary visits and received medication, whilst owner age and breed size category also featured. For the significant illness outcome, received medication, veterinary visits, dog age and were again the most important predictors for both logistic regression (AUC 0.903) and XGBoost (AUC 0.887), whilst breed size category, education and owner age also featured in the latter. Any contribution from the dog vegan diet variable was negligible. The results of the current study extend the previous research using the same dataset and suggest that diet has limited impact on owner-perceived dog health status; instead, dog age, frequency of veterinary visits and receiving medication are most important.

Identification and characterisation of functional Kir6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane.

BACKGROUND AND PURPOSE: The canonical Kir6.2/SUR2A ventricular KATP channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of KATP channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second KATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active Kir6.1-containing KATP channel in ventricular cardiomyocytes. EXPERIMENTAL APPROACH: Patch-clamp recordings from rat ventricular myocytes in combination with well-defined pharmacological modulators was used to characterise these newly identified K+ channels. Action potential recording, calcium (Fluo-4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation. KEY RESULTS: Our data show a ventricular K+ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with Kir6.1-containing channels. These Kir6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active. CONCLUSION AND IMPLICATIONS: We conclude there are two functionally distinct populations of ventricular KATP channels: constitutively active Kir6.1-containing channels that play an important role in fine-tuning the action potential and Kir6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether Kir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.

Temperature modulates PVN pre-sympathetic neurones via transient receptor potential ion channels.

The paraventricular nucleus (PVN) of the hypothalamus plays a vital role in maintaining homeostasis and modulates cardiovascular function via autonomic pre-sympathetic neurones. We have previously shown that coupling between transient receptor potential cation channel subfamily V Member 4 (Trpv4) and small-conductance calcium-activated potassium channels (SK) in the PVN facilitate osmosensing, but since TRP channels are also thermosensitive, in this report we investigated the temperature sensitivity of these neurones. Methods: TRP channel mRNA was quantified from mouse PVN with RT-PCR and thermosensitivity of Trpv4-like PVN neuronal ion channels characterised with cell-attached patch-clamp electrophysiology. Following recovery of temperature-sensitive single-channel kinetic schema, we constructed a predictive stochastic mathematical model of these neurones and validated this with electrophysiological recordings of action current frequency. Results: 7 thermosensitive TRP channel genes were found in PVN punches. Trpv4 was the most abundant of these and was identified at the single channel level on PVN neurones. We investigated the thermosensitivity of these Trpv4-like channels; open probability (Po) markedly decreased when temperature was decreased, mediated by a decrease in mean open dwell times. Our neuronal model predicted that PVN spontaneous action current frequency (ACf) would increase as temperature is decreased and in our electrophysiological experiments, we found that ACf from PVN neurones was significantly higher at lower temperatures. The broad-spectrum channel blocker gadolinium (100 µM), was used to block the warm-activated, Ca2+-permeable Trpv4 channels. In the presence of gadolinium (100 µM), the temperature effect was largely retained. Using econazole (10 µM), a blocker of Trpm2, we found there were significant increases in overall ACf and the temperature effect was inhibited. Conclusion: Trpv4, the abundantly transcribed thermosensitive TRP channel gene in the PVN appears to contribute to intrinsic thermosensitive properties of PVN neurones. At physiological temperatures (37°C), we observed relatively low ACf primarily due to the activity of Trpm2 channels, whereas at room temperature, where most of the previous characterisation of PVN neuronal activity has been performed, ACf is much higher, and appears to be predominately due to reduced Trpv4 activity. This work gives insight into the fundamental mechanisms by which the body decodes temperature signals and maintains homeostasis.

Long QT syndrome-associated calmodulin variants disrupt the activity of the slowly activating delayed rectifier potassium channel.

Calmodulin (CaM) is a highly conserved mediator of calcium (Ca2+ )-dependent signalling and modulates various cardiac ion channels. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS). LQTS patients display prolonged ventricular recovery times (QT interval), increasing their risk of incurring life-threatening arrhythmic events. Loss-of-function mutations to Kv7.1 (which drives the slow delayed rectifier potassium current, IKs, a key ventricular repolarising current) are the largest contributor to congenital LQTS (>50% of cases). CaM modulates Kv7.1 to produce a Ca2+ -sensitive IKs, but little is known about the consequences of LQTS-associated CaM mutations on Kv7.1 function. Here, we present novel data characterising the biophysical and modulatory properties of three LQTS-associated CaM variants (D95V, N97I and D131H). We showed that mutations induced structural alterations in CaM and reduced affinity for Kv7.1, when compared with wild-type (WT). Using HEK293T cells expressing Kv7.1 channel subunits (KCNQ1/KCNE1) and patch-clamp electrophysiology, we demonstrated that LQTS-associated CaM variants reduced current density at systolic Ca2+ concentrations (1 µm), revealing a direct QT-prolonging modulatory effect. Our data highlight for the first time that LQTS-associated perturbations to CaM's structure impede complex formation with Kv7.1 and subsequently result in reduced IKs. This provides a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype. KEY POINTS: Calmodulin (CaM) is a ubiquitous, highly conserved calcium (Ca2+ ) sensor playing a key role in cardiac muscle contraction. Genotyping has revealed several CaM mutations associated with long QT syndrome (LQTS), a life-threatening cardiac arrhythmia syndrome. LQTS-associated CaM variants (D95V, N97I and D131H) induced structural alterations, altered binding to Kv7.1 and reduced IKs. Our data provide a novel mechanistic insight into how the perturbed structure-function relationship of CaM variants contributes to the LQTS phenotype.

Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review.

Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has been made in musculoskeletal stem cell research, osteoarthritis, the most-common musculoskeletal disorder, still lacks curative treatment. To fine-tune stem-cell-based therapy, it is necessary to focus on the underlying biological mechanisms. Ion channels and the bioelectric signals they generate control the proliferation, differentiation, and migration of musculoskeletal progenitor cells. Calcium- and voltage-activated potassium (KCa) channels are key players in cell physiology in cells of the musculoskeletal system. This review article focused on the big conductance (BK) KCa channels. The regulatory function of BK channels requires interactions with diverse sets of proteins that have different functions in tissue-resident stem cells. In this narrative review article, we discuss the main ion channels of musculoskeletal stem cells, with a focus on calcium-dependent potassium channels, especially on the large conductance BK channel. We review their expression and function in progenitor cell proliferation, differentiation, and migration and highlight gaps in current knowledge on their involvement in musculoskeletal diseases.

TRPC1 channel clustering during store-operated Ca2+ entry in keratinocytes.

Skin is the largest organ in the human body with ∼95% of its surface made up of keratinocytes. These cells maintain a healthy skin barrier through regulated differentiation driven by Ca2+-transcriptional coupling. Many important skin conditions arise from disruption of this process although not all stages are fully understood. We know that elevated extracellular Ca2+ at the skin surface is detected by keratinocyte Gαq-coupled receptors that signal to empty endoplasmic reticulum Ca2+ stores. Orai channel store-operated Ca2+ entry (SOCE) and Ca2+ influx via "canonical" transient receptor potential (TRPC)-composed channels then activates transcription factors that drive differentiation. While STIM-mediated activation of Orai channels following store depletion is well defined, how TRPC channels are activated is less clear. Multiple modes of TRPC channel activation have been proposed, including 1) independent TRPC activation by STIM, 2) formation of Orai-TRPC-STIM complexes, and 3) the insertion of constitutively-active TRPC channels into the membrane during SOCE. To help distinguish between these models, we used high-resolution microscopy of intact keratinocyte (HaCaT) cells and immunogold transmission electron microscopy (TEM) of HaCaT plasma membrane sheets. Our data shows no evidence of significant insertion of Orai1 or TRPC subunits into the membrane during SOCE. Analysis of transmission electron microscopy data shows that during store-depletion and SOCE, Orai1 and TRPC subunits form separate membrane-localized clusters that migrate towards each other. This clustering of TRPC channel subunits in keratinocytes may support the formation of TRPC-STIM interactions at ER-plasma membrane junctions that are distinct from Orai-STIM junctions.

The temporal transcriptomic signature of cartilage formation.

Chondrogenesis is a multistep process, in which cartilage progenitor cells generate a tissue with distinct structural and functional properties. Although several approaches to cartilage regeneration rely on the differentiation of implanted progenitor cells, the temporal transcriptomic landscape of in vitro chondrogenesis in different models has not been reported. Using RNA sequencing, we examined differences in gene expression patterns during cartilage formation in micromass cultures of embryonic limb bud-derived progenitors. Principal component and trajectory analyses revealed a progressively different and distinct transcriptome during chondrogenesis. Differentially expressed genes (DEGs), based on pairwise comparisons of samples from consecutive days were classified into clusters and analysed. We confirmed the involvement of the top DEGs in chondrogenic differentiation using pathway analysis and identified several chondrogenesis-associated transcription factors and collagen subtypes that were not previously linked to cartilage formation. Transient gene silencing of ATOH8 or EBF1 on day 0 attenuated chondrogenesis by deregulating the expression of key osteochondrogenic marker genes in micromass cultures. These results provide detailed insight into the molecular mechanism of chondrogenesis in primary micromass cultures and present a comprehensive dataset of the temporal transcriptomic landscape of chondrogenesis, which may serve as a platform for new molecular approaches in cartilage tissue engineering.

1H NMR Metabolite Monitoring during the Differentiation of Human Induced Pluripotent Stem Cells Provides New Insights into the Molecular Events That Regulate Embryonic Chondrogenesis.

The integration of cell metabolism with signalling pathways, transcription factor networks and epigenetic mediators is critical in coordinating molecular and cellular events during embryogenesis. Induced pluripotent stem cells (IPSCs) are an established model for embryogenesis, germ layer specification and cell lineage differentiation, advancing the study of human embryonic development and the translation of innovations in drug discovery, disease modelling and cell-based therapies. The metabolic regulation of IPSC pluripotency is mediated by balancing glycolysis and oxidative phosphorylation, but there is a paucity of data regarding the influence of individual metabolite changes during cell lineage differentiation. We used 1H NMR metabolite fingerprinting and footprinting to monitor metabolite levels as IPSCs are directed in a three-stage protocol through primitive streak/mesendoderm, mesoderm and chondrogenic populations. Metabolite changes were associated with central metabolism, with aerobic glycolysis predominant in IPSC, elevated oxidative phosphorylation during differentiation and fatty acid oxidation and ketone body use in chondrogenic cells. Metabolites were also implicated in the epigenetic regulation of pluripotency, cell signalling and biosynthetic pathways. Our results show that 1H NMR metabolomics is an effective tool for monitoring metabolite changes during the differentiation of pluripotent cells with implications on optimising media and environmental parameters for the study of embryogenesis and translational applications.

Systemic application of the transient receptor potential vanilloid-type 4 antagonist GSK2193874 induces tail vasodilation in a mouse model of thermoregulation.

In humans, skin is a primary thermoregulatory organ, with vasodilation leading to rapid body cooling, whereas in Rodentia the tail performs an analogous function. Many thermodetection mechanisms are likely to be involved including transient receptor potential vanilloid-type 4 (TRPV4), an ion channel with thermosensitive properties. Previous studies have shown that TRPV4 is a vasodilator by local action in blood vessels, so here, we investigated whether constitutive TRPV4 activity affects Mus muscularis tail vascular tone and thermoregulation. We measured tail blood flow by pressure plethysmography in lightly sedated M. muscularis (CD1 strain) at a range of ambient temperatures, with and without intraperitoneal administration of the blood-brain barrier crossing TRPV4 antagonist GSK2193874. We also measured heart rate (HR) and blood pressure. As expected for a thermoregulatory organ, we found that tail blood flow increased with temperature. However, unexpectedly, we found that GSK2193874 increased tail blood flow at all temperatures, and we observed changes in HR variability. Since local TRPV4 activation causes vasodilation that would increase tail blood flow, these data suggest that increases in tail blood flow resulting from the TRPV4 antagonist may arise from a site other than the blood vessels themselves, perhaps in central cardiovascular control centres.

DeepGANnel: Synthesis of fully annotated single molecule patch-clamp data using generative adversarial networks.

Development of automated analysis tools for "single ion channel" recording is hampered by the lack of available training data. For machine learning based tools, very large training sets are necessary with sample-by-sample point labelled data (e.g., 1 sample point every 100microsecond). In an experimental context, such data are labelled with human supervision, and whilst this is feasible for simple experimental analysis, it is infeasible to generate the enormous datasets that would be necessary for a big data approach using hand crafting. In this work we aimed to develop methods to generate simulated ion channel data that is free from assumptions and prior knowledge of noise and underlying hidden Markov models. We successfully leverage generative adversarial networks (GANs) to build an end-to-end pipeline for generating an unlimited amount of labelled training data from a small, annotated ion channel "seed" record, and this needs no prior knowledge of theoretical dynamical ion channel properties. Our method utilises 2D CNNs to maintain the synchronised temporal relationship between the raw and idealised record. We demonstrate the applicability of the method with 5 different data sources and show authenticity with t-SNE and UMAP projection comparisons between real and synthetic data. The model would be easily extendable to other time series data requiring parallel labelling, such as labelled ECG signals or raw nanopore sequencing data.

Surgical treatment of wrist joint dysfunction in rheumatoid arthritis: A report of two cases.

In rheumatoid arthritis (RA), it is important to actively treat wrist dysfunction to improve patient outcomes. Herein, we report two cases of wrist dysfunction in RA patients who required partial wrist fusion soon after drug initiation. Case 1: A 38-year-old woman was referred to our hospital because of left wrist joint pain. At the time of examination, swelling and tenderness of the left wrist joint were observed. After 6 months of medication, no improvement in symptoms was noted; therefore, partial wrist fusion was performed. Case 2: A 38-year-old woman was referred to our hospital because of right wrist joint pain. A plain X-ray image showed fusion of the carpal bones. Due to previous failure of drug treatment, the patient opted for arthrodesis. The postoperative course was good in both cases, and the pain improved. In these cases of monoarthritic RA, synovitis and bone destruction were observed, but blood tests showed no features of active disease, and drug treatment was ineffective. In such cases, early surgical treatment should be considered, rather than continuing conservative treatment, to ensure the best outcomes.

Transcriptome-based screening of ion channels and transporters in a migratory chondroprogenitor cell line isolated from late-stage osteoarthritic cartilage.

Chondrogenic progenitor cells (CPCs) may be used as an alternative source of cells with potentially superior chondrogenic potential compared to mesenchymal stem cells (MSCs), and could be exploited for future regenerative therapies targeting articular cartilage in degenerative diseases such as osteoarthritis (OA). In this study, we hypothesised that CPCs derived from OA cartilage may be characterised by a distinct channelome. First, a global transcriptomic analysis using Affymetrix microarrays was performed. We studied the profiles of those ion channels and transporter families that may be relevant to chondroprogenitor cell physiology. Following validation of the microarray data with quantitative reverse transcription-polymerase chain reaction, we examined the role of calcium-dependent potassium channels in CPCs and observed functional large-conductance calcium-activated potassium (BK) channels involved in the maintenance of the chondroprogenitor phenotype. In line with our very recent results, we found that the KCNMA1 gene was upregulated in CPCs and observed currents that could be attributed to the BK channel. The BK channel inhibitor paxilline significantly inhibited proliferation, increased the expression of the osteogenic transcription factor RUNX2, enhanced the migration parameters, and completely abolished spontaneous Ca2+ events in CPCs. Through characterisation of their channelome we demonstrate that CPCs are a distinct cell population but are highly similar to MSCs in many respects. This study adds key mechanistic data to the in-depth characterisation of CPCs and their phenotype in the context of cartilage regeneration.

Consideration of differences in drug usage between young-onset and elderly-onset rheumatoid arthritis with target of low disease activity.

OBJECTIVES: Elderly-onset rheumatoid arthritis (EORA) is reported to differ from young-onset rheumatoid arthritis (YORA) with regard to patient background and drug treatment. We examined the amount of drug administered to patients who achieved low disease activity (LDA) for rheumatoid arthritis at our hospital. METHODS: Demographics, clinical history, and treatments were compared between patients with EORA (n = 70) and YORA (n = 190). RESULTS: There was a significant difference in the average age (73.8 vs. 57.8 years), disease duration (6.66 vs. 14.7 years), and sex (62.9% males vs. 83.7% females), but no difference in rheumatoid factor positivity (85.3% vs. 80.7%), anti-citrullinated peptide antibody positivity (86.5% vs. 87.7%), simplified disease activity index (4.28 vs. 4.59), or disease activity score 28-CRP (1.99 vs. 2.04) in the EORA and YORA groups, respectively. There were also no significant differences in prednisolone use (37.1% vs. 36.3%), amount of methotrexate administered (MTX) (1.45 vs. 1.41 mg), and MTX use (55.7% vs. 65.3%). However, the MTX dose (2.89 vs. 4.09 mg/week, p = .011) and overall biologics use (32.9% vs. 56.3%, p = .0012) were significantly lower in patients with EORA than in those with YORA. CONCLUSION: Patients with EORA may be able to achieve LDA with lower drug dosage than those with YORA.

Heart rate variability: Measurement and emerging use in critical care medicine.

Variation in the time interval between consecutive R wave peaks of the QRS complex has long been recognised. Measurement of this RR interval is used to derive heart rate variability. Heart rate variability is thought to reflect modulation of automaticity of the sinus node by the sympathetic and parasympathetic components of the autonomic nervous system. The clinical application of heart rate variability in determining prognosis post myocardial infarction and the risk of sudden cardiac death is well recognised. More recently, analysis of heart rate variability has found utility in predicting foetal deterioration, deterioration due to sepsis and impending multiorgan dysfunction syndrome in critically unwell adults. Moreover, reductions in heart rate variability have been associated with increased mortality in patients admitted to the intensive care unit. It is hypothesised that heart rate variability reflects and quantifies the neural regulation of organ systems such as the cardiovascular and respiratory systems. In disease states, it is thought that there is an 'uncoupling' of organ systems, leading to alterations in 'inter-organ communication' and a clinically detectable reduction in heart rate variability. Despite the increasing evidence of the utility of measuring heart rate variability, there remains debate as to the methodology that best represents clinically relevant outcomes. With continuing advances in technology, our understanding of the physiology responsible for heart rate variability evolves. In this article, we review the current understanding of the physiological basis of heart rate variability and the methods available for its measurement. Finally, we review the emerging use of heart rate variability analysis in intensive care medicine and conditions in which heart rate variability has shown promise as a potential physiomarker of disease.

Pro-inflammatory Cytokines Drive Deregulation of Potassium Channel Expression in Primary Synovial Fibroblasts.

The synovium secretes synovial fluid, but is also richly innervated with nociceptors and acts as a gateway between avascular joint tissues and the circulatory system. Resident fibroblast-like synoviocytes' (FLS) calcium-activated potassium channels (K Ca) change in activity in arthritis models and this correlates with FLS activation. OBJECTIVE: To investigate this activation in an in vitro model of inflammatory arthritis; 72 h treatment with cytokines TNFα and IL1ß. METHODS: FLS cells were isolated from rat synovial membranes. We analyzed global changes in FLS mRNA by RNA-sequencing, then focused on FLS ion channel genes and the corresponding FLS electrophysiological phenotype and finally modeling data with ingenuity pathway analysis (IPA) and MATLAB. RESULTS: IPA showed significant activation of inflammatory, osteoarthritic and calcium signaling canonical pathways by cytokines, and we identified ∼200 channel gene transcripts. The large K Ca (BK) channel consists of the pore forming Kcnma1 together with ß-subunits. Following cytokine treatment, a significant increase in Kcnma1 RNA abundance was detected by qPCR and changes in several ion channels were detected by RNA-sequencing, including a loss of BK channel ß-subunit expression Kcnmb1/2 and an increase in Kcnmb3. In electrophysiological experiments, there was a decrease in over-all current density at 20 mV without change in chord conductance at this potential. CONCLUSION: TNFα and IL1ß treatment of FLS in vitro recapitulated several common features of inflammatory arthritis at the transcriptomic level, including increase in Kcnma1 and Kcnmb3 gene expression.

Anti-arrhythmic properties of non-antiarrhythmic medications.

Traditional anti-arrhythmic drugs are classified by the Vaughan-Williams classification scheme based on their mechanisms of action, which includes effects on receptors and/or ion channels. Some known anti-arrhythmic drugs do not perfectly fit into this classification scheme. Other medications/molecules with established non-anti-arrhythmic indications have shown anti-arrhythmic properties worth exploring. In this narrative review, we discuss the molecular mechanisms and evidence base for the anti-arrhythmic properties of traditional non-antiarrhythmic drugs such as inhibitors of the renin angiotensin system (RAS), statins and polyunsaturated fatty acids (PUFAs). In summary, RAS antagonists, statins and PUFAs are 'upstream target modulators' that appear to have anti-arrhythmic roles. RAS blockers prevent the downstream arrhythmogenic effects of angiotensin II - the main effector peptide of RAS - and the angiotensin type 1 receptor. Statins have pleiotropic effects including anti-inflammatory, immunomodulatory, modulation of autonomic nervous system, anti-proliferative and anti-oxidant actions which appear to underlie their anti-arrhythmic properties. PUFAs have the ability to alter ion channel function and prevent excessive accumulation of calcium ions in cardiac myocytes, which might explain their benefits in certain arrhythmic conditions. Clearly, whilst a number of anti-arrhythmic drugs exist, there is still a need for randomised trials to establish whether additional agents, including those already in clinical use, have significant anti-arrhythmic effects.

Deep-Channel uses deep neural networks to detect single-molecule events from patch-clamp data.

Single-molecule research techniques such as patch-clamp electrophysiology deliver unique biological insight by capturing the movement of individual proteins in real time, unobscured by whole-cell ensemble averaging. The critical first step in analysis is event detection, so called "idealisation", where noisy raw data are turned into discrete records of protein movement. To date there have been practical limitations in patch-clamp data idealisation; high quality idealisation is typically laborious and becomes infeasible and subjective with complex biological data containing many distinct native single-ion channel proteins gating simultaneously. Here, we show a deep learning model based on convolutional neural networks and long short-term memory architecture can automatically idealise complex single molecule activity more accurately and faster than traditional methods. There are no parameters to set; baseline, channel amplitude or numbers of channels for example. We believe this approach could revolutionise the unsupervised automatic detection of single-molecule transition events in the future.

Fine Motor Control Underlies the Association Between Response Inhibition and Drawing Skill in Early Development.

Previous research shows that the development of response inhibition and drawing skill are linked. The current research investigated whether this association reflects a more fundamental link between response inhibition and motor control. In Experiment 1, 3- and 4-year-olds (n = 100) were tested on measures of inhibition, fine motor control, and drawing skill. Data revealed an association between inhibition and fine motor control, which was responsible for most of the association observed with drawing skill. Experiment 2 (n = 100) provided evidence that, unlike fine motor control, gross motor control and inhibition were not associated (after controlling for IQ). Alternative explanations for the link between inhibition and fine motor control are outlined, including a consideration of how these cognitive processes may interact during development.

Emerging Roles of the Membrane Potential: Action Beyond the Action Potential.

Whilst the phenomenon of an electrical resting membrane potential (RMP) is a central tenet of biology, it is nearly always discussed as a phenomenon that facilitates the propagation of action potentials in excitable tissue, muscle, and nerve. However, as ion channel research shifts beyond these tissues, it became clear that the RMP is a feature of virtually all cells studied. The RMP is maintained by the cell's compliment of ion channels. Transcriptome sequencing is increasingly revealing that equally rich compliments of ion channels exist in both excitable and non-excitable tissue. In this review, we discuss a range of critical roles that the RMP has in a variety of cell types beyond the action potential. Whereas most biologists would perceive that the RMP is primarily about excitability, the data show that in fact excitability is only a small part of it. Emerging evidence show that a dynamic membrane potential is critical for many other processes including cell cycle, cell-volume control, proliferation, muscle contraction (even in the absence of an action potential), and wound healing. Modulation of the RMP is therefore a potential target for many new drugs targeting a range of diseases and biological functions from cancer through to wound healing and is likely to be key to the development of successful stem cell therapies.

Ion Channels in the Paraventricular Hypothalamic Nucleus (PVN); Emerging Diversity and Functional Roles.

The paraventricular nucleus of the hypothalamus (PVN) is critical for the regulation of homeostatic function. Although also important for endocrine regulation, it has been referred to as the "autonomic master controller." The emerging consensus is that the PVN is a multifunctional nucleus, with autonomic roles including (but not limited to) coordination of cardiovascular, thermoregulatory, metabolic, circadian and stress responses. However, the cellular mechanisms underlying these multifunctional roles remain poorly understood. Neurones from the PVN project to and can alter the function of sympathetic control regions in the medulla and spinal cord. Dysfunction of sympathetic pre-autonomic neurones (typically hyperactivity) is linked to several diseases including hypertension and heart failure and targeting this region with specific pharmacological or biological agents is a promising area of medical research. However, to facilitate future medical exploitation of the PVN, more detailed models of its neuronal control are required; populated by a greater compliment of constituent ion channels. Whilst the cytoarchitecture, projections and neurotransmitters present in the PVN are reasonably well documented, there have been fewer studies on the expression and interplay of ion channels. In this review we bring together an up to date analysis of PVN ion channel studies and discuss how these channels may interact to control, in particular, the activity of the sympathetic system.