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The poor activity of Pt-based-catalysts for alkaline hydrogen oxidation/evolution reaction (HOR/HER) encourages scientific society to design an effective electrocatalyst to develop alkaline fuel cells/electrolyzers. Herein, platinum/rhodium oxide-nitrogen-doped carbon (Pt/Rh2O3-CNx) composite is prepared for alkaline HER and HOR inspired by hydrogen spillover. The HER performance of Pt/Rh2O3-CNx is â¼ 6 times higher than Pt/C. In HOR, Pt/Rh2O3-CNx possesses an exchange current density of 657.60 mA/mgmetal, which is â¼ 3.4 times higher than Pt/C. Hydrogen and hydroxyl binding energy (HBE and OHBE) contribute equally to alkaline HOR/HER. The experimental and theoretical evidence suggests that the enhanced HER and HOR activity of Pt/Rh2O3-CNx may be due to hydrogen spillover from Pt to Rh2O3. Small work function difference [0.08 eV] of the system suggested hydrogen-spillover is feasible, which has been justified by reaction-free energy calculations. We proposed that the dissociation of hydrogen (H2) and water (H2O) occurs at Pt to form Pt-adsorbed hydrogen species (Pt-Had). Then, some Had moves to Rh2O3 through hydrogen spillover and reacts with neighboring Had or adsorbed hydroxyl species (OHad) to form H2 or H2O, which enhances the HER and HOR activity, respectively. The role of water-metal-hydroxyl species in the electrical double layer was also demonstrated on alkaline HOR/HER. This work may help to design the hydrogen-spillover-based catalysts for several renewable energy technologies.
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Electrochemical carbon dioxide (CO2) conversion has enormous potential for reducing high atmospheric CO2 levels and producing valuable products simultaneously; however the development of inexpensive catalysts remains a great challenge. In this work, we successfully synthesised a 1D Cu-based metal-organic framework [Cu(PyDC)(H2O)], which crystallizes in an orthorhombic system with the Pccn space group, by the hydrothermal method. Among the different catalysts utilized, the heterostructures of cathodized Cu-Cu2O@CC demonstrate increased efficiency in producing CH3OH and C2H4, achieving maximum FE values of 37.4% and 40.53%, respectively. Also, the product formation rates of CH3OH and C2H4 reach up to 667 and 1921 µmol h-1 cm-2. On the other side, Cu-Cu2O/NC-700 carbon composites simultaneously produced C1-C3 products with a total FE of 23.27%. Furthermore, a comprehensive study involving detailed DFT simulations is used to calculate the energetic stability and catalytic activity towards the CO2 reduction of Cu(111), Cu2O(111), and Cu@Cu2O(111) surfaces. During the early phase of electrochemical treatment, Cu(II) carboxylate nodes (Cu-O) in the Cu(PyDC)(H2O) MOF were reduced to Cu and Cu2O, with a possible synergistic enhancement from the PyDC ligands. Thus, the improved activity and product enhancement are closely associated with the cathodized reconstruction of Cu-Cu2O@CC heterostructures on carbon cloth. Hence, this study provides efficient derivatives of Cu-based MOFs for notable electrocatalytic activity in CO2 reduction and gives valuable insights towards the advancement of practical CO2 conversion technology.
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Efficient and cost-effective electrocatalysts for the hydrogen oxidation/evolution reaction (HOR/HER) are essential for commercializing alkaline fuel cells and electrolyzers. The sluggish HER/HOR reaction kinetics in base is the key issue that requires resolution so that commercialization may proceed. It is also quite challenging to decrease the noble metal loading without sacrificing performance. Herein, we report improved HER/HOR activity as a result of hydrogen spillover on platinum-supported MoO3 (Pt/MoO3-CNx-400) with a Pt loading of 20%. The catalyst exhibited a decreased over-potential of 66.8 mV to reach 10 mA cm-2 current density with a Tafel slope of 41.2 mV dec-1 for the HER in base. The Pt/MoO3-CNx-400 also exhibited satisfactory HOR activity in base. The mass-specific exchange current density of Pt/MoO3-CNx-400 and commercial Pt/C are 505.7 and 245 mA mgPt-1, respectively. The experimental results suggest that the hydrogen binding energy (HBE) is the key descriptor for the HER/HOR. We also demonstrated that the enhanced HER/HOR performance was due to the hydrogen spillover from Pt to MoO3 sites that enhanced the Volmer/Heyrovsky process, which led to high HER/HOR activity and was supported by the experimental and theoretical investigations. The work function value of Pt [Φ = 5.39 eV) is less than that of ß-MoO3 (011) [Φ = 7.09 eV], which revealed the charge transfer from Pt to the ß-MoO3 (011) surface. This suggested the feasibility of hydrogen spillover, and was further confirmed by the relative hydrogen adsorption energy [ΔGH] at different sites. Based on these findings, we propose that the H2O or H2 dissociation takes place on Pt and interfaces to form Pt-Had or (Pt/MoO3)-Had, and some of the Had shifted to MoO3 sites through hydrogen spillover. Then, Had at the Pt and interface, and MoO3 sites reacted with H2O and HO- to form H2 or H2O molecules, thereby boosting the HER/HOR activity. This work may provide valuable information for the development of hydrogen-spillover-based electrocatalysts for use in various renewable energy devices.
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BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.
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Dieta Cetogénica , Epilepsia Refractaria , Epilepsia , Niño , Adulto , Humanos , Masculino , Lactante , Femenino , Preescolar , Dieta Cetogénica/efectos adversos , Epilepsia Refractaria/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Reino Unido , Resultado del TratamientoRESUMEN
Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like gene <i>DNM1L</i>, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathological <i>DNM1L</i> variants impair mitochondrial network maintenance by divergent mechanisms.
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Dinámicas Mitocondriales , Proteínas Mitocondriales , Dinaminas/genética , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/metabolismo , Dinámicas Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismoRESUMEN
Five new anionic aqueous dioxidovanadium(V) complexes, [{VO2L1,2}A(H2O)n]α (1-5), with the aroylhydrazone ligands pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L1) and furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L2) incorporating different alkali metals (A = Na+, K+, Cs+) as countercation were synthesized and characterized by various physicochemical techniques. The solution-phase stabilities of 1-5 were determined by time-dependent NMR and UV-vis, and also the octanol/water partition coefficients were obtained by spectroscopic techniques. X-ray crystallography of 2-4 confirmed the presence of vanadium(V) centers coordinated by two cis-oxido-O atoms and the O, N, and O atoms of a dianionic tridentate ligand. To evaluate the biological behavior, all complexes were screened for their DNA/protein binding propensity through spectroscopic experiments. Finally, a cytotoxicity study of 1-5 was performed against colon (HT-29), breast (MCF-7), and cervical (HeLa) cancer cell lines and a noncancerous NIH-3T3 cell line. The cytotoxicity was cell-selective, being more active against HT-29 than against other cells. In addition, the role of hydrophobicity in the cytotoxicity was explained in that an optimal hydrophobicity is essential for high cytotoxicity. Moreover, the results of wound-healing assays indicated antimigration in case of HT-29 cells. Remarkably, 1 with an IC50 value of 5.42 ± 0.15 µM showed greater activity in comparison to cisplatin against the HT-29 cell line.
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Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , ADN/química , Hidrazonas/farmacología , Albúmina Sérica Bovina/química , Compuestos de Vanadio/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazonas/química , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Modelos Moleculares , Estructura Molecular , Células 3T3 NIH , Solubilidad , Compuestos de Vanadio/química , Agua/químicaRESUMEN
Active catalysts for HER/HOR are crucial to develop hydrogen-based renewable technologies. The interface of hetero-nanostructures can integrate different components into a single synergistic hybrid with high activity. Here, the synthesis of PdO-RuO2 -C with abundant interfaces/defects was achieved for the hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR). It exhibited a current density of 10â
mA cm-2 at 44â
mV with a Tafel slope of 34â
mV dec-1 in 1â
m KOH. The HER mass activity was 3 times higher in base and comparable to Pt/C in acid. The stability test confirmed high HER stability. The catalyst also exhibited excellent HOR activity in both media; in alkaline HOR it outperformed Pt/C. The exchange current density i0,m of PdO-RuO2 /C was 522â
mA mg-1 in base, which is 58 and 3.4 times higher than those of Pd/C and Pt/C. The HOR activity of PdO-RuO2 /C was 22 and 300 times higher than those of PdO/C in acid and base. Improvement of HER/HOR kinetics in different alkaline electrolytes was observed in the order K+
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OBJECTIVE: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. METHODS: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. RESULTS: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. CONCLUSIONS: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.
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Epilepsias Parciales/genética , Epilepsias Parciales/metabolismo , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Canales de Potasio/genética , Canales de Potasio/metabolismo , Edad de Inicio , Animales , Anticonvulsivantes , Preescolar , Simulación por Computador , Epilepsias Parciales/epidemiología , Epilepsias Parciales/terapia , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Modelos Genéticos , Modelos Moleculares , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Oocitos , Fenotipo , Bloqueadores de los Canales de Potasio/uso terapéutico , Canales de potasio activados por Sodio , Quinidina/uso terapéutico , Relación Estructura-Actividad , XenopusRESUMEN
OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.