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Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.
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Ansiedad , Vías Nerviosas , Corteza Prefrontal , Estrés Psicológico , Animales , Ansiedad/psicología , Ansiedad/fisiopatología , Masculino , Estrés Psicológico/psicología , Estrés Psicológico/fisiopatología , Corteza Prefrontal/fisiopatología , Vías Nerviosas/fisiopatología , Vías Nerviosas/fisiología , Ratones , Miedo/fisiología , Miedo/psicología , Ratones Endogámicos C57BL , Área Tegmental Ventral/fisiopatología , Tálamo/fisiopatología , Núcleo Talámico Mediodorsal/fisiología , Núcleo Talámico Mediodorsal/fisiopatologíaRESUMEN
Revealing the genetic basis for stress-resistant traits in extremophile plants will yield important information for crop improvement. Zygophyllum xanthoxylum, an extant species of the ancient Mediterranean, is a succulent xerophyte that can maintain a favorable water status under desert habitats; however, the genetic basis of this adaptive trait is poorly understood. Furthermore, the phylogenetic position of Zygophyllales, to which Z. xanthoxylum belongs, remains controversial. In this study, we sequenced and assembled the chromosome-level genome of Z. xanthoxylum. Phylogenetic analysis showed that Zygophyllales and Myrtales form a separated taxon as a sister to the clade comprising fabids and malvids, clarifying the phylogenetic position of Zygophyllales at whole-genome scale. Analysis of genomic and transcriptomic data revealed multiple critical mechanisms underlying the efficient osmotic adjustment using Na+ and K+ as "cheap" osmolytes that Z. xanthoxylum has evolved through the expansion and synchronized expression of genes encoding key transporters/channels and their regulators involved in Na+/K+ uptake, transport, and compartmentation. It is worth noting that ZxCNGC1;1 (cyclic nucleotide-gated channels) and ZxCNGC1;2 constituted a previously undiscovered energy-saving pathway for Na+ uptake. Meanwhile, the core genes involved in biosynthesis of cuticular wax also featured an expansion and upregulated expression, contributing to the water retention capacity of Z. xanthoxylum under desert environments. Overall, these findings boost the understanding of evolutionary relationships of eudicots, illustrate the unique water retention mechanism in the succulent xerophyte that is distinct from glycophyte, and thus provide valuable genetic resources for the improvement of stress tolerance in crops and insights into the remediation of sodic lands.
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Filogenia , Agua , Zygophyllum , Agua/metabolismo , Zygophyllum/genética , Zygophyllum/metabolismo , Genoma de Planta , Regulación de la Expresión Génica de las Plantas , Genómica/métodosRESUMEN
The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.
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Astrocitos , Depresión , Ratones Transgénicos , Corteza Prefrontal , Animales , Astrocitos/metabolismo , Corteza Prefrontal/metabolismo , Masculino , Depresión/genética , Depresión/patología , Femenino , Ratones Endogámicos C57BL , Ratones , Modelos Animales de Enfermedad , Restricción Física , Ácido 2-Aminoadípico , Estrés Psicológico/patología , Estrés Psicológico/metabolismoRESUMEN
Nuclear factor (NF)-κB signaling is not only important for the immune and inflammatory responses but also for the normal development of epithelial cells, such as those in the skin and tooth. Here, we generated epithelial cell-specific p65-deficient (p65Δepi-/-) mice to analyze the roles of NF-κB signaling in epithelial cell developent. Notably, p65Δepi-/- mice exhibited no abnormalities in their appearance compared to the control (p65flox/flox) littermates. Furthermore, no major changes were observed in the skin, hair growth, and shape and color of the incisors and molars. However, 65 % of p65Δepi-/- mice exhibited corneal thickening after 8 weeks of age, and 30 % of p65Δepi-/- mice exhibited hair growth from the mandibular incisors around 24 weeks of age. No hair growth was observed at 36 and 42 weeks of age. However, micro-computed tomography images revealed a large cavity below the mandibular incisors extending to the root of the incisor. Histological analysis revealed that the cavity was occupied by a connective tissue containing hair-like structures with many dark brown granules that disappeared after melanin bleaching, confirming the presence of hair. Although inflammatory cells were also observed near the eruption site of the incisor teeth of p65Δepi-/- mice, no major disturbance was observed in the arrangement of enamel epithelial cells. Overall, these results highlight the role of p65 in the maintenance of epithelial cell homeostasis during aging.
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Senescencia Celular , Células Epiteliales , Factor de Transcripción ReIA , Animales , Ratones , Envejecimiento/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/citología , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIA/genéticaRESUMEN
Tea is an important cash crop that is often consumed by chewing pests, resulting in reduced yields and economic losses. It is important to establish a method to quickly identify the degree of damage to tea plants caused by leaf-eating insects and screen green control compounds. This study was performed through the combination of deep learning and targeted metabolomics, in vitro feeding experiment, enzymic analysis and transient genetic transformation. A small target damage detection model based on YOLOv5 with Transformer Prediction Head (TPH-YOLOv5) algorithm for the tea canopy level was established. Orthogonal partial least squares (OPLS) was used to analyze the correlation between the degree of damage and the phenolic metabolites. A potential defensive compound, (-)-epicatechin-3-O-caffeoate (EC-CA), was screened. In vitro feeding experiments showed that compared with EC and epicatechin gallate, Ectropis grisescens exhibited more significant antifeeding against EC-CA. In vitro enzymatic experiments showed that the hydroxycinnamoyl transferase (CsHCTs) recombinant protein has substrate promiscuity and can catalyze the synthesis of EC-CA. Transient overexpression of CsHCTs in tea leaves effectively reduced the degree of damage to tea leaves. This study provides important reference values and application prospects for the effective monitoring of pests in tea gardens and screening of green chemical control substances.
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Camellia sinensis , Aprendizaje Profundo , Lepidópteros , Animales , Camellia sinensis/metabolismo , Insectos , Té/química , Té/metabolismoRESUMEN
BACKGROUND: Multiple genetic and epigenetic regulatory mechanisms are crucial in the development and tumorigenesis process. Transcriptional regulation often involves intricate relationships and networks with post-transcriptional regulatory molecules, impacting the spatial and temporal expression of genes. However, the synergistic relationship between transcription factors and N6-methyladenosine (m6A) modification in regulating gene expression, as well as their influence on the mechanisms underlying the occurrence and progression of non-small cell lung cancer (NSCLC), requires further investigation. The present study aimed to investigate the synergistic relationship between transcription factors and m6A modification on NSCLC. METHODS: The transcription factor NFIC and its potential genes was screened by analyzing publicly available datasets (ATAC-seq, DNase-seq, and RNA-seq). The association of NFIC and its potential target genes were validated through ChIP-qPCR and dual-luciferase reporter assays. Additionally, the roles of NFIC and its potential genes in NSCLC were detected in vitro and in vivo through silencing and overexpression assays. RESULTS: Based on multi-omics data, the transcription factor NFIC was identified as a potential tumor suppressor of NSCLC. NFIC was significantly downregulated in both NSCLC tissues and cells, and when NFIC was overexpressed, the malignant phenotype and total m6A content of NSCLC cells was suppressed, while the PI3K/AKT pathway was inactivated. Additionally, we discovered that NFIC inhibits the expression of METTL3 by directly binding to its promoter region, and METTL3 regulates the expression of KAT2A, a histone acetyltransferase, by methylating the m6A site in the 3'UTR of KAT2A mRNA in NSCLC cells. Intriguingly, NFIC was also found to negatively regulate the expression of KAT2A by directly binding to its promoter region. CONCLUSIONS: Our findings demonstrated that NFIC suppresses the malignant phenotype of NSCLC cells by regulating gene expression at both the transcriptional and post-transcriptional levels. A deeper comprehension of the genetic and epigenetic regulatory mechanisms in tumorigenesis would be beneficial for the development of personalized treatment strategies.
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We synthesized Sr-doped spinel CoCr2O4 using the solution combustion method and characterized the structure, morphology, chemical state, and photocatalytic properties through different techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance (EPR), and electrochemical impedance spectroscopy (EIS). 30-50 nm cuboid CoCr2O4 nanocrystals with Sr doping levels ranging from 0 to 0.6% were obtained; the increasing Sr doping deformed the coordination number of Co and Cr, transitioning to octahedral and tetrahedral units, inducing the phase transition from spinel to inverse spinel at 0.6% Sr content. This modification enhanced optical absorption, reduced the energy band gap, increased photoluminescence intensity, and maintained a high-spin state with oxygen vacancies. 0.6% Sr-doped CoCr2O4 demonstrated the highest photocatalytic efficiency at 93%. The XRD structure and photocatalytic activity remained at 87% over 7 cycles after 14 h. Employing degradation pathways and Mott-Schottky curves elucidated the enhancement mechanism.
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Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.
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Células Piramidales , Receptores de Dopamina D2 , Ratones , Masculino , Animales , Receptores de Dopamina D2/metabolismo , Células Piramidales/fisiología , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Núcleo Accumbens/fisiología , Conducta SocialRESUMEN
A novel bacterial strain, designated WL0086T, was isolated from a marine sediment sample collected in Lianyungang city, Jiangsu province, PR China. This strain showed the highest 16S rRNA gene sequence similarity to Geminisphaera colitermitum TAV2T (92.7â%) of the family Opitutaceae, and all the unclassified cultured and uncultured isolates with similarities >95â% were from marine environments. Cells were Gram-stain-negative, aerobic, non-motile cocci with a size of 0.6-0.8 µm in diameter. Strain WL0086T was positive for both oxidase and catalase, and grew at 20-37â°C (optimum, 28â°C), with 1.5-11.0â% NaCl (w/v; optimum, 2.5-4.0â%) and at pH 5.0-9.0 (optimum, pH 7.0). The major polar lipid profile of strain WL0086T consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, and phosphatidylcholine. The major isoprenoid quinone was menaquinone-7 and the predominant fatty acids were iso-C14â:â0, anteiso-C15â:â0, C16â:â0 and C16â:â1 ω9c. The complete genome consisted of a chromosome with 6â109â182 bp. The G+C content of genomic DNA was 64.0%. Results of phylogenomic analysis based on the 16S rRNA gene sequence and the whole genome suggested that strain WL0086T formed a distinct clade closely neighbouring the members of the family Opitutaceae. On the basis of phylogenetic, phenotypic, and chemotaxonomic evidences, strain WL0086T should represent a novel genus of the family Opitutaceae, for which the name Actomonas aquatica gen. nov., sp. nov. is proposed. The type strain is WL0086T (=MCCC 1K05844T=JCM 34677T=GDMCC 1.2411T).
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Carbono , Fijación del Nitrógeno , Composición de Base , Ácidos Grasos/química , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , ADN Bacteriano/genética , Técnicas de Tipificación BacterianaRESUMEN
Using event-related potentials (ERPs), this study examined the impact of reward expectations on working memory of emotional faces under different levels of cognitive load in a task combining the N-back paradigm and the reward expectation paradigm. The experiment involved presenting high- or low-reward cues followed by an N-back task for emotional faces with different loads. The accuracy results showed that under a high task load, both reward and emotion effects were significantly observed. However, these effects disappeared under a low task load. Analysis of the ERP data revealed that the early P2 and VPP components exhibited greater responses to fearful faces than to neutral faces. In the later stages, the P3 and LPP components showed greater reactions to high rewards than to low rewards. Additionally, the P2 component was found to be modulated by task load in relation to rewards, the EPN component demonstrated task load modulation with respect to emotions, and the N170 component showed an interaction effect between rewards and emotions. These findings imply that load regulates the reward effect and the emotional superiority effect in the process of working memory for emotional faces. In the cognitive processing of working memory, motivation and emotion jointly influence processing. Emotional factors have a greater impact in the early stage of processing, while motivation factors have a greater impact in the late stage of processing.
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Electroencefalografía , Motivación , Humanos , Memoria a Corto Plazo , Emociones/fisiología , Potenciales Evocados/fisiología , Cognición , Recompensa , Expresión FacialRESUMEN
Dengue illness can range from mild illness to life-threatening haemorrhage. It is an Aedes-borne infectious disease caused by the dengue virus, which has four serotypes. Each serotype acts as an independent infectious agent. The antibodies against one serotype confer homotypic immunity but temporary protection against heterotypic infection. Dengue has become a growing health concern for up to one third of the world's population. Currently, there is no potent anti-dengue medicine, and treatment for severe dengue relies on intravenous fluid management and pain medications. The burden of dengue dramatically increases despite advances in vector control measures. These factors underscore the need for a vaccine. Various dengue vaccine strategies have been demonstrated, that is, live attenuated vaccine, inactivated vaccine, DNA vaccine, subunit vaccine, and viral-vector vaccines, some of which are at the stage of clinical testing. Unfortunately, the forefront candidate vaccine is less than satisfactory, and its performance depends on serostatus and age factors. The lessons from clinical studies depicted ambiguity concerning the efficacy of dengue vaccine. Our study highlighted that viral structural heterogeneity, epitope accessibility, autoimmune complications, genetic variants, genetic diversities, antigen competition, virulence variation, host-pathogen specific interaction, antibody-dependent enhancement, cross-reactive immunity among Flaviviruses, and host-susceptibility determinants not only influence infection outcomes but also hampered successful vaccine development. This review integrates dengue determinants allocated necessities and challenges, which would provide insight for universal dengue vaccine development.
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Vacunas contra el Dengue , Virus del Dengue , Vacunas Virales , Animales , Humanos , Anticuerpos Antivirales , Mosquitos Vectores , Desarrollo de VacunasRESUMEN
Autophagy is a ubiquitous pathological/physiological antioxidant cellular reaction in eukaryotic cells. Vacuolar protein sorting 34 (Vps34 or PIK3C3), which plays a crucial role in autophagy, has received much attention. As the only Class III phosphatidylinositol-3 kinase in mammals, Vps34 participates in vesicular transport, nutrient signaling and autophagy. Dysfunctionality of Vps34 induces carcinogenesis, and abnormal autophagy mediated by dysfunction of Vps34 is closely related to the pathological progression of various human diseases, which makes Vps34 a novel target for tumor immunotherapy. In this review, we summarize the molecular mechanisms underlying macroautophagy, and further discuss the structure-activity relationship of Vps34 inhibitors that have been reported in the past decade as well as their potential roles in anticancer immunotherapy to better understand the antitumor mechanism underlying the effects of these inhibitors.
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Autofagia , Fosfatidilinositol 3-Quinasas Clase III , Animales , Humanos , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Transporte de Proteínas , Proteínas Relacionadas con la Autofagia/metabolismo , Transducción de Señal , Mamíferos/metabolismoRESUMEN
BACKGROUND: Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear. METHODS: Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression. RESULTS: With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (ß = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (Ptrend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (Pmodification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (Pmediation >0.05). CONCLUSION: Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications.
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Cotinina , Depresión , Encuestas Nutricionales , Humanos , Masculino , Femenino , Estudios Transversales , Adulto , Depresión/epidemiología , Persona de Mediana Edad , Estados Unidos/epidemiología , Cotinina/sangre , Cotinina/análisis , Trastornos del Sueño-Vigilia/epidemiología , Fumar/epidemiología , Prevalencia , Hormonas Esteroides Gonadales/sangre , Adulto Joven , Testosterona/sangre , AncianoRESUMEN
AIMS AND OBJECTIVES: The main aim of this study is to synthesize the prevalent predictive models for pressure injuries in hospitalized patients, with the goal of identifying common predictive factors linked to pressure injuries in hospitalized patients. This endeavour holds the potential to provide clinical nurses with a valuable reference for providing targeted care to high-risk patients. BACKGROUND: Pressure injuries (PIs) are a frequently occurring health problem throughout the world. There are mounting studies about risk prediction model of PIs reported and published. However, the prediction performance of the models is still unclear. DESIGN: Systematic review and meta-analysis: The Cochrane Library, PubMed, Embase, CINAHL, Web of Science and Chinese databases including CNKI (China National Knowledge Infrastructure), Wanfang Database, Weipu Database and CBM (China Biology Medicine). METHODS: This systematic review was conducted following PRISMA recommendations. The databases of Cochrane Library, PubMed, Embase, CINAHL, Web of Science, and CNKI, Weipu Database, Wanfang Database and CBM were searched for all studies published before September 2023. We included studies with cohort, case-control designs, reporting the development of risk model and have been validated externally and internally among the hospitalized patients. Two researchers selected the retrieved studies according to the inclusion and exclusion criteria, and critically evaluated the quality of studies based on the CHARMS checklist. The PRISMA guideline was used to report the systematic review and meta-analysis. RESULTS: Sixty-two studies were included, which contained 99 pressure injuries risk prediction models. The AUC (area under ROC curve) of modelling in 32 prediction models were reported ranged from .70 to .99, while the AUC of verification in 38 models were reported ranged from .70 to .98. Gender (OR = 1.41, CI: .99 ~ 1.31), age (WMD = 8.81, CI: 8.11 ~ 9.57), diabetes mellitus (OR = 1.64, CI: 1.36 ~ 1.99), mechanical ventilation (OR = 2.71, CI: 2.05 ~ 3.57), length of hospital stay (WMD = 7.65, CI: 7.24 ~ 8.05) were the most common predictors of pressure injuries. CONCLUSION: Studies of PIs risk prediction model in hospitalized patients had high research quality, and the risk prediction models also had good predictive performance. However, some of the included studies lacked of internal or external validation in modelling, which affected the stability and extendibility. The aged, male patient in ICU, albumin, haematocrit, low haemoglobin level, diabetes, mechanical ventilation and length of stay in hospital were high-risk factors for pressure injuries in hospitalized patients. In the future, it is recommended that clinical nurses, in practice, select predictive models with better performance to identify high-risk patients based on the actual situation and provide care targeting the high-risk factors to prevent the occurrence of diseases. RELEVANCE TO CLINICAL PRACTICE: The risk prediction model is an effective tool for identifying patients at the risk of developing PIs. With the help of risk prediction tool, nurses can identify the high-risk patients and common predictive factors, predict the probability of developing PIs, then provide specific preventive measures to improve the outcomes of these patients. REGISTRATION NUMBER (PROSPERO): CRD42023445258.
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BACKGROUND AND AIM: Inflammatory diseases often result in bone loss due to persistent inflammation, which activates osteoclasts and increases bone resorption. Oxysophocarpine (OSC), a bioalkaloid extracted from the roots of Sophora japonica and other leguminous plants, has neuroprotective and anti-tumor properties. However, it is still uncertain whether OSC can effectively inhibit the differentiation of osteoclasts and bone resorption. Therefore, this study explored the potential role of OSC in osteoclast formation and inflammatory osteolysis and its underlying mechanisms. EXPERIMENTAL PROCEDURE: This study involved inducing primary mouse bone marrow macrophages (BMMs) into osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) and examined the effects of OSC on osteoclast (OC) differentiation, function, and intracellular reactive oxygen species (ROS) production. The impact of OSC on the expression of osteoclast-specific genes and inflammation-related factors was assessed using real-time quantitative PCR. Additionally, changes in oxidative stress-related factors, NF-κB, and MAPK signaling pathways were examined using western blotting. Finally, this study investigated the influence of OSC on a mouse cranial bone resorption model induced by titanium (Ti) particles in vivo. RESULTS: OSC inhibited OC differentiation and resorption and reduces intracellular ROS levels. Moreover, OSC suppressed IL-1ß, TNF-α, IL-6, and osteoclast-specific gene transcription while increasing Nrf2 and HO-1 protein expression. Furthermore, OSC inhibited the expression and autoregulation of the NFATc1 gene, ultimately leading to a reduction in Ti particle-induced bone resorption in mice. CONCLUSION: OSC could be regarded as an innovative medication for the treatment of osteoclast-associated inflammatory osteolytic diseases.
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EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons.
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Comunicación Celular , Neoplasias Colorrectales , Humanos , Animales , Ratones , Neoplasias Colorrectales/metabolismo , Intestinos/patología , Neuronas/metabolismo , Neuronas/patología , Ácido gamma-Aminobutírico , Microambiente TumoralRESUMEN
Reward and punishment have long been recognized as potent modulators of human behavior. Although reinforcement learning is a significant motor learning process, the exact mechanisms underlying how the brain learns movements through reward and punishment are not yet fully understood. Beyond the memory of specific examples, investigating the ability to generalize to new situations offers a better understanding of motor learning. This study hypothesizes that reward and punishment engage qualitatively different motivational systems with different neurochemical and neuroanatomical substrates, which would have differential effects on reinforcement-based motor learning and generalization. To test this hypothesis, two groups of participants learn a motor task in one direction and then relearn the same task in a new direction, receiving only performance-based reward or punishment score feedback. Our findings support our hypothesis, showing that reward led to slower learning but promoted generalization. On the other hand, punishment led to faster learning but impaired generalization. These behavioral differences may be due to different tendencies of movement variability in each group. The punishment group tended to explore more actively than the reward group during the initial learning phase, possibly due to loss aversion. In contrast, the reward group tended to explore more actively than the initial learning phase during the generalization test phase, seemingly recalling the strategy that led to the reward. These results suggest that reward and punishment may engage different neural mechanisms during reinforcement-based motor learning and generalization, with important implications for practical applications such as sports training and motor rehabilitation.NEW & NOTEWORTHY Although reinforcement learning is a significant motor learning process, the mechanisms underlying how the brain learns movements through reward and punishment are not fully understood. We modified a well-established motor adaptation task and used savings (faster relearning) to measure generalization. We found reward led to slower learning but promoted generalization, whereas punishment led to faster learning but impaired generalization, suggesting that reward and punishment may engage different neural mechanisms during reinforcement-based motor learning and generalization.
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Castigo , Refuerzo en Psicología , Humanos , Aprendizaje , Recompensa , Generalización PsicológicaRESUMEN
BACKGROUND: Human umbilical cord mesenchymal stem cells (hUCMSCs)-derived exosomes carrying microRNAs (miRNAs) have promising therapeutic potential in various disorders, including premature ovarian failure (POF). Previous evidence has revealed the low plasma level of miR-22-3p in POF patients. Nevertheless, exosomal miR-22-3p specific functions underlying POF progression are unclarified. METHODS: A cisplatin induced POF mouse model and in vitro murine ovarian granulosa cell (mOGC) model were established. Exosomes derived from miR-22-3p-overexpressed hUCMSCs (Exos-miR-22-3p) were isolated. CCK-8 assay and flow cytometry were utilized for measuring mOGC cell viability and apoptosis. RT-qPCR and western blotting were utilized for determining RNA and protein levels. The binding ability between exosomal miR-22-3p and Kruppel-like factor 6 (KLF6) was verified using luciferase reporter assay. Hematoxylin-eosin staining, ELISA, and TUNEL staining were performed for examining the alteration of ovarian function in POF mice. RESULTS: Exos-miR-22-3p enhanced mOGC viability and attenuated mOGC apoptosis under cisplatin treatment. miR-22-3p targeted KLF6 in mOGCs. Overexpressing KLF6 reversed the above effects of Exos-miR-22-3p. Exos-miR-22-3p ameliorated cisplatin-triggered ovarian injury in POF mice. Exos-miR-22-3p repressed ATF4-ATF3-CHOP pathway in POF mice and cisplatin-treated mOGCs. CONCLUSION: Exosomal miR-22-3p from hUCMSCs alleviates OGC apoptosis and improves ovarian function in POF mouse models by targeting KLF6 and ATF4-ATF3-CHOP pathway.
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Exosomas , Células Madre Mesenquimatosas , MicroARNs , Insuficiencia Ovárica Primaria , Femenino , Humanos , Ratones , Animales , Insuficiencia Ovárica Primaria/metabolismo , Cisplatino/farmacología , Exosomas/genética , Exosomas/metabolismo , Factor 6 Similar a Kruppel/metabolismo , Apoptosis , MicroARNs/metabolismo , Células Madre Mesenquimatosas/metabolismo , Cordón Umbilical , Células de la Granulosa/metabolismo , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/farmacología , Factor de Transcripción Activador 4/metabolismoRESUMEN
The translocation of Drp1 from the cytosol to mitochondria leads to Drp1 activation and mitochondrial fission in myocardial ischemia/reperfusion (MI/R). However, the molecular mechanism underlying mitochondrial Drp1 translocation remains poorly understood. Mitochondrial Drp1 recruitment relies on 4 binding partners including MiD49, MiD51, Mff and Fis1. This study was to elucidate which one facilitate mitochondrial Drp1 translocation and its role in MI/R injury. MI/R was induced by ligating the left anterior descending coronary artery for 30 min and subsequent reperfusion for 3 h. Primary neonatal cardiomyocytes were subjected to hypoxia for 2 h and reoxygenation for 4 h. SiRNA or Adeno-associated virus (AAV) expressing shRNA was used to knock down the key binding partner in vitro or in vivo respectively. The expression of MiD51 rather than other binding partners (MiD49, Mff or Fis1) was increased after MI/R. MiD51 knockdown inhibited hypoxia/reoxygenation (H/R) or ischemia/reperfusion (I/R)-induced mitochondrial Drp1 translocation. SiRNA-induced knockdown of MiD51 suppressed mitochondrial oxidative stress, improved mitochondrial function and alleviate cellular injury in H/R cardiomyocytes. AAV-mediated knockdown of MiD51 reduced myocardial injury and improved cardiac function in the I/R hearts, while mitochondrial Drp1 translocation and cardiac function were not affected by MiD51 knockdown in the hearts without I/R. MiD51 is identified as the binding partner that promotes mitochondrial Drp1 translocation and contributes to MI/R injury. Inhibition of MiD51 may be a potential therapeutic target to alleviate MI/R injury.
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Dinaminas , Isquemia Miocárdica , Humanos , Recién Nacido , Apoptosis , Dinaminas/metabolismo , Isquemia/metabolismo , Mitocondrias/metabolismo , Dinámicas Mitocondriales , Isquemia Miocárdica/metabolismo , Reperfusión , ARN Interferente Pequeño/metabolismo , Regulación hacia ArribaRESUMEN
It is urgent to design a low-cost electrocatalyst with high activity to enhance the efficiency of oxygen evolution reaction (OER), which is limited by the slow four-electron transfer kinetics process. Nevertheless, traditional synthetic methods, including calcination and solvothermal, of the electrocatalysts are high-cost, low-yield, and energy-hogging, which limits their industrial application. Herein, an ambient fast synthetic method is developed to prepare terrace-like Fe/Co bimetal-organic framework (TFC-MOF) electrocatalyst materials in gram scale in 1 h. The method in this paper is designable based on coordination chemistry. Fe and Co ions can coordinate with the carboxyl groups on benzene-1,3,5-tricarboxylic acid (H3 BTC) to form a 2D-MOF structure. Structural characterizations, including SEM, TEM, and XRD are conducted to verify that the TFC-MOF is a terrace-like layered structure with uniform-sized mesoporous, which reduces the adsorption steric hindrance and facilitates the mass and electron transfer efficiency of OER. The TFC-MOF shows low overpotential, 255 mV at a current density of 10 mA cm-2 , and a low Tafel slope of 49.9 mV dec-1 , in an alkaline solution. This work provides a planar coordination strategy to synthesize 2D-MOF OER electrocatalyst on a large scale with low cost and low energy consumption, which will promote its practical OER applications.