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Recent studies have shown that the 5-HT1a receptor (5-HT1aR) in the central 5-HT (Serotonergic) system is involved in the pathophysiology of schizophrenia through its various receptors, and the dysfunction of the ventral hippocampus may be a key causative factor in schizophrenia. To date, whether the 5-HT1a receptor is involved in ventral hippocampal dysfunction and its internal mechanism remain unclear. In this study, schizophrenia-like animal model was induced by intraperitoneal injection of aspartate receptor antagonist MK-801 in male Sprague Dawley rats, and the role of 5-HT1aR in this animal model was investigated by bilaterally micro-infusing the 5-HT1aR antagonist WAY100635 into the ventral subiculum (vSub) of the hippocampus of rats. Behavioral experiments such as open field test (OFT) and prepulse inhibition (PPI) were performed. The results showed that MK-801 induced hyperactivity and impaired prepulse inhibition in rats, whereas, micro-infusion of 5-HT1aR antagonist WAY100635 into the vSub ameliorated these phenomena. Immunofluorescence analysis revealed that WAY100635 significantly increased the c-Fos expression in vSub. Western blot and immunohistochemical analysis showed that MK-801 induced up-regulation of 5-HT1aR and phospho-extracellular regulated protein kinase (p-ERK) pathway, while micro-infusion of the WAY100635 down-regulated 5-HT1aR and p-ERK in the vSub. Therefore, the results of the present study suggested that in vSub, the 5-HT1aR antagonist WAY100635 may attenuate MK-801-induced schizophrenia-like activity by modulating excitatory neurons and downregulating p-ERK.
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Maleato de Dizocilpina , Hipocampo , Piperazinas , Piridinas , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina , Esquizofrenia , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Maleato de Dizocilpina/farmacologia , Masculino , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Piperazinas/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Ratos , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Inibição Pré-Pulso/efeitos dos fármacos , MicroinjeçõesRESUMO
Chronic kidney disease(CKD) is an insidious disease that has become a significant global public health issue due to its high incidence rate, low awareness, low diagnostic rate, poor prognosis, and high medical costs. Recent studies have shown that CKD development is associated with varying degrees of ferroptosis features. Traditional Chinese medicine(TCM) can regulate iron metabolism, lipid peroxidation, antioxidant systems to inhibit ferroptosis and delay the progression of CKD. Consequently, the intervention mechanism of ferroptosis has become one of the focuses of CKD research. TCM has thousands of years of traditional experience and wisdom. It focuses on the overall regulation of human body functions and can stimulate the body's disease resistance and recovery capabilities, which has certain advantages in treating CKD. However, there is currently a lack of comprehensive articles on the application of TCM in intervening ferroptosis to treat CKD and the pathogenesis of ferroptosis in CKD. Therefore, this article summarizes the latest research progress both domestically and internationally, briefly introduces the main mechanisms of ferroptosis, and systematically reviews the relationship between ferroptosis and CKD. The article integrates TCM theories related to ferroptosis in CKD, including "deficiency" "stasis" "phlegm turbidity" and "toxins" and summarizes the research status of active ingredients and herbal formulas in intervening ferroptosis to treat CKD. By considering ferroptosis from a new perspective, this article aims to provide new targets and directions for the application of TCM in treating CKD.
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Ferroptose , Medicina Tradicional Chinesa , Insuficiência Renal Crônica , Ferroptose/efeitos dos fármacos , Humanos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Ferro/metabolismoRESUMO
An increasing body of research suggests that promoting microglial autophagy hinders the neuroinflammation initiated though the NLRP3 inflammasome activation in Alzheimer's disease (AD). The function of FoxG1, a crucial transcription factor involved in cell survival by regulating mitochondrial function, remains unknown during the AD process and neuroinflammation occurs. In the present study, we firstly found that Aß peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aß25-35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aß25-35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aß25-35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aß25-35 stimulation, we employed siRNA to decrease the expression of FoxG1 in N2A cells. A substantial reduction in autophagy level (Beclin1, LC3II, SQSTM1/P62) and a notable growth in inflammatory response (NLRP3, TNF-α, and IL-6) were observed. In addition, we found FoxG1 overexpression owned the effect on the activation of AMPK/mTOR autophagy pathway and siRNA-FoxG1 successfully abolished this effect. Lastly, FoxG1 suppressed the NLRP3 inflammasome and enhanced the cognitive function in AD-like mouse model induced by Aß25-35. Confirmed by cellular and animal experiments, FoxG1 suppressed NLRP3-mediated neuroinflammation, which was strongly linked to autophagy regulated by AMPK/mTOR. Taken together, FoxG1 may be a critical node in the pathologic progression of AD and has the potential to serve as therapeutic target.
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Doença de Alzheimer , Fatores de Transcrição Forkhead , Inflamassomos , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Proteínas Quinases Ativadas por AMP , Autofagia , Doenças Neuroinflamatórias , Proteína 3 que Contém Domínio de Pirina da Família NLR , RNA Interferente Pequeno , Fatores de Transcrição Forkhead/antagonistas & inibidoresRESUMO
Burn injuries result in localised tissue damage and precipitate systemic responses; routine clinical treatments, which typically include metabolic nutritional support and anti-infection therapies, do not yield optimal outcomes. Therefore, we aimed to systematically evaluate the effects of ulinastatin on wound infection and healing in patients with burns to provide reliable evidence-based recommendations for burn treatment. An electronic search of the Web of Science, PubMed, Cochrane Library, Embase, Wanfang, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure databases, supplemented by manual searches, was conducted from database inception to October 2023 to collect randomised controlled trials (RCTs) assessing the efficacy of ulinastatin for the treatment of burns. Two researchers screened all retrieved articles according to the inclusion and exclusion criteria; the included studies were evaluated for quality, and the relevant data were extracted. Stata 17.0 software was employed for data analysis. Overall, 8 RCTs with 803 patients were included, with 404 and 399 in the ulinastatin and conventional treatment groups, respectively. The analysis revealed that wound infections (odds ratio [OR] = 0.08, 95% CI: 0.02-0.35, p = 0.001) and complications (OR = 0.21, 95% CI: 0.10-0.42, p < 0.001) were significantly lower, and wound healing time (standardised mean differences [SMD] = -1.31, 95% CI: -2.05 to -0.57, p = 0.001) was significantly shorter, in the ulinastatin groups than in the control group. This meta-analysis revealed that ulinastatin can effectively reduce the incidence of wound infections and complications and significantly shorten the duration of wound healing in patients with burns, thereby promoting early recovery in these patients.
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Queimaduras , Glicoproteínas , Cicatrização , Infecção dos Ferimentos , Humanos , Queimaduras/tratamento farmacológico , Queimaduras/complicações , Cicatrização/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/prevenção & controle , Glicoproteínas/uso terapêutico , Glicoproteínas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Inibidores da Tripsina/uso terapêuticoRESUMO
The surface electronic structures of catalysts play a crucial role in CO2 adsorption and activation. Here, sulfur vacancies are introduced into CuInS2 nanosheets (Vs-CuInS2) to evaluate the effect of electronic structures at the surface-active sites on the electrochemical CO2 reduction reaction (CO2RR). Vs-CuInS2 exhibits a significant disparity in the highest FEformate/FECO (6.50) compared to that of CuInS2 (1.86). Specifically, the maximum current density (Jmax) of carbon products on Vs-CuInS2 is 78.78 mA cm-2, and a Faraday efficiency of carbon products (FEcarbon products) of ≥80% is achieved in 600 mV wide potential windows. In situ Raman measurements and density functional theory calculations elucidate the origin of the apparent alterations in the carbon product selectivity. The introduction of sulfur vacancies realizes the controllable regulation of the local electronic density around the metal active sites, inducing the transformation of *COOH and *OCHO from competitive adsorption on CuInS2 to specific adsorption on Vs-CuInS2. In addition, the regulation of electronic structures on Vs-CuInS2 inhibits *H adsorption. This work reveals the transfer of adsorption of CO2RR intermediates via regulation of the electronic structure, complementing the understanding of the mechanism for the enhanced CO2RR.
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We establish a statistical two-body fractal (STF) model to study the spectrum of J/ψ. J/ψ serves as a reliable probe in heavy-ion collisions. The distribution of J/ψ in hadron gas is influenced by flow, quantum and strong interaction effects. Previous models have predominantly focused on one or two of these effects while neglecting the others, resulting in the inclusion of unconsidered effects in the fitted parameters. Here, we study the issue from a new point of view by analyzing the fact that all three effects induce a self-similarity structure, involving a J/ψ-π two-meson state and a J/ψ, π two-quark state, respectively. We introduce modification factor qTBS and q2 into the probability and entropy of charmonium. qTBS denotes the modification of self-similarity on J/ψ, q2 denotes that of self-similarity and strong interaction between c and c¯ on quarks. By solving the probability and entropy equations, we derive the values of qTBS and q2 at various collision energies and centralities. Substituting the value of qTBS into distribution function, we successfully obtain the transverse momentum spectrum of low-pT J/ψ, which demonstrates good agreement with experimental data. The STF model can be employed to investigate other mesons and resonance states.
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Peroxisome proliferator-activated receptor PPARγ coactivator-α (PGC-1α) is concentrated in inhibitory interneurons and plays a vital role in neuropsychiatric diseases. We previously reported some characteristic features of schizophrenia (SZ) in GABAergic neuron-specific Pgc-1alpha knockout (KO) mice (Dlx5/6-Cre: Pgc-1alphaf/f). However, there is a fundamental gap in the molecular mechanism by which the Pgc-1alpha gene is involved in the neurobehavioral abnormalities of SZ. The loss of critical period (CP) triggers-maturations of parvalbumin interneurons (PVIs) and brakes-and the formation of perineuronal nets (PNNs) implicates mistimed trajectories during adult brain development. In this study, using the Pgc-1alpha KO mouse line, we investigated the association of Pgc-1alpha gene deletion with SZ-like behavioral deficits, PVI maturation, PNN integrity and synaptic ultrastructure. These findings suggest that Pgc-1alpha gene deletion resulted in a failure of CP onset and closure, thereby prolonging cortical plasticity timing. To determine whether the manipulation of the PNN structure is a potential method of altering neuronal plasticity, GM6001, a broad-spectrum matrix metalloproteinase (MMP)-inhibitor was applied. Here we confirmed that the treatment could effectively correct the CP plasticity window and ameliorate the synaptic ultrastructure in the Pgc-1alpha KO brain. Moreover, the intervention effect on neuronal plasticity was followed by the rescue of short-term habituation deficits and the mitigation of aberrant salience, which are some characteristic features of SZ. Taken collectively, these findings suggest that the role of PGC-1α in regulating cortical plasticity is mediated, at least partially, through the regulation of CP onset/closure. Strategically introduced reinforcement of molecular brakes may be a novel preventive therapy for psychiatric disorders associated with PGC-1α dysregulation.
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Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.
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Antipsicóticos , Receptor DCC , Esquizofrenia , Animais , Camundongos , Antipsicóticos/uso terapêutico , Receptor DCC/genética , Camundongos Endogâmicos C57BL , Olanzapina/farmacologia , Fenótipo , Córtex Pré-Frontal , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genéticaRESUMO
The sluggish kinetics of CO2 activation and reduction severely limit the energy conversion efficiency of electrocatalytic CO2 reduction into fuels. Here, ZnSn(OH)6 with an alternating arrangement of Zn(OH)6 and Sn(OH)6 octahedral units and SrSn(OH)6 with an alternating arrangement of SrO6 and Sn(OH)6 octahedral units were adopted to check the effects of frustrated Lewis pairs (FLPs) on electrochemical CO2 reduction. The FLPs were in situ electrochemically reconstructed on ZnSn(OH)6 by reducing the electrochemically unstable Sn-OH to Sn-oxygen vacancies (Sn-OVs) as a Lewis acid site, which are able to create strong interactions with the adjacent electrochemically stable Zn-OH, a Lewis base site. Compared to SrSn(OH)6 without FLPs, the higher formate selectivity of ZnSn(OH)6 originates from the strong ability of FLPs to capture protons and activate CO2via the electrostatic field of FLPs triggering better electron transfer and strong orbital interactions under negative potentials. Our findings may guide the design of electrocatalysts for CO2 reduction with high catalytic performances.
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Background: When users inquire about knowledge in a certain field using the internet, the intelligent question-answering system based on frequently asked questions (FAQs) provides numerous concise and accurate answers that have been manually verified. However, there are few specific question-answering systems for chronic diseases, such as rheumatoid arthritis, and the related technology to construct a question-answering system about chronic diseases is not sufficiently mature. Methods: Our research embedded the classification information of the question into the sentence vector based on the bidirectional encoder representations from transformers (BERT) language model. First of all, we calculated the similarity using edit distance to recall the candidate set of similar questions. Then, we took advantage of the BERT pretraining model to map the sentence information to the corresponding embedding representation. Finally, each dimensional feature of the sentence was obtained by passing a sentence vector through the multihead attention layer and the fully connected feedforward layer. The features that were stitched and fused were used for the semantic similarity calculation. Results: Our improved model achieved a Top-1 precision of 0.551, Top-3 precision of 0.767, and Top-5 precision of 0.813 on 176 testing question sentences. In the analysis of the actual application effect of the model, we found that our model performed well in understanding the actual intention of users. Conclusions: Our deep learning model takes into account the background and classifications of questions and combines the efficiency of deep learning technology and the comprehensibility of semantics. The model enables the deep meaning of the user's question to be better understood by the intelligent question answering system, and answers that are more relevant to the original query are provided.
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Developing stable catalysts with higher selectivity and activity within a wide potential range is critical for efficiently converting CO2 to ethanol. Here, the carbon-encapsulated CuNi nanoparticles anchored on nitrogen-doped nanoporous graphene (CuNi@C/N-npG) composite are designedly prepared and display the excellent CO2 reduction performance with the higher ethanol Faradaic effiency (FEethanol ≥ 60%) in a wide potential window (600 mV). The optimal cathodic energy efficiency (47.6%), Faradaic efficiency (84%), and selectivity (96.6%) are also obtained at -0.78 V versus reversible hydrogen electrode (RHE). Combining with the density functional theory (DFT) calculations, it is demonstrated that the stronger metal-support interaction (Ni-N-C) can regulate the surface electronic structure effectively, boosting the electron transfer and stabilizing the active sites (Cu0 -Cuδ+ ) on the surface of CuNi@C/N-npG, finally realizing the controllable transition of reaction intermediates. This work may guide the designs of electrocatalysts with highly catalytic performance for CO2 reduction to C2+ products.
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OBJECTIVE: Attractin (ATRN) is a widely expressed member of the cell adhesion and guidance protein family in humans that is closely related to cellular immunity and neurodevelopment. However, while previous studies in our laboratory have confirmed the effect of ATRN mutations on long-term memory, its specific role and the molecular mechanism by which it influences spatial cognition are poorly understood. METHODS: This study aimed to examine the effect of ATRN mutations on working memory in water maze with a novel ATRN-mutant rat generated by the CRISPR/Cas9 system; the mutation involved the substitution of the 505th amino acid, glycine (G), with cysteine (C), namely, a mutation from GGC to TGC. The changes in myelin basic protein (MBP) expression in rats were also analyzed with the western blot. RESULTS: The ATRN-G505C(KI/KI) rats exhibited significant increases in the required latency and distance traveled to locate the escape platform in a Morris water maze test of working memory. In addition, the expression of MBP was reduced in ATRN-mutant rats, as shown in the western blot analysis. CONCLUSION: Our results indicate that ATRN gene mutations may directly lead to the impairment of working memory in the water maze; this impairment may be due to the inhibition of MBP expression, which in turn affects the spatial cognition.
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Memória de Curto Prazo , Animais , Humanos , Ratos , Aprendizagem em Labirinto , MutaçãoRESUMO
The meniscus is a kind of fibrous cartilage structure that serves as a cushion in the knee joint to alleviate the mechanical load. It is commonly injured, but it cannot heal spontaneously. Traditional meniscectomy is not currently recommended as this treatment tends to cause osteoarthritis. Due to their good biocompatibility and versatile regulation, hydrogels are emerging biomaterials in tissue engineering. Hydrogels are excellent candidates in meniscus rehabilitation and regeneration because they are fine-tunable, easily modified, and capable of delivering exogenous drugs, cells, proteins, and cytokines. Various hydrogels have been reported to work well in meniscus-damaged animals, but few hydrogels are effective in the clinic, indicating that hydrogels possess many overlooked problems. In this review, we summarize the applications and problems of hydrogels in extrinsic substance delivery, meniscus rehabilitation, and meniscus regeneration. This study will provide theoretical guidance for new therapeutic strategies for meniscus repair.
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Strategies to enhance hippocampal precursor cells efficiently differentiate into neurons could be crucial for structural repair after neurodegenerative damage. FOXG1 has been shown to play an important role in pattern formation, cell proliferation, and cell specification during embryonic and early postnatal neurogenesis. Thus far, the role of FOXG1 in adult hippocampal neurogenesis is largely unknown. Utilizing CAG-loxp-stop-loxp-Foxg1-IRES-EGFP (Foxg1fl/fl), a specific mouse line combined with CreAAV infusion, we successfully forced FOXG1 overexpressed in the hippocampal dentate gyrus (DG) of the genotype mice. Thereafter, we explored the function of FOXG1 on neuronal lineage progression and hippocampal neurogenesis in adult mice. By inhibiting p21cip1 expression, FOXG1-regulated activities enable the expansion of the precursor cell population. Besides, FOXG1 induced quiescent radial-glia like type I neural progenitor, giving rise to intermediate progenitor cells, neuroblasts in the hippocampal DG. Through increasing the length of G1 phase, FOXG1 promoted lineage-committed cells to exit the cell cycle and differentiate into mature neurons. The present results suggest that FOXG1 likely promotes neuronal lineage progression and thereby contributes to adult hippocampal neurogenesis. Elevating FOXG1 levels either pharmacologically or through other means could present a therapeutic strategy for disease related with neuronal loss.
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Células-Tronco Neurais , Neurogênese , Camundongos , Animais , Neurogênese/genética , Hipocampo/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Proliferação de Células , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismoRESUMO
With rapid development of technologies in medical diagnosis and treatment, the novel and complicated concepts and usages of clinical terms especially of surgical procedures have become common in daily routine. Expected to be performed in an operating room and accompanied by an incision based on expert discretion, surgical procedures imply clinical understanding of diagnosis, examination, testing, equipment, drugs and symptoms, etc., but terms expressing surgical procedures are difficult to recognize since the terms are highly distinctive due to long morphological length and complex linguistics phenomena. To achieve higher recognition performance and overcome the challenge of the absence of natural delimiters in Chinese sentences, we propose a Named Entity Recognition (NER) model named Structural-SoftLexicon-Bi-LSTM-CRF (SSBC) empowered by pre-trained model BERT. In particular, we pre-trained a lexicon embedding over large-scale medical corpus to better leverage domain-specific structural knowledge. With input additionally augmented by BERT, rich multigranular information and structural term information is transferred from Structural-SoftLexicon to downstream model Bi-LSTM-CRF. Therefore, we could get a global optimal prediction of input sequence. We evaluate our model on a self-built corpus and results show that SSBC with pre-trained model outperforms other state-of-the-art benchmarks, surpassing at most 3.77% in F1 score. This study hopefully would benefit Diagnostic Related Groups (DRGs) and Diagnosis Intervention Package (DIP) grouping system, medical records statistics and analysis, Medicare payment system, etc.
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Compared with the Haber Bosch process, the electrochemical nitrogen reduction reaction (NRR) under mild conditions provides an alternative and promising route for ammonia synthesis due to its green and sustainable features. However, the great energy barrier to break the stable N≡N bond hinders the practical application of NRR. Though Fe is the only common metal element in all biological nitrogenases in nature, there is still a lack of study on developing highly efficient and low-cost Fe-based catalysts for N2 fixation. Herein, Co-doped Fe3S4 nanoflowers were fabricated as the intended catalyst for NRR. The results indicate that 4% Co-doped Fe3S4 nanoflowers achieve a high Faradaic efficiency of 17% and a NH3 yield rate of 37.5 µg·h-1·mg-1cat. at -0.55 V versus RHE potential in 0.1 M HCl, which is superior to most Fe-based catalysts. The introduction of Co atoms can not only shift the partial density states of Fe3S4 toward the Fermi level but also serve as new active centers to promote N2 absorption, lowering the energy barrier of the potential determination step to accelerate the catalytic process. This work paves a pathway of the morphology and doping engineering for Fe-based electrocatalysts to enhance ammonia synthesis.
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Amônia , Fixação de Nitrogênio , Nitrogenase , NitrogênioRESUMO
Emerging evidence suggests that the proper control of mitochondrial dynamics provides a window for therapeutic intervention for Alzheimer's disease (AD) progression. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1 (PGC-1a) has been shown to regulate mitochondrial biogenesis in neurons. Thus far, the roles of PGC-1a in Alzheimer's disease and its potential value for restoring mitochondrial dysfunction remain largely unknown. In the present study, we explored the impacts of PGC-1a on AD pathology and neurobehavioral dysfunction and its potential mechanisms with a particular focus on mitochondrial dynamics. Paralleling AD-related pathological deposits, neuronal apoptosis, abnormal mitochondrial dynamics and lowered membrane potential, a remarkable reduction in the expression of PGC-1a was shown in the cortex of APP/PS1 mice at 6 months of age. By infusing AAV-Ppargc1α into the lateral parietal association (LPtA) cortex of the APP/PS1 brain, we found that PGC-1a ameliorated AD-like behavioral abnormalities, such as deficits in spatial reference memory, working memory and sensorimotor gating. Notably, overexpressed PGC-1a in LPtA rescued mitochondrial swelling and damage in neurons, likely through correcting the altered balance in mitochondrial fission-fusion and its abnormal distribution. Our findings support the notion that abnormal mitochondrial dynamics is likely an important mechanism that leading to mitochondrial dysfunction and AD-related pathological and cognitive impairments, and they indicate the potential value of PGC-1a for restoring mitochondrial dynamics as an innovative therapeutic target for AD.
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Doença de Alzheimer , Dinâmica Mitocondrial , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Doença de Alzheimer/metabolismo , Animais , Camundongos , Biogênese de Organelas , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismoRESUMO
Parkinson's disease (PD) is a common neurodegenerative disease. The main pathological changes are the loss of dopaminergic neurons and the formation of Lewy bodies. There is still no effective cure for PD, and cell replacement therapy has entered a bottleneck period due to tumorigenicity and rejection. Therefore, stem cell secretome has received widespread attention. However, the exploration of the secretome components of neural stem cells (NSCs) is still in its infancy. In this study, 6-hydroxydopamine (6-OHDA) was used to establish a PD rat model in vito and the PC12 cell-damaged model in vitro. The results indicated that the injection of neural stem cell-conditioned medium (NSC-CM) into the striatum and substantia nigra could improve the motor and non-motor deficits of PD rats and rescue the loss of dopaminergic neurons. In addition, NSC-CM alleviated 6-OHDA-induced apoptosis of PC12 cells, reduced the level of oxidative stress, and improved mitochondrial dysfunction in vitro. Parkinson disease protein 7 (Park7) was found in NSC-CM by Liquid chromatography-tandem mass spectrometry (LC-MS/MS), and it may be related to the protective effect of NSC-CM on 6-OHDA-injured neurons through Sirt1 pathway. In conclusion, NSC secretome might provide new ideas for the treatment of PD.
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Células-Tronco Neurais , Doenças Neurodegenerativas , Doença de Parkinson , Secretoma , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Mitocôndrias/metabolismo , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/metabolismo , Oxidopamina/farmacologia , Doença de Parkinson/metabolismo , Proteína Desglicase DJ-1/metabolismo , Ratos , Secretoma/metabolismo , Substância Negra/metabolismo , Espectrometria de Massas em TandemRESUMO
BACKGROUND: With the prevalence of online consultation, many patient-doctor dialogues have accumulated, which, in an authentic language environment, are of significant value to the research and development of intelligent question answering and automated triage in recent natural language processing studies. OBJECTIVE: The purpose of this study was to design a front-end task module for the network inquiry of intelligent medical services. Through the study of automatic labeling of real doctor-patient dialogue text on the internet, a method of identifying the negative and positive entities of dialogues with higher accuracy has been explored. METHODS: The data set used for this study was from the Spring Rain Doctor internet online consultation, which was downloaded from the official data set of Alibaba Tianchi Lab. We proposed a composite abutting joint model, which was able to automatically classify the types of clinical finding entities into the following 4 attributes: positive, negative, other, and empty. We adapted a downstream architecture in Chinese Robustly Optimized Bidirectional Encoder Representations from Transformers Pretraining Approach (RoBERTa) with whole word masking (WWM) extended (RoBERTa-WWM-ext) combining a text convolutional neural network (CNN). We used RoBERTa-WWM-ext to express sentence semantics as a text vector and then extracted the local features of the sentence through the CNN, which was our new fusion model. To verify its knowledge learning ability, we chose Enhanced Representation through Knowledge Integration (ERNIE), original Bidirectional Encoder Representations from Transformers (BERT), and Chinese BERT with WWM to perform the same task, and then compared the results. Precision, recall, and macro-F1 were used to evaluate the performance of the methods. RESULTS: We found that the ERNIE model, which was trained with a large Chinese corpus, had a total score (macro-F1) of 65.78290014, while BERT and BERT-WWM had scores of 53.18247117 and 69.2795315, respectively. Our composite abutting joint model (RoBERTa-WWM-ext + CNN) had a macro-F1 value of 70.55936311, showing that our model outperformed the other models in the task. CONCLUSIONS: The accuracy of the original model can be greatly improved by giving priority to WWM and replacing the word-based mask with unit to classify and label medical entities. Better results can be obtained by effectively optimizing the downstream tasks of the model and the integration of multiple models later on. The study findings contribute to the translation of online consultation information into machine-readable information.
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The substantia gelatinosa (SG, lamina II of spinal cord gray matter) is pivotal for modulating nociceptive information from the peripheral to the central nervous system. γ-Aminobutyric acid type B receptors (GABABRs), the metabotropic GABA receptor subtype, are widely expressed in pre- and postsynaptic structures of the SG. Activation of GABABRs by exogenous agonists induces both pre- and postsynaptic inhibition. However, the actions of endogenous GABA via presynaptic GABABRs on glutamatergic synapses, and the postsynaptic GABABRs interaction with glutamate, remain elusive. In the present study, first, using in vitro whole-cell recordings and taking minimal stimulation strategies, we found that in rat spinal cord glutamatergic synapses, blockade of presynaptic GABABRs switched "silent" synapses into active ones and increased the probability of glutamate release onto SG neurons; increasing ambient GABA concentration mimicked GABABRs activation on glutamatergic terminals. Next, using holographic photostimulation to uncage glutamate on postsynaptic SG neurons, we found that postsynaptic GABABRs modified glutamate-induced postsynaptic potentials. Taken together, our data identify that endogenous GABA heterosynaptically constrains glutamate release via persistently activating presynaptic GABABRs; and postsynaptically, GABABRs modulate glutamate responses. The results give new clues for endogenous GABA in modulating the nociception circuit of the spinal dorsal horn and shed fresh light on the postsynaptic interaction of glutamate and GABA.