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Accumulating research shows that prenatal exposure to maternal stress increases the risk of behavioral and mental health problems for offspring later in life. However, how prenatal stress affects offspring behavior remains unknown. Here, we found that prenatal stress (PNS) leads to reduced Ahi1, decreased synaptic plasticity and cognitive impairment in offspring. Mechanistically, Ahi1 and GR stabilize each other, inhibit GR nuclear translocation, promote Ahi1 and WDR68 binding, and inhibit DYRK1A and WDR68 binding. When Ahi1 deletion or prenatal stress leads to hyperactivity of the HPA axis, it promotes the release of GC, leading to GR nuclear translocation and Ahi1 degradation, which further inhibits the binding of Ahi1 and WDR68, and promotes the binding of DYRK1A and WDR68, leading to elevated DYRK1A, reduced synaptic plasticity, and cognitive impairment. Interestingly, we identified RU486, an antagonist of GR, which increased Ahi1/GR levels and improved cognitive impairment and synaptic plasticity in PNS offspring. Our study contributes to understanding the signaling mechanisms of prenatal stress-mediated cognitive impairment in offspring.
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Disfunção Cognitiva , Sistema Hipotálamo-Hipofisário , Feminino , Gravidez , Humanos , Sistema Hipófise-Suprarrenal , Disfunção Cognitiva/etiologia , Plasticidade NeuronalRESUMO
Human pose estimation is the basis of many downstream tasks, such as motor intervention, behavior understanding, and human-computer interaction. The existing human pose estimation methods rely too much on the similarity of keypoints at the image feature level, which is vulnerable to three problems: object occlusion, keypoints ghost, and neighbor pose interference. We propose a dual-space-driven topology model for the human pose estimation task. Firstly, the model extracts relatively accurate keypoints features through a Transformer-based feature extraction method. Then, the correlation of keypoints in the physical space is introduced to alleviate the error localization problem caused by excessive dependence on the feature-level representation of the model. Finally, through the graph convolutional neural network, the spatial correlation of keypoints and the feature correlation are effectively fused to obtain more accurate human pose estimation results. The experimental results on real datasets also further verify the effectiveness of our proposed model.
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Fontes de Energia Elétrica , Redes Neurais de Computação , HumanosRESUMO
Assisted reproductive technology (ART) has been used globally among infertile couples. However, many epidemiological investigations have indicated that ART is associated with a range of long-term adverse health outcomes in offspring, including cardiovascular disease, obesity, and increased plasma lipid levels. Until now, direct evidence has been limited regarding the pathological changes in vascular function in fetuses with ART. In this study, human umbilical cords were collected from healthy normal pregnancies and in vitro fertilization and embryo transfer (IVF-ET) pregnancies. Vascular functional studies involving acetylcholine (ACh), antagonists of its specific receptors, and L-type calcium channel/PKC-MLC20 phosphorylation pathway specific inhibitors were conducted. Quantitative real-time PCR, Western blotting, and methylation analyses were performed on umbilical vein samples. We found that the umbilical vein constriction induced by ACh in the IVF-ET group was significantly attenuated compared with that in the healthy normal pregnancy group, which was not only associated with the hypermethylation of ACh muscarinic receptor subtype 3 (CHRM3) and decreased expression of CHRM3, PKCß, and CaV1.2, but was also related to the reduced phosphorylation of MLC20. This study revealed that the hypermethylation of CHRM3, leading to a reduction in CHRM3 expression and downregulation of the CaV1.2/PKC-MLC20 phosphorylation pathway, was responsible for the decreased sensitivity to ACh observed in the umbilical vein under IVF-ET conditions. The hypermethylation of CHRM3 caused by IVF-ET might play an important role in altered vasoconstriction and impact cardiovascular systems in the long run.
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Transferência Embrionária , Receptor Muscarínico M3 , Técnicas de Reprodução Assistida , Acetilcolina , Metilação de DNA , Transferência Embrionária/métodos , Feminino , Fertilização in vitro/métodos , Humanos , Gravidez , Receptor Muscarínico M3/metabolismo , Veias UmbilicaisRESUMO
Fluoride exposure has a detrimental effect on neurodevelopment, while the underlying processes remain unknown. The goal of this study was to investigate how fluoride impacts synaptogenesis, with a focus on the phosphorylation of Creb1 (p-Creb1)-brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) pathway. We generated a sodium fluoride (NaF) model using C57 BL/6 J mice exposed to 100 mg/L NaF from gestation day 1 (GD1) to GD20. It was identified that NaF treatment impaired the learning and memory abilities of the male offspring, reduced dendritic spine density, lowered postsynaptic density protein-95 (PSD95) and synaptophysin (SYN) expression in the male offspring's hippocampus, indicating that synaptic dysfunction may contribute to the cognitive impairment in the NaF model. In addition, in vivo experiment demonstrated that the protein abundance of BDNF and the ratio of p-Creb1 to Creb1 were increased in the hippocampus of NaF offspring, while the level of TrkB was reduced. Similarly, PC12 cells treated with NaF also showed increased expression of BDNF and decreased levels of TrkB. Notably, fluoride treatment increased p-Creb1 in vitro, while inhibiting p-Creb1 by 66615 significantly alleviated the effects of NaF exposure, indicating that p-Creb1 exerts a regulatory function in the BDNF-TrkB pathway. Altogether, these results demonstrated prenatal fluoride exposure triggered neurotoxicity in the male offspring hippocampus was linked to synaptogenesis damage caused by activating p-Creb1, which disrupted the BDNF-TrkB pathway.
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Fator Neurotrófico Derivado do Encéfalo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Fluoretos , Efeitos Tardios da Exposição Pré-Natal , Receptor trkB , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Fluoretos/toxicidade , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Proteínas Tirosina Quinases/metabolismo , Ratos , Receptor trkB/metabolismo , Transdução de SinaisRESUMO
Introduction: The purpose of this study is to systematically compare and assess the differences in perceptual-cognitive skills between expert and non-expert sports officials, and further explore the potential differences caused by different types of sports officials, in order to provide a more comprehensive understanding of the perceptual-cognitive skills of sports officials. Methods: Relevant literature published before 31 December 2022 was searched in four English databases. Review Manager 5.4 and Stata 12.0 software were used for meta-analysis and bias test. Results: Expert sports officials are significantly more accurate in their decision-making than non-expert sports officials, and exhibit a large amount of effect size (SMD = 1.09; 95%CI: 0.52, 1.66; P < 0.05). Expert sports officials had significantly fewer number of fixations than non-expert sports officials and showed a moderate amount of effect size (SMD = 0.71; 95%CI: 1.25, 0.17; P < 0.05). Expert sports officials' duration of fixation (SMD = 0.23; 95%CI: 0.25, 0.71; P = 0.35) were not significantly different from non-expert sports officials. Discussion: It can be seen that there are differences in the Perceptual-cognitive skills of expert and non-expert sports officials. Decision-making accuracy can serve as an important indicator for distinguishing the perceptual-cognitive skills of expert and non-expert sports officials. Number of fixations can serve as important indicators to differentiate the perceptual-cognitive skills of monitors. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=418594, identifier: CRD42023418594.
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Prenatal hypoxia (PH) is one of the most common complications of obstetrics and is closely associated with many neurological disorders such as depression, anxiety, and cognitive impairment. Our previous study found that Zfp462 heterozygous (Het) mice exhibit significant anxiety-like behavior. Interestingly, offspring mice with PH also have anxiety-like behaviors in adulthood, accompanied by reduced expression of Zfp462 and increased expression of miR-377-3p; however, the exact regulatory mechanisms remain unclear. In this study, western blotting, gene knockdown, immunofluorescence, dual-luciferase reporter assay, immunoprecipitation, cell transfection with miR-377-3p mimics or inhibitors, quantitative real-time PCR, and rescue assay were used to detect changes in the miR-377-3p-Zfp462-Pbx1 (pre-B-cell leukemia homeobox1) pathway in the brains of prenatal hypoxic offspring to explain the pathogenesis of anxiety-like behaviors. We found that Zfp462 deficiency promoted Pbx1 protein degradation through ubiquitination and that Zfp462 Het mice showed downregulation of the protein kinase B (PKB, also called Akt)-glycogen synthase kinase-3ß (GSK3ß)-cAMP response element-binding protein (CREB) pathway and hippocampal neurogenesis with anxiety-like behavior. In addition, PH mice exhibited upregulation of miR-377-3p, downregulation of Zfp462/Pbx1-Akt-GSK3ß-CREB pathway activity, reduced hippocampal neurogenesis, and an anxiety-like phenotype. Intriguingly, miR-377-3p directly targets the 3'UTR of Zfp462 mRNA to regulate Zfp462 expression. Importantly, microinjection of miR-377-3p antagomir into the hippocampal dentate gyrus of PH mice upregulated Zfp462/Pbx1-Akt-GSK3ß-CREB pathway activity, increased hippocampal neurogenesis, and improved anxiety-like behaviors. Collectively, our findings demonstrated a crucial role for miR-377-3p in the regulation of hippocampal neurogenesis and anxiety-like behaviors via the Zfp462/Pbx1-Akt-GSK3ß-CREB pathway. Therefore, miR-377-3p could be a potential therapeutic target for anxiety-like behavior in prenatal hypoxic offspring.
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MicroRNAs , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Ansiedade , Proteínas de Ligação a DNA/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/metabolismo , Hipóxia/metabolismo , MicroRNAs/genética , Proteínas do Tecido Nervoso/metabolismo , Neurogênese , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Basketball, as one of the most popular sports in the world, has millions of followers and massive economic value. Basketball evolves so fast that it requires teams with smarter strategies, better skills, and stronger players. However, the competition strategies and training methods in basketball are still experience-based, lacking precise data to drive for more efficient training and strategies. On the other hand, flexible sensors, as a new class of sensors, have been a hotspot for scientific research and widely applied in various fields. Due to their excellent characteristics of flexibility, wearing comfort, convenience, and response speed, integrating flexible sensors into basketball has the potential to greatly promote all aspects of the sport. This paper aims to bring more fusion between basketball and flexible sensors. In this perspective, we first perform a review of the history of sensing technologies in the basketball sport and discuss mechanisms of flexible sensors applied on basketball players. Then specific scenarios for flexible sensors applied in basketball were elaborated on in detail. Finally, we envision the potential applications of flexible sensors in basketball and present our views on future development directions. We hope this paper can depict how flexible sensing technology is integrated into basketball systems and point out the future development of basketball with the help of flexible sensors.
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OBJECTIVE: Cognitive impairment, especially impaired social cognition, is largely responsible for the deterioration of the social life of patients with schizophrenia (SZ). Oxytocin (OT) is a neuropeptide that offers promising therapy for SZ. This study aimed to explore whether OT could affect dizocilpine (MK801)-induced cognitive impairment and to investigate the effect of exogenous OT on the endogenous OT system in the hippocampus. METHODS: The SZ mouse model was established by repeated administration of dizocilpine [MK801, 0.6â¯mg/kg, intraperitoneal (i.p.)], and then OT (6-60⯵g/kg, intranasal) or risperidone (0.3â¯mg/kg, i.p.) was administered to explore the effect of OT on cognitive impairment. RESULTS: OT at a dose of 6⯵g/kg alleviated MK801-induced hyperactivity, sociability impairment, and spatial memory impairment. OT at a dose of 20 or 60⯵g/kg attenuated the hyperactivity and social novelty impairment. In MK801-injected mice, the compensatory upregulation of OT mRNA in the hippocampus was reversed by three OT doses, whereas 60⯵g/kg OT reversed the compensatory upregulation of CD38 protein expression. CONCLUSION: OT alleviated cognitive impairment in the SZ mouse model to varying degrees, reversing the compensatory upregulation of OT signaling in the hippocampus.
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Administração Intranasal , Disfunção Cognitiva , Modelos Animais de Doenças , Maleato de Dizocilpina , Hipocampo , Ocitocina , Esquizofrenia , Transdução de Sinais , Regulação para Cima , Animais , Ocitocina/farmacologia , Ocitocina/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/induzido quimicamente , Camundongos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Masculino , Regulação para Cima/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Esquizofrenia/metabolismo , Esquizofrenia/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Comportamento SocialRESUMO
PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including â¼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.
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Neoplasias da Mama , Hiperinsulinismo , Humanos , Feminino , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Microscopia Crioeletrônica , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/genética , DNARESUMO
Objective: We aim to test whether leukocyte telomere length (LTL) is causally associated with the risk of bipolar disorder (BD) using the Mendelian randomization (MR) method. Methods: Results of a genome-wide association study (GWAS) conducted with 472,174 individuals of European descent were used to screen for single-nucleotide polymorphisms (SNPs) related with LTL traits. Summary-level data for BD (7,647 cases and 27,303 controls) were obtained from UK Biobank. An inverse-variance-weighted (IVW) method was employed as the primary MR analysis. Sensitivity analyses were conducted via MR-Egger, maximum likelihood, MR-pleiotropy residual sum outlier (MR-PRESSO), and MR-robust adjusted profile score (MR-RAPS) methods. Finally, the MR Steiger test was utilized to validate the hypothesized relationship between exposure and outcome. Results: Two-sample MR analysis revealed inverse relationships between genetically predicted LTL and BD risk (IVW OR [odds ratio] = 0.800, 95% CI [0.647-0.989] P = 0.039). Genetically predicted LTL exhibits a consistent connection with BD across five MR methods. Sensitivity analyses showed that the genetically determined effect of LTL on BD was stable and reliable. Furthermore, the MR Steiger test demonstrated that LTL was causal for BD rather than the opposite (P < 0.001). Conclusion: Our findings show that genetically determined LTL reduces the risk of BD. More research is required to clarify the mechanisms underlying this apparent causal connection. In addition, these findings may be useful for developing strategies for the prevention and treatment of BD.
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Transtorno Bipolar , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Leucócitos , TelômeroRESUMO
Objective: We aim to test whether body mass index (BMI) is causally associated with the risk of basal cell carcinoma (BCC) using Mendelian randomization (MR) analysis. Methods: Single-nucleotide polymorphisms (SNPs) associated with four BMI-related traits were screened via a genome-wide association study (GWAS) with 681,275, 336,107, 454,884, and 461,460 European-descent individuals, respectively. Summary-level data for BCC (17,416 cases and 375,455 controls) were extracted from UK Biobank. An inverse variance weighted (IVW) method was employed as the primary MR analysis. Sensitivity analyses were conducted via MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. The assumption that exposure causes outcome was verified using the MR Steiger test. Meta-analysis was also used to estimate the average genetically predicted effect of BMI on BCC. Results: Two-sample MR analysis showed inverse associations between genetically predicted BMI and BCC risk. Moreover, when exposure and outcome were switched to see if reverse causation was possible, there was no evidence of a cause-and-effect relationship from BCC to BMI. Finally, the meta-analysis also showed a strong negative causal relationship between BMI and BCC. Conclusion: Genetical predicted higher BMI were associated with lower BCC risk. Further research is required to comprehend the mechanisms underlying this putative causative association.
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Carcinoma Basocelular , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Índice de Massa Corporal , Causalidade , Carcinoma Basocelular/epidemiologiaRESUMO
Body pain, often considered as an early sign of injury in young players, warrants thorough study. This study aimed to examine the distribution of badminton-related pain and prevalence in pre-adolescent and adolescent badminton players. Profiles of badminton-related pain were surveyed using a questionnaire among 366 pre-adolescent and adolescent badminton players aged 7-12 years. The distribution of badminton-related pain was described, and the pain incidence was calculated. Proportions of pain per 1000-training-hour exposures were the main outcome measures. The analysis considered various age groups (7-8, 9-10, and 11-12 years) and years of badminton experience (≤2, 2-3, and > 3 years). In total, 554 cases of badminton-related pain were reported. The ankle was the most common site, followed by knee, plantar, shoulder, and lower back. The overall pain rate per 1000-training-hour exposure was 3.06. The 11-12-year-old group showed the highest pain rate, significantly greater than the 7-8-year-old group and the 9-10-year-old group. Additionally, the prevalence of pain exhibited an increasing trend with age. Finally, regardless of the age groups, participants with 2-3 years of badminton experience had the highest pain rate. These findings might help inform targeted interventions to reduce the high prevalence of pain in various body regions across pre-adolescent and adolescent badminton players.
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The purposes were to evaluate kinetics in lower limbs using single leg countermovement jump (SLCMJ) and to identify the differences in SLCMJ kinetics between sprinting fast players and sprinting slow players in elite university female soccer players. Seventeen participants at the national tournament level completed the survey. SLCMJ and 30 m sprinting tests were performed. A force-plate was used to collect the data of the SLCMJ test. Significant differences of concentric maximum rate of force development (RFD), concentric RFD, concentric RFD/body weight (BW), peak net takeoff force/BW, peak power, and peak power/BW existed between both legs during the SLCMJ among all the participants. For further analysis, the participants were divided into fast group and slow group based on sprinting performance. Significant differences existed between the two groups in concentric peak velocity (nondominant, p = 0.028) and vertical velocity at takeoff (nondominant, p = 0.021). Concentric maximum RFD (p = 0.036) was significantly different between both legs in the slow group. Among elite university female soccer players, the players who presented more increased asymmetry of kinetic characteristics of jumping, also showed weak sprinting performance. Moreover, the players presented the best performance in velocity of the jumping variables and also had the best sprinting performance. Coaches and players should focus on keeping inter-limb balance and developing jumping velocity to improve sports performance. In future, the cause-and-effect relationship between jumping and sprinting should be identified.
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Prenatal hypoxia (PH) is one of the most common adverse stimulation during pregnancy. The brain is fragile in the fetal period and sensitive to hypoxia. The offspring who have experienced PH may be at increased risk of developing neurodevelopmental disorders after birth and various neuropsychiatric diseases after adulthood. In this study, pregnant mice used to generate PH offspring were treated with hypoxia (10.5% oxygen) from gestational day 12.5-17.5. Compared with control mice, the birth weight of offspring in the PH group was significantly lower and the male adult offspring exhibited significant depression-like behavior. The expression of the oxygen-sensitive subunit of hypoxia-inducible factor (Hif-1α) was significantly elevated, whereas Ten-eleven translocated methylcytosine dioxygenase 1 (Tet1) and c-Myc, which is closely related to cell proliferation, were significantly decreased in the hippocampus of the male offspring in the PH group. In addition, the PH group showed increased binding of Hif-1α to Tet1, and decreased binding of Tet1 to c-Myc, resulting in increased ubiquitinated degradation of c-Myc and decreased neurogenesis in the hippocampus of the male offspring. These findings suggest that Hif-1α regulates Tet1-c-Myc binding involved in depression-like behavior in PH offspring and Hif-1α can be used as a detection index of stress-related diseases.
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Dioxigenases , Animais , Feminino , Masculino , Camundongos , Gravidez , Hipóxia Celular/fisiologia , Depressão , Dioxigenases/metabolismo , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , OxigênioRESUMO
Background: First-episode schizophrenia (FES) and anti-NMDAR encephalitis are different disorders with similar psychiatric symptoms, and both diseases are associated with the inflammatory system. In this study, we compared hematological parameters and inflammation ratios in anti-NMDAR encephalitis, FES, and healthy control. Methods: We enrolled 106 patients (53 FES patients and 53 anti-NMDAR encephalitis patients) and 59 healthy controls. The values of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) were used to evaluate inflammation. Other parameters such as the white blood cell (WBC), platelet (PLT), uric acid (UA), total bilirubin (TBIL), total bile acid (TBA), and serum albumin counts were also used to compare inflammation ratios between these two diseases. Results: SII, NLR, PLR, MLR, and serum albumin levels were statistically significantly different between these three groups (p < 0.05). The values of SII, NLR, PLR, and MLR were significantly higher in the anti-NMDAR encephalitis group than those in the FES group (p < 0.05), and the values in both diseases were more increased than those in HC (p < 0.05). The serum albumin level was significantly lower in anti-NMDAR encephalitis than in FES (p < 0.05). WBC, neutrophil, lymphocyte, and monocyte counts showed significantly higher levels in the anti-NMDAR encephalitis group and FES group separately (p < 0.05). Other parameters like TBA, TBIL, and UA showed no difference between groups. Conclusion: In summary, this is a relatively new study that is innovative by comparing some inflammation markers of peripheral blood in two diseases with clinically psychotic symptoms. These two diseases are related to the inflammatory system, proving that NMDAR dysfunction is related to psychotic symptoms. Besides, NLR, PLR, MLR, and serum albumin can be used as biomarkers to distinguish the two diseases. The serum albumin level in patients with anti-NMDAR encephalitis was lower than that in patients with schizophrenia.
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Background: Paternal lifestyle, stress and environmental exposures play a crucial role in the health of offspring and are associated with non-genetic inheritance of acquired traits, however the underlying mechanisms are unclear. In this study, we aimed to find out how the sperm tsRNA involved in paternal high-fat diet induced abnormal gluconeogenesis of F1 offspring, and explore the underlying molecular mechanism of its regulation. Method: We generated a paternal high fat diet (42% kcal fat) model to investigate the mechanism by which paternal diet affects offspring metabolism. Four-week-old C57BL/6J male mice were randomly assigned into two groups to receive either a control diet (CD; 10% kcal fat) or a high-fat (HFD; 42% kcal fat) diet for 10 weeks, and mice from each group were then mated with 8-week-old females with control diet in a 1:2 ratio to generate F1. F0 sperms were isolated and small RNAs was sequenced by high-throughput sequencing. Metabolic phenotypes were examined with both F0 and F1. Results: A significant increase in body weight was observed with HFD-F0 mice at 8 weeks of age as compared to CD mice at the same age. F0 mice showed impaired glucose tolerance (GTT), resistance to insulin tolerance (ITT) and increased pyruvate tolerance (PTT) at 14 weeks. HFD-F1 male mice showed no significant difference in body weight. An increase in PTT was found at 13 weeks of age and no significant changes in GTT and ITT. PEPCK and G6Pase that related to gluconeogenesis increased significantly in the liver of HFD-F1 male mice. Sperm sequencing results showed that 5'tsRNA-Gly-GCC derived from tRNA-Gly-GCC-2 specifically was remarkably upregulated in sperm of HFD F0 mice. Q-PCR further showed that this tsRNA was also increased in the liver of HFD-F1 comparison with CD-F1 mice. In addition, we found that 5'tsRNA-Gly-GCC can regulate Sirt6-FoxO1 pathway and be involved in the gluconeogenesis pathway in liver. Conclusion: 5'tsRNA-Gly-GCC that increased in HFD mice mature sperms can promote gluconeogenesis in liver by regulating Sirt6-FoxO1 pathway, which might represent a potential paternal epigenetic factor mediating the intergenerational inheritance of diet-induced metabolic alteration.
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The fetal origins of adult disease (FOAD) hypothesis, which was proposed by David Barker in the United Kingdom in the late 1980s, posited that adult chronic diseases originated from various adverse stimuli in early fetal development. FOAD is associated with a wide range of adult chronic diseases, including cardiovascular disease, cancer, type 2 diabetes and neurological disorders such as schizophrenia, depression, anxiety, and autism. Intrauterine hypoxia/prenatal hypoxia is one of the most common complications of obstetrics and could lead to alterations in brain structure and function; therefore, it is strongly associated with neurological disorders such as cognitive impairment and anxiety. However, how fetal hypoxia results in neurological disorders remains unclear. According to the existing literature, we have summarized the causes of prenatal hypoxia, the effects of prenatal hypoxia on brain development and behavioral phenotypes, and the possible molecular mechanisms.
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A novel approach for a dentritic cells (DCs)-based tumor vaccine was developed for the formation of hybrid-engineered J558 after fusion with DCs. To make the hybrid-tumor vaccine generate more efficient specific CTL cytotoxicity against wild-type tumor cells, we genetically engineered tumor cells with mIL-12 gene prior to the cell fusion. mIL-12 was detected at 870 +/- 60 pg/(10(5) cells/ml) in the culture supernatants and the fusion ratio was about 30% by the co-focal microscopic analysis. Vaccination of mice with DCs fused with engineered J558 induced more efficient tumor-specific CTL cytotoxicity against wild-type tumor cells in vitro and with efficient antitumor immunity in vivo. These results suggest that this approach of using DCs fused with engineered tumor cells could be applied in clinical settings of DCs-based cancer vaccines.
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Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Linfoma de Células B/patologia , Animais , Fusão Celular , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Feminino , Técnicas de Transferência de Genes , Células Híbridas , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Linfócitos T Citotóxicos/imunologia , Transfecção , Vacinas de DNA/imunologiaAssuntos
Materiais Biocompatíveis , Colágeno , Técnicas Citológicas , Combinação de Medicamentos , Aparelho Lacrimal/fisiologia , Laminina , Proteoglicanas , Animais , Carbacol/farmacologia , Divisão Celular , Tamanho Celular , Células Cultivadas , Feminino , Aparelho Lacrimal/citologia , Aparelho Lacrimal/efeitos dos fármacos , Microscopia Eletrônica , Coelhos , Componente Secretório/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
OBJECTIVE: To study the antitumor activity of engineered fusion of tumor cell and dendritic cells (DC). METHODS: J558 tumor cells were transfected with mouse IL-12 (mIL-12) gene and then fused with DCs to develop a hybrid-engineered tumor vaccine. BALB/c mice were challenged with wild-type J558 tumor cells 14 days after vaccinated with hybrid-engineered J558. RESULTS: mIL-12 was detected at (870 +/- 60) pg.(10(5) cells)(-1).ml(-1) in the culture supernatants and the cell-fusion rate was about 30% by co-focal microscopy. In addition, the lymphocytes from popliteal nodes and groin nodes of these mice vaccinated with hybrid-engineered J558 secreted higher levels of IFN-gamma than that of other control mice, and vaccination of mice with the fusion vaccine induced more efficient tumor-specific CTL cytotoxicity against wild-type tumor cells in vitro and with efficient antitumor immunity in vivo. CONCLUSION: It suggested that vaccination of mice with the fusion vaccine induced stronger Th1-dominant responses and this approach could perhaps be applied to clinical settings of DCs-based cancer vaccines.