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During development, motor neurons originating in the brainstem and spinal cord form elaborate synapses with skeletal muscle fibres1. These neurons release acetylcholine (ACh), which binds to nicotinic ACh receptors (AChRs) on the muscle, initiating contraction. Two types of AChR are present in developing muscle cells, and their differential expression serves as a hallmark of neuromuscular synapse maturation2-4. The structural principles underlying the switch from fetal to adult muscle receptors are unknown. Here, we present high-resolution structures of both fetal and adult muscle nicotinic AChRs, isolated from bovine skeletal muscle in developmental transition. These structures, obtained in the absence and presence of ACh, provide a structural context for understanding how fetal versus adult receptor isoforms are tuned for synapse development versus the all-or-none signalling required for high-fidelity skeletal muscle contraction. We find that ACh affinity differences are driven by binding site access, channel conductance is tuned by widespread surface electrostatics and open duration changes result from intrasubunit interactions and structural flexibility. The structures further reveal pathogenic mechanisms underlying congenital myasthenic syndromes.
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Acetilcolina , Modelos Moleculares , Músculo Esquelético , Receptores Nicotínicos , Animais , Acetilcolina/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/citologia , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/química , Bovinos , Sítios de Ligação , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/química , Feto/metabolismo , Eletricidade Estática , Síndromes Miastênicas Congênitas/metabolismo , Microscopia Crioeletrônica , Humanos , Receptores Colinérgicos/metabolismo , Receptores Colinérgicos/química , Desenvolvimento Muscular , Contração MuscularRESUMO
Female willows exhibit greater drought tolerance and benefit more from exogenous acetic acid (AA)-improved drought tolerance than males. However, the potential mechanisms driving these sex-specific responses remain unclear. To comprehensively investigate the sexually dimorphic responsive mechanisms of willows to drought and exogenous AA, here, we performed physiological, proteomic, Lys-acetylproteomic, and transgenic analyses in female and male Salix myrtillacea exposed to drought and AA-applicated drought treatments, focusing on protein abundance and lysine acetylation (LysAc) changes. Drought-tolerant females suffered less drought-induced photosynthetic and oxidative damage, did not activate AA and acetyl-CoA biosynthesis, TCA cycle, fatty acid metabolism, and jasmonic acid signaling as strongly as drought-sensitive males. Exogenous AA caused overaccumulation of endogenous AA and inhibition of acetyl-CoA biosynthesis and utilization in males. However, exogenous AA greatly enhanced acetyl-CoA biosynthesis and utilization and further enhanced drought performance of females, possibly determining that AA improved drought tolerance more in females than in males. Interestingly, overexpression of acetyl-CoA synthetase (ACS) could reprogram fatty acids, increase LysAc levels, and improve drought tolerance, highlighting the involvement of ACS-derived acetyl-CoA in drought responses. In addition, drought and exogenous AA induced sexually dimorphic LysAc associated with histones, transcription factors, and metabolic enzymes in willows. Especially, exogenous AA may greatly improve the photosynthetic capacity of S. myrtillacea males by decreasing LysAc levels and increasing the abundances of photosynthetic proteins. While hyperacetylation in glycolysis, TCA cycle, and fatty acid biosynthesis potentially possibly serve as negative feedback to acclimate acetyl-CoA biosynthesis and utilization in drought-stressed males and AA-applicated females. Thus, acetyl-CoA biosynthesis and utilization determine the sexually dimorphic responses of S. myrtillacea to drought and exogenous AA.
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Ácido Acético , Acetilcoenzima A , Secas , Acetilcoenzima A/metabolismo , Ácido Acético/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Acetilação , Estresse FisiológicoRESUMO
Lactylation was initially discovered on human histones. Given its nascence, its occurrence on nonhistone proteins and downstream functional consequences remain elusive. Here we report a cyclic immonium ion of lactyllysine formed during tandem mass spectrometry that enables confident protein lactylation assignment. We validated the sensitivity and specificity of this ion for lactylation through affinity-enriched lactylproteome analysis and large-scale informatic assessment of nonlactylated spectral libraries. With this diagnostic ion-based strategy, we confidently determined new lactylation, unveiling a wide landscape beyond histones from not only the enriched lactylproteome but also existing unenriched human proteome resources. Specifically, by mining the public human Meltome Atlas, we found that lactylation is common on glycolytic enzymes and conserved on ALDOA. We also discovered prevalent lactylation on DHRS7 in the draft of the human tissue proteome. We partially demonstrated the functional importance of lactylation: site-specific engineering of lactylation into ALDOA caused enzyme inhibition, suggesting a lactylation-dependent feedback loop in glycolysis.
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Histonas , Proteoma , Glicólise , Histonas/metabolismo , Humanos , Oxirredutases/metabolismo , Proteoma/metabolismo , Espectrometria de Massas em Tandem/métodosRESUMO
Drought is one of the major threats to forest productivity. Oxidation stress is common in drought-stressed plants, and plants need to maintain normal life activities through complex reactive oxygen scavenging mechanisms. However, the molecular links between epigenetics, oxidation stress, and drought in poplar (Populus) remain poorly understood. Here, we found that Populus plants overexpressing PtrMYB94, which encodes a R2R3 MYB transcription factor that regulates the ABA signaling pathway, displayed increased tolerance to extreme drought stress via up-regulation of embryogenic cell phosphoprotein 44 (PtrECPP44) expression. Further investigation revealed that PtrMYB94 could recruit the histone deacetylases PtrHDA907/908 to the promoter of PtrECPP44 and decrease acetylation at lysine residues 9, 14 and 27 of histone H3, leading to relatively low transcriptional expression levels under normal conditions. Drought induced the expression of PtrMYB94 while preventing interaction of PtrMYB94 with PtrHDA907/908, which relaxed the chromatin structure and facilitated the binding of RNA polymerase II to the PtrECPP44 promoter. The upregulation of PtrECPP44 helped poplar alleviate oxidative damage and maintain normal cell activities. This study establishes a PtrMYB94-PtrECPP44 transcriptional regulatory module modified by PtrHDA907/908 in modulating drought-induced oxidative stress recovery. Therefore, our study reveals a oxidative regulatory mechanism in response to drought stress and provides insights into molecular breeding for stress resistance in poplar.
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How to achieve a high-precision suicide attempt classifier based on the three-dimensional psychological pain model is a valuable issue in suicide research. The aim of the present study is to explore the importance of pain avoidance and its related neural features in suicide attempt classification models among patients with major depressive disorder. By recursive feature elimination with cross-validation and support-vector-machine algorithms, scores from the measurements and the task-based EEG signals were chosen to achieve a suicide attempt classification model. In the multimodal suicide attempt classifier with an accuracy of 83.91% and an area under the curve of 0.90, pain avoidance ranked as the top one in the optimal feature set. Theta (reward positive feedback minus neutral positive feedback) was the shared neural representation ranking as the top one of event-related potential features in pain avoidance and suicide attempt classifiers. In conclusion, the suicide attempt classifier based on pain avoidance and its related affective processing neural features has excellent accuracy among patients with major depressive disorder. Pain avoidance is a stable and strong indicator for identifying suicide risks in both traditional analyses and machine-learning approaches. A novel methodology is needed to clarify the relationship between cognitive and affective processing evoked by punishment stimuli and pain avoidance.
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Transtorno Depressivo Maior , Humanos , Tentativa de Suicídio , Dor , Potenciais Evocados , Aprendizado de MáquinaRESUMO
Fine audiovocal control is a hallmark of human speech production and depends on precisely coordinated muscle activity guided by sensory feedback. Little is known about shared audiovocal mechanisms between humans and other mammals. We hypothesized that real-time audiovocal control in bat echolocation uses the same computational principles as human speech. To test the prediction of this hypothesis, we applied state feedback control (SFC) theory to the analysis of call frequency adjustments in the echolocating bat, Hipposideros armiger. This model organism exhibits well-developed audiovocal control to sense its surroundings via echolocation. Our experimental paradigm was analogous to one implemented in human subjects. We measured the bats' vocal responses to spectrally altered echolocation calls. Individual bats exhibited highly distinct patterns of vocal compensation to these altered calls. Our findings mirror typical observations of speech control in humans listening to spectrally altered speech. Using mathematical modeling, we determined that the same computational principles of SFC apply to bat echolocation and human speech, confirming the prediction of our hypothesis.
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Quirópteros , Ecolocação , Retroalimentação Sensorial , Vocalização Animal , Animais , Percepção Auditiva/fisiologia , Quirópteros/fisiologia , Ecolocação/fisiologia , Retroalimentação Sensorial/fisiologia , Feminino , Humanos , Modelos Biológicos , Fala/fisiologia , Vocalização Animal/fisiologiaRESUMO
Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy, yet approximately one-third of patients are refractory to current anticonvulsive drugs, which target neurons and synapses. Astrocytic and microglial dysfunction is commonly found in epileptic foci and has been shown to contribute to neuroinflammation and hyperexcitability in chronic epilepsy. Accumulating evidence points to a key role for glial hemichannels in epilepsy, but inhibiting both connexin (Cx) gap junctions and hemichannels can lead to undesirable side effects because the former coordinate physiological functions of cell assemblies. It would be a great benefit to use an orally available small molecule to block hemichannels to alleviate epileptic symptoms. Here, we explored the effect of D4, a newly developed compound that inhibits the Cx hemichannels but not Cx gap junctions using the pilocarpine mouse model of TLE. In vitro application of D4 caused a near-complete reduction in the pilocarpine-induced cell membrane permeability associated with increased Cx hemichannel activity. Moreover, preadministration of D4 in vivo effectively reduced neuroinflammation and altered synaptic inhibition, which then enhanced the animal survival rate. Posttreatment with a single dose of D4 in vivo has prolonged effects on suppressing the activation of astrocytes and microglia and rescued the changes in neuroinflammatory and synaptic gene expression induced by pilocarpine. Collectively, these results indicate that targeting Cx hemichannels by D4 is an effective and promising strategy for treating epilepsy in which neuroinflammation plays a critical role.
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Epilepsia do Lobo Temporal , Epilepsia , Animais , Camundongos , Conexinas/metabolismo , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/metabolismo , Pilocarpina , Doenças NeuroinflamatóriasRESUMO
BACKGROUND: Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are involved in plant growth and development as well as in response to environmental changes, by dynamically regulating gene acetylation levels. Although there have been numerous reports on the identification and function of HDAC and HAT in herbaceous plants, there are fewer report related genes in woody plants under drought stress. RESULTS: In this study, we performed a genome-wide analysis of the HDAC and HAT families in Populus trichocarpa, including phylogenetic analysis, gene structure, conserved domains, and expression analysis. A total of 16 PtrHDACs and 12 PtrHATs were identified in P. trichocarpa genome. Analysis of cis-elements in the promoters of PtrHDACs and PtrHATs revealed that both gene families could respond to a variety of environmental signals, including hormones and drought. Furthermore, real time quantitative PCR indicated that PtrHDA906 and PtrHAG3 were significantly responsive to drought. PtrHDA906, PtrHAC1, PtrHAC3, PtrHAG2, PtrHAG6 and PtrHAF1 consistently responded to abscisic acid, methyl jasmonate and salicylic acid under drought conditions. CONCLUSIONS: Our study demonstrates that PtrHDACs and PtrHATs may respond to drought through hormone signaling pathways, which helps to reveal the hub of acetylation modification in hormone regulation of abiotic stress.
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Secas , Regulação da Expressão Gênica de Plantas , Histona Acetiltransferases , Histona Desacetilases , Filogenia , Populus , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Populus/genética , Populus/enzimologia , Estresse Fisiológico/genética , Perfilação da Expressão Gênica , Regiões Promotoras Genéticas , Genoma de Planta , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Dynamically populating triplet excitons under external stimuli is desired to develop smart optoelectronic materials, but it remains a formidable challenge. Herein, we report a resonance-induced excited state regulation strategy to dynamically modulate the triplet exciton population by introducing a self-adaptive N-CâO structure to phosphors. The developed phosphors activated under high-power ultraviolet irradiation exhibited enhanced photoactivated organic ultralong room temperature phosphorescence (PA-OURTP) with lifetimes of up to â¼500 ms. The enhanced PA-OURTP was ascribed to activated N-CâO resonance variation-induced intersystem crossing to generate excess triplet excitons. The excellent PA-OURTP performance and ultralong deactivation time under ambient conditions of the developed materials could function as a reusable recorded medium for time-sensitive information encryption through optical printing. This study provides an effective approach to dynamically regulating triplet excitons and offers valuable guidance to develop high-performance PA-OURTP materials for security printing applications.
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Lithium-sulfur (Li-S) battery is identified as an ideal candidate for next-generation energy storage systems in consideration of its high theoretical energy density and abundant sulfur resources. However, the shuttling behavior of soluble polysulfides (LiPSs) and their sluggish reaction kinetics severely limit the practical application of the current Li-S battery. In this work, a series of In2O3 nanocubes with different oxygen vacancy concentrations are designed and prepared via a facile self-template method. The introduced oxygen vacancy on In2O3 can effectively rearrange the charge distribution and enhance sulfiphilic property. Moreover, the In2O3 with high oxygen vacancy concentration (H-In2O3) can slightly slow down the solid-liquid conversion process and significantly accelerate the liquid-solid conversion process, thus reducing the accumulation of LiPSs in electrolyte and inhibiting the shuttle effect. Contributed by the unique selective catalytic capability, the prepared H-In2O3 exhibits excellent electrochemical performance when used as sulfur host. For instance, a high reversible capacity of 609 mAh g-1 is obtained with only 0.044% capacity decay per cycle over 1000 cycles at 1.0 C. This work presents a typical example for designing advanced sulfur hosts, which is crucial for the commercialization of Li-S battery.
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The tubular architecture with multiple components can bring synergistic effects to improve the enzyme-like activity of molybdenum-based nanomaterials. Here, a facile polypyrrole (PPy)-protected hydrothermal sulfidation process was implemented to engineer MoS2/Ag2S heterointerfaces encapsulated in one-dimensional (1D) PPy nanotubes with MoO3@Ag nanorods as the self-sacrificing precursor. Notably, the sulfidation treatment led to the generation of MoS2 nanosheets (NSs) and Ag2S nanoparticles (NPs) and the creation of a tubular structure with a "kill three birds with one stone" role. The Ag2S/MoS2@PPy nanotubes showed the synergistic combined effects of Ag2S NPs, MoS2 NSs, and the 1D tube-like nanostructure. Based on the synergistic effects from these multiple components and the tubular structure, Ag2S/MoS2@PPy nanocomposites were used as a colorimetric sensing platform for detecting H2O2. Moreover, the reduction of 4-nitrophenol (4-NP) revealed excellent catalytic activity in the presence of NaBH4 and Ag2S/MoS2@PPy nanocomposites. This work highlights the effects of MoS2/Ag2S heterointerfaces and the hierarchical tubular structure in catalysis, thereby providing a new avenue for reducing 4-NP and the enzyme-like catalytic field.
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Human fertility is impacted by changes in lifestyle and environmental deterioration. To increase human fertility, assisted reproductive technology (ART) has been extensively used around the globe. As early as 2009, the Endocrine Society released its first scientific statement on the potential adverse effects of environmental endocrine-disrupting chemicals (EDCs) on human health and disease development. Chemicals known as phthalates, frequently employed as plasticizers and additives, are common EDCs. Numerous studies have shown that phthalate metabolites in vivo exert estrogen-like or anti-androgenic effects in both humans and animals. They are associated with the progression of a range of diseases, most notably interference with the reproductive process, damage to the placenta, and the initiation of chronic diseases in adulthood. Phthalates are ingested by infertile couples in a variety of ways, including household products, diet, medical treatment, etc. Exposure to phthalates may exacerbate their infertility or poor ART outcomes, however, the available data on phthalate exposure and ART pregnancy outcomes are sparse and contradictory. Therefore, this review conducted a systematic evaluation of 16 papers related to phthalate exposure and ART pregnancy outcomes, to provide more aggregated results, and deepen our understanding of reproductive outcomes in infertile populations with phthalate exposure.
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Fertilização in vitro , Infertilidade , Ácidos Ftálicos , Ácidos Ftálicos/toxicidade , Ácidos Ftálicos/urina , Humanos , Feminino , Gravidez , Infertilidade/induzido quimicamente , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/efeitos adversos , Poluentes Ambientais/toxicidade , Exposição Ambiental/efeitos adversos , Resultado da Gravidez/epidemiologia , MasculinoRESUMO
PURPOSE: To compare the pathological characteristics of the vitreomacular interface of the idiopathic epiretinal membrane with and without disorganization of retinal inner layers (DRIL) and to correlate with clinical data. METHODS: In this clinicopathologic study, the samples of epiretinal membrane and internal limiting membrane were extracted from DRIL(+) (19 eyes) and DRIL(-) (22 eyes) idiopathic epiretinal membrane eyes. Ultrathin series sectioning for transmission electron microscopy was observed and correlated with surgery status and prognosis. RESULTS: All idiopathic epiretinal membrane eyes presented fibrocellular membranes accompanied by vitreous collagen, glial cells, and myofibroblasts, regardless of association with DRIL. A robust signal indicative of Collagen Type VI was observed in eyes DRIL(-), whereas Collagen Type I was discovered in DRIL eyes. Cell debris and microvascular basement membrane were seen on the retinal side of DRIL eyes and a larger cell count on the vitreous side. These have more intraoperative complications and less surgery benefit. CONCLUSION: Although internal limiting membrane peeling seems important, the histopathologic findings underscore the potential for retinal injury in DRIL(+) idiopathic epiretinal membrane eyes. This suggests that further research is needed to investigate individual preoperative assessment and to modify surgical procedures.
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Membrana Epirretiniana , Vitrectomia , Corpo Vítreo , Humanos , Membrana Epirretiniana/cirurgia , Membrana Epirretiniana/metabolismo , Membrana Epirretiniana/diagnóstico , Membrana Epirretiniana/patologia , Idoso , Masculino , Feminino , Corpo Vítreo/patologia , Corpo Vítreo/metabolismo , Pessoa de Meia-Idade , Microscopia Eletrônica de Transmissão , Membrana Basal/patologia , Membrana Basal/cirurgia , Membrana Basal/metabolismo , Idoso de 80 Anos ou mais , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Macula Lutea/patologia , Retina/patologiaRESUMO
BACKGROUND: Severe neonatal hyperbilirubinemia could lead to kernicterus and neonatal death. This study aimed to analyze the association between single nucleotide polymorphisms in genes involved in bilirubin metabolism and the incidence of severe hyperbilirubinemia. METHODS: A total of 144 neonates with severe hyperbilirubinemia and 50 neonates without or mild hyperbilirubinemia were enrolled in 3 institutions between 2019 and 2020. Twelve polymorphisms of 5 genes (UGT1A1, SLCO1B1, SLCO1B3, BLVRA, and HMOX1) were analyzed by PCR amplification of genomic DNA. Genotyping was performed using an improved multiplex ligation detection reaction technique based on ligase detection reaction. RESULTS: The frequencies of the A allele in UGT1A1-rs4148323 and the C allele in SLCO1B3-rs2417940 in the severe hyperbilirubinemia group (30.2% and 90.6%, respectively) were significantly higher than those in the controls (30.2% vs.13.0%, 90.6% vs. 78.0%, respectively, both p < 0.05). Haplotype analysis showed the ACG haplotype of UGT1A1 were associated with an increased hyperbilirubinemia risk (OR 3.122, p = 0.001), whereas the GCG haplotype was related to a reduced risk (OR 0.523, p = 0.018). CONCLUSION: The frequencies of the A allele in rs4148323 and the C allele in rs2417940 are highly associated with the incidence of severe hyperbilirubinemia in Chinese Han neonates. TRIAL REGISTRATION: Trial registration number:ChiCTR1800020424; Date of registration:2018-12-29.
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Hiperbilirrubinemia Neonatal , Polimorfismo de Nucleotídeo Único , Recém-Nascido , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Alelos , Hiperbilirrubinemia Neonatal/genética , Glucuronosiltransferase/genética , China/epidemiologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismoRESUMO
Maritime terrorist accidents have a significant low-frequency-high-consequence feature and, thus, require new research to address the associated inherent uncertainty and the scarce literature in the field. This article aims to develop a novel method for maritime security risk analysis. It employs real accident data from maritime terrorist attacks over the past two decades to train a data-driven Bayesian network (DDBN) model. The findings help pinpoint key contributing factors, scrutinize their interdependencies, ascertain the probability of different terrorist scenarios, and describe their impact on different manifestations of maritime terrorism. The established DDBN model undergoes a thorough verification and validation process employing various techniques, such as sensitivity, metrics, and comparative analyses. Additionally, it is tested against recent real-world cases to demonstrate its effectiveness in both retrospective and prospective risk propagation, encompassing both diagnostic and predictive capabilities. These findings provide valuable insights for the various stakeholders, including companies and government bodies, fostering comprehension of maritime terrorism and potentially fortifying preventive measures and emergency management.
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PURPOSE: This retrospective cohort study aims to investigate whether high-normal fasting blood glucose (FBG) affects assisted reproductive technology (ART) outcomes undergoing single blastocyst frozen-thawed embryo transfer (FET) cycles in women with normal body mass index (BMI). METHODS: 944 women with normal BMI and FBG levels undergoing single blastocyst FET cycles were enrolled. Based on the median of FBG (4.97 mmol/L, 1 mmol/L = 18 mg/dL), the subjects were categorized into the low-normal group (3.90 ≤ FBG ≤ 4.97 mmol/L, n = 472) and the high-normal group (4.97 < FBG < 6.10 mmol/L, n = 472). Multivariable logistic regression and receiver operating characteristic (ROC) were used to analyze the relationship between high-normal FBG and ART outcomes. PRIMARY OUTCOME: live birth rate (LBR). RESULTS: LBR was significantly lower in the high-normal group than in the low-normal group (36.8% vs. 45.1%, p = 0.010), and the miscarriage rate was considerably higher than that in the low-normal group (23.9% vs. 16.5%, p = 0.041). High-normal FBG of female was an independent predictor of live birth (adjusted OR:0.747, 95% CI: 0.541-0.963, p = 0.027) and miscarriage (adjusted OR:1.610, 95% CI: 1.018-2.547, p = 0.042). ROC analyses showed that the cut-off values of FBG (endpoints: live birth and miscarriage) were 5.07 mmol/L, and 5.01 mmol/L, respectively. CONCLUSIONS: In women with normal BMI, high-normal FBG is an independent risk factor for lower LBR and higher miscarriage rate in single blastocyst FET cycles. Attention to preconception FBG monitoring in this particular population may allow early intervention to improve ART outcomes.
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In the present study, neuroprotective effect of sevoflurane in combination with ketamine was investigated on TNF-α induced necroptosis of neurons and cognitive impairment in the rat model. The results demonstrated that exposure to TNF-α/z-VAD led to a significant decrease in viability of HT-22 neuronal cells. However, incubation of HT-22 cells with ketamine plus sevoflurane inhibited decrease in viability induced by TNF-α/z-VAD exposure. The increase in production of ROS by TNF-α/z-VAD exposure in HT-22 cells was effectively suppressed on pre-treatment with ketamine plus sevoflurane. Moreover, suppression of TNF-α/z-VAD induced ROS production in HT-22 cells by ketamine plus sevoflurane pretreatment was higher in comparison to ketamine or sevoflurane treatment alone. Treatment of HT-22 cells with ketamine plus sevoflurane suppressed TNF-α/z-VAD induced increase in RIP1 and p-MLKL protein expression. Ketamine plus sevoflurane treatment effectively reversed decrease in movement speed as well as total distance traveled in TNF-α injected rats. The number of neurons in rat hippocampus injected with TNF-α showed a significant decrease more specifically in carbonic anhydrase-3 region. However, no significant change in the density of neurons was observed in the hippocampus of rats pretreated with ketamine plus sevoflurane by TNF-α injection. The increase in expression of p-MLKL and p-RIP3 by TNF-α injection was effectively reversed in rats on treatment with ketamine plus sevoflurane. In silico studies revealed that ketamine interacts with p-MLKL protein in different confirmations with the binding affinities ranging from -9.7 to -8.4 kcal/mol. It was found that ketamine binds to p-MLKL protein by interacting with alanine (ALA A:295), proline (PRO A:306), glutamine (GLN A: 307) and isoleucine (ILE A:293) amino acid residues. In summary, ketamine plus sevoflurane combination alleviates TNF-α/z-VAD induced decrease in viability of HT-22 cells in vitro and rat hippocampus neurons in vivo. Moreover, ketamine plus sevoflurane combination prevented TNF-α injection induced cognitive impairment in rats. Therefore, sevoflurane plus ketamine combination can be developed as a potential therapeutic regimen for treatment of isoflurone induced cognitive impairment.
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Disfunção Cognitiva , Ketamina , Fármacos Neuroprotetores , Ratos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Sevoflurano , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Tea-garden pest control is crucial to ensure tea quality. In this context, the time-series prediction of insect pests in tea gardens is very important. Deep-learning-based time-series prediction techniques are advancing rapidly but research into their use in tea-garden pest prediction is limited. The current study investigates the time-series prediction of whitefly populations in the Tea Expo Garden, Jurong City, Jiangsu Province, China, employing three deep-learning algorithms, namely Informer, the Long Short-Term Memory (LSTM) network, and LSTM-Attention. RESULTS: The comparative analysis of the three deep-learning algorithms revealed optimal results for LSTM-Attention, with an average root mean square error (RMSE) of 2.84 and average mean absolute error (MAE) of 2.52 for 7 days' prediction length, respectively. For a prediction length of 3 days, LSTM achieved the best performance, with an average RMSE of 2.60 and an average MAE of 2.24. CONCLUSION: These findings suggest that different prediction lengths influence model performance in tea garden pest time series prediction. Deep learning could be applied satisfactorily to predict time series of insect pests in tea gardens based on LSTM-Attention. Thus, this study provides a theoretical basis for the research on the time series of pest and disease infestations in tea plants. © 2024 Society of Chemical Industry.
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Camellia sinensis , Jardins , Hemípteros , Animais , Camellia sinensis/química , Camellia sinensis/parasitologia , China , Aprendizado Profundo , Doenças das Plantas/parasitologia , Insetos , JardinagemRESUMO
This study aimed to demonstrate the potential of using porous microneedles (PMNs) as a promising tool for the noninvasive quantification of topically applied pharmaceutical products. We fabricated a porous microneedle (PMN) from a blend of cellulose acetate and dimethyl sulfoxide by casting and phase separation; it was characterized using scanning electron microscopy, Raman spectroscopy, differential scanning calorimetry, and a Texture Analyzer. An ex vivo study was conducted as a proof-of-concept study to assess whether this PMN could be used to quantify drug absorption through the skin after the topical administration of two nonequivalent products of sodium ibuprofen (gel and dissolving microneedles). Three cellulose acetate formulations (PMN1: 37.5%, PMN-2: 44.4%, and PMN-3: 50%) were used to prepare PMN patches; subsequently, these were evaluated for their morphological and insertion properties. Only PMN-2 microneedle patches were chosen to continue with the ex vivo study. The ex vivo study results demonstrated that PMNs could absorb and release sodium ibuprofen (SDIB) and differentiate between two different SDIB topical products. This can be attributed to the porous and interconnected architecture of these microneedles. This developmental study highlights the potential success of such a tool for the quantification of dermal drug concentration and supports moving to in vivo tests.
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Ibuprofeno , Agulhas , Preparações Farmacêuticas , Porosidade , Estudo de Prova de Conceito , Pele , Sistemas de Liberação de Medicamentos/métodos , Administração Cutânea , SódioRESUMO
Enantiomerically pure organoperoxides serve as valuable precursors in organic transformations. Herein, we present the first examples of unspecific peroxygenase catalyzed kinetic resolution of racemic organoperoxides through asymmetric reduction. Through meticulous investigation of the reaction conditions, it is shown that the unspecific peroxygenase from Agrocybe aegerita (AaeUPO) exhibits robust catalytic activity in the kinetic resolution reactions of the model substrate with turnover numbers up to 60000 and turnover frequency of 5.6â s-1. Various aralkyl organoperoxides were successfully resolved by AaeUPO, achieving excellent enantioselectivities (e.g., up to 99 % ee for the (S)-organoperoxide products). Additionally, we screened commercial peroxygenase variants to obtain the organoperoxides with complementary chirality, with one mutant yielding the (R)-products. While unspecific peroxygenases have been extensively demonstrated as a powerful oxidative catalysts, this study highlights their usefulness in catalyzing the reduction of organoperoxides and providing versatile chiral synthons.