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Aquaporin-4 (AQP4) is a water channel protein that links the astrocytic endfeet to the blood-brain barrier (BBB) and regulates water and potassium homeostasis in the brain, as well as the glymphatic clearance of waste products that would otherwise potentiate neurological diseases. Recently, translational readthrough was shown to generate a C-terminally extended variant of AQP4, known as AQP4x, which preferentially localizes around the BBB through interaction with the scaffolding protein α-syntrophin, and loss of AQP4x disrupts waste clearance from the brain. To investigate the function of AQP4x, we generated a novel AQP4 mouse line (AllX) to increase relative levels of the readthrough variant above the ~15% of AQP4 in the brain of wild-type (WT) mice. We validated the line and assessed characteristics that are affected by the presence of AQP4x, including AQP4 and α-syntrophin localization, integrity of the BBB, and neurovascular coupling. We compared AllXHom and AllXHet mice to WT and to previously characterized AQP4 NoXHet and NoXHom mice, which cannot produce AQP4x. An increased dose of AQP4x enhanced perivascular localization of α-syntrophin and AQP4, while total protein expression of the two was unchanged. However, at 100% readthrough, AQP4x localization and the formation of higher order complexes were disrupted. Electron microscopy showed that overall blood vessel morphology was unchanged except for an increased proportion of endothelial cells with budding vesicles in NoXHom mice, which may correspond to a leakier BBB or altered efflux that was identified in NoX mice using MRI. These data demonstrate that AQP4x plays a small but measurable role in maintaining BBB integrity as well as recruiting structural and functional support proteins to the blood vessel. This also establishes a new set of genetic tools for quantitatively modulating AQP4x levels.
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De novo mutations cause a variety of neurodevelopmental disorders including autism. Recent whole genome sequencing from individuals with autism has shown that many de novo mutations also occur in untranslated regions (UTRs) of genes, but it is difficult to predict from sequence alone which mutations are functional, let alone causal. Therefore, we developed a high throughput assay to screen the transcriptional and translational effects of 997 variants from 5'UTR patient mutations. This assay successfully enriched for elements that alter reporter translation, identifying over 100 potentially functional mutations from probands. Studies in patient-derived cell lines further confirmed that these mutations can alter protein production in individuals with autism, and some variants fall in genes known to cause syndromic forms of autism, suggesting a diagnosis for these individual patients. Since UTR function varies by cell type, we further optimized this high throughput assay to enable assessment of mutations in neurons in vivo. First, comparing in cellulo to in vivo results, we demonstrate neurons have different principles of regulation by 5'UTRs, consistent with a more robust mechanism for reducing the impact of RNA secondary structure. Finally, we discovered patient mutations specifically altering the translational activity of additional known syndromic genes LRRC4 and ZNF644 in neurons of the brain. Overall our results highlight a new approach for assessing the impact of 5'UTR mutations across cell types and suggest that some cases of neurodevelopmental disorder may be caused by such variants.
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Machine learning has played transformative roles in numerous chemical and biophysical problems such as protein folding where large amount of data exists. Nonetheless, many important problems remain challenging for data-driven machine learning approaches due to the limitation of data scarcity. One approach to overcome data scarcity is to incorporate physical principles such as through molecular modeling and simulation. Here, we focus on the big potassium (BK) channels that play important roles in cardiovascular and neural systems. Many mutants of BK channel are associated with various neurological and cardiovascular diseases, but the molecular effects are unknown. The voltage gating properties of BK channels have been characterized for 473 site-specific mutations experimentally over the last three decades; yet, these functional data by themselves remain far too sparse to derive a predictive model of BK channel voltage gating. Using physics-based modeling, we quantify the energetic effects of all single mutations on both open and closed states of the channel. Together with dynamic properties derived from atomistic simulations, these physical descriptors allow the training of random forest models that could reproduce unseen experimentally measured shifts in gating voltage, ∆V1/2, with a RMSE ~ 32 mV and correlation coefficient of R ~ 0.7. Importantly, the model appears capable of uncovering nontrivial physical principles underlying the gating of the channel, including a central role of hydrophobic gating. The model was further evaluated using four novel mutations of L235 and V236 on the S5 helix, mutations of which are predicted to have opposing effects on V1/2 and suggest a key role of S5 in mediating voltage sensor-pore coupling. The measured ∆V1/2 agree quantitatively with prediction for all four mutations, with a high correlation of R = 0.92 and RMSE = 18 mV. Therefore, the model can capture nontrivial voltage gating properties in regions where few mutations are known. The success of predictive modeling of BK voltage gating demonstrates the potential of combining physics and statistical learning for overcoming data scarcity in nontrivial protein function prediction.
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Calcio , Canales de Potasio de Gran Conductancia Activados por el Calcio , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Modelos Moleculares , Biofisica , Calcio/metabolismoRESUMEN
Aquaporin-4 (AQP4) is a water channel protein that links astrocytic endfeet to the blood-brain barrier (BBB) and regulates water and potassium homeostasis in the brain, as well as the glymphatic clearance of waste products that would otherwise potentiate neurological diseases. Recently, translational readthrough was shown to generate a C-terminally extended variant of AQP4, known as AQP4x, that preferentially localizes around the BBB through interaction with the scaffolding protein α-syntrophin, and loss of AQP4x disrupts waste clearance from the brain. To investigate the function of AQP4x, we generated a novel mouse AQP4 line (AllX) to increase relative levels of the readthrough variant above the ~15% of AQP4 in the brain of wildtype (WT) mice. We validated the line and assessed characteristics that are affected by the presence of AQP4x, including AQP4 and α-syntrophin localization, integrity of the BBB, and neurovascular coupling. We compared AllXHom and AllXHet mice to wildtype, and to previously characterized AQP4 NoXHet and NoXHom mice, which cannot produce AQP4x. Increased dose of AQP4x enhanced perivascular localization of α-syntrophin and AQP4, while total protein expression of the two were unchanged. However, at 100% readthrough, AQP4x localization and formation of higher-order complexes was disrupted. Electron microscopy showed that overall blood vessel morphology was unchanged except for increased endothelial cell vesicles in NoXHom mice, which may correspond to a leakier BBB or altered efflux that was identified in NoX mice using MRI. These data demonstrate that AQP4x plays a small but measurable role in maintaining BBB integrity as well as recruiting structural and functional support proteins to the blood vessel. This also establishes a new set of genetic tools for quantitatively modulating AQP4x levels.
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Machine learning has played transformative roles in numerous chemical and biophysical problems such as protein folding where large amount of data exists. Nonetheless, many important problems remain challenging for data-driven machine learning approaches due to the limitation of data scarcity. One approach to overcome data scarcity is to incorporate physical principles such as through molecular modeling and simulation. Here, we focus on the big potassium (BK) channels that play important roles in cardiovascular and neural systems. Many mutants of BK channel are associated with various neurological and cardiovascular diseases, but the molecular effects are unknown. The voltage gating properties of BK channels have been characterized for 473 site-specific mutations experimentally over the last three decades; yet, these functional data by themselves remain far too sparse to derive a predictive model of BK channel voltage gating. Using physics-based modeling, we quantify the energetic effects of all single mutations on both open and closed states of the channel. Together with dynamic properties derived from atomistic simulations, these physical descriptors allow the training of random forest models that could reproduce unseen experimentally measured shifts in gating voltage, ΔV 1/2 , with a RMSE â¼ 32 mV and correlation coefficient of R â¼ 0.7. Importantly, the model appears capable of uncovering nontrivial physical principles underlying the gating of the channel, including a central role of hydrophobic gating. The model was further evaluated using four novel mutations of L235 and V236 on the S5 helix, mutations of which are predicted to have opposing effects on V 1/2 and suggest a key role of S5 in mediating voltage sensor-pore coupling. The measured ΔV 1/2 agree quantitatively with prediction for all four mutations, with a high correlation of R = 0.92 and RMSE = 18 mV. Therefore, the model can capture nontrivial voltage gating properties in regions where few mutations are known. The success of predictive modeling of BK voltage gating demonstrates the potential of combining physics and statistical learning for overcoming data scarcity in nontrivial protein function prediction. Author Summary: Deep machine learning has brought many exciting breakthroughs in chemistry, physics and biology. These models require large amount of training data and struggle when the data is scarce. The latter is true for predictive modeling of the function of complex proteins such as ion channels, where only hundreds of mutational data may be available. Using the big potassium (BK) channel as a biologically important model system, we demonstrate that a reliable predictive model of its voltage gating property could be derived from only 473 mutational data by incorporating physics-derived features, which include dynamic properties from molecular dynamics simulations and energetic quantities from Rosetta mutation calculations. We show that the final random forest model captures key trends and hotspots in mutational effects of BK voltage gating, such as the important role of pore hydrophobicity. A particularly curious prediction is that mutations of two adjacent residues on the S5 helix would always have opposite effects on the gating voltage, which was confirmed by experimental characterization of four novel mutations. The current work demonstrates the importance and effectiveness of incorporating physics in predictive modeling of protein function with scarce data.
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Alzheimer's disease is initiated by the toxic aggregation of amyloid-ß. Immunotherapeutics aimed at reducing amyloid beta are in clinical trials but with very limited success to date. Identification of orthogonal approaches for clearing amyloid beta may complement these approaches for treating Alzheimer's disease. In the brain, the astrocytic water channel Aquaporin 4 is involved in clearance of amyloid beta, and the fraction of Aquaporin 4 found perivascularly is decreased in Alzheimer's disease. Further, an unusual stop codon readthrough event generates a conserved C-terminally elongated variant of Aquaporin 4 (AQP4X), which is exclusively perivascular. However, it is unclear whether the AQP4X variant specifically mediates amyloid beta clearance. Here, using Aquaporin 4 readthrough-specific knockout mice that still express normal Aquaporin 4, we determine that this isoform indeed mediates amyloid beta clearance. Further, with high-throughput screening and counterscreening, we identify small molecule compounds that enhance readthrough of the Aquaporin 4 sequence and validate a subset on endogenous astrocyte Aquaporin 4. Finally, we demonstrate these compounds enhance brain amyloid-ß clearance in vivo, which depends on AQP4X. This suggests derivatives of these compounds may provide a viable pharmaceutical approach to enhance clearance of amyloid beta and potentially other aggregating proteins in neurodegenerative disease.
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Enfermedad de Alzheimer , Acuaporina 4/metabolismo , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Acuaporina 4/genética , Encéfalo/metabolismo , Codón de Terminación , Ratones , Enfermedades Neurodegenerativas/metabolismoRESUMEN
KCNQ2 and KCNQ3 form the M-channels that are important in regulating neuronal excitability. Inherited mutations that alter voltage-dependent gating of M-channels are associated with neonatal epilepsy. In the homolog KCNQ1 channel, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, physiological, and pharmacological properties of KCNQ1. However, whether the M-channel shares the same mechanism is unclear. Here, we show that KCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore opening. We identified some epilepsy-linked mutations in KCNQ2 and KCNQ3 that disrupt E-M coupling. The antiepileptic drug retigabine rescued KCNQ3 currents that were abolished by a mutation disrupting E-M coupling, suggesting that modulating the E-M coupling in KCNQ channels presents a potential strategy for antiepileptic therapy.
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BACKGROUND: Medical innovations offer tremendous hope. Yet, similar innovations in governance (law, policy, ethics) are likely necessary if society is to realize medical innovations' fruits and avoid their pitfalls. As innovations in artificial intelligence (AI) advance at a rapid pace, scholars across multiple disciplines are articulating concerns in health-related AI that likely require legal responses to ensure the requisite balance. These scholarly perspectives may provide critical insights into the most pressing challenges that will help shape and advance future regulatory reforms. Yet, to the best of our knowledge, there is no comprehensive summary of the literature examining legal concerns in relation to health-related AI. We thus aim to summarize and map the literature examining legal concerns in health-related AI using a scoping review approach. METHODS: The scoping review framework developed by (J Soc Res Methodol 8:19-32, 2005) and extended by (Implement Sci 5:69, 2010) and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for scoping reviews (PRISMA-ScR) guided our protocol development. In close consultation with trained librarians, we will develop a highly sensitive search for MEDLINE® (OVID) and adapt it for multiple databases designed to comprehensively capture texts in law, medicine, nursing, pharmacy, other healthcare professions (e.g., dentistry, nutrition), public health, computer science, and engineering. English- and French-language records will be included if they examine health-related AI, describe or prioritize a legal concern in health-related AI or propose a solution thereto, and were published in 2012 or later. Eligibility assessment will be conducted independently and in duplicate at all review stages. Coded data will be analyzed along themes and stratified across discipline-specific literatures. DISCUSSION: This first-of-its-kind scoping review will summarize available literature examining, documenting, or prioritizing legal concerns in health-related AI to advance law and policy reform(s). The review may also reveal discipline-specific concerns, priorities, and proposed solutions to the concerns. It will thereby identify priority areas that should be the focus of future reforms and regulatory options available to stakeholders in reform processes. TRIAL REGISTRATION: This protocol was submitted to the Open Science Foundation registration database. See https://osf.io/zav7w .
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Inteligencia Artificial , Políticas , Humanos , Literatura de Revisión como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
The COVID-19 pandemic has driven home the serious vulnerabilities plaguing Canada's long-term care system. We argue for significant new federal investments tied to clear, enforceable quality standards (particularly around staffing); new investments in home care so that more people can "age in place"; and additional support for informal care providers, including respite programs and cash benefits. We explore how to achieve these reforms within the framework of Canadian federalism and call for the creation of a national governance framework - overseen by experts independent of federal and provincial governments - tasked with establishing evidence-based standards for the quality, safety and timeliness of long-term care services.
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COVID-19 , Cuidados a Largo Plazo , Canadá , Humanos , Pandemias , SARS-CoV-2RESUMEN
Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.
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Potenciales de Acción/efectos de los fármacos , Canal de Potasio KCNQ1/genética , Miocitos Cardíacos/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Potenciales de Acción/fisiología , Sustitución de Aminoácidos , Animales , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Calcio/metabolismo , Perros , Furanos/farmacología , Expresión Génica , Cobayas , Atrios Cardíacos/citología , Atrios Cardíacos/metabolismo , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/metabolismo , Humanos , Canal de Potasio KCNQ1/química , Canal de Potasio KCNQ1/metabolismo , Moxifloxacino/farmacología , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Oocitos/citología , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Técnicas de Placa-Clamp , Fenetilaminas/farmacología , Potasio/metabolismo , Cultivo Primario de Células , Piridinas/farmacología , Pirimidinas/farmacología , Sodio/metabolismo , Sulfonamidas/farmacología , Transgenes , Xenopus laevisRESUMEN
Calmodulin (CaM) and phosphatidylinositol 4,5-bisphosphate (PIP2) are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the cardiac I Ks current. Although cryo-electron microscopy structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully activated state allows PIP2 to compete with CaM for binding to VSD. This leads to conformational changes that alter VSD-pore coupling to stabilize open states. We identify a motif in the KCNQ1 cytosolic domain, which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2 and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its physiological function.
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KCNQ family K+ channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP2) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP2 was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP2, can substitute for PIP2 to mediate VSD-pore coupling. Both PIP2 and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP2. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP2 regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.
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Canales de Potasio KCNQ/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Potenciales de Acción , Animales , Simulación por Computador , Cobayas , Canales de Potasio KCNQ/química , Canal de Potasio KCNQ1/química , Canal de Potasio KCNQ1/metabolismo , Miocitos Cardíacos/metabolismo , Oocitos , Técnicas de Placa-Clamp , Fosfatidilinositol 4,5-Difosfato/análogos & derivados , Fosfatidilinositol 4,5-Difosfato/química , Estructura Terciaria de Proteína , Xenopus laevisRESUMEN
Canada's single-payer healthcare system is at a critical crossroads. A legal challenge underway in British Columbia alleges that legislative restrictions on privately financed care infringe the right to "life, liberty and security" guaranteed under Section 7 of the Canadian Charter of Rights and Freedoms. The greatest challenge for the court will be comparing healthcare systems across disparate jurisdictions, with the future of single-tier healthcare system hanging in the balance. If successful, the case may require a major overhaul of Canada's single-payer system - a perilous task politically, if history is any guide, and this may be the system's undoing.
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Política de Salud/legislación & jurisprudencia , Jurisprudencia , Programas Nacionales de Salud/legislación & jurisprudencia , Colombia Británica , Canadá , Humanos , Política , Listas de EsperaRESUMEN
This quasi-experimental study used a convenience sample of nursing students (n = 49) to evaluate the effectiveness of mindfulness meditation on anxiety. Students participated in mindfulness meditation sessions and completed the State-Trait Anxiety Inventory. A statistically significant reduction in trait anxiety was found in the intervention group (p = .000); state anxiety decreased but not significantly. In contrast, anxiety increased significantly in the comparison group, but progression was not significantly different between groups. Trait anxiety may decrease with mindfulness meditation.
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Ansiedad/prevención & control , Meditación/psicología , Atención Plena , Estudiantes de Enfermería/psicología , Ansiedad/epidemiología , HumanosRESUMEN
In voltage-gated potassium (KV) channels, the voltage-sensing domain (VSD) undergoes sequential activation from the resting state to the intermediate state and activated state to trigger pore opening via electro-mechanical (E-M) coupling. However, the spatial and temporal details underlying E-M coupling remain elusive. Here, utilizing KV7.1's unique two open states, we report a two-stage E-M coupling mechanism in voltage-dependent gating of KV7.1 as triggered by VSD activations to the intermediate and then activated state. When the S4 segment transitions to the intermediate state, the hand-like C-terminus of the VSD-pore linker (S4-S5L) interacts with the pore in the same subunit. When S4 then proceeds to the fully-activated state, the elbow-like hinge between S4 and S4-S5L engages with the pore of the neighboring subunit to activate conductance. This two-stage hand-and-elbow gating mechanism elucidates distinct tissue-specific modulations, pharmacology, and disease pathogenesis of KV7.1, and likely applies to numerous domain-swapped KV channels.
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Canales de Potasio con Entrada de Voltaje/química , Canales de Potasio con Entrada de Voltaje/fisiología , Humanos , Activación del Canal Iónico/fisiología , Canal de Potasio KCNQ1/química , Canal de Potasio KCNQ1/fisiología , Simulación del Acoplamiento Molecular , Oocitos/metabolismo , Canales de Potasio , Conformación ProteicaRESUMEN
Voltage-gated ion channels feature voltage sensor domains (VSDs) that exist in three distinct conformations during activation: resting, intermediate, and activated. Experimental determination of the structure of a potassium channel VSD in the intermediate state has previously proven elusive. Here, we report and validate the experimental three-dimensional structure of the human KCNQ1 voltage-gated potassium channel VSD in the intermediate state. We also used mutagenesis and electrophysiology in Xenopus laevisoocytes to functionally map the determinants of S4 helix motion during voltage-dependent transition from the intermediate to the activated state. Finally, the physiological relevance of the intermediate state KCNQ1 conductance is demonstrated using voltage-clamp fluorometry. This work illuminates the structure of the VSD intermediate state and demonstrates that intermediate state conductivity contributes to the unusual versatility of KCNQ1, which can function either as the slow delayed rectifier current (IKs) of the cardiac action potential or as a constitutively active epithelial leak current.
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Canal de Potasio KCNQ1/fisiología , Animales , Electrofisiología , Fluorometría , Humanos , Canal de Potasio KCNQ1/química , Canal de Potasio KCNQ1/metabolismo , Espectroscopía de Resonancia Magnética , Oocitos , Técnicas de Placa-Clamp , Estructura Terciaria de Proteína , Xenopus laevisRESUMEN
Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form IKs channels that regulate heart rhythm. KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Here, we tested modulations of human KCNQ1 channels by an activator ML277 in Xenopus oocytes. It exclusively changes the pore opening properties of the AO state without altering the IO state, but does not affect VSD activation. These observations support a distinctive mechanism responsible for the VSD-pore coupling at the AO state that is sensitive to ML277 modulation. ML277 provides insights and a tool to investigate the gating mechanism of KCNQ1 channels, and our study reveals a new strategy for treating long QT syndrome by specifically enhancing the AO state of native IKs currents.
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Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/tratamiento farmacológico , Canales de Potasio con Entrada de Voltaje/genética , Animales , Membrana Celular/genética , Membrana Celular/fisiología , Polaridad Celular/genética , Humanos , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/patología , Oocitos/efectos de los fármacos , Oocitos/crecimiento & desarrollo , Piperidinas/farmacología , Potasio/metabolismo , Tiazoles/farmacología , Compuestos de Tosilo/farmacología , Xenopus/genéticaRESUMEN
Nursing students need innovative educational approaches to bridge generational and cultural differences and improve communication skills with patients who are cognitively impaired. An individualized music and memory intervention for older adults with dementia and communication issues was implemented. A review of weekly student journals provided information regarding the use of the approach as an alternative therapy and benefit for students. The usefulness of the music and memory program as an innovative learning tool has widespread applicability to various health care settings.