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Aims Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM–10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2 -p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3–10 µM (by 20–32%/25–30%/44–45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1 -p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1 -p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1 -p.A341V hiPSC-CMs or KCNQ1 -p.Y315S rabbit CMs at 0.3–3 µM. Conclusion A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a developmental disorder characterized by the early onset of problems with communication, learning, and behavior. The syndromic form of ASD is caused by monogenic mutations. When it is not possible to find genetic or other known mechanisms, the term "idiopathic autism" is used. A significant part of both syndromic and idiopathic autism is associated with translational deregulation dependent on the mechanistic target of rapamycin (mTOR). In this review, we present both bioinformatic and experimental data that link the mTOR signaling pathway to maternal autoantibody related autism and childhood autoimmune neuropsychiatric disorders such as Sydenham's chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). The need for ASD subtyping and the prospects of mechanism-based therapy with inhibitors of the mTOR signaling pathway are also discussed. [ABSTRACT FROM AUTHOR]

Chronic pain is a constantly recurring and persistent illness, presenting a formidable healthcare challenge for patients and physicians alike. Current first‐line analgesics offer only low‐modest efficacy when averaged across populations, further contributing to this debilitating disease burden. Moreover, many recent trials for novel analgesics have not met primary efficacy endpoints, which is particularly striking considering the pharmacological advances have provided a range of highly relevant new drug targets. Heterogeneity within chronic pain cohorts is increasingly understood to play a critical role in these failures of treatment and drug discovery, with some patients deriving substantial benefits from a given intervention while it has little‐to‐no effect on others. As such, current treatment failures may not result from a true lack of efficacy, but rather a failure to target individuals whose pain is driven by mechanisms which it therapeutically modulates. This necessitates a move towards phenotypical stratification of patients to delineate responders and non‐responders in a mechanistically driven manner. In this article, we outline a bench‐to‐bedside roadmap for this transition to mechanistically informed personalised pain medicine. We emphasise how the successful identification of novel analgesics is dependent on rigorous experimental design as well as the validity of models and translatability of outcome measures between the animal model and patients. Subsequently, we discuss general and specific aspects of human trial design to address heterogeneity in patient populations to increase the chance of identifying effective analgesics. Finally, we show how stratification approaches can be brought into clinical routine to the benefit of patients. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders are a separate group of defects with a very high genetic component. Genetic screening has identified hundreds of mutations and other genetic variations associated with autism, and bioinformatic analysis of signaling pathways and gene networks has led to understanding that many of these mutational changes are involved in the functioning of synapses. A synapse is a site of electrochemical communication between neurons and an essential subunit for learning and memory. Interneuronal communicative relationships are plastic. The most prominent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in neuron body and in dendrites. Protein biosynthesis or translation is a carefully regulated process, with a central role played by mTOR (mammalian or mechanistic target of rapamycin). Normally mTOR-regulated translation is slightly inhibited, and in most cases mutational damage to at least one of the links of the mTOR signaling pathway, increases translation and leads to impaired synaptic plasticity and behavior. Deregulation of the local translation in dendrites is connected with the following monogenic autism spectrum disorders: neurofibromatosis type 1, Noonan syndrome, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X chromosome, syndrome, and Rett syndrome. The review considers the most important mutations leading to monogenic autism, as well as the possibility of a mechanism-based treatment of certain disorders of the autism spectrum.

Newborn neurons in developing brains actively migrate from germinal zones to designated regions before being wired into functional circuits. The motility and trajectory of migrating neurons are regulated by both extracellular factors and intracellular signaling cascades. Defects in the molecular machinery of neuronal migration lead to mis-localization of affected neurons and are considered as an important etiology of multiple developmental disorders including epilepsy, dyslexia, schizophrenia (SCZ), and autism spectrum disorders (ASD). However, the mechanisms that link neuronal migration deficits to the development of these diseases remain elusive. This review focuses on neuronal migration deficits in ASD. From a translational perspective, we discuss (1) whether neuronal migration deficits are general neuropathological characteristics of ASD; (2) how the phenotypic heterogeneity of neuronal migration disorders is generated; (3) how neuronal migration deficits lead to functional defects of brain circuits; and (4) how therapeutic intervention of neuronal migration deficits can be a potential treatment for ASD.

Autism spectrum disorders (ASDs) are a separate group of developmental disorders with a very large genetic component. Genetic screening has identified hundreds of mutations and other genetic variations associated with autism, and bioinformatic analysis of signaling pathways and gene networks has led to the understanding that many of these mutational changes are involved in the functioning of synapses. A synapse is a site of electrochemical communication between neurons and is a required subunit for learning and memory. Interneuronal communicative connections are plastic. The most prominent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in the neuron body and in dendrites. Protein biosynthesis, or translation, is a finely regulated process, with the central role played by mTOR kinase (mammalian or mechanistic target of rapamycin). A mutational aberration in at least one of the links of the mTOR signaling pathway impairs the synaptic plasticity and behavior. The deregulation of local translation in dendrites is connected with the following monogenic ASDs: neurofibromatosis type 1, Noonan syndrome, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X syndrome, and Rett syndrome (RS). The review considers the most important mutations leading to monogenic autism. The possibility of a mechanism-based treatment of certain ASDs is discussed. [ABSTRACT FROM AUTHOR]

Aims: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2., Methods and Results: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM., Conclusion: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Quantitative sensory testing (QST) is a widely accepted tool to investigate somatosensory changes in pain patients. Many different protocols have been developed in clinical pain research within recent years. In this review, we provide an overview of QST and tested neuroanatomical pathways, including peripheral and central structures. Based on research studies using animal and human surrogate models of neuropathic pain, possible underlying mechanisms of chronic pain are discussed. Clinically, QST may be useful for 1) the identification of subgroups of patients with different underlying pain mechanisms; 2) prediction of therapeutic outcomes; and 3) quantification of therapeutic interventions in pain therapy. Combined with sensory mapping, QST may provide useful information on the site of neural damage and on mechanisms of positive and negative somatosensory abnormalities. The use of QST in individual patients for diagnostic purposes leading to individualized therapy is an interesting concept, but needs further validation. [ABSTRACT FROM AUTHOR]

Patients with postherpetic neuralgia may experience various sensory signs and symptoms of pain. Despite this, the recommendations for medicinal treatment do not differ accordingly. In order to find the appropriate treatment options for postherpetic neuralgia, several attempts have been made in the past. The crucial obstacle to these attempts was insufficient or no subgrouping of patients according to their sensory phenotype, mostly resulting in an unsatisfactory treatment response. Recently, a new concept of retrospective stratification according to the patients' sensory phenotype has been made in a large cohort of pain patients. This new stratification tool allows a predictive validity for treatment response in subgroups of patients and might be of potential value in determining the optimal treatment in postherpetic neuralgia patients. [ABSTRACT FROM AUTHOR]

Newborn neurons in developing brains actively migrate from germinal zones to designated regions before being wired into functional circuits. The motility and trajectory of migrating neurons are regulated by both extracellular factors and intracellular signaling cascades. Defects in the molecular machinery of neuronal migration lead to mis-localization of affected neurons and are considered as an important etiology of multiple developmental disorders including epilepsy, dyslexia, schizophrenia (SCZ), and autism spectrum disorders (ASD). However, the mechanisms that link neuronal migration deficits to the development of these diseases remain elusive. This review focuses on neuronal migration deficits in ASD. From a translational perspective, we discuss (1) whether neuronal migration deficits are general neuropathological characteristics of ASD; (2) how the phenotypic heterogeneity of neuronal migration disorders is generated; (3) how neuronal migration deficits lead to functional defects of brain circuits; and (4) how therapeutic intervention of neuronal migration deficits can be a potential treatment for ASD., (Copyright © 2019 Pan, Wu and Yuan.)