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IntroductionCompression of the nerve root by a lumbar disc herniation can cause radiating pain in the lower limbs, and the nerve root decompression treatment may leave some patients with motor dysfunction and reduced sensory function. Studies have shown that nerve growth factor (NGF) can promote nerve growth and repair, but high doses, long duration, and immune response have become bottlenecks of its clinical application.MethodsTo overcome this obstacle, we developed Prussian blue (PBs) nanoparticles with the bio-delivery function and antioxidant effects of nanoenzymes. NGF was conjugated to the surface of PBs nanoparticles (PBs-NGF), which can be directly delivered to nerve cells.ResultsThe results showed that free PBs showed great advantages in scavenging oxygen free radicals and antioxidants, while PBs-NGF showed good biocompatibility. At the cellular level, cell proliferation assay and fluorescence microscopy analysis confirmed that PBs-NGF significantly promoted the proliferation, differentiation, and neurite outgrowth of neuron-like PC12 cells compared with free NGF. In a nerve root compression (NRC) rat model, behavioral observations (paw withdrawal threshold, PWT, and paw withdrawal latency, PWL) confirmed that PBs-NGF eased the pain caused by nerve root compression. H&E staining showed that PBs-NGF could significantly reduce the inflammatory infiltration of nerve roots, and ELISA results showed that the concentrations of inflammatory markers (IL-6, IL-1β, and TNF-α) were also significantly reduced.ConclusionIn summary, the developed functional nanoplatform provides a basis for the clinical application of NGF in lumbar nerve root injury with disc herniation compression and a new treatment strategy for patients.

Abstract N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a +/− and Grin2a −/− mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a +/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a +/− mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a −/− mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients.

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.

We investigate the effect of the adoption of electric vehicles (EVs) on CO2 emissions using spatial econometric models and have three findings. First, there are spatial spillover effects of EV adoption on CO2 emissions, implying that the CO2 mitigation of a city depends on local sales of EVs and sales of EVs in neighboring cities. A 1% increase in the sale of EVs in a city can reduce CO2 emissions locally by 0.096% and by 0.087% in a nearby city. Second, EVs indirectly impact CO2 emissions through the substitution effect, energy consumption effect, and technological effect. The overall impact of EV adoption on CO2 emissions is negative. Finally, we demonstrate the moderating effect of urban energy structure on EVs’ CO2 emissions mitigation. A 1% increase in the proportion of renewable energy generation increases the decarbonization of EVs by 0.036%. These findings provide policy implications for the coordinated development of EV market and energy system.

This paper uses the China Family Panel Studies’ micro-level data and the ordered logit model to study intergenerational transmission of education and examines whether the nine-year compulsory schooling system affects equity in education. The results show that when parents have higher educational attainments, their children will have higher educational attainments. Full-sample results show that when the mother has higher education, the probability that her children have higher education increases by 7.97%, whereas for the sub-sample after the compulsory schooling policy carried out, the probability increases by 22.42%. We find that the compulsory schooling system strengthens intergenerational transmission of education in the level of higher education. An implication is that the compulsory schooling system may promote equity in compulsory education but does not promote equity in higher education.

Quantifying the level of CO2, the main greenhouse gas (GHG), is essential for research on regional and global climate change, especially in the densely populated North China Plain with its severe CO2 emissions. In this study, 12 airborne flights were managed and conducted during the autumn–winter period of 2018–2019 in downtown Shijiazhuang and its surrounding areas, which are representative of the typical urban conditions in the North China Plain, to explore the spatial and temporal distributions of CO2. The results showed that the measured columnar averages of CO2 ranged between 399.9 ± 1.5 and 443.8 ± 31.8 ppm; the average of the 12 flights was 412.1 ppm, slightly higher than the globally averaged 410.5 ± 0.20 ppm and the 2 background concentrations of 411.6 ± 2.1 ppm and 411.4 ± 0.2 ppm in low-latitude Mauna Loa and middle-latitude Waliguan in 2019, indicating the potential influences of anthropogenic activities. The typical stratification of the planetary boundary layer (PBLH), residual layer (RL), and elevated inversion layer (IL) was crucial in constraining the high CO2 concentrations. This illustrated that the warming effect of CO2 within the PBLH may also have some influences on regulating the thermal structure of the low troposphere. Based on a backward trajectory analysis, it was evidenced that there were three different categories of air masses for autumn and one category for winter. Both trajectories in the PBL, i.e., below 1000 m, from the local and southern areas with tremendous anthropogenic emissions (autumn) and from the western regions (winter) led to comparatively high levels of CO2, but the mid-tropospheric CO2 concentrations above 1000 m were commonly homogeneously distributed, with higher levels appearing in winter because the concentration in the free troposphere followed the global seasonal pattern, with a summer minimum and winter maximum as a result of the seasonality of the net CO2 exchange and the balance between photosynthesis and respiration. These results provide an in-depth understanding of the vertical concentrations of tropospheric CO2 in the North China Plain, which will offer scientific references for the evaluation of carbon accounting and carbon emissions.

Abstract 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 patient’s 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 patient’s 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.

The purpose of this study was to investigate the effect of ultrasound-assisted enzymolysis on modified solubilization of yeast β-glucan and its related mechanism. The depolymerization effects of this system on the physicochemical properties and structural features of the degraded fragments were studied systematically. The structure and physicochemical properties of the samples showed that the solubility of yeast β-glucan achieved 75.35 % after modification; and ultrasonic enzymatic enhanced the degradation efficiency. The yeast β-glucan obtained after solubilization and modification owned better antioxidant activities. The yeast β-glucan particles become obviously smaller, sparsely dispersed in the aqueous solution and the stability was improved. In addition, the hydrogen bonds in yeast β-glucan native triple helix structure were partially broken. Moreover, the disruption of yeast β-glucan's original structure made it decreased thermostability and easier to dissolve in water. The atomic force microscope (AFM) imaging directly verified the branched-chain morphology of yeast β-glucan and the small-strand degradation fragments. Therefore, this research can provide a feasible and effective approach for improving solubility of water-insoluble yeast β-glucan to enlarge its food and biomedical applications.

N-Methyl-D-aspartate receptors (NMDARs) are highly expressed in brain and play important roles in neurodevelopment and various neuropathologic conditions. Here, we describe a new phenotype in an individual associated with a novel de novo deleterious variant in GRIN1 (c.1595C>A, p.Pro532His). The clinical phenotype is characterized with developmental encephalopathy, striking stimulus-sensitive myoclonus, and frontal lobe and frontal white matter hypoplasia, with no apparent seizures detected. NMDARs that contained the P532H within the glycine-binding domain of GluN1 with either the GluN2A or GluN2B subunits were evaluated for changes in their pharmacological and biophysical properties, which surprisingly revealed only modest changes in glycine potency but a significant decrease in glutamate potency, an increase in sensitivity to endogenous zinc inhibition, a decrease in response to maximally effective concentrations of agonists, a shortened synaptic-like response time course, a decreased channel open probability, and a reduced receptor cell surface expression. Molecule dynamics simulations suggested that the variant can lead to additional interactions across the dimer interface in the agonist-binding domains, resulting in a more open GluN2 agonist-binding domain cleft, which was also confirmed by single-molecule fluorescence resonance energy transfer measurements. Based on the functional deficits identified, several positive modulators were evaluated to explore potential rescue pharmacology.

Abstract Background Chronic pain usually accompanied by tissue damage and inflammation. However, the pathogenesis of chronic pain remains unclear. Methods We investigated the role of nerve growth factor (NGF) in chronic inflammatory pain induced by complete Freund’s adjuvant (CFA), explored the methylation status of CpG islands in the promoter region of the NGF gene, and clarified the function and mechanism of C/EBPα-NGF signaling pathway from epigenetic perspective in the chronic inflammatory pain model. Results CFA induced significant hyperalgesia and continuous upregulation of NGF mRNA and protein levels in the L4–6 dorsal root ganglions (DRGs) in rats. Hypomethylation of CpG islands occurred in the NGF gene promoter region after CFA treatment. At the same time, the miR-29b expression level was significantly increased, while the DNA methyltransferase 3b (DNMT3b) level reduced significantly. Moreover, CFA treatment promoted binding of C/EBPα to the NGF gene promoter region and C/EBPα siRNA treatment obviously decreased expression of NGF levels and also alleviate inflammatory hyperalgesia significantly in rats. Conclusion Collectively, the results indicated that CFA leads to the upregulation of miR-29b level, which represses the expression of DNMT3b, enhances the demethylation of the NGF gene promoter region, and promotes the binding of C/EBPα with the NGF gene promoter, thus results in the upregulation of NGF gene expression and maintenance of chronic inflammatory pain.

Abstract Background Splice sites prediction has been a long-standing problem in bioinformatics. Although many computational approaches developed for splice site prediction have achieved satisfactory accuracy, further improvement in predictive accuracy is significant, for it is contributing to predict gene structure more accurately. Determining a proper window size before prediction is necessary. Overly long window size may introduce some irrelevant features, which would reduce predictive accuracy, while the use of short window size with maximum information may performs better in terms of predictive accuracy and time cost. Furthermore, the number of false splice sites following the GT–AG rule far exceeds that of true splice sites, accurate and rapid prediction of splice sites using imbalanced large samples has always been a challenge. Therefore, based on the short window size and imbalanced large samples, we developed a new computational method named chi-square decision table (χ2-DT) for donor splice site prediction. Results Using a short window size of 11 bp, χ2-DT extracts the improved positional features and compositional features based on chi-square test, then introduces features one by one based on information gain, and constructs a balanced decision table aimed at implementing imbalanced pattern classification. With a 2000:271,132 (true sites:false sites) training set, χ2-DT achieves the highest independent test accuracy (93.34%) when compared with three classifiers (random forest, artificial neural network, and relaxed variable kernel density estimator) and takes a short computation time (89 s). χ2-DT also exhibits good independent test accuracy (92.40%), when validated with BG-570 mutated sequences with frameshift errors (nucleotide insertions and deletions). Moreover, χ2-DT is compared with the long-window size-based methods and the short-window size-based methods, and is found to perform better than all of them in terms of predictive accuracy. Conclusions Based on short window size and imbalanced large samples, the proposed method not only achieves higher predictive accuracy than some existing methods, but also has high computational speed and good robustness against nucleotide insertions and deletions. Reviewers This article was reviewed by Ryan McGinty, Ph.D. and Dirk Walther.

Context-dependent inhibition of NMDA receptors has important therapeutic implications for treatment of neurological diseases. Here, the authors use structural biology and biophysics to describe the basis for pH-dependent inhibition for a class of allosteric NMDAR inhibitors, called the 93-series.

Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.

The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-d-aspartate receptor (NMDAR) gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders. Studies that provide functional analysis of variants are still lacking, however current analysis of de novo variants that segregate with disease cases such as intellectual disability, developmental delay, ASD or epileptic encephalopathies reveal altered NMDAR function. Here, we summarize the current reports of disease-associated variants in GRIN2B from patients with multiple neurodevelopmental disorders, and discuss implications, highlighting the importance of functional analysis and precision medicine therapies.

β-Glucan exhibits many biological activities and functions such as stimulation of the immune system and anti-inflammatory, anti-microbial, anti-infective, anti-viral, anti-tumor, anti-oxidant, anti-coagulant, cholesterol-lowering, radio protective, and wound healing effects. It has a wide variety of uses in pharmaceutical, cosmetic, and chemical industries as well as in food processing units. However, due to its dense triple helix structure, formed by the interaction of polyhydroxy groups in the β-d-glucan molecule, it features poor solubility, which not only constrains its applications, but also inhibits its physiological function in vivo. One aim is to expand the applications for modified β-glucan with potential to prevent disease, various therapeutic purposes and as health-improving ingredients in functional foods and cosmetics. This review introduces the major modification methods required to understand the bioactivity of β-glucan and critically provides a literature survey on the structural features of this molecule and reported biological activity. We also discuss a new method to create novel opportunities to exploit maximally various properties of β-glucan, namely ultrasound-assisted enzymatic modification.

N-methyl-D-aspartate receptors (NMDARs), ligand-gated ionotropic glutamate receptors, play key roles in normal brain development and various neurological disorders. Here we use standing variation data from the human population to assess which protein domains within NMDAR GluN1, GluN2A and GluN2B subunits show the strongest signal for being depleted of missense variants. We find that this includes the GluN2 pre-M1 helix and linker between the agonist-binding domain (ABD) and first transmembrane domain (M1). We then evaluate the functional changes of multiple missense mutations in the NMDAR pre-M1 helix found in children with epilepsy and developmental delay. We find mutant GluN1/GluN2A receptors exhibit prolonged glutamate response time course for channels containing 1 or 2 GluN2A-P552R subunits, and a slow rise time only for receptors with 2 mutant subunits, suggesting rearrangement of one GluN2A pre-M1 helix is sufficient for rapid activation. GluN2A-P552R and analogous mutations in other GluN subunits increased the agonist potency and slowed response time course, suggesting a functionally conserved role for this residue. Although there is no detectable change in surface expression or open probability for GluN2A-P552R, the prolonged response time course for receptors that contained GluN2A-P552R increased charge transfer for synaptic-like activation, which should promote excitotoxic damage. Transfection of cultured neurons with GluN2A-P552R prolonged EPSPs, and triggered pronounced dendritic swelling in addition to excitotoxicity, which were both attenuated by memantine. These data implicate the pre-M1 region in gating, provide insight into how different subunits contribute to gating, and suggest that mutations in the pre-M1 helix can compromise neuronal health. Evaluation of FDA-approved NMDAR inhibitors on the mutant NMDAR-mediated current response and neuronal damage provides a potential clinical path to treat individuals harboring similar mutations in NMDARs.

OBJECTIVE:N-methyl-D-aspartate receptors (NMDAR) subunit GRIN2A/GluN2A mutations have been identified in patients with various neurological diseases, such as epilepsy and intellectual disability / developmental delay (ID/DD). In this study, we investigated the phenotype and underlying molecular mechanism of a GRIN2A missense mutation identified by next generation sequencing on idiopathic focal epilepsy using in vitro electrophysiology. METHODS:Genomic DNA of patients with epilepsy and ID/DD were sequenced by targeted next-generation sequencing within 300 genes related to epilepsy and ID/DD. The effects of one missense GRIN2A mutation on NMDAR function were evaluated by two-electrode voltage clamp current recordings and whole cell voltage clamp current recordings. RESULTS:We identified one de novo missense GRIN2A mutation (Asp731Asn, GluN2A(D731N)) in a child with unexplained epilepsy and DD. The D731N mutation is located in a portion of the agonist-binding domain (ABD) in the GluN2A subunit, which is the binding pocket for agonist glutamate. This residue in the ABD is conserved among vertebrate species and all other NMDAR subunits, suggesting an important role in receptor function. The proband shows developmental delay as well as EEG-confirmed seizure activity. Functional analyses reveal that the GluN2A(D731N) mutation decreases glutamate potency by over 3,000-fold, reduces amplitude of current response, shortens synaptic-like response time course, and decreases channel open probability, while enhancing sensitivity to negative allosteric modulators, including extracellular proton and zinc inhibition. The combined effects reduce NMDAR function. SIGNIFICANCE:We identified a de novo missense mutation in the GRIN2A gene in a patient with childhood focal epilepsy and acquired epileptic aphasia. The mutant decreases NMDAR activation suggesting NMDAR hypofunction may contribute to the epilepsy pathogenesis.

Investigators from Yokohama City University and other medical centers in Israel and Japan reported mutations on N-methyl-D-aspartate (NMDA) receptors subunit GRIN1 (GluN1) identified in patients with nonsyndromic intellectual disability and early-onset epileptic encephalopathy.

Besides medical expenses, hospitalizations associated with air pollution will incur the welfare loss due to activity restrictions and the wage loss due to inability to work. We fill in the gap in the literature by examining the impact of air pollution on volume and intensity of hospitalizations, which allows us to incorporate the welfare loss and the wage loss. Using a data set that covers most of the inpatients in a major Chinese city during 2015-16, we find that worse air quality causes more hospital admissions, more total inpatient days, and higher total inpatient expenditure for various diseases, particularly diseases of the respiratory and circulatory systems. We also find that there would be an underestimate of the loss from air pollution if we had ignored the loss associated with activity restrictions and the wage loss during hospitalization. [ABSTRACT FROM AUTHOR]

Background Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs. Methods We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in GRIN1 are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in GRIN1. Results Heterozygous variants in GRIN1 and GRIN2B were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous GRIN1 variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous GRIN1 variants in an individual with microcephaly with simplified gyral pattern. Conclusion These findings expand our understanding of the clinical and imaging features of the 'NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients. [ABSTRACT FROM AUTHOR]