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OBJECTIVE: Genetic variants in the GRIN genes that encode N-methyl-D-aspartate receptor (NMDAR) subunits have been identified in various neurodevelopmental disorders, including epilepsy. We identified a GRIN1 variant from an individual with early-onset epileptic encephalopathy, evaluated functional changes to NMDAR properties caused by the variant, and screened FDA-approved therapeutic compounds as potential treatments for the patient. METHODS: Whole exome sequencing identified a missense variant in GRIN1. Electrophysiological recordings were made from Xenopus oocytes and transfected HEK cells to determine the NMDAR biophysical properties as well as the sensitivity to agonists and FDA-approved drugs that inhibit NMDARs. A beta-lactamase reporter assay in transfected HEK cells evaluated the effects of the variant on the NMDAR surface expression. RESULTS: A recurrent de novo missense variant in GRIN1 (c.1923G>A, p.Met641Ile), which encodes the GluN1 subunit, was identified in a pediatric patient with drug-resistant seizures and early-onset epileptic encephalopathy. In vitro analysis indicates that GluN1-M641I containing NMDARs showed enhanced agonist potency and reduced Mg2+ block, which may be associated with the patients phenotype. Results from screening FDA-approved drugs suggested that GluN1-M641I containing NMDARs are more sensitive to the NMDAR channel blockers memantine, ketamine, and dextromethorphan compared to the wild-type receptors. The addition of memantine to the seizure treatment regimen significantly reduced the patients seizure burden. INTERPRETATION: Our finding contributes to the understanding of the phenotype-genotype correlations of patients with GRIN1 gene variants, provides a molecular mechanism underlying the actions of this variant, and explores therapeutic strategies for treating GRIN1-related neurological conditions.

N‐methyl‐D‐aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re‐entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage‐dependent Mg2+ inhibition. Voltage‐dependent Mg2+ block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg2+ block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg2+ inhibition. Each variant was evaluated for tolerance to genetic variation using the 3‐dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA‐approved NMDAR drugs—memantine, dextromethorphan, and ketamine—were chosen based on their ability to bind near the M2 re‐entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage‐dependent Mg2+ block. These results provide insight of structural determinants of FDA‐approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology. [ABSTRACT FROM AUTHOR]

Background: Dorsal ramus medial branch radiofrequency ablation is reported to be effective for refractory lumbar facet joint syndrome. However, as nerve fibers can regenerate, the therapeutic effect was reported to be short and last only 6 to 12 months. Previously, we reported a novel endoscopic joint capsule and articular process excision procedure. In that case, a satisfying effect was achieved by removing the culprit hyperplastic articular synovial entrapped in the joint space endoscopically. We presume this treatment is an etiologic treatment and can exert longer-term efficacy. Aim: This retrospective clinical trial aimed to elucidate the longer-term efficacy as well as the safety profile of the procedure. Methods: This was a retrospective descriptive study. The participants underwent endoscopic joint capsule and articular process excision procedures. The Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) before the operation, and at 3 months, 6 months, 1 year, and 2 years post-operation were recorded by reviewing medical charts and conducting telephone interviews. Results: A total of 234 participants were evaluated in the trial. After participant screening, 13 participants were included in the final analysis. The VAS score was reduced from (median (P25, P75)) 6 (4.5, 6) at pre-operation to 2 (0, 4) at 1-year post-operation and 0 (0, 1) at 2-year pre-operation. The ODI score was reduced from 37.78 (27.09, 59.95) at pre-operation to 8.89 (2.22, 24.34) at 1-year post-operation and 6 (0.02, 11.11) at 2-year post-operation. The difference was statistically significant. Further subgroup analysis demonstrated that a narrowed intervertebral space was a possible relevant factor for poor outcomes. No procedure-related complications were reported. Conclusion: Endoscopic joint capsule and articular process excision is an effective and safe procedure for refractory lumbar facet joint syndrome. The effectiveness duration can last up to 1 to 2 years. [ABSTRACT FROM AUTHOR]

N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+ block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novo mutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.

ObjectiveEarly-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband.MethodsThree modern translational medicine tools were utilized: 1) high-throughput sequencing technology to identify a novel de novo mutation; 2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and 3) screening of existing drug libraries to identify potential therapeutic compounds.ResultsA de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden.InterpretationThis case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.

NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy.

Joint source–channel coding (JSCC) based on deep learning has shown significant advancements in image transmission tasks. However, previous channel-adaptive JSCC methods often rely on the signal-to-noise ratio (SNR) of the current channel for encoding, which overlooks the neural network's self-adaptive capability across varying SNRs. This paper investigates the self-adaptive capability of deep learning-based JSCC models to dynamically changing channels and introduces a novel method named Channel-Blind JSCC (CBJSCC). CBJSCC leverages the intrinsic learning capability of neural networks to self-adapt to dynamic channels and diverse SNRs without relying on external SNR information. This approach is advantageous, as it is not affected by channel estimation errors and can be applied to one-to-many wireless communication scenarios. To enhance the performance of JSCC tasks, the CBJSCC model employs a specially designed encoder–decoder. Experimental results show that CBJSCC outperforms existing channel-adaptive JSCC methods that depend on SNR estimation and feedback, both in additive white Gaussian noise environments and under slow Rayleigh fading channel conditions. Through a comprehensive analysis of the model's performance, we further validate the robustness and adaptability of this strategy across different application scenarios, with the experimental results providing strong evidence to support this claim. [ABSTRACT FROM AUTHOR]

Borrowing decisions typically involve processing large amounts of financial information. However, it has been understudied whether cognitive capacity factors such as air pollution affect borrowing behaviours. In this paper, we estimate the causal impact of air pollution on borrowing behaviours by using the universe of borrowing application data on an online peer-to-peer platform and a thermal inversion instrument. We find that a 1% increase in air pollution reduces the number of borrowing applications and the total amount requested by 0.05% and 0.31% respectively. The impact is stronger when the borrowing is for more complex and less necessary purposes, and when we examine the areas with lower educational attainment. The results suggest that the adverse effect of air pollution on cognitive capacity prevents people from borrowing. [ABSTRACT FROM AUTHOR]

Carbohydrazide electrooxidation reaction (COR) is a potential alternative to oxygen evolution reaction in water splitting process. However, the sluggish kinetics process impels to develop efficient catalysts with the aim of the widespread use of such catalytic system. Since COR concerns the adsorption/desorption of reactive species on catalysts, the electronic structure of electrocatalyst can affect the catalytic activity. Interface charge distribution engineering can be considered to be an efficient strategy for improving catalytic performance, which facilitates the cleavage of chemical bond. Herein, highly dispersed Pd nanoparticles on CeO2/C catalyst are prepared and the COR catalytic performance is investigated. The self‐driven charge transfer between Pd and CeO2 can form the local nucleophilic and electrophilic region, promoting to the adsorption of electron‐withdrawing and electron‐donating group in carbohydrazide molecule, which facilitates the cleavage of C−N bond and the carbohydrazide oxidation. Due to the local charge distribution, the Pd‐CeO2/C exhibits superior COR catalytic activity with a potential of 0.27 V to attain 10 mA cm−2. When this catalyst is used for energy‐efficient electrolytic hydrogen production, the carbohydrazide electrolysis configuration exhibits a low cell voltage (0.6 V at 10 mA cm−2). This interface charge distribution engineering can provide a novel strategy for improving COR catalytic activity. [ABSTRACT FROM AUTHOR]