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Neuropeptides play a critical role in regulating behaviors across organisms, but the precise mechanisms by which neuropeptides orchestrate complex behavioral programs are not fully understood. Here, we show that the FMRFamide-like neuropeptide FLP-12 signaling from the SMB head motor neurons modulates head locomotive behaviors, including stomatal oscillation in Caenorhabditis elegans. lim-4 mutants, in which the SMB neurons are not properly specified, exhibited various head and body locomotive defects, including stomatal oscillation. Chronic activation or inhibition of neuropeptidergic signaling in the SMB motor neurons resulted in a decrease or increase in stomatal oscillation, respectively. The flp-12 neuropeptide gene is expressed and acts in the SMB neurons to regulate head and body locomotion, including stomatal oscillation. Moreover, the frpr-8 G protein-couple receptor (GPCR) and gpa-7 Gα genes are expressed in the AVD command interneurons to relay the FLP-12 signal to mediate stomatal oscillation. Finally, heterologous expression of FRPR-8 either Xenopus oocytes or HEK293T cells conferred FLP-12 induced responses. Taken together, these results indicate that the C. elegans FMRFamide neuropeptide FLP-12 acts as a modulator of stomatal oscillation via the FRPR-8 GPCR and the GPA-7 G-protein., Competing Interests: DECLARATION OF COMPETING INTERESTS The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Proton-activated chloride (PAC) channels, ubiquitously expressed in tissues, regulate intracellular Cl - levels and cell death following acidosis. However, molecular mechanisms and signaling pathways involved in PAC channel modulation are largely unknown. Herein, we determine that phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] of the plasma membrane inner leaflet is essential for the proton activation of PAC channels. PI(4,5)P 2 depletion by activating phosphatidylinositol 5-phosphatases or G q protein-coupled muscarinic receptors substantially inhibits human PAC currents. In excised inside-out patches, PI(4,5)P 2 application to the cytoplasmic side increases the currents. Structural simulation reveals that the putative PI(4,5)P 2 -binding site is localized within the cytosol in resting state but shifts to the cell membrane's inner surface in an activated state and interacts with inner leaflet PI(4,5)P 2 . Alanine neutralization of basic residues near the membrane-cytosol interface of the transmembrane helice 2 significantly attenuates PAC currents. Overall, our study uncovers a modulatory mechanism of PAC channel through inner membrane PI(4,5)P 2 ., (© 2024. The Author(s).)

Appropriate ingestion of salt is essential for physiological processes such as ionic homeostasis and neuronal activity. Generally, low concentrations of salt elicit attraction, while high concentrations elicit aversive responses. Here, we observed that sugar neurons in the L sensilla of the Drosophila labellum cf. responses to NaCl, while sugar neurons in the S-c sensilla do not respond to NaCl, suggesting that gustatory receptor neurons involved in NaCl sensing may employ diverse molecular mechanisms. Through an RNAi screen of the entire Ir and ppk gene families and molecular genetic approaches, we identified IR76b, IR25a, and IR56b as necessary components for NaCl sensing in the Drosophila labellum. Co-expression of these three IRs in heterologous systems such as S2 cells or Xenopus oocytes resulted in a current in response to sodium stimulation, suggesting formation of a sodium-sensing complex. Our results should provide insights for research on the diverse combinations constituting salt receptor complexes., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Purpose: Mobile health (mHealth) technology has increased dramatically in the wake of the pandemic. Less research has focused on people with mobility impairing (PMI) disabilities. This study determined the prevalence of mHealth use among PMI adults during the COVID-19 escalation and examines demographic, health and COVID-19 concerns correlates., Methods: PMI adults ( N  = 304) completed an online survey investigating mHealth use and COVID-19 concerns related to food access in June of 2020. Smartphone and mHealth use were measured with an adapted version of the survey used in the Pew Internet & American Life project. Descriptive and multivariable analyses were conducted to determine associations of demographics, health status, and COVID-19 concerns with mHealth use. About two-thirds ( N  = 201) of the sample were mHealth users (owned a smartphone and engaged in health-promoting behaviors with the smartphone; e.g., sought online information, tracked health behaviors, used patient portals)., Results: Having hypertension was associated with higher mHealth use, and having higher COVID-19 concerns about food access was associated with higher mHealth use. Those who used mHealth were also more engaged with smartphone apps for communication, services, and entertainment. Only the association between educational attainment and mHealth use remained significant after adjusting for other covariates in multivariable logistic regression models., Discussion: PMIs continue to need support in the use of mHealth technology to help maximize access to potentially important tools for rehabilitation and health management. There is a need to continue to investigate mHealth and its applications for people with disabilities.Implications for RehabilitationMany people with mobility impairing disabilities may be missing opportunities for mHealth rehabilitation and healthcare.COVID-19 has widened existing gaps in access and use of mHealth technology among people with mobility impairing disabilities.Focused education is needed to help people with disabilities exploit the full range of services of their smartphones to increase access to care, social connectivity, and other important goods and services to enhance rehabilitation and health management.

Purpose: Nerve conduction study (NCS) is essential for subclassifying Guillain-Barré syndrome (GBS). It is well known that the GBS subclassification can change through serial NCSs. However, the usefulness of serial NCSs is debatable, especially in patients with early stage GBS., Methods: Follow-up NCS data within 3 weeks (early followed NCS, EFN) and within 3 to 10 weeks (late-followed NCS, LFN) were collected from 60 patients with GBS who underwent their first NCS (FN) within 10 days after symptom onset. Each NCS was classified into five subtypes (normal, demyelinating, axonal, inexcitable, and equivocal), according to Hadden's and Rajabally's criteria. We analyzed the frequency of significant changes in classification (SCCs) comprising electrodiagnostic aggravation and subtype shifts between demyelinating and axonal types according to follow-up timing., Results: Between FN and EFN, 33.3% of patients with Hadden's criteria and 18.3% with Rajabally's criteria showed SCCs. Between FN and LFN, 23.3% of patients with Hadden's criteria and 21.7% with Rajabally's criteria showed SCCs, of which 71.4% (Hadden's criteria) and 46.2% (Rajabally's criteria) already showed SCCs from the EFN. The conditions of delayed SCCs between EFN and LFN were very early FN, mild symptoms at the FN, or persistent electrophysiological deterioration 3 weeks after symptom onset., Conclusions: A substantial proportion of patients with GBS showed significant changes in neurophysiological classification at the early stage. Serial NCS may be helpful for precise neurophysiological classification. This study suggests that follow-up NCSs should be performed within 3 weeks of symptom onset in patients with GBS in whom FN was performed within 10 days of symptom onset., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 by the American Clinical Neurophysiology Society.)

Declining adolescent mental health is a significant public health concern during the COVID-19 pandemic. Social distancing and stay-at-home orders have led to missed social connections with peers and adults outside households, and this has increased the risk of mental health problems in children and adolescents, particularly those with adverse childhood experiences (ACEs). Studies have shown that strong interpersonal support improves adolescent mental health. We examined the association between ACEs and poor mental health (including stress, anxiety, and depression) and how the presence of interpersonal support from caring adults and friends and school connectedness can mitigate this relationship among adolescents in Arizona. This study analyzed data from the 2021 Arizona Youth Risk Behavior Survey (YRBS; n = 1181), a population-based survey conducted biennially across the United States. The Arizona sample included high school students in grades 9-12 who were enrolled in public and charter schools. This study revealed that nearly three of four adolescents experienced an ACE, and one of five experienced ≥4 ACEs. Compared with adolescents who experienced zero ACEs, those with ≥4 ACEs experienced less interpersonal support from caring adults, friends, and school and more frequently reported poor mental health and suicidal thoughts. However, adolescents with interpersonal support consistently reported lower rates of mental health issues, even with exposure to multiple ACEs. Post-pandemic programs to improve social relationships with adults, peers, and schools are critical, especially for adolescents with multiple adversities.

Introduction: The purpose of this study was to identify course of the corticobulbar tract and factors associated with the occurrence of facial paresis (FP) in lateral medullary infarction (LMI)., Methods: Patients diagnosed with LMI who were admitted to tertiary hospital were retrospectively investigated and divided into two groups based on the presence of FP. FP was defined as grade 2 or more by the House-Brackmann scale. Differences between the two groups were analyzed with respect to anatomical location of the lesions, demographic data (age, sex), risk factors (diabetes, hypertension, smoking, prior stroke, atrial fibrillation, and other cardiac risk factors for stroke), large vessel involvement on magnetic resonance angiography, other symptoms and signs (sensory symptoms, gait ataxia, limb ataxia, dizziness, Horner syndrome, hoarseness, dysphagia, dysarthria, nystagmus, nausea/vomiting, headache, neck pain, diplopia, and hiccup)., Results: Among 44 LMI patients, 15 patients (34%) had FP, and all of them had ipsilesional central-type FP. The FP group tended to involve upper (p < 0.0001) and relative ventral (p = 0.019) part of the lateral medulla. Horizontally large lesion was also related to the presence of FP (p = 0.044). Dysphagia (p = 0.001), dysarthria (p = 0.003), and hiccups (p = 0.034) were more likely to be accompanied by FP. Otherwise, there were no significant differences., Conclusion: The results of present study indicate that the corticobulbar fibers innervating the lower face decussate at the upper level of the medulla and ascend through the dorsolateral medulla, where the concentration of the fibers is densest near the nucleus ambiguus., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: To understand the characteristics of Korean patients with anti-3-hydroxy-3-methylglutaryl-coenxyme A reductase (HMGCR) myopathy, we measured anti-HMGCR antibodies and analyzed the clinical, radiological, and pathological features of patients with anti-HMGCR myopathy., Methods: We measured titers of anti-HMGCR antibodies in the sera of 99 patients with inflammatory myopathy, 36 patients with genetic myopathy, and 63 healthy subjects using an enzyme-linked immunosorbent assay. We tested 16 myositis-specific autoantibodies (MSAs) in all patients with anti-HMGCR myopathy., Results: Positivity for the anti-HMGCR antibody was observed in 17 (4 males and 13 females) of 99 patients with inflammatory myopathy. The median age at symptom onset was 60 years. Ten (59%) of the patients with anti-HMGCR positivity had taken statins. The titer of anti-HMGCR antibodies was significantly higher in the statin-naïve group (median=230 U/mL, interquartile range=170-443 U/mL) than in the statin-exposed group (median=178 U/mL, interquartile range=105-210 U/mL, p =0.045). The most common symptom was proximal muscle weakness in 15 patients (88%), followed by myalgia in 9 (53%), neck weakness in 4 (24%), dysphagia in 3 (18%), and skin lesions in 2 (12%). The median titer of anti-HMGCR antibody was 202 U/mL. We found eight different MSAs in nine (53%) patients. The median disease duration from symptom onset to diagnosis was significantly shorter in the MSA-positive group than in the MSA-negative group ( p =0.027)., Conclusions: Our study was the first to measure anti-HMGCR antibodies in inflammatory myopathy. It has provided new findings, including the suggestion of the coexistence of other MSAs in Korean patients., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2023 Korean Neurological Association.)

Background and Purpose: The description of pain is the most-important indicator leading to the adequate treatment of patients with neuropathic pain (NeP). The purpose of this study was to identify and characterize the unique features of Korean verbal descriptions in patients with peripheral NeP., Methods: This study included 400 patients (167 males and 233 females) and their 1,387 pain-description responses. Patients with peripheral NeP freely described their symptoms in Korean. Collected verbal descriptions were grouped according to terminologies with similar meanings. Participants completed validated patient-reported outcome scales including the neuropathic pain symptom inventory (NPSI) and painDETECT questionnaire (PD-Q). The frequencies of each verbal pain descriptor were compared between the NPSI and PD-Q scores., Results: ' Jeorim ' (tingling) was the most common among 17 types of organized verbal pain descriptors, and the ' Sirim ' (cold) symptom had a significantly higher rate of use in the 2 high-severity groups when participants were classified by their total scores on the NPSI and PD-Q., Conclusions: Korean verbal NeP descriptors were significantly diverse. The Jeorim (tingling) and Sirim (cold) descriptors can be utilized in evaluations of Korean patients with NeP., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2023 Korean Neurological Association.)

To explore the clinical significance of anti-cytosolic 5'-nucleoditase 1A (NT5c1A) antibody seropositivity in inflammatory myopathies, we measured anti-NT5c1A antibodies and analyzed their clinical features. Anti-NT5c1A antibodies were measured in the sera of 103 patients with inflammatory myopathies using an enzyme-linked immunosorbent assay. Positivity for anti-NT5c1A antibody was found in 13 (12.6%) of 103 patients with inflammatory myopathy. Anti-NT5c1A antibody was most frequently identified in patients with inclusion body myositis (IBM) (8/20, 40%), followed by dermatomyositis (2/13, 15.4%), immune-mediated necrotizing myopathy (2/28, 7.1%), and polymyositis (1/42, 2.4%). In eight patients with the anti-NT5c1A antibody-seropositive IBM, the median age at symptom onset was 54 years (interquartile range [IQR]: 48-57 years), and the median disease duration was 34 months (IQR: 24-50 months]. Knee extension weakness was greater than or equal to hip flexion weakness in eight (100%) patients, and finger flexion strength was less than shoulder abduction in three (38%) patients. Dysphagia symptoms were found in three (38%) patients. The median serum CK level was 581 IU/l (IQR: 434-868 IU/L]. Clinically significant differences were not found between anti-NT5c1A antibody-seropositive and seronegative IBM groups with respect to gender, age at symptom onset, age at diagnosis, disease duration, serum CK values, presence of other autoantibodies, dysphagia, and the pattern of muscle impairment. Although anti-NT5c1A antibody is known to be associated with IBM, seropositivity has also been noted in non-IBM inflammatory myopathies, and is insufficient to have clinical significance by itself. These findings have important implications for interpreting anti-NT5c1A antibody test results as the first study in Korea., Competing Interests: All authors certify that there are no affiliations with or involvement in any organization or entity with direct financial interest in the subject matter or materials discussed in the manuscript. All authors have approved the final version of the manuscript and have no potential conflicts of interest to declare., (Copyright: © 2023 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

G protein-coupled receptors (GPCRs) regulate diverse intracellular signaling pathways through the activation of heterotrimeric G proteins. However, the effects of the sequential activation-deactivation cycle of G protein on the conformational changes of GPCRs remains unknown. By developing a Förster resonance energy transfer (FRET) tool for human M3 muscarinic receptor (hM3R), we find that a single-receptor FRET probe can display the consecutive structural conversion of a receptor by G protein cycle. Our results reveal that the G protein activation evokes a two-step change in the hM3R structure, including the fast step mediated by G q protein binding and the subsequent slower step mediated by the physical separation of the Gα q and Gβγ subunits. We also find that the separated Gα q -GTP forms a stable complex with the ligand-activated hM3R and phospholipase Cβ. In sum, the present study uncovers the real-time conformational dynamics of innate hM3R during the downstream G q protein cycle., (© 2023. The Author(s).)

Normal alcohols (n-alcohols) can induce anesthetic effects by acting on neuronal ion channels. Recent studies have revealed the effects of n-alcohols on various ion channels; however, the underlying molecular mechanisms remain unclear. Here, we provide evidence that long-chain n-alcohols have dual effects on Kv7.2/7.3 channels, resulting in channel activation as the net effect. Using heterologous expression systems, we found that n-alcohols could differentially regulate the Kv7.2/7.3 channel depending on their chain length. Treatment with short-chain ethanol and propanol diminished Kv7.2/7.3 currents, whereas treatment with long-chain hexanol and octanol enhanced the currents. However, the long-chain alcohols failed to potentiate Kv7.2 currents pre-activated by retigabine. Instead, they inhibited the currents, similar to short-chain ethanol. The stimulatory effect of the long-chain n-alcohols was also converted into an inhibitory one in the mutant Kv7.2(W236L) channels, while the inhibitory effect of ethanol did not differ between wild-type Kv7.2 and mutant Kv7.2(W236L). The inhibition of currents by n-alcohols was also seen in Kv7.1 channel which does not have the tryptophan (W) residue in S5. These findings suggest that long-chain n-alcohols exhibit dual effects through independent working sites on the Kv7.2 channel. Finally, we confirmed that the hydroxyl group with a negative electrostatic potential surface is essential for the dual actions of n-alcohol. Together, our data suggest that long-chain n-alcohols regulate Kv7.2/7.3 channels by interacting with both stimulatory and inhibitory sites and that their stimulatory action depends on the conserved tryptophan 236 residue in S5 and could be important for triggering their anesthetic effects., (© 2022 Jeong et al.)

Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRAS G12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRAS G12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRAS G12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRAS G12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRAS G12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Early Care and Education (ECE) sites are critical hubs for social, emotional, and physical learning development of preschool children (ages 3-5). The COVID-19 pandemic has impacted ECE enrollment and participation; until June 2022, preschool children in the US were ineligible for COVID-19 vaccines. It is critical to identify perceptions of teachers/directors and parents to enhance safe return-to-school efforts., Methods: Focus groups (n = 7; 22 participants) were conducted with ECE teachers/directors throughout Arizona to examine perceptions of COVID-19 testing for families and staff at ECE sites, and current and possible COVID-19 mitigation strategies during Summer 2021. Preschool parents from underserved families in Phoenix (n = 41) completed a brief survey on their perceptions of benefits of ECE for themselves and their children, thoughts on COVID-19 mitigation strategies, and timing for safe return to school during Spring 2021. Focus groups were transcribed and analyzed for themes using constant comparison., Results: There were 4 focus group themes: 1) perceptions of saliva-based COVID-19 testing, 2) logistical strategies for COVID-19 testing at ECE sites; 3) successes and challenges with current COVID-19 mitigation strategies; 4) ideas to support improved COVID-19 mitigation, including outdoor gardening. Parents rated peace of mind about the child's education as the most important benefit for themselves of in-person ECE (74.6%), and social development for children as the most important benefit for their children (54.4%). Over 40% of parents reported it would not be safe to send children back until 2022., Conclusions: COVID-19 continues to impact attendance at ECE sites, despite parents reporting key benefits to attending ECE sites. Teachers/directors supported COVID-19 mitigation strategies including saliva-based testing and gardening education to improve safe return to schools., (© 2022. The Author(s).)

High-voltage-activated Ca 2+ (Ca V ) channels that adjust Ca 2+ influx upon membrane depolarization are differentially regulated by phosphatidylinositol 4,5-bisphosphate (PIP 2 ) in an auxiliary Ca V β subunit-dependent manner. However, the molecular mechanism by which the β subunits control the PIP 2 sensitivity of Ca V channels remains unclear. By engineering various α1B and β constructs in tsA-201 cells, we reported that at least two PIP 2 -binding sites, including the polybasic residues at the C-terminal end of I-II loop and the binding pocket in S4 II domain, exist in the Ca V 2.2 channels. Moreover, they were distinctly engaged in the regulation of channel gating depending on the coupled Ca V β2 subunits. The membrane-anchored β subunit abolished the PIP 2 interaction of the phospholipid-binding site in the I-II loop, leading to lower PIP 2 sensitivity of Ca V 2.2 channels. By contrast, PIP 2 interacted with the basic residues in the S4 II domain of Ca V 2.2 channels regardless of β2 isotype. Our data demonstrated that the anchoring properties of Ca V β2 subunits to the plasma membrane determine the biophysical states of Ca V 2.2 channels by regulating PIP 2 coupling to the nonspecific phospholipid-binding site in the I-II loop., Competing Interests: CP, WY, BS No competing interests declared, (© 2022, Park et al.)

Understanding pollen tube growth is critical for crop yield maintenance. The pollen tube provides a path for sperm cells for fertilization with egg cells. Cells must be subdivided into functionally and structurally distinct compartments for polar tip growth, and phosphoinositides are thought to be one of the facilitators for polarization during pollen tube growth. OsSNDP3 encodes Sec14-nodulin domain-containing protein and localizes in the nucleus and the microdomains of the plasma membrane in tobacco leaf epidermis cells. OsSNDP3 is thought to bind with phosphatidylinositol 4,5-bisphosphate based on the data including the information of basic amino acids in the C-terminal and colocalization with 2X Pleckstrin homology domain of Phospholipase C delta-1. OsSNDP3 interacts with a protein that contains a class I nodulin domain. We discovered that OsSNDP3 plays a significant role in pollen tube germination using CRISPR/Cas9 systems, whereas another pollen-preferential Sec14-nodulin domain-containing protein, OsSNDP2, additively functions with OsSNDP3 during pollen tube germination. Gene Ontology analysis using downregulated genes in ossndp3 indicated that the expression of genes involved in the phosphatidylinositol metabolic process and tip growth was significantly altered in ossndp3. OsSNDP3 aids pollen polar tip growth by binding with phosphatidylinositol 4,5-bisphosphate. We can better understand the roles of phosphoinositides during pollen tube growth by studying the functions of OsSNDP3 and OsSNDP2. And downregulated genes in ossndp3 might be useful targets for future research on polar tip growth., (© 2022. The Author(s).)

Phosphoinositide membrane lipids are ubiquitous low-abundance signaling molecules. They direct many physiological processes that involve ion channels, membrane identification, fusion of membrane vesicles, and vesicular endocytosis. Pools of these lipids are continually broken down and refilled in living cells, and the rates of some of these reactions are strongly accelerated by physiological stimuli. Recent biophysical experiments described here measure and model the kinetics and regulation of these lipid signals in intact cells. Rapid on-line monitoring of phosphoinositide metabolism is made possible by optical tools and electrophysiology. The experiments reviewed here reveal that as for other cellular second messengers, the dynamic turnover and lifetimes of membrane phosphoinositides are measured in seconds, controlling and timing rapid physiological responses, and the signaling is under strong metabolic regulation. The underlying mechanisms of this metabolic regulation remain questions for the future., (© 2022 Jensen et al.)

Physical activity and nutrition preschool programming must involve parents in positive long-term healthy habits. This paper describes parent outreach in the Sustainability via Active Garden Education (SAGE) study. Newsletters were sent home with children to promote family opportunities to increase physical activity and fruit and vegetable intake. The content was generated via a community advisory board participatory process. Messages linked SAGE curriculum topics with home and community activities. Parents rated frequency of receipt, helpfulness, satisfaction, and use of content. Most participants were Hispanic (>78%) and women (>95%). Most reported receiving newsletters; nearly all reported that they were helpful. Favorite newsletter components included recipes, pictures of their children and seasonal produce spotlights. Most reported doing physical activities from the newsletters (51.9%). Few reported doing featured physical activity (8.9%) and fruit and vegetable (12.7%) community activities. Newsletter outreach methods are a simple strategy to add value to preschool-based interventions promoting healthy families.

Background: A culturally validated Korean version of the PainDETECT Questionnaire (PD-Q) was used to identify neuropathic pain components (NeP) in patients suffering from chronic pain. The purpose of this study was to determine if the Korean PD-Q can be used to subgroup patients with peripheral NeP according to sensory symptom profiles., Methods: This study included 400 Korean patients with peripheral neuropathic pain diagnosed as probable or definite NeP. The total scores and subscores for each item in PD-Q were transformed into a Z-score for standardization. Hierarchical cluster analysis was performed to identify clusters of subjects by PD-Q scores., Results: The mean total PD-Q score of the study participants was 14.57 ± 6.46. A hierarchical cluster analysis identified 5 clusters with distinct pain characteristic profiles. Cluster 1 had relatively severe burning and tingling sensations. The mean total PD-Q score for cluster 2 was the lowest of the 5 clusters. Cluster 3 tended to be vulnerable to pain in response to cold/heat stimulation. Cluster 4 showed relatively severe pain induced by physical stimuli, such as light touch or slight pressure. Cluster 5 had high scores for all NeP symptoms., Conclusion: This study demonstrates the ability of patients to cluster by symptoms using the Korean PD-Q. Subgrouping of peripheral neuropathic pain by sensory symptom profile may be useful in making effective drug treatment decisions., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

MicroRNAs (miRNAs) have recently emerged as important regulators of ion channel expression. We show here that select miR-106b family members repress the expression of the KCNQ2 K + channel protein by binding to the 3'-untranslated region of KCNQ2 messenger RNA. During the first few weeks after birth, the expression of miR-106b family members rapidly decreases, whereas KCNQ2 protein level inversely increases. Overexpression of miR-106b mimics resulted in a reduction in KCNQ2 protein levels. Conversely, KCNQ2 levels were up-regulated in neurons transfected with antisense miRNA inhibitors. By constructing more specific and stable forms of miR-106b controlling systems, we further confirmed that overexpression of precursor-miR-106b-5p led to a decrease in KCNQ current density and an increase in firing frequency of hippocampal neurons, while tough decoy miR-106b-5p dramatically increased current density and decreased neuronal excitability. These results unmask a regulatory mechanism of KCNQ2 channel expression in early postnatal development and hint at a role for miR-106b up-regulation in the pathophysiology of epilepsy., Competing Interests: The authors declare no competing interest.

Objective: Approximately one in ten adults under the age of 65 in the USA has a mobility impairing disability. People with mobility impairment generally have poorer dietary habits contributing to obesity and related negative health outcomes. This article presents the psychometric properties of the Food Environment Assessment Survey Tool (FEAST) instrument that measures barriers to accessing healthy food from the perspective of people with mobility impairment (PMI)., Design: The current study presents cross-sectional data from two sequential independent surveys., Setting: Surveys were administered online to a national sample of PMI., Participants: Participants represented PMI living throughout the USA. The pilot FEAST survey involved 681 participants and was used to shape the final instrument; 25 % completed a retest survey. After following empirically and theoretically guided item reduction strategies, the final FEAST instrument was administered to a separate sample of 304 PMI., Results: The final twenty-seven-item FEAST instrument includes items measuring Neighbourhood Environment, Home Environment, Personal Control and Access to Support (Having Help, Food Delivery Services, Parking/Transportation). The final four scales had acceptable intra-class correlations, indicating that the scales could be used as reliable measures of the hypothesised constructs in future studies., Conclusions: The FEAST instrument is the first of its kind developed to assess the food environment from the perspective of PMI themselves. Future studies would benefit from using this measure in research and practice to help guide the development of policy aimed at improving access to healthy food and promoting healthy eating in community-dwelling PMI.

In animals, proper locomotion is crucial to find mates and foods and avoid predators or dangers. Multiple sensory systems detect external and internal cues and integrate them to modulate motor outputs. Proprioception is the internal sense of body position, and proprioceptive control of locomotion is essential to generate and maintain precise patterns of movement or gaits. This proprioceptive feedback system is conserved in many animal species and is mediated by stretch-sensitive receptors called proprioceptors. Recent studies have identified multiple proprioceptive neurons and proprioceptors and their roles in the locomotion of various model organisms. In this review we describe molecular and neuronal mechanisms underlying proprioceptive feedback systems in C. elegans, Drosophila, and mice. [BMB Reports 2021; 54(8): 393-402].

Ethanol often causes critical health problems by altering the neuronal activities of the central and peripheral nerve systems. One of the cellular targets of ethanol is the plasma membrane proteins including ion channels and receptors. Recently, we reported that ethanol elevates membrane excitability in sympathetic neurons by inhibiting Kv7.2/7.3 channels in a cell type-specific manner. Even though our studies revealed that the inhibitory effects of ethanol on the Kv7.2/7.3 channel was diminished by the increase of plasma membrane phosphatidylinositol 4,5-bisphosphate (PI (4,5)P2), the molecular mechanism of ethanol on Kv7.2/7.3 channel inhibition remains unclear. By investigating the kinetics of Kv7.2/7.3 current in high K+ solution, we found that ethanol inhibited Kv7.2/7.3 channels through a mechanism distinct from that of tetraethylammonium (TEA) which enters into the pore and blocks the gate of the channels. Using a non-stationary noise analysis (NSNA), we demonstrated that the inhibitory effect of ethanol is the result of reduction of open probability (PO) of the Kv7.2/7.3 channel, but not of a single channel current (i) or channel number (N). Finally, ethanol selectively facilitated the kinetics of Kv7.2 current suppression by voltage-sensing phosphatase (VSP)-induced PI(4,5)P2 depletion, while it slowed down Kv7.2 current recovery from the VSP-induced inhibition. Together our results suggest that ethanol regulates neuronal activity through the reduction of open probability and PI(4,5)P2 sensitivity of Kv7.2/7.3 channels. [BMB Reports 2021; 54(6): 311-316].

TMEM16A is a Ca 2+ -activated Cl - channel that controls broad cellular processes ranging from mucus secretion to signal transduction and neuronal excitability. Recent studies have reported that membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) is an important cofactor that allosterically regulates TMEM16A channel activity. However, the detailed regulatory actions of PIP 2 in splice variants of TMEM16A remain unclear. Here, we demonstrated that the attenuation of membrane phosphoinositide levels selectively inhibited the current amplitude of the TMEM16A(ac) isoform by decreasing the slow, but not instantaneous, Cl - currents, which are independent of the membrane potential and specific to PI(4,5)P 2 depletion. The attenuation of endogenous PI(4,5)P 2 levels by the activation of Danio rerio voltage-sensitive phosphatase (Dr-VSP) decreased the Cl - currents of TMEM16A(ac) but not the TMEM16A(a) isoform, which was abolished by the co-expression of PIP 5-kinase type-1γ (PIPKIγ). Using the rapamycin-inducible dimerization of exogenous phosphoinositide phosphatases, we further revealed that the stimulatory effects of phosphoinositide on TMEM16A(ac) channels were similar in various membrane potentials and specific to PI(4,5)P 2 , not PI4P and PI(3,4,5)P 3 . Finally, we also confirmed that PI(4,5)P 2 resynthesis is essential for TMEM16A(ac) recovery from Dr-VSP-induced current inhibition. Our data demonstrate that membrane PI(4,5)P 2 selectively modulates the gating of the TMEM16A(ac) channel in an agonistic manner, which leads to the upregulation of TMEM16A(ac) functions in physiological conditions.

Possible segregation of plasma membrane (PM) phosphoinositide metabolism in membrane lipid domains is not fully understood. We exploited two differently lipidated peptide sequences, L10 and S15, to mark liquid-ordered, cholesterol-rich (L o ) and liquid-disordered, cholesterol-poor (L d ) domains of the PM, often called raft and nonraft domains, respectively. Imaging of the fluorescent labels verified that L10 segregated into cholesterol-rich L o phases of cooled giant plasma-membrane vesicles (GPMVs), whereas S15 and the dye FAST DiI cosegregated into cholesterol-poor L d phases. The fluorescent protein markers were used as Förster resonance energy transfer (FRET) pairs in intact cells. An increase of homologous FRET between L10 probes showed that depleting membrane cholesterol shrank L o domains and enlarged L d domains, whereas a decrease of L10 FRET showed that adding more cholesterol enlarged L o and shrank L d Heterologous FRET signals between the lipid domain probes and phosphoinositide marker proteins suggested that phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5) P 2 ] and phosphatidylinositol 4-phosphate (PtdIns4 P ) are present in both L o and L d domains. In kinetic analysis, muscarinic-receptor-activated phospholipase C (PLC) depleted PtdIns(4,5) P 2 and PtdIns4 P more rapidly and produced diacylglycerol (DAG) more rapidly in L o than in L d Further, PtdIns(4,5) P 2 was restored more rapidly in L o than in L d Thus destruction and restoration of PtdIns(4,5) P 2 are faster in L o than in L d This suggests that L o is enriched with both the receptor G protein/PLC pathway and the PtdIns/PI4-kinase/PtdIns4 P pathway. The significant kinetic differences of lipid depletion and restoration also mean that exchange of lipids between these domains is much slower than free diffusion predicts.

Among youth from high-achieving schools, adverse childhood experiences (ACEs) were examined in relation to (a) internalizing and externalizing symptoms in adolescence (n = 527), and (b) symptoms plus psychiatric diagnoses-based on multiple annual interviews-in adulthood (n = 316). Also examined were associations for a "Proxy ACEs" (P-ACEs) measure, containing items similar to those on standard ACEs measures without reference to abuse or neglect. Rates of ACEs were comparable with those in other studies; most commonly endorsed were perceived parental depression followed by aspects of emotional neglect. Groups exposed to zero, 1, 2, 3, and 4+ ACEs differed on symptoms in adulthood, with small to moderate effect sizes; in parallel comparisons of P-ACEs groups on Grade 12 symptoms, differences had large effect sizes. In relation to psychiatric diagnoses, comparisons with the zero ACEs group showed that groups with 1, 2, 3 ACEs, versus 4+ ACES, respectively, had twofold and over fivefold greater odds of having any lifetime diagnosis. The odds for internalizing diagnoses specifically were 2-6 times greater for individuals with 1, 2, and 3 ACEs, and 12 times greater for those reporting 4 ACEs. Remarkably, Grade 12 reports of 2, 3, and 4+ P-ACEs were linked to 2-3 times greater odds of a psychiatric disorder in adulthood, and 3-6 times greater odds for internalizing diagnoses specifically. In the future, assessments of ACEs and P-ACEs could facilitate early detection of problems among HAS students, informing interventions to mitigate vulnerability processes and promote resilience among these youth and their families. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The dynamic metabolism of membrane phosphoinositide lipids involves several cellular compartments including the ER, Golgi, and plasma membrane. There are cycles of phosphorylation and dephosphorylation and of synthesis, transfer, and breakdown. The simplified phosphoinositide cycle comprises synthesis of phosphatidylinositol in the ER, transport, and phosphorylation in the Golgi and plasma membranes to generate phosphatidylinositol 4,5-bisphosphate, followed by receptor-stimulated hydrolysis in the plasma membrane and return of the components to the ER for reassembly. Using probes for specific lipid species, we have followed and analyzed the kinetics of several of these events during stimulation of M1 muscarinic receptors coupled to the G-protein Gq. We show that during long continued agonist action, polyphosphorylated inositol lipids are initially depleted but then regenerate while agonist is still present. Experiments and kinetic modeling reveal that the regeneration results from gradual but massive up-regulation of PI 4-kinase pathways rather than from desensitization of receptors. Golgi pools of phosphatidylinositol 4-phosphate and the lipid kinase PI4KIIIα (PI4KA) contribute to this homeostatic regeneration. This powerful acceleration, which may be at the level of enzyme activity or of precursor and product delivery, reveals strong regulatory controls in the phosphoinositide cycle., (© 2020 Myeong et al.)

Transmembrane 16A (TMEM16A, anoctamin1), 1 of 10 TMEM16 family proteins, is a Cl - channel activated by intracellular Ca 2+ and membrane voltage. This channel is also regulated by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ]. We find that two splice variants of TMEM16A show different sensitivity to endogenous PI(4,5)P 2 degradation, where TMEM16A(ac) displays higher channel activity and more current inhibition by PI(4,5)P 2 depletion than TMEM16A(a). These two channel isoforms differ in the alternative splicing of the c-segment (exon 13). The current amplitude and PI(4,5)P 2 sensitivity of both TMEM16A(ac) and (a) are significantly strengthened by decreased free cytosolic ATP and by conditions that decrease phosphorylation by Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). Noise analysis suggests that the augmentation of currents is due to a rise of single-channel current ( i ), but not of channel number ( N ) or open probability ( P O ). Mutagenesis points to arginine 486 in the first intracellular loop as a putative binding site for PI(4,5)P 2 , and to serine 673 in the third intracellular loop as a site for regulatory channel phosphorylation that modulates the action of PI(4,5)P 2 In silico simulation suggests how phosphorylation of S673 allosterically and differently changes the structure of the distant PI(4,5)P 2 -binding site between channel splice variants with and without the c-segment exon. In sum, our study reveals the following: differential regulation of alternatively spliced TMEM16A(ac) and (a) by plasma membrane PI(4,5)P 2 , modification of these effects by channel phosphorylation, identification of the molecular sites, and mechanistic explanation by in silico simulation., Competing Interests: The authors declare no competing interest.

Introduction: To develop a new method to quantify the density of nerves, vessels, and the neurovascular contacts, we studied skin biopsies in diabetes and control subjects., Methods: Skin biopsies with dual immunofluorescent staining were used to visualize nerves and blood vessels. The density of nerves, vessels, and their neurovascular contacts were quantified with unbiased stereology. Results were compared with examination findings, validated questionnaires, and autonomic function., Results: In tissue from 19 controls and 20 patients with diabetes, inter-rater and intra-rater intraclass correlation coefficients were high (>0.85; P < .001) for all quantitative methods. In diabetes, the nerve densities (P < .05), vessel densities (P < .01), and the neurovascular densities (P < .01) were lower compared with 20 controls. Results correlated with autonomic function, examination and symptom scores., Discussion: We report an unbiased, stereological method to quantify the cutaneous nerve, vessel and neurovascular density and offer new avenues of investigation into cutaneous neurovascular innervation in health and disease., (© 2020 Wiley Periodicals, Inc.)

Competing Interests: The authors have no potential conflicts of interest to disclose.

Competing Interests: The authors have no potential conflicts of interest to disclose.

Background and Purpose: Diagnosing small-fiber neuropathy (SFN) is challenging because there is no gold-standard test and few diagnostic tests. This study investigated the clinical symptom profile and its associations with the results of quantitative sensory testing (QST) and the quantitative sudomotor axon reflex test (QSART) as well as the quality of life (QOL) in patients with clinically suspected SFN., Methods: This study involved 63 patients with clinically suspected length-dependent SFN. Assessments were performed using QST, QSART, SFN Symptoms Inventory Questionnaire, Neuropathic Pain Symptom Inventory, 'Sirim' frequency and 'Sirim' (cold) pain severity, and 36-item Short-Form Health Survey. Multiple logistic and linear regression analyses were performed to predict risk factors for QST or QSART abnormalities and QOL, respectively., Results: 'Sirim' and 'Sirim' pain was the most-common (84%) and the most-severe complaint (mean score of 6.3 on a numerical rating scale ranging from 0 to 10) in patients with clinically suspected SFN. The findings of QST [cold detection threshold (CDT)] and QSART were abnormal in 71% ( n =45/57) and 62% ( n =39/56) of the patients, respectively. An abnormal CDT was correlated with more-severe stabbing pain (odds ratio=2.23, 95% CI=1.02-4.87, p =0.045). Restless-leg symptoms (β=-7.077) and pressure-evoked pain (β=-5.034) were independent predictors of the physical aspects of QOL., Conclusions: 'Sirim' pain, similar to cold pain, should be considered a major neuropathic pain in SFN. Among pain characteristics, stabbing pain of a spontaneous paroxysmal nature may be more pronounced in the setting of dysfunctional Aδ fibers with functional autonomic C fibers., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2019 Korean Neurological Association.)

Alcohol causes diverse acute and chronic symptoms that often lead to critical health problems. Exposure to ethanol alters the activities of sympathetic neurons that control the muscles, eyes, and blood vessels in the brain. Although recent studies have revealed the cellular targets of ethanol, such as ion channels, the molecular mechanism by which alcohol modulates the excitability of sympathetic neurons has not been determined. Here, we demonstrated that ethanol increased the discharge of membrane potentials in sympathetic neurons by inhibiting the M-type or Kv7 channel consisting of the Kv7.2/7.3 subunits, which were involved in determining the membrane potential and excitability of neurons. Three types of sympathetic neurons, classified by their threshold of activation and firing patterns, displayed distinct sensitivities to ethanol, which were negatively correlated with the size of the Kv7 current that differs depending on the type of neuron. Using a heterologous expression system, we further revealed that the inhibitory effects of ethanol on Kv7.2/7.3 currents were facilitated or diminished by adjusting the amount of plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ). These results suggested that ethanol and PI(4,5)P 2 modulated gating of the Kv7 channel in superior cervical ganglion neurons in an antagonistic manner, leading to regulation of the membrane potential and neuronal excitability, as well as the physiological functions mediated by sympathetic neurons.

Acid-sensing ion channels (ASICs), sensory molecules that continuously monitor the concentration of extracellular protons and initiate diverse intracellular responses through an influx of cations, are assembled from six subtypes that can differentially combine to form various trimeric channel complexes and elicit unique electrophysiological responses. For instance, homomeric ASIC1a channels have been shown to exhibit prolonged desensitization, and acid-evoked currents become smaller when the channels are repeatedly activated by extracellular protons, whereas homomeric or heteromeric ASIC2a channels continue to respond to repetitive acidic stimuli without exhibiting such desensitization. Although previous studies have provided evidence that both the desensitization of ASIC1a and rapid resensitization of ASIC2a commonly require domains that include the N terminus and the first transmembrane region of these channels, the biophysical basis of channel gating at the amino acid level has not been clearly determined. Here, we confirm that domain-swapping mutations replacing the N terminus of ASIC2a with that of ASIC2b result in de novo prolonged desensitization in homomeric channels following activation by extracellular protons. Such desensitization of chimeric ASIC2a mutants is due neither to internalization nor to degradation of the channel proteins. We use site-directed mutagenesis to narrow down the relevant portion of the N terminus of ASIC2a, identifying three amino acid residues within the N terminus (T25, T39, and I40) whose mutation is sufficient to phenocopy the desensitization exhibited by the chimeric mutants. A similar desensitization is observed in heteromeric ASICs containing the mutant subunit. These results suggest that T25, T39, and I40 of ASIC2a are key residues determining the rapid resensitization of homomeric and heteromeric ASIC2a channels upon proton activation., (© 2019 Lee et al.)

β subunits of high voltage-gated Ca 2+ (Ca V ) channels promote cell-surface expression of pore-forming α1 subunits and regulate channel gating through binding to the α-interaction domain (AID) in the first intracellular loop. We addressed the stability of Ca V α1B-β interactions by rapamycin-translocatable Ca V β subunits that allow drug-induced sequestration and uncoupling of the β subunit from Ca V 2.2 channel complexes in intact cells. Without Ca V α1B/α2δ1, all modified β subunits, except membrane-tethered β2a and β2e, are in the cytosol and rapidly translocate upon rapamycin addition to anchors on target organelles: plasma membrane, mitochondria, or endoplasmic reticulum. In cells coexpressing Ca V α1B/α2δ1 subunits, the translocatable β subunits colocalize at the plasma membrane with α1B and stay there after rapamycin application, indicating that interactions between α1B and bound β subunits are very stable. However, the interaction becomes dynamic when other competing β isoforms are coexpressed. Addition of rapamycin, then, switches channel gating and regulation by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] lipid. Thus, expression of free β isoforms around the channel reveals a dynamic aspect to the α1B-β interaction. On the other hand, translocatable β subunits with AID-binding site mutations are easily dissociated from Ca V α1B on the addition of rapamycin, decreasing current amplitude and PI(4,5)P 2 sensitivity. Furthermore, the mutations slow Ca V 2.2 current inactivation and shift the voltage dependence of activation to more positive potentials. Mutated translocatable β subunits work similarly in Ca V 2.3 channels. In sum, the strong interaction of Ca V α1B-β subunits can be overcome by other free β isoforms, permitting dynamic changes in channel properties in intact cells., Competing Interests: The authors declare no conflict of interest.

Background and Purpose: Antiganglioside antibodies are known to play a pathogenic role in Guillain-Barré syndrome (GBS). Either an immunoglobulin (Ig)G- or IgM-type anti-GM2 antibody is detected in rare cases in GBS patients. However, the specific pathogenic role of these antibodies in GBS has not been reported previously. This study aimed to define and characterize the clinical spectrum of GBS with anti-GM2 positivity., Methods: We reviewed the database of the Dong-A University Neuroimmunology Team, which has collected sera of GBS and its variants from more than 40 general and university-based hospitals in Korea. Detailed information about the involved patients was often obtained and then corrected by the charge doctor applying additional questionnaires., Results: Four patients with acute monophasic peripheral neuropathy or cranial neuropathy with isolated IgM-type anti-GM2-antibody positivity were recruited. In addition, IgG-type anti-GM2 antibody was solely detected in the sera of another four patients. The IgM-positive group comprised heterogeneous syndromes: two cases of acute motor axonal neuropathy, one of acute inflammatory demyelinating polyneuropathy, and one of isolated facial diplegia. In contrast, all of the cases enrolled in the IgG-positive group manifested with dizziness with or without oculomotor palsy due to cranial neuropathy syndrome., Conclusions: This study has identified that anti-GM2 antibody can be found in various subtypes of GBS and its variants in rare cases. Compared to the clinical heterogeneity of the IgM-positive group, the IgG-positive group can be characterized by cranial-dominant GBS variants presenting mainly with oculomotor and vestibular dysfunctions., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2018 Korean Neurological Association.)

Although magnesium alloys, as the lightest structural alloys, offer significant potential for automotive applications, their applications remain limited due to their poor formability at room temperature. Since the strategies used for improving formability usually result in a degradation of strength, there are no high strength magnesium alloys showing good formability. Here we report an alloy design concept that can simultaneously provide high strength and good formability. Such designed alloy when subjected to an appropriate processing technique shows a combination of strength and formability that surpasses those of the existing magnesium alloys reported so far. The alloy design concept used in the present study is based on the utilization of alloying elements that can induce precipitation, as well as maximize the segregation of other texture-controlling alloying elements. Such developed alloy is expected to broaden the application of Mg alloy sheets, which are now starting to gain acceptance by automotive industries.

Background and Purpose: Neurolymphomatosis is a rare manifestation of hematological malignancy and is characterized by direct infiltration of the peripheral nervous system. The objective of this study was to identify the clinical and electrophysiological features of neurolymphomatosis., Methods: We retrospectively analyzed the medical records of 13 patients with neurolymphomatosis. Seven (54%) of the patients were men, and the median age at symptom onset was 60.0 years., Results: The most common type of underlying malignancy was diffuse large B-cell lymphoma (69%). Twelve patients had painful asymmetric neuropathies. The median survival time after diagnosis was 7 months, and 12 patients died during the study period. Thirty-eight motor nerve conduction studies (NCSs) were performed in the affected nerves. Ten and 28 motor nerves were classified into the conduction-block and simple-axon-degeneration groups, respectively. The median time interval between symptom onset and the NCS was significantly shorter in the conduction-block group than in the simple-axon-degeneration group (p=0.032). However, no significant differences in the motor nerve conduction velocities, terminal latencies, and distal compound muscle action potential amplitudes were identified between the conduction-block and simple-axon-degeneration groups. The conduction-block group showed excessive temporal dispersion in only five of the ten NCSs (50%). Follow-up NCSs revealed that partial conduction blocks had changed into axonal degeneration patterns., Conclusions: This is the first study to analyze the electrophysiological features of patients with neurolymphomatosis. Our findings showed that a partial conduction block is not rare and is an early nerve conduction abnormality in neurolymphomatosis., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2018 Korean Neurological Association.)

Background and Purpose: Upper respiratory infection (URI), including influenza, may exacerbate the symptoms of myasthenia gravis (MG), which is an autoimmune disease that causes muscle weakness. There is also concern that the influenza vaccine may trigger or worsen autoimmune diseases. The objective of this study was to determine the impacts of influenza infection and vaccination on symptom severity in MG patients., Methods: Patients diagnosed with MG were enrolled from 10 university-affiliated hospitals between March and August 2015. Subjects completed a questionnaire at the first routine follow-up visit after enrolling in the study. The patient history was obtained to determine whether a URI had been experienced during the previous winter, if an influenza vaccination had been administered before the previous winter, and whether their MG symptoms were exacerbated during or following either a URI or vaccination. Influenza-like illness (ILI) was defined and differentiated from the common cold as a fever of ≥38°C accompanied by a cough and/or a sore throat., Results: Of the 258 enrolled patients [aged 54.1±15.2 years (mean±SD), 112 men, and 185 with generalized MG], 133 (51.6%) had received an influenza vaccination and 121 (46.9%) had experienced a common cold (96 patients) or ILI (25 patients) during the analysis period. MG symptoms were aggravated in 10 (40%) patients after ILI, whereas only 2 (1.5%) experienced aggravation following influenza vaccination. The rate of symptom aggravation was significantly higher in patients experiencing an ILI (10/25, 40%) than in those with the common cold (15/96, 15.6%, p=0.006)., Conclusions: The results of this study suggest that the potential risk of aggravating autoimmune disease is higher for ILI than for influenza vaccination, which further suggests that influenza vaccination can be offered to patients with MG., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2017 Korean Neurological Association)

Recently, we showed that the HOOK region of the β2 subunit electrostatically interacts with the plasma membrane and regulates the current inactivation and phosphatidylinositol 4,5-bisphosphate (PIP 2 ) sensitivity of voltage-gated Ca 2+ (Ca V ) 2.2 channels. Here, we report that voltage-dependent gating and current density of the Ca V 2.2 channels are also regulated by the HOOK region of the β2 subunit. The HOOK region can be divided into 3 domains: S (polyserine), A (polyacidic), and B (polybasic). We found that the A domain shifted the voltage-dependent inactivation and activation of Ca V 2.2 channels to more hyperpolarized and depolarized voltages, respectively, whereas the B domain evoked these responses in the opposite directions. In addition, the A domain decreased the current density of the Ca V 2.2 channels, while the B domain increased it. Together, our data demonstrate that the flexible HOOK region of the β2 subunit plays an important role in determining the overall Ca V channel gating properties.

Introduction: Several clinical studies using tacrolimus revealed reasonable therapeutic mechanisms and efficacy in patients with myasthenia gravis (MG). However, long-period studies in a large number of patients with MG are limited; therefore, the aim of this study was to investigate the therapeutic efficacies and safety of tacrolimus in patients with MG during a 12-month follow-up period., Methods: Tacrolimus was administered to 150 patients with MG who were recruited based on the inclusion criteria. Fifteen medical centers in Korea participated in this study. The efficacy of tacrolimus was assessed using MG composite scales (MGCS) and the prednisolone-sparing effect. And the adverse drug reactions (ADRs) of tacrolimus were monitored in each patient from the beginning of tacrolimus treatment to the end of the follow-up period., Results: After starting tacrolimus, the 32 patients were affected by ADRs, and consequentially 134 patients of the enrolled patients were followed up for 12months. They showed that the mean prednisolone dosage significantly decreased (6.1±7.6mg/day), compared to that in the baseline (11.3±9.5mg/day), and MGCS significantly improved after 12months of tacrolimus treatment, compared to that at the baseline., Conclusions: Our study showed that tacrolimus would be an effective immunosuppressant as an initial therapeutic agent in patients with MG; in addition, it showed tolerable safety profiles during the 12-month follow-up evaluation., (Copyright © 2017. Published by Elsevier B.V.)

Guillain-Barré syndrome (GBS) is the most common immune-mediated polyradiculoneuropathy and it is also the most commonly reported severe adverse event following immunization in adults. To evaluate the results of clinical and laboratory features of GBS after vaccination in Korea, we analyzed the claims-based data from 2002 to 2014 using materials collected for the Advisory Committee Vaccination Injury Compensation (ACVIC) meeting including, clinical features, nerve conduction studies (NCSs), cerebrospinal fluid (CSF) profiles, treatment, and outcomes. Forty-eight compensated GBS cases (median age, 15 years; interquartile range [IQR], 13-51; male:female ratio, 1:1) of 68 suspected GBS were found following immunization and all of them with influenza immunizations with either monovalent (n = 35) or trivalent (n = 13). Among them, 30 cases fulfilled the Brighton criteria level 1-3 (62.5%). The median duration between the onset of symptoms to nadir, duration of the nadir, and total admission period were 3 (IQR, 2-7 days), 2 (IQR, 1-5 days), and 14 (IQR, 6-33 days) days, respectively. The most frequently reported symptom was quadriparesis which was present in 36 cases (75%) at nadir. CSF examination revealed albuminocytologic dissociation in 25.0% and NCS was abnormal in 61.8%. After treatment, most of them showed improvement. Clinical features were similar to typical post-infectious GBS and there were both demyelinating and axonal forms suggesting heterogeneous pathogenic mechanism. In order to improve the diagnostic certainty of post-vaccination GBS, careful documentation of clinical features and timely diagnostic work-up with follow-up studies are needed., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2017 The Korean Academy of Medical Sciences.)

The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200-11. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The β subunit of voltage-gated Ca 2+ (Ca V ) channels plays an important role in regulating gating of the α1 pore-forming subunit and its regulation by phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Subcellular localization of the Ca V β subunit is critical for this effect; N-terminal-dependent membrane targeting of the β subunit slows inactivation and decreases PIP 2 sensitivity. Here, we provide evidence that the HOOK region of the β subunit plays an important role in the regulation of Ca V biophysics. Based on amino acid composition, we broadly divide the HOOK region into three domains: S (polyserine), A (polyacidic), and B (polybasic). We show that a β subunit containing only its A domain in the HOOK region increases inactivation kinetics and channel inhibition by PIP 2 depletion, whereas a β subunit with only a B domain decreases these responses. When both the A and B domains are deleted, or when the entire HOOK region is deleted, the responses are elevated. Using a peptide-to-liposome binding assay and confocal microscopy, we find that the B domain of the HOOK region directly interacts with anionic phospholipids via polybasic and two hydrophobic Phe residues. The β2c-short subunit, which lacks an A domain and contains fewer basic amino acids and no Phe residues in the B domain, neither associates with phospholipids nor affects channel gating dynamically. Together, our data suggest that the flexible HOOK region of the β subunit acts as an important regulator of Ca V channel gating via dynamic electrostatic and hydrophobic interaction with the plasma membrane., (© 2017 Park et al.)

Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. Proton sensing by ASICs has been known to mediate pain, mechanosensation, taste transduction, learning and memory, and fear. In this study, we investigated the differential subcellular localization of ASIC2a and ASIC3 in heterologous expression systems. While ASIC2a targeted the cell surface itself, ASIC3 was mostly accumulated in the ER with partial expression in the plasma membrane. However, when ASIC3 was co-expressed with ASIC2a, its surface expression was markedly increased. By using bimolecular fluorescence complementation (BiFC) assay, we confirmed the heteromeric association between ASIC2a and ASIC3 subunits. In addition, we observed that the ASIC2a-dependent surface trafficking of ASIC3 remarkably enhanced the sustained component of the currents. Our study demonstrates that ASIC2a can increase the membrane conductance sensitivity to protons by facilitating the surface expression of ASIC3 through herteromeric assembly. [BMB Reports 2016; 49(10): 542-547].

Background and Purpose: Serial nerve conduction studies (NCSs) are recommended for differentiating axonal and demyelinating Guillain-Barré syndrome (GBS), but this approach is not suitable for early diagnoses. This study was designed to identify possible NCS parameters for differentiating GBS subtypes., Methods: We retrospectively reviewed the medical records of 70 patients with GBS who underwent NCS within 10 days of symptom onset. Patients with axonal GBS and acute inflammatory demyelinating polyneuropathy (AIDP) were selected based on clinical characteristics and serial NCSs. An antiganglioside antibody study was used to increase the diagnostic certainty., Results: The amplitudes of median and ulnar nerve sensory nerve action potentials (SNAPs) were significantly smaller in the AIDP group than in the axonal-GBS group. Classification and regression-tree analysis revealed that the distal ulnar sensory nerve SNAP amplitude was the best predictor of axonal GBS., Conclusions: Early upper extremity sensory NCS findings are helpful in differentiating axonal-GBS patients with antiganglioside antibodies from AIDP patients., Competing Interests: The authors have no financial conflicts of interest.