Diiminium Nucleophile Adducts Are Stable and Convenient Strong Lewis Acids.

Strong Lewis acids are essential tools for manifold chemical procedures, but their scalable deployment is limited by their costs and safety concerns. We report a scalable, convenient, and inexpensive synthesis of stable diiminium-based reagents with a Lewis acidic carbon centre. Coordination with pyridine donors stabilises these centres; the 2,2'-bipyridine adduct shows a chelation effect at carbon. Due to high fluoride, hydride, and oxide affinities, the diiminium pyridine adducts are promising soft and hard Lewis acids. They effectively produce acylpyridinium salts from carboxylates that can acylate amines to give amides and imides even from electronically intractable coupling partners.

Risk Control Values and Remediation Goals for Benzo[a]pyrene in Contaminated Sites: Sectoral Characteristics, Temporal Trends, and Empirical Implications.

Benzo[a]pyrene (BaP) is a highly carcinogenic pollutant of global concern. There is a need for a comprehensive assessment of regulation decisions for BaP-contaminated site management. Herein, we present a quantitative evaluation of remediation decisions from 206 contaminated sites throughout China between 2011 and 2021 using the cumulative distribution function (CDF) and related statistical methodologies. Generally, remediation decisions seek to establish remediation goals (RGs) based on the risk control values (RCVs). Cumulative frequency distributions, followed non-normal S-curve, emerged multiple nonrandom clusters. These clusters are consistent with regulatory guidance values (RGVs), of national and local soil levels in China. Additionally, priority interventions for contaminated sites were determined by prioritizing RCVs and identifying differences across industrial sectors. Notably, we found that RCVs and RGs became more relaxed over time, effectively reducing conservation and unsustainable social and economic impacts. The joint probability curve was applied to model decision values, which afforded a generic empirically important RG of 0.57 mg/kg. Overall, these findings will help decision-makers and governments develop appropriate remediation strategies for BaP as a ubiquitous priority pollutant.

Health risk assessment of heavy metals and disinfection by-products in drinking water in megacities in China: A study based on age groups and Monte Carlo simulations.

Heavy metal(loid)s (HMs) and disinfection by-products (DBPs) in drinking water pose risks to human health and jeopardize drinking water. Water-related behaviors vary significantly among different age groups and regions. In this study, the carcinogenic and non-carcinogenic risks of HMs (As, Cd, Cr6+, Cu, Pb, and Zn) and DBPs (bromodichloromethane (BDCM), bromoform, chloroform, dibromochloromethane (DBCM), dichloroacetic acid (DCAA), and trichloroacetic acid (TCAA)) in drinking water in two Chinese megacities (Beijing in North China and Guangzhou in South China) via multiple exposure pathways were assessed. The results showed that children aged 9 months to 2 years had a total carcinogenic risk (TCR) and hazard index (HI) above acceptable levels, indicating that despite the drinking water quality in the selected megacities meeting the current Chinese national standards (GB 5749-2022), the health risks of exposure to HMs and DBPs in drinking water for local young children should not be neglected. Specifically, the carcinogenic risk (CR) of exposure to As in drinking water for children < 18-years-old, who were divided into different age groups, was 1.5-2.0- and 4.5-5.9-times higher than the TCR of exposure to DBPs in Beijing and Guangzhou, respectively. Regarding children aged 9 months to 2 years, the exposure to TCAA accounted for the largest proportion (35.6 %) of the TCR of exposure to DBPs in Beijing drinking water, 5.4-times higher than that in Guangzhou; whereas, the TCR of exposure to DBPs in Guangzhou drinking water was predominantly caused by exposure to chloroform, accounting for 40.6 % of the TCR and 1.5-times higher than that in Beijing. In addition, the CR of exposure to DCAA in drinking water in both megacities accounted for a large proportion of the TCR for children aged 9 months to 2 years. Monte Carlo simulations showed that 62.2 % and 42.6 % of the TCR of simultaneous exposure to As and DBPs in drinking water exceeded the acceptable level for sensitive populations, that is, children aged 1-2 years in Beijing (95th percentile = 4.2 × 10-4) and children aged 9-12 months in Guangzhou (95th percentile = 5.2 × 10-4), respectively. This elaborate health risk assessment sheds light on improving the water quality indices to guarantee drinking water safety in China.

Subicular Caspase-1 Contributes to Pharmacoresistance in Temporal Lobe Epilepsy.

OBJECTIVE: Unidentified mechanisms largely restrict the viability of effective therapies in pharmacoresistant epilepsy. Our previous study revealed that hyperactivity of the subiculum is crucial for the genesis of pharmacoresistance in temporal lobe epilepsy (TLE), but the underlying molecular mechanism is not clear. METHODS: Here, we examined the role of subicular caspase-1, a key neural pro-inflammatory enzyme, in pharmacoresistant TLE. RESULTS: We found that the expression of activated caspase-1 in the subiculum, but not the CA1, was upregulated in pharmacoresistant amygdaloid-kindled rats. Early overexpression of caspase-1 in the subiculum was sufficient to induce pharmacoresistant TLE in rats, whereas genetic ablation of caspase-1 interfered with the genesis of pharmacoresistant TLE in both kindled rats and kainic acid-treated mice. The pro-pharmacoresistance effect of subicular caspase-1 was mediated by its downstream inflammasome-dependent interleukin-1ß. Further electrophysiological results showed that inhibiting caspase-1 decreased the excitability of subicular pyramidal neurons through influencing the excitation/inhibition balance of presynaptic input. Importantly, a small molecular caspase-1 inhibitor CZL80 attenuated seizures in pharmacoresistant TLE models, and decreased the neuronal excitability in the brain slices obtained from patients with pharmacoresistant TLE. INTERPRETATION: These results support the subicular caspase-1-interleukin-1ß inflammatory pathway as a novel alternative mechanism hypothesis for pharmacoresistant TLE, and present caspase-1 as a potential target. ANN NEUROL 2021;90:377-390.

Persistent Uptake of H2O2 onto Ambient PM2.5 via Dark-Fenton Chemistry.

Particulate matter (PM) and gaseous hydrogen peroxide (H2O2) interact ubiquitously to influence atmospheric oxidizing capacity. However, quantitative information on H2O2 loss and its fate on urban aerosols remain unclear. This study investigated the kinetics of heterogeneous reactions of H2O2 on PM2.5 and explored how these processes are affected by various experimental conditions (i.e., relative humidity, temperature, and H2O2 concentration). We observed a persistent uptake of H2O2 by PM2.5 (with the uptake coefficients (γ) of 10-4-10-3) exacerbated by aerosol liquid water and temperature, confirming the critical role of water-assisted chemical decomposition during the uptake process. A positive correlation between the γ values and the ratio of dissolved iron concentration to H2O2 concentration suggests that Fenton catalytic decomposition may be an important pathway for H2O2 conversion on PM2.5 under dark conditions. Furthermore, on the basis of kinetic data gained, the parameterization of H2O2 uptake on PM2.5 was developed and was applied into a box model. The good agreement between simulated and measured H2O2 uncovered the significant role that heterogeneous uptake plays in the sink of H2O2 in the atmosphere. These findings suggest that the composition-dependent particle reactivity toward H2O2 should be considered in atmospheric models for elucidating the environmental and health effects of H2O2 uptake by ambient aerosols.

Computerized application for epilepsy in China: Does the era of artificial intelligence comes?

Epilepsy, one of the most common neurological diseases in China, is notorious for its spontaneous, unprovoked and recurrent seizures. The etiology of epilepsy varies among individual patients, including congenital gene mutation, traumatic injury, infections, etc. This heterogeneity partly hampered the accurate diagnosis and choice of appropriate treatments. Encouragingly, great achievements have been achieved in computational science, making it become a key player in medical fields gradually and bringing new hope for rapid and accurate diagnosis as well as targeted therapies in epilepsy. Here, we historically review the advances of computerized applications in epilepsy-especially those tremendous findings achieved in China-for different purposes including seizure prediction, localization of epileptogenic zone, post-surgical prognosis, etc. Special attentions are paid to the great progress based on artificial intelligence (AI), which is more "sensitive", "smart" and "in-depth" than human capacities. At last, we give a comprehensive discussion about the disadvantages and limitations of current computerized applications for epilepsy and propose some future directions as further stepping stones to embrace "the era of AI" in epilepsy.

Nicotinamide mononucleotide improves spermatogenic function in streptozotocin-induced diabetic mice via modulating the glycolysis pathway.

Spermatogenic dysfunction is one of the major secondary complications of diabetes; however, the underlying mechanisms remain ill-defined, and there is no available drug or strategy for the radical treatment of diabetic spermatogenic dysfunction. Therefore, the objective of this study is to investigate the protective effects of nicotinamide mononucleotide (NMN) on testicular spermatogenic function in streptozotocin (STZ)-induced diabetic mice. The results show that oral administration of NMN significantly increases the body and testis weight and the number of sperms. Moreover, the abnormal sperm count and the rate of sperm malformation are significantly decreased compared with the saline-treated diabetic mice. Histological analysis reveals that NMN treatment significantly increases the area and diameter of seminiferous tubules, accompanied by an increased number of spermatogenic cells and sperms. Immunohistochemistry and qRT-PCR results show that NMN increases Bcl-2 expression and decreases Bax expression in the testis. NMN also increases the protein expression of Vimentin and the mRNA expressions of WT1 and GATA4. In addition, qRT-PCR, western blot analysis and immunohistochemistry results also show that NMN increases the expressions of glycolysis-related rate-limiting enzymes including HK2, PKM2, and LDHA. In summary, this study demonstrates the protective effects of NMN on the testis in an STZ-induced diabetic mice model. NMN exerts its protective effects via reducing spermatogenic cell apoptosis by regulating glycolysis of Sertoli cells in diabetic mice. This study provides an experimental basis for the future clinical application of NMN in diabetes-induced spermatogenic dysfunction.

Is hand-to-mouth contact the main pathway of children's soil and dust intake?

Children (n = 240) between the ages of 2 and 17 years were randomly selected from three cities in China. The total amount of soil and dust (SD) on their hands was measured and ranged from 3.50-187.39 mg (median = 19.49 mg). We screened for seven elements (Ce, V, Y, Al, Ba, Sc, and Mn), and Ce levels were used to calculate hand SD by variability and soil elements. The main factors affecting SD amount were location and age group, as identified using a conditional inference tree. Hand SD and the hand SD intake rate were highest in Gansu Province, followed by Guangdong and Hubei provinces, respectively. Hand SD and the hand SD intake rate were highest among children in primary school, followed by kindergarten and secondary school, respectively. The hand SD intake rate of the three typical areas was 11.9 mg/d, which was about 26.6% of the children's soil intake rate (44.8 mg/d), indicating that hand-to-mouth contact is not the main route for children's soil intake in the three areas of China.

Water Significantly Changes the Ring-Cleavage Process During Aqueous Photooxidation of Toluene.

As a major constituent of aromatic compounds, toluene exists widely in environmental aqueous phases. This research investigated the aqueous-phase OH oxidation of toluene to determine how liquid water changes the radical chemistry of ring-cleavage pathways. Results show that ring-cleavage pathways through the C7 bicyclic peroxy radical (BPR) account for about 70% of total aqueous-phase oxidation pathways, which is similar to that in the gas-phase oxidation. However, detailed ring-cleavage pathways in the aqueous phase change significantly compared with those in the gas phase as shown by the decreased production of glyoxal and methylglyoxal and the enhanced production of formic acid and acetic acid as primary products, which can be attributed to the presence of liquid water. Water facilitates the formation of the BPR whose structure is different from that in the gas-phase oxidation and results in different ring-cleavage pathways through hydrogen-shift reactions. Furthermore, water helps the hydration of acyl radicals formed by the BPR to produce organic acids. With the suggested ring-cleavage mechanisms, a box model can simulate aqueous-phase product distributions better than that with the classical ring-cleavage mechanisms. Given the influence of water on reaction mechanisms, aqueous-phase oxidation of hydrophobic organic compounds may be more important than previously assumed.

Status of arsenic accumulation in agricultural soils across China (1985-2016).

Based on 1677 published studies, 1648 sites across China collected from 1985 to 2016 were used to research the concentrations of arsenic in agricultural soils. In order to understand the status of arsenic pollution in agricultural soils in China over the past three decades, and to learn about the arsenic stocks in agricultural soils in various regions, and compared the relationship with annual arsenic emissions in China, and finally evaluated the potential ecological risks and human health risks. The median arsenic concentration in the surface agricultural soils of China was 10.40 mg Kg-1, and it ranged from 0.4 mg Kg-1 to 175.8 mg Kg-1. The inventory of arsenic in Chinese agricultural surface soils was estimated to be 3.71 × 106 t. In this study, the arsenic concentrations were found to be higher in Central, South, and Southwest China than those in other regions. The trend of arsenic pollution in agricultural soils has gradually increased over the past three decades. However, the growth rate of arsenic concentrations pollution in farmlands agricultural in China slowed during 2012-2016. The ecological risk index and geoaccumulation index revealed that arsenic in Chinese agricultural soil poses a low risk to the ecosystem. For human health assessment, the dietary pathway was the main pathway of exposure to arsenic in farmland soil of China. However, children's soil intake also contributed 34.48% to the exposure to arsenic, owing to their behavior. This study can provide a reference for the management of arsenic agricultural pollution in farmland soils in China.

Status of mercury accumulation in agricultural soils across China (1976-2016).

Soil contamination with mercury (Hg) is a serious and widespread issue in China, with particularly severe effects on the quality of agricultural soils. To analyse long-term, nation-wide trends in Hg contamination of agriculture soil, we conducted a review of Hg concentrations in agricultural soils over four decades, based on 791 studies comprising 1411 sites, published between 1976 and 2016. We assessed spatiotemporal variations in Hg concentration, along with ecological and health risks. While Hg concentrations in agricultural soils showed an increasing trend between 1979 and 2010, they declined thereafter. Moreover, Hg concentrations in agricultural soils were generally high in western (e.g. Guizhou), southern (e.g. Hunan) and north-eastern provinces (e.g. Liaoning), where mining activities were concentrated. Using the geoaccumulation index (Igeo) and other ecological and health risk indices, we found most sampling sites to be uncontaminated, or to have a low level of contamination, although some mining sites showed moderate to extreme Hg contamination. The noncarcinogenic risk to exposure groups followed the order of children (4.42) > adult females (2.71) > adult males (2.45). Therefore, children were identified as the priority risk group. Noncarcinogenic risk values exceeded 100 in some areas in Guizhou and Hunan provinces; these areas should be prioritised for Hg control measures. This review examined Hg pollution in Chinese agricultural soils to provide insight to policymakers for the development of targeted contamination prevention measures.

Organophosphate Flame Retardants in Soils of Zhejiang Province, China: Levels, Distribution, Sources, and Exposure Risks.

Organophosphate flame retardants (OPFRs) are an emerging class of pollutants. In this study, 62 soil samples were collected from Zhejiang Province China, and screened for 8 typical OPFRs. All compounds were detected in soil at 100% detection frequency, except for triethyl phosphate (TEP) compounds (93.6%). The sum of the eight OPFR concentrations ranged from 9.15 to 132 ng/g dry weight (dw), with mean and median values of 24.9 and 19.0 ng/g dw, respectively. Triphenyl phosphate (TPHP) was identified as the most abundant analog, with a median concentration of 9.94 ng/g dw, followed by tris(2-ethylhexyl)phosphate (TEHP). Significantly higher OPFR concentrations were detected in northern Zhejiang; concentrations decreased sharply from the north to the south. OPFR concentrations in soils from cities or economically developed counties were much higher than those from rural areas. OPFR sources in Zhejiang Province mainly originated from PVC-made products and traffic emissions.  Dermal absorption of OPFRs via soil was the primary pathway for human exposure. Health risks due to exposure to OPFRs through soil ingestion were found to be negligible.

Development and validation of nomograms for prediction of overall survival and cancer-specific survival of patients with Stage IV colorectal cancer.

BACKGROUND: Surgical resection of patients with resectable Stage IV colorectal cancer (CRC) is regarded as first choice if possible. However, its influence on overall survival (OS) has not been thoroughly explored. In this study, we aimed to construct nomograms to help predict 1-, 3- and 5-year OS rate and colorectal cancer-specific survival (CCSS) rate. METHODS: A total of 2996 cases who underwent primary and metastatic resection were selected in the study from surveillance, epidemiology and end results (SEER) database. About 48 Stage IV CRC patients after resection from the Fudan University Shanghai Cancer Center (FUSCC) were assigned as an independent external validation group. Log-rank and multivariate Cox regression analysis were used. The competing-risks model was used to estimate the cumulative incidence of death. Nomograms were built for prediction of OS and CCSS after surgical resection in patients with Stage IV CRC. RESULTS: The 1-, 3- and 5-year probabilities of OS were 76.6%, 41.4% and 23.2%, respectively. The 1-, 3- and 5-year colorectal cumulative incidence of death were 23.0%, 54.9% and 71.3%, respectively. The calibration curves for probability of 1-, 3- and 5-year OS and CCSS showed optimal agreement between nomogram prediction and actual observation, and the Harrell's C-indexes for the nomograms to predict OS and CCSS were 0.662 and 0.650, respectively. For FUSCC validation set, the C-index for this model to predict OS was 0.657. CONCLUSION: Nomograms for prediction of OS and CCSS of patients with Stage IV CRC who underwent primary and metastatic resection were built. Performance of the model was excellent. These nomograms may be helpful for patients and physicians when making a decision.

BRAF and EGFR inhibitors synergize to increase cytotoxic effects and decrease stem cell capacities in BRAF(V600E)-mutant colorectal cancer cells.

Mutations in the oncogene BRAF(V600E) are found in ~10% of colorectal cancers (CRCs) and are associated with poor prognosis. However, BRAF(V600E) has a limited response to the small-molecule drug, vemurafenib, a BRAF inhibitor, and BRAF inhibition is thought to cause a feedback activation of EGFR signaling that supports continued proliferation. In this study, we explored the effect of combined use of dabrafenib, a BRAF inhibitor, and cetuximab, an EGFR inhibitor, on BRAF(V600E)-mutant CRC stem cells and its possible mechanisms. Through cell viability analysis, flow cytometry, sphere forming, and western blot analysis, we found that the dabrafenib can synergize with cetuximab to reduce cell viability, induce enhanced apoptotic rates and cell cycle arrest in BRAF(V600E)-mutant HT-29 cells and inhibits stem cell capacities. Further, western blot analysis revealed that PTEN/Src/c-Myc pathway is possibly involved in the synergism between dabrafenib and cetuximab. Overall, our study shows that the combination of dabrafenib and cetuximab results in increased antitumor activity and decreased stem cell capacities in BRAF(V600E)-mutant CRC cells.

Inventories of heavy metal inputs and outputs to and from agricultural soils: A review.

Heavy metal pollution of agricultural soils is an important issue around the world. To understand the overall pollution process, accurate determination of every input and output pathway of heavy metals to and from soils is essential. Hence, input and output inventory, a quantitative analysis method of heavy metals balance in agricultural soils, has been widely used. However, due to differences in geography, climate, socioeconomic factors, industrial and agricultural production, substantial variation exists among existing input and output inventories for different countries and regions. In this study, we systematically analyzed these differences and the findings will improve the compilation of inventories worldwide.

Gender-related prognostic value and genomic pattern of intra-tumor heterogeneity in colorectal cancer.

Intra-tumor heterogeneity (ITH) is crucial in tumorigenesis and resistance to target therapy. Here, we used mutant-allele tumor heterogeneity (MATH) to measure ITH based on next-generation sequencing data and high MATH was proven as an independent risk prognostic factor in male CRC patients in both a training set of 284 colorectal cancer (CRC) patients with from The Cancer Genome Atlas (TCGA) and a validating set of 187 CRC patients from International Cancer Genome Consortium (ICGC). Further, the genomic pattern according to MATH demonstrated that mutation rates of TP53, IRF5 and KRAS were independently associated with MATH, and the latter two were only significant in male patients. As MATH increased, the fraction of somatic copy number alteration (SCNA) elevated. Moreover, more SCNA events was independently associated with MATH in male than in female. WNT pathway, TGF-ß pathway and DNA repair deficiency was enriched in high MATH group and the latter two showed up only in male patients. In summary, we reveal the gender-related prognostic value of MATH and relevant genomic pattern in CRC. Potential mechanisms are provided and it remains to be proven whether they are drivers of subclone formation and ITH. Taking MATH into consideration in clinical trial might contribute to better therapeutic strategies in CRC with researches added on in the future.

Low-frequency Stimulation at the Subiculum Prevents Extensive Secondary Epileptogenesis in Temporal Lobe Epilepsy.

Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus. It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy, but still lacks effective treatments. Here, we aimed to test the effects of low-frequency stimulation (LFS) at the subiculum for secondary epileptogenesis in a mouse model. Here, secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli. Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice. LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex, characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci. Only application along with the primary epileptogenesis was effective. Notably, the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci. These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.

New brominated flame retardant decabromodiphenyl ethane (DBDPE) in water sediments: A review of contamination characteristics, exposure pathways, ecotoxicological effects and health risks.

As an alternative to polybrominated diphenyl ethers (PBDEs), decabromodiphenyl ethane (DBDPE) has become one of the most important new brominated flame retardants (NBFRs). However, little is known about whether this emerging contaminant may has an environmental fate similar to PBDEs. Sediments are the main sink for DBDPE in the aqueous phase. Worldwide concentration data, since it was first found in sediments to date, have been collated, and the following conclusions have been drawn. (1) DBDPE concentrations in sediments have increased rapidly, often with a higher risk of contamination in source discharge areas. Compared with other countries, DBDPE contamination in China is more severe, especially in Guangdong Province, which is closely related to its being an e-waste dismantling area. (2) The amount of DBDPE in surface sediments has exceeded that of legacy brominated flame retardants (BFRs), and data recorded in sediment cores also corroborate that DBDPE is replacing decabromodiphenyl ether (BDE-209) as one of the most dominant NBFRs in the environment. (3) The exposure pathways of DBDPE include dietary intake, air or indoor dust intake, cutaneous absorption and endogenous exposure. For sediments, dietary exposure and endogenous exposure pathways need to be considered. Sediment DBDPE can enter the human body through bioenrichment such as contaminated seafood and the food chain. (4) DBDPE can exhibit neurotoxicity, thyrotoxicity, reproductive and developmental toxicity, hepatotoxicity and oxidative stress in organisms. Long-term DBDPE exposure may increase hyperthyroidism risk and inhibit normal cells activity. This review focuses on the distribution characteristics and exposure risks of DBDPE in global water sediments, providing a strong reference for environmental management and related legal policy formulation. The next steps are to focus on continuous source monitoring, process control and sediment clean-up of DBDPE. The development of sustainable water management options for waste microplastics (MPs) and e-waste spiked with DBDPE is a priority.

The role of ATP1A3 gene in epilepsy: We need to know more.

The ATP1A3 gene, which encodes the Na+/K+-ATPase α3 catalytic subunit, plays a crucial role in both physiological and pathological conditions in the brain, and mutations in this gene have been associated with a wide variety of neurological diseases by impacting the whole infant development stages. Cumulative clinical evidence suggests that some severe epileptic syndromes have been linked to mutations in ATP1A3, among which inactivating mutation of ATP1A3 has been intriguingly found to be a candidate pathogenesis for complex partial and generalized seizures, proposing ATP1A3 regulators as putative targets for the rational design of antiepileptic therapies. In this review, we introduced the physiological function of ATP1A3 and summarized the findings about ATP1A3 in epileptic conditions from both clinical and laboratory aspects at first. Then, some possible mechanisms of how ATP1A3 mutations result in epilepsy are provided. We think this review timely introduces the potential contribution of ATP1A3 mutations in both the genesis and progression of epilepsy. Taken that both the detailed mechanisms and therapeutic significance of ATP1A3 for epilepsy are not yet fully illustrated, we think that both in-depth mechanisms investigations and systematic intervention experiments targeting ATP1A3 are needed, and by doing so, perhaps a new light can be shed on treating ATP1A3-associated epilepsy.