The electrophysiologic effects of KCNQ1 extend beyond expression of IKs: evidence from genetic and pharmacologic block.

AIMS: While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human-induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. METHODS AND RESULTS: We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss-of-function (LOF) KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small IKs was readily recorded but the pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). In contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute IKr block: the concentration (µM) of moxifloxacin required to prolong APD90 100 msec was 237.4 [median, interquartile range (IQR) 100.6-391.6, n = 7] in population cells vs. 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300 µM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs and markedly prolonged APD90. CONCLUSION: Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs.

Respiratory virus surveillance in hospitalized children less than two-years of age in Kenema, Sierra Leone during the COVID-19 pandemic (October 2020- October 2021).

Globally, viral pathogens are the leading cause of acute respiratory infection in children under-five years. We aim to describe the epidemiology of viral respiratory pathogens in hospitalized children under-two years of age in Eastern Province of Sierra Leone, during the second year of the SARS-CoV-2 pandemic. We conducted a prospective study of children hospitalized with respiratory symptoms between October 2020 and October 2021. We collected demographic and clinical characteristics and calculated each participant´s respiratory symptom severity. Nose and throat swabs were collected at enrollment. Total nucleic acid was purified and tested for multiple respiratory viruses. Statistical analysis was performed using R version 4.2.0 software. 502 children less than two-years of age were enrolled. 376 (74.9%) had at least one respiratory virus detected. The most common viruses isolated were HRV/EV (28.2%), RSV (19.5%) and PIV (13.1%). Influenza and SARS-CoV-2 were identified in only 9.2% and 3.9% of children, respectively. Viral co-detection was common. Human metapneumovirus and RSV had more than two-fold higher odds of requiring O2 therapy while hospitalized. Viral pathogen prevalence was high (74.9%) in our study population. Despite this, 100% of children received antibiotics, underscoring a need to expand laboratory diagnostic capacity and to revisit clinical guidelines implementation in these children. Continuous surveillance and serologic studies among more diverse age groups, with greater geographic breadth, are needed in Sierra Leone to better characterize the long-term impact of COVID-19 on respiratory virus prevalence and to better characterize the seasonality of respiratory viruses in Sierra Leone.

Understanding the temporal dynamics of problem anger using sequence analysis.

Problem anger is a common, and potentially destructive mental health issue in trauma-affected populations, affecting up to 30% of veteran and military populations. Problem anger is associated with a range of psychosocial and functional difficulties and elevated risk of harm to self and others. Increasingly, ecological momentary assessment (EMA) is being used to understand the microlevel dynamics of emotions, and this information is valuable to inform treatment approaches. Using a data-driven approach, we used sequence analysis to determine whether heterogeneity exists amongst veterans with problem anger using EMA-recorded experiences of anger intensity. Veterans with problem anger (N = 60; Mage = 40.28) completed 10 days of EMA with four prompts per day. We identified four subtypes of veterans within the data, whose anger intensity dynamics differed significantly, and the subtypes mapped onto macrolevel indicators of anger and well-being. Taken together, these results highlight the importance of microlevel investigations of mood states in clinical populations, and in some instances, the novel use of sequence analysis may be appropriate. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Design, development and randomised controlled trial protocol of a smartphone-delivered version of 'SOLAR' for emergency service workers to manage stress and trauma.

IntroductionEmergency service workers are routinely exposed to stress and trauma, and there is a need to address mental health symptoms early to prevent chronic impairment and/or psychiatric disorder. Digital health innovations mean that face-to-face psychosocial interventions can now be delivered remotely, which is particularly appealing to populations who have strong preferences for digital delivery, such as emergency service workers. This two phase study aims to first adapt the Skills fOr Life Adjustment and Resilience (SOLAR) programme into a smartphone application ('app'), and then evaluate the effectiveness of this new app. METHODS AND ANALYSES: First, focus groups and codesign activities with mental health professionals and emergency service workers will be conducted to develop and test the prototype smartphone version of SOLAR (ie, SOLAR-m). Second, a multicentre randomised controlled trial will investigate the effectiveness of the new app, compared with an active control app, in reducing symptoms of anxiety and depression (primary outcome), as well as other indicators of mental health and work performance. Firefighters from one of the largest urban fire and rescue services in Australia who are currently experiencing distress will be invited to participate. After screening and baseline assessment, 240 will be randomised to receive either SOLAR-m or the control app for 5 weeks, with measurements pre, post and 3-month follow-up. Analyses will be conducted within an intention-to-treat framework using mixed modelling. ETHICS AND DISSEMINATION: The current trial has received ethics approval from the University of Melbourne Human Research Ethics Committee (2021-20632-18826-5). Study results will be disseminated through peer-reviewed journals and conferences, with a focus on how to expand the new app to other trauma-affected populations if proven effective. TRIAL REGISTRATION NUMBER: ANZCTRN12621001141831.

Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.

BACKGROUND: Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant. METHODS: We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals). RESULTS: TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (INa), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A down-regulation caused decreased peak INa, and that reduced PDGF receptor (PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late INa. Tbx5 regulation of the PDGF axis increased arrhythmia risk due to disruption of PDGF signaling and was conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (P<0.001). CONCLUSIONS: These results not only establish decreased SCN5A transcription by the TBX5 variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.

Ambulatory assessment to predict problem anger in trauma-affected adults: Study protocol.

BACKGROUND: Problem anger is common after experiencing a traumatic event. Current evidence-driven treatment options are limited, and problem anger negatively affects an individual's capacity to engage with traditional psychological treatments. Smartphone interventions hold significant potential in mental health because of their ability to deliver low-intensity, precision support for individuals at the time and place they need it most. While wearable technology has the capacity to augment smartphone-delivered interventions, there is a dearth of evidence relating to several key areas, including feasibility of compliance in mental health populations; validity of in vivo anger assessment; ability to predict future mood states; and delivery of timely and appropriate interventions. METHODS: This protocol describes a cohort study that leverages 10 days of ambulatory assessment in the form of ecological momentary assessment and a wearable. Approximately 100 adults with problem anger will complete four-hourly in vivo mobile application-delivered micro-surveys on anger intensity, frequency, and verbal and physical aggression, as well as other self-reported mental health and wellbeing measures. Concurrently, a commercial wearable device will continuously record indicators of physiological arousal. The aims are to test the feasibility and acceptability of ambulatory assessment in a trauma-affected population, and determine whether a continuously measured physiological indicator of stress predicts self-reported anger intensity. DISCUSSION: This study will contribute new data around the ability of physiological indicators to predict mood state in individuals with psychopathology. This will have important implications for the design of smartphone-delivered interventions for trauma-affected individuals, as well as for the digital mental health field more broadly.

Corrigendum to: Identification of salt tolerance QTL in a wheat RIL mapping population using destructive and non-destructive phenotyping.

Bread wheat (Triticum aestivum L.) is one of the most important food crops, however it is only moderately tolerant to salinity stress. To improve wheat yield under saline conditions, breeding for improved salinity tolerance of wheat is needed. We have identified nine quantitative trail loci (QTL) for different salt tolerance sub-traits in a recombinant inbred line (RIL) population, derived from the bi-parental cross of Excalibur × Kukri. This population was screened for salinity tolerance subtraits using a combination of both destructive and non-destructive phenotyping. Genotyping by sequencing (GBS) was used to construct a high-density genetic linkage map, consisting of 3236 markers, and utilised for mapping QTL. Of the nine mapped QTL, six were detected under salt stress, including QTL for maintenance of shoot growth under salinity (QG ( 1-5 ) .asl -5A , QG ( 1-5 ) .asl -7B ) sodium accumulation (QNa.asl -2A ), chloride accumulation (QCl.asl -2A , QCl.asl -3A ) and potassium : sodium ratio (QK :Na.asl -2DS2 ). Potential candidate genes within these QTL intervals were shortlisted using bioinformatics tools. These findings are expected to facilitate the breeding of new salt tolerant wheat cultivars. Soil salinity causes major yield losses in bread wheat, which is moderately tolerant to salinity stress. Using high throughput genotyping and phenotyping techniques, we identified quantitative trail loci (QTL) for different salt tolerance sub-traits in bread wheat and shortlisted potential candidate genes. These QTL and candidate genes may prove useful in breeding for salt tolerant wheat cultivars.

Dominant negative effects of SCN5A missense variants.

PURPOSE: Up to 30% of patients with Brugada syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A encoding for the protein NaV1.5. Recent studies suggested that NaV1.5 can dimerize, and some variants exert dominant negative effects. In this study, we sought to explore the generality of missense variant NaV1.5 dominant negative effects and their clinical severity. METHODS: We identified 35 LoF variants (<10% of wild type [WT] peak current) and 15 partial LoF variants (10%-50% of WT peak current) that we assessed for dominant negative effects. SCN5A variants were studied in HEK293T cells, alone or in heterozygous coexpression with WT SCN5A using automated patch clamp. To assess the clinical risk, we compared the prevalence of dominant negative vs putative haploinsufficient (frameshift, splice, or nonsense) variants in a BrS consortium and the Genome Aggregation Database population database. RESULTS: In heterozygous expression with WT, 32 of 35 LoF and 6 of 15 partial LoF variants showed reduction to <75% of WT-alone peak current, showing a dominant negative effect. Individuals with dominant negative LoF variants had an elevated disease burden compared with the individuals with putative haploinsufficient variants (2.7-fold enrichment in BrS cases, P = .019). CONCLUSION: Most SCN5A missense LoF variants exert a dominant negative effect. This class of variant confers an especially high burden of BrS.

Modulation of the brain's core-self network by self-appraisal processes.

The 'core' regions of the default mode network (DMN) - the medial prefrontal cortex (MPFC), the posterior cingulate cortex (PCC), and inferior parietal lobules (IPL) - show consistent engagement across mental states that involve self-oriented processing. Precisely how these regions interact in support of such processes remains an important unanswered question. In the current functional magnetic resonance imaging (fMRI) study, we examined dynamic interactions of the 'core-self' DMN regions during two forms of self-referential cognition: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about oneself from a third-person perspective). One-hundred and eleven participants completed our dual self-appraisal task during fMRI, and general linear models were used to characterize common and distinct neural responses to these conditions. Informed by these results, we then applied dynamic causal modelling to examine causal interactions among the 'core-self' regions, and how they were specifically modulated under the influence of direct and reflected self-appraisal. As a primary observation, this network modelling revealed a distinct inhibitory influence of the left IPL on the PCC during reflected compared to direct self-appraisal, which was accompanied by evidence of greater activation in both regions during the reflected self-appraisal condition. We suggest that the greater engagement of posterior DMN regions during reflected self-appraisal is a function of the higher-order processing needed for this form of self-appraisal, with the left IPL supporting abstract self-related processes including episodic memory retrieval and shifts of perspective. Overall, we show that core DMN regions interact in functionally unique ways in support of self-referential processes, even when these processes are inter-related. Further characterization of DMN functional interactions across self-related mental states is likely to inform a deeper understanding of how this brain network orchestrates the self.

Self-other referential neural processing in social anxiety disorder and major depressive disorder.

BACKGROUND: Social anxiety disorder (SAD) and major depressive disorder (MDD) are highly comorbid and share impairments in self-referential and social processing. Many naturalistic judgements activate these processes concurrently, which can be referred to as "self-other referential processing". We sought to examine its neural correlates in young people with SAD and MDD using a novel experimental task. METHODS: Fifty six young people aged 16 to 25 with diagnoses of SAD and/or MDD (15 with SAD [M = 20.3 years, 60% female], 17 with MDD [M = 19.8 years, 53% female], 24 with comorbid SAD and MDD [M = 19.8 years, 67% female]) and 76 age and gender-matched healthy controls (HCs; M = 20.7 years, 66% female) completed a novel self-other referential processing fMRI task that involved rating how much one related to emotional faces in active conditions and judging how far apart each person's eyes were in control conditions. RESULTS: Participants with SAD had more and those with MDD had less activity in social cognitive areas than HCs when processing social information across all conditions and emotion types. Participants with comorbid SAD-MDD exhibited a distinct pattern of neural activity to patients with single diagnoses. Across the whole sample, the activation of reward system areas (the medial orbitofrontal cortex and caudate) in response to increasing relatedness correlated positively with a dimensional measure of social anxiety. CONCLUSIONS: Young people with SAD, MDD and comorbid SAD-MDD showed deficits in social processing, but they were not specifically related to self-other referential processing. Dimensional social anxiety symptoms were correlated with reward system activation, suggesting that such symptoms are associated with an overestimation of the hedonic value of social stimuli. These novel findings have implications for our understanding of the neural correlates of SAD and MDD, suggesting that alterations in social processing and reward functioning underlie the impairments in self and social processing that characterize both disorders.

Identification of salt tolerance QTL in a wheat RIL mapping population using destructive and non-destructive phenotyping.

Bread wheat (Triticum aestivum L.) is one of the most important food crops, however it is only moderately tolerant to salinity stress. To improve wheat yield under saline conditions, breeding for improved salinity tolerance of wheat is needed. We have identified nine quantitative trail loci (QTL) for different salt tolerance sub-traits in a recombinant inbred line (RIL) population, derived from the bi-parental cross of Excalibur × Kukri. This population was screened for salinity tolerance subtraits using a combination of both destructive and non-destructive phenotyping. Genotyping by sequencing (GBS) was used to construct a high-density genetic linkage map, consisting of 3236 markers, and utilised for mapping QTL. Of the nine mapped QTL, six were detected under salt stress, including QTL for maintenance of shoot growth under salinity (QG(1-5).asl-5A, QG(1-5).asl-7B) sodium accumulation (QNa.asl-2A), chloride accumulation (QCl.asl-2A, QCl.asl-3A) and potassium:sodium ratio (QK:Na.asl-2DS2). Potential candidate genes within these QTL intervals were shortlisted using bioinformatics tools. These findings are expected to facilitate the breeding of new salt tolerant wheat cultivars.

Neural correlates of integrated self and social processing.

Self-referential and social processing are often engaged concurrently in naturalistic judgements and elicit activity in overlapping brain regions. We have termed this integrated processing 'self-other referential processing' and developed a task to measure its neural correlates. Ninety-eight healthy young people aged 16-25 (M = 21.5 years old, 67% female) completed our novel functional magnetic resonance imaging task. The task had two conditions, an active self-other referential processing condition in which participants rated how much they related to emotional faces and a control condition. Rating relatedness required thinking about oneself (self-referential processing) and drawing a comparison to an imagined other (social processing). Self-other referential processing elicited activity in the default mode network and social cognition system; most notably in the 'core self' regions of the medial prefrontal cortex and posterior cingulate cortex. Relatedness and emotional valence directly modulated activity in these core self areas, while emotional valence additionally modulated medial prefrontal cortex activity. This shows the key role of the medial prefrontal cortex in constructing the 'social-affective self'. This may help to unify disparate models of medial prefrontal cortex function, demonstrating its role in coordinating multiple processes-self-referential, social and affective processing-to allow the self to exist in a complex social world.

High-Throughput Reclassification of SCN5A Variants.

Partial or complete loss-of-function variants in SCN5A are the most common genetic cause of the arrhythmia disorder Brugada syndrome (BrS1). However, the pathogenicity of SCN5A variants is often unknown or disputed; 80% of the 1,390 SCN5A missense variants observed in at least one individual to date are variants of uncertain significance (VUSs). The designation of VUS is a barrier to the use of sequence data in clinical care. We selected 83 variants: 10 previously studied control variants, 10 suspected benign variants, and 63 suspected Brugada syndrome-associated variants, selected on the basis of their frequency in the general population and in individuals with Brugada syndrome. We used high-throughput automated patch clamping to study the function of the 83 variants, with the goal of reclassifying variants with functional data. The ten previously studied controls had functional properties concordant with published manual patch clamp data. All 10 suspected benign variants had wild-type-like function. 22 suspected BrS variants had loss of channel function (<10% normalized peak current) and 22 variants had partial loss of function (10%-50% normalized peak current). The previously unstudied variants were initially classified as likely benign (n = 2), likely pathogenic (n = 10), or VUSs (n = 61). After the patch clamp studies, 16 variants were benign/likely benign, 45 were pathogenic/likely pathogenic, and only 12 were still VUSs. Structural modeling identified likely mechanisms for loss of function including altered thermostability and disruptions to alpha helices, disulfide bonds, or the permeation pore. High-throughput patch clamping enabled reclassification of the majority of tested VUSs in SCN5A.

Improved Yield and Photosynthate Partitioning in AVP1 Expressing Wheat (Triticum aestivum) Plants.

A fundamental factor to improve crop productivity involves the optimization of reduced carbon translocation from source to sink tissues. Here, we present data consistent with the positive effect that the expression of the Arabidopsis thaliana H+-PPase (AVP1) has on reduced carbon partitioning and yield increases in wheat. Immunohistochemical localization of H+-PPases (TaVP) in spring wheat Bobwhite L. revealed the presence of this conserved enzyme in wheat vasculature and sink tissues. Of note, immunogold imaging showed a plasma membrane localization of TaVP in sieve element- companion cell complexes of Bobwhite source leaves. These data together with the distribution patterns of a fluorescent tracer and [U14C]-sucrose are consistent with an apoplasmic phloem-loading model in wheat. Interestingly, 14C-labeling experiments provided evidence for enhanced carbon partitioning between shoots and roots, and between flag leaves and milk stage kernels in AVP1 expressing Bobwhite lines. In keeping, there is a significant yield improvement triggered by the expression of AVP1 in these lines. Green house and field grown transgenic wheat expressing AVP1 also produced higher grain yield and number of seeds per plant, and exhibited an increase in root biomass when compared to null segregants. Another agriculturally desirable phenotype showed by AVP1 Bobwhite plants is a robust establishment of seedlings.

Community Based Support for People at Risk for Suicide and Those Who Care for them - Areas for Improvement.

To systematically review the quality of evidence regarding the effectiveness of supports for people affected by suicide. EMBASE, MEDLINE, and PsychINFO were searched for evaluations of community-based supports for people affected by suicide. Outcomes included suicide-related behavior, depression, grief, quality of life, caring ability, and qualitative experiences. Fifteen studies evaluated 15 supports of various modalities. Study quality was generally poor; most studies examined bereaved individuals with mixed findings. Few reduced suicide-related behavior, half improved depression, and grief, while studies of caring ability, quality of life, or qualitative experiences reported positive effects. Supports associated with better outcomes connected peers with similar experiences, were provided over a period of months, and involved veteran rather than novice facilitators. Supports for people affected by suicide may be effective for improving suicide-related behavior, psychological adjustment, quality of life and caregiving, but require further evaluation.

A Survey of People With Lived Experience of Suicide-Related Behavior in Queensland, Australia.

Background: Many organizations provide support to people affected by suicide-related behavior, for example, those bereaved by suicide, those who have attempted suicide, and their informal carers. However, evidence regarding how well used, and acceptable, these resources are is lacking. Aims: To investigate the views about and experiences with support and resources of people with lived experience of suicide bereavement, suicide attempt, or caring. Method: The study was conducted in Queensland, Australia. In total, 175 people completed the survey. Data were analyzed using SPSS Statistics 22. Results: Participants found resources helpful and user-friendly, but many had never searched for support, did not know it was available, or felt no better after using it. Respondents who had attempted suicide were more likely to look for resources, but less likely to feel better after using them and endorsed more barriers to accessing support. Limitations: This study used a convenience sample of individuals living in Queensland, was biased toward help-seeking populations, and included mostly women, and therefore it was not representative. Conclusion: Support and resources that are more flexible and accessible, and are offered in a more proactive manner could improve the user experiences of people affected by suicide-related behavior.

Mapping of novel salt tolerance QTL in an Excalibur × Kukri doubled haploid wheat population.

KEY MESSAGE: Novel QTL for salinity tolerance traits have been detected using non-destructive and destructive phenotyping in bread wheat and were shown to be linked to improvements in yield in saline fields. Soil salinity is a major limitation to cereal production. Breeding new salt-tolerant cultivars has the potential to improve cereal crop yields. In this study, a doubled haploid bread wheat mapping population, derived from the bi-parental cross of Excalibur × Kukri, was grown in a glasshouse under control and salinity treatments and evaluated using high-throughput non-destructive imaging technology. Quantitative trait locus (QTL) analysis of this population detected multiple QTL under salt and control treatments. Of these, six QTL were detected in the salt treatment including one for maintenance of shoot growth under salinity (QG(1-5).asl-7A), one for leaf Na+ exclusion (QNa.asl-7A) and four for leaf K+ accumulation (QK.asl-2B.1, QK.asl-2B.2, QK.asl-5A and QK:Na.asl-6A). The beneficial allele for QG(1-5).asl-7A (the maintenance of shoot growth under salinity) was present in six out of 44 mainly Australian bread and durum wheat cultivars. The effect of each QTL allele on grain yield was tested in a range of salinity concentrations at three field sites across 2 years. In six out of nine field trials with different levels of salinity stress, lines with alleles for Na+ exclusion and/or K+ maintenance at three QTL (QNa.asl-7A, QK.asl-2B.2 and QK:Na.asl-6A) excluded more Na+ or accumulated more K+ compared to lines without these alleles. Importantly, the QK.asl-2B.2 allele for higher K+ accumulation was found to be associated with higher grain yield at all field sites. Several alleles at other QTL were associated with higher grain yields at selected field sites.

Contrasting Nav1.8 Activity in Scn10a-/- Ventricular Myocytes and the Intact Heart.

BACKGROUND: Genome-wide association studies have implicated variants in SCN10A, which encodes Nav1.8, as modulators of cardiac conduction. Follow-up work has indicated the SCN10A sequence includes an intronic enhancer for SCN5A. Yet the role of the Nav1.8 protein in the myocardium itself is still unclear. To investigate this, we use homozygous knockout mice (Scn10a-/-) generated by disruption of exons 4 and 5, leaving the Scn5a enhancer intact. METHODS AND RESULTS: We previously reported that pharmacologic blockade of Nav1.8 in wild-type animals blunts action potential prolongation by ATX-II at slow drive rates (≤1 Hz). Here we present evidence of the same blunting in Scn10a-/- compared to wild-type ventricular myocytes, supporting the conclusion that Nav1.8 contributes to late sodium current at slow rates. In contrast to earlier studies, we found no differences in electrocardiographic parameters between genotypes. Low-dose ATX-II exposure in lightly anesthetized animals and Langendorff-perfused hearts prolonged QTc and generated arrhythmias to the same extent in wild-type and Scn10a-/-. RNA sequencing failed to identify full-length Scn10a transcripts in wild-type or knockout isolated ventricular myocytes. However, loss of late current in Scn10a-/- myocytes was replicated independently in a blinded set of experiments. CONCLUSIONS: While Scn10a transcripts are not detectible in ventricular cardiomyocytes, gene deletion results in reproducible loss of late sodium current under extreme experimental conditions. However, there are no identifiable consequences of this Scn10a deletion in the intact mouse heart at usual rates. These findings argue that common variants in SCN10A that affect ventricular conduction do so by modulating SCN5A.

The 'Self' and Borderline Personality Disorder: Conceptual and Clinical Considerations.

Some concept of self has been used by many, although not all, researchers and clinicians as an 'organising construct' for borderline personality disorder (BPD). There is considerable variation in this usage and how clearly researchers have defined the self. Given this diversity, and that 'self' is often used interchangeably with parallel concepts (e.g., psyche, brain-mind, 'person') or with features of self (e.g., self-awareness, identity), unqualified use of the term is problematic. This is further complicated by the heterogeneity and 'comorbidity' of BPD and the limitations of syndromally based psychiatric nosology. Still, BPD remains in current classification systems and can be reliably diagnosed. A considerable body of research on self and BPD has accrued, including a recent profusion and confluence of neuroscientific and sociopsychological findings. These have generated supporting evidence for a supra-ordinate, functionally constituted entity of the self ranging over multiple, interacting levels from an unconscious, 'core' self, through to a reflective, phenotypic, 'idiographic' and relational self constituted by interpersonal and sociocultural experience. Important insights have been generated regarding emotional and social-cognitive dysregulation, disorder of self-awareness, relationality, identity, and coherence and continuity of the self. Many of these are shared by various trauma-related, dissociative disorders. A construct of the self could be useful as an explanatory principle in BPD, which could be construed as a 'self-state' (and relational) disorder, as opposed to a less severe disorder of aspects of the self (e.g., mood or memory). We offer a tentative description of 'Self' in this context, noting that any such construct will require a clear definition and to be evaluable.

SCN10A/Nav1.8 modulation of peak and late sodium currents in patients with early onset atrial fibrillation.

AIMS: To test the hypothesis that vulnerability to atrial fibrillation (AF) is associated with rare coding sequence variation in the SCN10A gene, which encodes the voltage-gated sodium channel isoform NaV1.8 found primarily in peripheral nerves and to identify potentially disease-related mechanisms in high-priority rare variants using in-vitro electrophysiology. METHODS AND RESULTS: We re-sequenced SCN10A in 274 patients with early onset AF from the Vanderbilt AF Registry to identify rare coding variants. Engineered variants were transiently expressed in ND7/23 cells and whole-cell voltage clamp experiments were conducted to elucidate their functional properties. Resequencing SCN10A identified 18 heterozygous rare coding variants (minor allele frequency ≤1%) in 18 (6.6%) AF probands. Four probands were carriers of two rare variants each and 14 were carriers of one coding variant. Based on evidence of co-segregation, initial assessment of functional importance, and presence in ≥1 AF proband, three variants (417delK, A1886V, and the compound variant Y158D-R814H) were selected for functional studies. The 417delK variant displayed near absent current while A1886V and Y158D-R814H exhibited enhanced peak and late (INa-L) sodium currents; both Y158D and R818H individually contributed to this phenotype. CONCLUSION: Rare SCN10A variants encoding Nav1.8 were identified in 6.6% of patients with early onset AF. In-vitro electrophysiological studies demonstrated profoundly altered function in 3/3 high-priority variants. Collectively, these data strongly support the hypothesis that rare SCN10A variants may contribute to AF susceptibility.