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The precise mechanisms that lead to cognitive decline in Alzheimer's disease are unknown. Here we identify amyloid-plaque-associated axonal spheroids as prominent contributors to neural network dysfunction. Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer's disease demonstrates severe disruption in long-range axonal connectivity. This disruption is caused by action-potential conduction blockades due to enlarging spheroids acting as electric current sinks in a size-dependent manner. Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked with Pld3-a potential Alzheimer's-disease-associated risk gene1 that encodes a lysosomal protein2,3 that is highly enriched in axonal spheroids. Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function. Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer's disease, independent of amyloid removal.
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Doença de Alzheimer , Axônios , Fosfolipase D , Animais , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Axônios/metabolismo , Axônios/patologia , Modelos Animais de Doenças , Fosfolipase D/metabolismo , Esferoides Celulares/metabolismoRESUMO
Transmissible gastroenteritis virus (TGEV)-induced enteritis is characterized by watery diarrhea, vomiting, and dehydration, and has high mortality in newborn piglets, resulting in significant economic losses in the pig industry worldwide. Conventional cell lines have been used for many years to investigate inflammation induced by TGEV, but these cell lines may not mimic the actual intestinal environment, making it difficult to obtain accurate results. In this study, apical-out porcine intestinal organoids were employed to study TEGV-induced inflammation. We found that apical-out organoids were susceptible to TGEV infection, and the expression of representative inflammatory cytokines was significantly upregulated upon TGEV infection. In addition, retinoic acid-inducible gene I (RIG-I) and the nuclear factor-kappa B (NF-κB) pathway were responsible for the expression of inflammatory cytokines induced by TGEV infection. We also discovered that the transcription factor hypoxia-inducible factor-1α (HIF-1α) positively regulated TGEV-induced inflammation by activating glycolysis in apical-out organoids, and pig experiments identified the same molecular mechanism as the ex vivo results. Collectively, we unveiled that the inflammatory responses induced by TGEV were modulated via the RIG-I/NF-κB/HIF-1α/glycolysis axis ex vivo and in vivo. This study provides novel insights into TGEV-induced enteritis and verifies intestinal organoids as a reliable model for investigating virus-induced inflammation. IMPORTANCE: Intestinal organoids are a newly developed culture system for investigating immune responses to virus infection. This culture model better represents the physiological environment compared with well-established cell lines. In this study, we discovered that inflammatory responses induced by TGEV infection were regulated by the RIG-I/NF-κB/HIF-1α/glycolysis axis in apical-out porcine organoids and in pigs. Our findings contribute to understanding the mechanism of intestinal inflammation upon viral infection and highlight apical-out organoids as a physiological model to mimic virus-induced inflammation.
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Gastroenterite Suína Transmissível , Glicólise , Inflamação , Organoides , Vírus da Gastroenterite Transmissível , Animais , Citocinas/metabolismo , Proteína DEAD-box 58/metabolismo , Proteína DEAD-box 58/genética , Gastroenterite Suína Transmissível/virologia , Gastroenterite Suína Transmissível/metabolismo , Gastroenterite Suína Transmissível/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamação/metabolismo , Inflamação/virologia , Intestinos/virologia , Intestinos/patologia , NF-kappa B/metabolismo , Organoides/virologia , Organoides/metabolismo , Organoides/patologia , Transdução de Sinais , Suínos , Vírus da Gastroenterite Transmissível/fisiologiaRESUMO
Swine enteric coronaviruses (SeCoVs) pose a significant threat to the global pig industry, but no effective drugs are available for treatment. Previous research has demonstrated that thapsigargin (TG), an ER stress inducer, has broad-spectrum antiviral effects on human coronaviruses. In this study, we investigated the impact of TG on transmissible gastroenteritis virus (TGEV) infection using cell lines, porcine intestinal organoid models, and piglets. The results showed that TG effectively inhibited TGEV replication both in vitro and ex vivo. Furthermore, animal experiments demonstrated that oral administration of TG inhibited TGEV infection in neonatal piglets and relieved TGEV-associated tissue injury. Transcriptome analyses revealed that TG improved the expression of the ER-associated protein degradation (ERAD) component and influenced the biological processes related to secretion, nutrient responses, and epithelial cell differentiation in the intestinal epithelium. Collectively, these results suggest that TG is a potential novel oral antiviral drug for the clinical treatment of TGEV infection, even for infections caused by other SeCoVs.
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Antivirais , Gastroenterite Suína Transmissível , Tapsigargina , Vírus da Gastroenterite Transmissível , Animais , Vírus da Gastroenterite Transmissível/efeitos dos fármacos , Vírus da Gastroenterite Transmissível/fisiologia , Suínos , Gastroenterite Suína Transmissível/tratamento farmacológico , Gastroenterite Suína Transmissível/virologia , Antivirais/farmacologia , Tapsigargina/farmacologia , Linhagem Celular , Replicação Viral/efeitos dos fármacosRESUMO
This study investigates the time-varying causal relationship between geopolitical risk and green finance during the period of 1 March 2012-February 16, 2022. By using the novel time-varying causality testing framework, our findings shed light on the nexus between geopolitical risk and green finance in informing environmental management decisions. First, we find that time heterogeneity does exist in the causal relations between geopolitical risk and green finance. Second, geopolitical risk has a more prolonged impact on the volatility of green bonds and renewable energy than the return. Yet, geopolitical risk tends to influence the return of clean energy more persistently than volatility. Third, we observe that geopolitical risk has a more sustained impact on the return and volatility of renewable energy than clean energy. This might be due to the distinct nature of the production of clean energy and renewable energy, thereby providing implications for effective environmental management. Lastly, this paper demonstrates that the impact of geopolitical risk on the return of European clean energy has diminished since the onset of 2015. The volatility of the European clean energy sector is not affected by global geopolitical risk, underscoring the necessity of promoting the development of this sector to reduce the dependence on fossil fuels and enhance energy independence.
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Conservação dos Recursos Naturais , Combustíveis Fósseis , Energia Renovável , Desenvolvimento Econômico , Dióxido de CarbonoRESUMO
2-deoxythiosugars are more stable than 2-deoxysugars occurring broadly in bioactive natural products and pharmaceutical agents. An effective and direct methodology to stereoselectively synthesize α-2-deoxythioglycosides catalyzed by AgOTf has been developed. Various alkyl thiols and thiophenols were explored and the desired products were formed in good yields with excellent α-selectivity. This method was further applied to the syntheses of S-linked disaccharides and late-stage 2-deoxyglycosylation of estrogen, L-menthol, and zingerone thiols successfully.
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Glicosídeos , Compostos de Sulfidrila , Estereoisomerismo , Catálise , GlicosilaçãoRESUMO
Transmissible gastroenteritis virus (TGEV) is characterized by watery diarrhea, vomiting, and dehydration and is associated with high mortality especially in newborn piglets, causing significant economic losses to the global pig industry. Hypoxia inducible factor-1α (HIF-1α) has been identified as a key regulator of TGEV-induced inflammation, but understanding of the effect of HIF-1α on TGEV infection remains limited. This study found that TGEV infection was associated with a marked increase in HIF-1α expression in ST cells and an intestinal organoid epithelial monolayer. Furthermore, HIF-1α was shown to facilitate TGEV infection by targeting viral replication, which was achieved by restraining type I and type III interferon (IFN) production. In vivo experiments in piglets demonstrated that the HIF-1α inhibitor BAY87-2243 significantly reduced HIF-1α expression and inhibited TGEV replication and pathogenesis by activating IFN production. In summary, we unveiled that HIF-1α facilitates TGEV replication by restraining type I and type III IFN production in vitro, ex vivo, and in vivo. The findings from this study suggest that HIF-1α could be a novel antiviral target and candidate drug against TGEV infection.
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Gastroenterite Suína Transmissível , Doenças dos Suínos , Vírus da Gastroenterite Transmissível , Animais , Suínos , Interferon lambda , Intestinos , Replicação Viral , Hipóxia/veterináriaRESUMO
As the world's population and income levels continue to rise, there is a substantial increase in the demand for meat, which poses significant environmental challenges due to large-scale livestock production. This review explores the potential of microalgae as a sustainable protein source for meat analogues. The nutritional composition, functional properties, and environmental advantages of microalgae are analyzed. Additionally, current obstacles to large-scale microalgal food production are addressed, such as strain development, contamination risks, water usage, and downstream processing. The challenges associated with creating meat-like textures and flavors using techniques like extrusion and emulsion formation with microalgae are also examined. Lastly, considerations related to consumer acceptance, marketing, and regulation are summarized. By focusing on improvements in cultivation, structure, sensory attributes, and affordability, microalgae demonstrate promise as a transformative and eco-friendly protein source to enhance the next generation of meat alternatives.
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Carne , Microalgas , Microalgas/química , Microalgas/metabolismo , Microalgas/crescimento & desenvolvimento , Animais , Humanos , Carne/análise , Valor Nutritivo , Substitutos da CarneRESUMO
In various applications, infrared (IR) detectors with quick responses and high sensitivity at room temperature are essential. This work synthesizes carbon nanotube aerogel films (CAFs) with an ultra-low density of 1.33 mg cm-3. Transient electrothermal (TET) technology is used to characterize the thermal and electrical transport of CAFs in the temperature range of 320 to 10 K. CAF has record-low thermal conductivity (2.5 mW m-1 K-1 at 320 K) and thermal diffusivity (2.24 × 10-6 m2 s-1 at 320 K) in vacuum. The TCR of CAF is -0.11%/K at 295 K, which is 57% higher than that of the MWCNT films. In addition, the comprehensive bolometric performance of carbon nanotube aerogels is tested and analyzed, including the photothermal response, resistivity responsivity, and response time to lasers of a broad spectrum from ultraviolet to near-infrared. The relative responsivity of CAF to lasers of different wavelengths is found to be consistent. The response time of CAF with 200 µm suspended length is measured to be as short as 2.95-3.03 ms (framing rate of 330-339 per second). In addition, the resistive response of the CAF sample to a blackbody radiator and the radiation of the human hand also shows good sensitivity and repeatability. These results demonstrate the promising application of CAF as a sensitive and fast-response uncooled bolometer.
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Microalgae have been recognized as emerging cell factories due to the high value-added bio-products. However, the balance between algal growth and the accumulation of metabolites is always the main contradiction in algal biomass production. Hence, the security and effectiveness of regulating microalgal growth and metabolism simultaneously have drawn substantial attention. Since the correspondence between microalgal growth and reactive oxygen species (ROS) level has been confirmed, improving its growth under oxidative stress and promoting biomass accumulation under non-oxidative stress by exogenous mitigators is feasible. This paper first introduced ROS generation in microalgae and described the effects of different abiotic stresses on the physiological and biochemical status of microalgae from these aspects associated with growth, cell morphology and structure, and antioxidant system. Secondly, the role of exogenous mitigators with different mechanisms in alleviating abiotic stress was concluded. Finally, the possibility of exogenous antioxidants regulating microalgal growth and improving the accumulation of specific products under non-stress conditions was discussed.
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Microalgas , Espécies Reativas de Oxigênio/metabolismo , Microalgas/metabolismo , Biomassa , Estresse Oxidativo , Estresse Fisiológico , Antioxidantes/metabolismo , BiocombustíveisRESUMO
As a next-generation anode material for lithium batteries, Li metal anode suffers from inherent drawbacks such as infinite volume expansion and uneven Li plating/stripping. Herein, we propose a lightweight lithiophilic Prussian blue analogue (PBA) with honeycomb-like structure on Cu foam by self-assembly method to address these issues. The unique honeycomb-like architecture could provide enlarged surface areas and abundant deposition sites for homogenizing Li+ flux during Li plating. Consequently, the elaborate PBA-decorated Cu foam current collector enables long-term (1800 h) reversible plating/stripping behavior and an observably improved Coulombic efficiency (98.3% after 350 cycles). The concept of the direct self-assembly synthesis method on metal foam provides new insights into the design of a lightweight 3-dimensional current collector for Li metal anode.
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Integrating carbon-coating and nanostructuring has been considered as the most promising strategy to accommodate the dramatic volume expansion represented by high-capacity antimony (Sb) upon sodiation. Suitable coating source and synthetic strategy that are both economical and strong are yet to be explored. In this regard, by using renewable bio-oil as carbon source and self-wrapping precursor, robust Sb@C composite anode with Sb nanoparticles homogeneously impregnated into the cross-linked 2D ultrathin carbon nanosheets is developed via a facile NaCl template-assisted self-assembly and followed carbothermal reduction method. Such judiciously crafted interconnected macroporous framework can mitigate of mechanical stress and alleviate the volume change of inner Sb, guaranteeing high-performance sodium-ion battery anode. At a current density of 0.1 A g-1, ultrahigh reversible capacity of 520 mAh g-1 can be achieved. Notably, a stable capacity of 391 mAh g-1 is even retained after 500 cycles at 1 A g-1. Such a facile and cost-effective synthetic method is promising for high-performance sodium-ion batteries.
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The development of Li-S batteries (LSBs) is largely impeded by sluggish redox kinetics and notorious polysulfide shuttling. Herein, hierarchical MoC@Ni-NCNT arrays are reported as a multifunctional sulfur host in Li-S batteries, which comprised a flexible carbon fiber cloth substrate decorated with vertical MoC porous nanorods rooted by interconnected nitrogen-doped carbon nanotubes (NCNTs). In the designed host, the inner MoC porous backbone (composed of nanoparticles) along with the in situ-grafted interwoven NCNT shell can greatly maximize the host-guest interactive surface for homogeneous sulfur dispersion, thus realizing decent high-sulfur-loading performance. Ni nanoparticles, encapsulated within NCNTs in the outer shell, act as strong chemical-anchoring centers effectively trap-escaped polysulfides and propel the bidirectional sulfur transformation kinetics. In merit of sufficient adsorption and catalytic sites, the cell configured with the MoC@Ni-NCNT cathode delivers not only high capacity (1421 mA h g-1 at 0.1 C) but also superior rate performance and ultralong lifespan. The cell can still achieve a superb areal capacity of 6.1 mA h cm2 under an increased sulfur loading up to 6 mg cm-2. This work could open a new avenue for the construction of a multifunctional cathode for high-performance LSBs.
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Most isolated strains of Staphylococcus sciuri contain mecA1, the evolutionary origin of mecA, but are sensitive to ß-lactams (OS-MRSS, oxacillin-susceptible mecA1-positive S. sciuri). In order to improve the efficacy of antibiotic treatment, it is important to clarify whether the resistance of OS-MRSS to ß-lactams is an inducible phenotype. In this study, three OS-MRSS strains with oxacillin MIC = 1 µg/ml were isolated from 29 retail pork samples. The resistance of OS-MRSS to ß-lactams (MIC > 256 µg/ml) was found to be induced by oxacillin, and the induced resistance was observed to remain stable within a certain period of time. Interestingly, the induced ß-lactam resistance was not caused by mecA1, heterogeneous resistance, or any genetic mutation, but mainly due to increased wall teichoic acid (WTA) synthesis that thickened the cell wall. The induced strains also showed slower growth rate, as well as decreased adhesion ability and biofilm thickness. These phenotypes were found to be achieved through altered gene expression in associated pathways, such as the citrate cycle and pentose phosphate pathway. The results challenge the traditional antibiotic sensitivity test. In the presence of ß-lactam antibiotics, OS-MRSS that was initially sensitive to ß-lactams was observed to gradually develop ß-lactam resistance in several days. This often-neglected phenomenon in antibiotic sensitivity tests requires further research attention.
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Laccases are multicopper oxidases with important industrial value. In the study, a novel laccase gene (mco) in a Staphylococcus haemolyticus isolate is identified and heterologously expressed in Escherichia coli. Mco shares less than 40% of amino acid sequence identities with the other characterized laccases, exhibiting the maximal activity at pH 4.0 and 60°C with 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) as a substrate. Additionally, the Mco is tolerant to a wide range of pH, heavy metal ions and many organic solvents, and it has a high decolorization capability toward textile dyes in the absence of redox mediators. The characteristics of the Mco make this laccase potentially useful for industrial applications such as textile finishing. Based on BLASTN results, mco is found to be widely distributed in both the bacterial genome and bacterial plasmids. Its potential role in oxidative defense ability of staphylococci may contribute to the bacterial colonization and survival.
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Proteínas de Bactérias/metabolismo , Corantes/metabolismo , Lacase/metabolismo , Staphylococcus haemolyticus/enzimologia , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Clonagem Molecular , Escherichia coli/genética , Temperatura Alta , Concentração de Íons de Hidrogênio , Lacase/química , Lacase/genética , Lacase/isolamento & purificação , Metais/metabolismo , Modelos Moleculares , Filogenia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Solventes/metabolismo , Especificidade da Espécie , Staphylococcus haemolyticus/classificação , Staphylococcus haemolyticus/genética , Especificidade por SubstratoRESUMO
Vanadium nitride (VN) with high conductivity exhibits the potential promising as anode materials for supercapacitors, but VN suffered the obvious performance fading due to the dissolution of VN in aqueous electrolyte. In this work, we solve these problems through realizing 3D structural VN microsheets shelled with N-doped carbon layer (VN@NC) by introducing melamine as nitrogen source and PVP as carbon source. The as-prepared VN@NC electrode display high capacitance of 368â¯Fâ¯g-1 and good rate property. A solid-state asymmetric supercapacitor (ASC) with NiCo2O4 nanowires as cathode materials and VN@NC as anode materials was fabricated. The ASC device exhibits the high energy density of 65.3â¯Wâ¯hâ¯kg-1, and good cycling stability (92% capacitance retention) after 4000 cycles. Moreover, the ASC device shows good mechanical flexibility with negligible capacitance loss after 1000 bending cycles.
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This paper first visits the clean energy consumption for 21 OECD countries and 14 Emerging market countries through a panel unit root test with both sharp and smooth breaks covering the period from 1965 to 2016. The time-varying fitted intercepts of the estimation could better fit the path of clean energy consumption for selected countries. The empirical results suggest that not only sharp breaks should be considered, but also smooth breaks. The economic implications are insightful for the convergence of clean energy consumption for 22 of 35 countries. For USA, Canada, Austria, Germany, Greece, Ireland, UK, Australia, New Zealand, South Korea, Hungary, China, Philippines, and Thailand, the clean energy consumption is divergence. Policy encouragement policy would permanently affect not only clean energy consumption path, but also aggregate economic sectors related to consume clean energy.
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Desenvolvimento Econômico/tendências , Modelos Econométricos , Energia Renovável/economia , Dióxido de Carbono/análise , Países Desenvolvidos , Países em Desenvolvimento , Método de Monte Carlo , Energia Renovável/estatística & dados numéricos , Crescimento SustentávelRESUMO
This study aims to examine the stochastic convergence of per capita carbon dioxide (CO2) emissions in 21 OECD countries and 19 emerging market economies. After approximating both sharp and smooth breaks, the panel unit root tests are performed to test the convergence. The empirical results suggest stochastic convergence for the two groups of countries. However, the results are different when tests for individual countries are conducted separately. Specifically, CO2 emissions of only four OECD countries and four emerging market economies show evidence of convergence if smooth breaks are not considered. With the inclusion of both sharp and smooth breaks, convergence is observed for 11 OECD countries and 10 emerging market economies. These findings may have implications for climate change policy making in selected economies.
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Poluentes Atmosféricos/análise , Dióxido de Carbono/análise , Desenvolvimento Econômico/tendências , Mudança Climática/economia , Países em Desenvolvimento/economia , Países em Desenvolvimento/estatística & dados numéricos , Desenvolvimento Econômico/estatística & dados numéricos , Pesquisa Empírica , Política Ambiental , Modelos Econômicos , Organização para a Cooperação e Desenvolvimento Econômico/economiaRESUMO
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. Recent studies suggest that miRNA expression changes are associated with the development of AD. Our previous study showed that the expression level of miR-409-5p was stably downregulated in the early stage of APP/PS1 double transgenic mice model of AD. We now report that miR-409-5p impairs neurite outgrowth, decreases neuronal viability, and accelerates the progression of Aß1 - 42-induced pathologies. In this study, we found that Aß1 - 42 peptide significantly decreased the expression of miR-409-5p, which was consistent with the expression profile of miR-409-5p in the APP/PS1 mice cortexes. Plek was confirmed to be a potential regulatory target of miR-409-5p by luciferase assay and Western blotting. Overexpression of miR-409-5p has an obvious neurotoxicity in neuronal cell viability and differentiation, whereas Plek overexpression could partially rescue neurite outgrowth from this toxicity. Some cytoskeleton regulatory proteins have been found to be related to AD pathogenesis. Our data show some clues that cytoskeletal reorganization may play roles in AD pathology. The early downregulation of miR-409-5p in AD progression might be a self-protective reaction to alleviate the synaptic damage induced by Aß, which may be used as a potential early biomarker of AD.
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Intrinsically poor conductivity, sluggish ion transfer kinetics, and limited specific area are the three main obstacles that confine the electrochemical performance of metal oxides in supercapacitors. Engineered hollow metal oxide nanostructures can effectively satisfy the increasing power demand of modern electronics. In this work, both triple-shelled MnO2 and hollow Fe2O3 microcubes have been synthesized from a single MnCO3 template. The oxygen vacancies are introduced in both the positive and negative electrodes through a facile method. The oxygen vacancies can not only improve the conductivity and facilitate ion diffusion but also increase the electrode/electrolyte interfaces and electrochemically active sites. Consequently, both the oxygen-deficient triple-shelled MnO2 and hollow Fe2O3 exhibit larger capacitance and rate capability than the samples without oxygen vacancies. Moreover, due to the matchable specific capacitance and potential window between the positive and negative electrodes, the asymmetric supercapacitor exhibits high specific capacitance (240 F g-1), excellent energy density of 133 W h kg-1 at 1176 W kg-1, excellent power density (23 529 W kg-1 at 73 W h kg-1), and high cycling stability (90.9% after 5000 cycles). This strategy is highly reproducible in oxide-based electrodes, which have the potential to meet the requirements of practical application.
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SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.