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MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.
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Sinergismo Farmacológico , Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Proteínas Proto-Oncogênicas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Animais , Camundongos , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular TumoralRESUMO
Sleep deprivation (SD) weakens the immune system and leads to increased susceptibility to infectious or inflammatory diseases. However, it is still unclear how SD affects humoral immunity. In the present study, sleep disturbance was conducted using an sleep deprivation instrument, and the bacterial endotoxin lipopolysaccharide (LPS) was used to activate the immune response. It was found that SD-pretreatment reduced LPS-induced IgG2b+ B cells and IgG2b isotype antibody production in lymphocytes of spleen. And, SD-pretreatment decreased the proportion of CD4+T cells, production of CD4+T cells derived TGF-ß1 and its contribution in helping IgG2b production. Additionally, BMAL1 and CLOCK were selectively up-regulated in lymphocytes after SD. Importantly, BMAL1 and CLOCK deficiency contributed to TGF-ß1 expression and production of IgG2b+ B cells. Thus, our results provide a novel insight to explain the involvement of BMAL1 and CLOCK under SD stress condition, and their roles in inhibiting TGF-ß1 expression and contributing to reduction of LPS induced IgG2b production.
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Fatores de Transcrição ARNTL , Formação de Anticorpos , Proteínas CLOCK , Imunoglobulina G , Privação do Sono , Privação do Sono/genética , Privação do Sono/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Ratos Sprague-Dawley , Camundongos Endogâmicos C57BL , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/imunologia , Proteínas CLOCK/genética , Proteínas CLOCK/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/genética , Estresse Fisiológico/imunologia , Animais , Camundongos , Ratos , Células CultivadasRESUMO
BACKGROUND: Little s antigen is mainly defined by a single nucleotide polymorphism at c.143C (p.Thr48) on the GYPB gene. Several variants on GYPB can alter the expression of s antigen. The aim of this study was to investigate the molecular basis of variant s antigen expression in the Chinese population. STUDY DESIGN AND METHODS: A total of 4983 whole blood samples were collected to screen the individuals with discrepant s typing results using two different monoclonal anti-s. Then, the sequence of GYPB exon 4 was analyzed by Sanger sequencing. Flow cytometry analysis was performed to quantify s antigen expression on red blood cells (RBCs). In vitro expression study was performed to verify the effect of the GYPB variants identified on the expression of s antigen. RESULTS: Four donors were identified to have discrepant s typing results. Sanger sequencing showed that three donors carried the c.173C > G variant (p.Pro58Arg) specific for sD antigen, the other one carried a novel GYPB (c.160C > T, p.Arg54Cys) variant. Flow cytometry identified a partial and weak expression of s antigen on the RBCs of the four donors. Furthermore, in vitro expression study confirmed the effect of the two variants on the s antigen expression. CONCLUSION: The results demonstrated that in addition to p.Thr48, the two extra amino acids p.Arg54 and p.Pro58 are also important for full expression of s antigen. Since the individuals with partial s antigen are at risk for the development of alloanti-s, it is important to select at least two different monoclonal anti-s for correct s typing.
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Antígenos de Grupos Sanguíneos , Glicoforinas , Humanos , Alelos , Glicoforinas/genética , Antígenos de Grupos Sanguíneos/genética , Fenótipo , Eritrócitos/metabolismo , Sistema do Grupo Sanguíneo Rh-Hr/metabolismoRESUMO
Meta-analysts often use standardized mean differences (SMD) to combine mean effects from studies in which the dependent variable has been measured with different instruments or scales. In this tutorial we show how the SMD is properly calculated as the difference in means divided by a between-subject reference-group, control-group, or pooled pre-intervention SD, usually free of measurement error. When combining mean effects from controlled trials and crossovers, most meta-analysts have divided by either the pooled SD of change scores, the pooled SD of post-intervention scores, or the pooled SD of pre- and post-intervention scores, resulting in SMDs that are biased and difficult to interpret. The frequent use of such inappropriate standardizing SDs by meta-analysts in three medical journals we surveyed is due to misleading advice in peer-reviewed publications and meta-analysis packages. Even with an appropriate standardizing SD, meta-analysis of SMDs increases heterogeneity artifactually via differences in the standardizing SD between settings. Furthermore, the usual magnitude thresholds for standardized mean effects are not thresholds for clinically important differences. We therefore explain how to use other approaches to combining mean effects of disparate measures: log transformation of factor effects (response ratios) and of percent effects converted to factors; rescaling of psychometrics to percent of maximum range; and rescaling with minimum clinically important differences. In the absence of clinically important differences, we explain how standardization after meta-analysis with appropriately transformed or rescaled pre-intervention SDs can be used to assess magnitudes of a meta-analyzed mean effect in different settings.
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Metanálise como Assunto , Humanos , Interpretação Estatística de Dados , Modelos EstatísticosRESUMO
Spreading depolarization (SD), the underlying mechanism of migraine aura, may trigger the opening of the pannexin 1 (PANX1) pore to sustain the cortical neuroinflammatory cascades involved in the genesis of headache. Yet, the mechanism underlying SD-evoked neuroinflammation and trigeminovascular activation remains incompletely understood. We characterized the identity of inflammasome activated following SD-evoked PANX1 opening. Pharmacological inhibitors targeting PANX1 or NLRP3 as well as genetic ablation of Nlrp3 and Il1b were applied to investigate the molecular mechanism of the downstream neuroinflammatory cascades. In addition, we examined whether SD-triggered microglial activation facilitates neuronal NLRP3-mediated inflammatory cascades. Pharmacological inhibition of toll-like receptors TLR2/4, the potential receptors of the damage-associated molecular pattern HMGB1, was further employed to interrogate the neuron-microglia interplay in SD-induced neuroinflammation. We found that NLRP3 but not NLRP1 or NLRP2 inflammasome was activated following PANX1 opening after single or multiple SDs evoked by either KCl topical application or non-invasively with optogenetics. The SD-evoked NLRP3 inflammasome activation was observed exclusively in neurons but not microglia or astrocytes. Proximity ligation assay demonstrated that the assembly of the NLRP3 inflammasome occurred as early as 15 min after SD. Genetic ablation of Nlrp3 or Il1b or pharmacological inhibition of PANX1 or NLRP3 ameliorated SD-induced neuronal inflammation, middle meningeal artery dilatation, calcitonin gene-related peptide expression in trigeminal ganglion and c-Fos expression in trigeminal nucleus caudalis. Moreover, multiple SDs induced microglial activation subsequent to neuronal NLRP3 inflammasome activation, which in turn orchestrated with neurons to mediate cortical neuroinflammation, as demonstrated by decreased neuronal inflammation after pharmacological inhibition of microglia activation or blockade of the TLR2/4 receptors. To conclude, single or multiple SDs evoked activation of neuronal NLRP3 inflammasomes and its downstream inflammatory cascades to mediate cortical neuroinflammation and trigeminovascular activation. In the context of multiple SDs, the cortical inflammatory processes could be facilitated by SD-evoked microglia activation. These findings may implicate the potential role of innate immunity in migraine pathogenesis.
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Inflamassomos , Transtornos de Enxaqueca , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doenças Neuroinflamatórias , Receptor 2 Toll-Like , Inflamação , Neurônios/metabolismo , Proteínas do Tecido Nervoso , ConexinasRESUMO
The attacks like distributed denial-of-service (DDoS) are termed as severe defence issues in data centres, and are considered real network threat. These types of attacks can produce huge disturbances in information technologies. In addition, it is a complex task to determine and fully alleviate DDoS attacks. The new strategy is developed to identify and alleviate DDoS attacks in the Software-Defined Internet of Things (SD-IoT) model. SD-IoT simulation is executed to gather data. The data collected through nodes of SD-IoT are fed to the selection of feature phases. Here, the hybrid process is considered to select features, wherein features, like wrapper-based technique, cosine similarity-based technique, and entropy-based technique are utilized to choose the significant features. Thereafter, the attack discovery process is done with Elephant Water Cycle (EWC)-assisted deep neuro-fuzzy network (DNFN). The EWC is adapted to train DNFN, and here EWC is obtained by grouping Elephant Herd Optimization (EHO) and water cycle algorithm (WCA). Finally, attack mitigation is carried out to secure the SD-IoT. The EWC-assisted DNFN revealed the highest accuracy of 96.9%, TNR of 98%, TPR of 90%, precision of 93%, and F1-score of 91%, when compared with other related techniques.
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KEY MESSAGE: We generated a new Koshihikari rice line with a drastically reduced content of glutelin proteins and higher lodging resistance by using new and conventional plant breeding techniques. Using CRISPR/Cas9-mediated genome editing, we generated mutant rice with drastically decreased contents of major glutelins. A Koshihikari rice mutant line, a123, lacking four glutelins (GluA1, GluA2, GluB4, and GluB5) was used as a host, and another five major glutelin genes (GluA3, GluB1a, GluB1b, GluB2, and GluC) were knocked out through two iterations of Agrobacterium-mediated transformation. Mutant seeds were deficient in the GluA family, GluB family, and GluC, and the line obtained was named GluABC KO. Glutelin content was much lower in GluABC KO than in the existing low-glutelin rice mutant LGC-1. A null segregant of GluABC KO was selected using new-generation sequencing and backcrossing, and the sd-1 allele for the semi-dwarf trait was introduced to increase lodging resistance.
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Glutens , Oryza , Glutens/genética , Glutens/metabolismo , Oryza/genética , Oryza/metabolismo , Melhoramento Vegetal , Sementes/genética , Sementes/metabolismo , FenótipoRESUMO
PURPOSE: To investigate changes in distal outflow tract vessels caused by VEGF-A and their impact on outflow. METHODS: We compared VEGF-A perfused porcine anterior segments with and without trabecular meshwork (TM) to control eyes. In the first experiment (n=48), we analyzed live changes of the outflow tract with spectral-domain optical coherence tomography (SD-OCT) over 3 h and reconstructed them in 3D. In a second experiment (n=32), we measured the intraocular pressure (IOP) variation in response to VEGF-A over 48 h and computed the outflow facility. RESULTS: VEGF-A increased the vessel volume of the distal outflow tract by 16.8±10.6% while control eyes remained unchanged (0.5±6.8%). Volume changes occurred within the first 100 min before plateauing at 140 min. VEGF-A enhanced the outflow facility in eyes without TM by 38.6±25.5% at 24 h as compared to controls (p<0.05). CONCLUSION: VEGF-A dilated vessels of the distal outflow tract and increased the outflow facility even after TM removal, pointing to a regulatory mechanism independent of proximal structures.
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Humor Aquoso , Fator A de Crescimento do Endotélio Vascular , Animais , Suínos , Humor Aquoso/fisiologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Malha Trabecular , Pressão IntraocularRESUMO
Growing concerns over declining male semen quality and rising infertility have shifted attention to male fertility. Sperm cryopreservation emerges as a crucial tool in preserving male fertility, especially for patients who need proactive preservation, such as cancer patients before undergoing radiation or chemotherapy. Although cryopreservation does not directly address infertility, effective preservation can support future fertility. However, the process may compromise sperm DNA integrity. Despite their impairment, damaged sperm often retain vitality and may still have the potential to fertilize an egg. Nonetheless, if damaged sperm fertilize an egg, excessive DNA damage could impede embryo implantation and development, despite the egg's repair capabilities. Consequently, precise detection of sperm DNA damage is crucial and urgent. To better address the issue of sperm DNA damage detection, we have introduced a novel fluorescence biosensor technology known as the TDT/SD Probe. This technology utilizes terminal deoxynucleotidyl transferase (TdT) and strand displacement probes to accurately detect the number of sperm DNA breakage points during the cryopreservation process. Experimental results reveal that the number of sperm DNA breakpoints significantly increases after both sperm vitrification (8.17 × 105) and conventional slow freezing (10.80 × 105), compared to the DNA breakpoints of fresh semen samples (5.19 × 105). However, sperm vitrification has the least impact on sperm breakage points. This research provides innovative means for further optimizing sperm preservation techniques by offering a novel DNA damage detection method, enabling more precise assessment of sperm DNA damage during the freezing process.
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PURPOSE: To determine the distribution of subfoveal choroidal thickness (SFCT) and its associated demographic, ocular, and systemic factors in an elderly population. METHODS: This report is part of the Tehran Geriatric Eye Study (TGES); a population-based cross-sectional study that was conducted on the urban elderly population of Tehran, aged 60 years and above using multi-stage stratified random cluster sampling. Choroidal imaging was performed using Spectralis SD-OCT with enhanced depth imaging mode. RESULTS: The average SFCT was 265.3 ± 25.9 µm (95% CI: 262.8-267.7) in the whole sample. According to the multiple generalized estimating equation (GEE) model, pseudophakia had a statistically significant direct relationship with SFCT (coefficient = 5.69), and history of cerebrovascular accident (CVA) was significantly inversely related to SFCT (coefficient=-4.77). Moreover, there was a significant interaction between age and sex in the average SFCT so that with increasing age, the SFCT increased in men and decreased in women. CONCLUSION: The normal values of SFCT in the present study can be used as a reference database for clinical and research purposes. Age-sex interaction, pseudophakia, and history of CVA were significantly associated with SFCT in the elderly population. It is recommended that these factors be taken into account when interpreting SFCT data.
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Corioide , Pseudofacia , Masculino , Humanos , Idoso , Feminino , Estudos Transversais , Irã (Geográfico) , Tomografia de Coerência Óptica/métodosRESUMO
Mongolian medicine Sendeng-4 (SD-4) has demonstrated satisfactory clinical treatment outcomes for rheumatoid arthritis (RA); nevertheless, its bioactive components and the related mechanisms have not yet been clearly elucidated. To explore the bioactive chemical components of SD-4 in the treatment of RA and its possible mechanisms, an High Performance Liquid Chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established to simultaneously quantify the main components in SD-4, and ultraperformance LC-Q-Exactive-MS/MS (UPLC-Q-Exactive-MS/MS) was used to identify the phytochemicals absorbed in the serum. Then, using network pharmacology methods, these components were constructed into a compound-target network of RA to predict possible biological targets of SD-4 as well as potential signaling pathways. Transcriptomics analysis and molecular docking were used to validate the results of network pharmacology. Subsequently, we established a complete Freund's adjuvant-induced RA rat model and observed the anti-RA effects of SD-4 through assessments of foot swelling, ankle diameter, arthritis score, morphology, serum inflammatory factors, and histopathological analysis of synovial tissue. Specifically, reverse transcription-quantitative polymerase chain reaction, Western blot, and immunohistochemical analysis were used in animal experiments to validate the pathways of serum phytochemistry, network pharmacology, and transcriptomics. Tannic acid, gallic acid, corilagin, crocin I, gardenoside, ferulic acid, quercetin, limonin, rutin, chlorogenic acid, verbascoside, catechin, epicatechin, myricetin, and dihydromyricetin in SD-4 showed good linearity within their respective concentration ranges (r ≥ 0.9991); the average recovery rate was 93.77%-109.17% (relative standard deviation < 2%). A total of 37 compounds were identified in serum samples. Based on this, network pharmacology methods collected 739 genes related to these identified compounds in SD-4 and 3807 genes related to RA. Network pharmacology and transcriptomic analysis demonstrated that the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway is the most relevant pathway affected by SD-4 in RA. In the experiments, SD-4 treatment reduced ankle swelling and arthritis scores in RA rats, improved symptoms, and reduced the production of inflammatory factors. Compared with the RA model group, SD-4 treatment significantly reduced the expression of PI3K-Akt pathway-related messenger RNA and proteins. In addition, immunohistochemical analysis confirmed these results. This study combined serum phytochemistry, network pharmacology, and transcriptomics to demonstrate that SD-4 can alleviate RA by regulating the PI3K-Akt signaling pathway. This research provides a theoretical basis for the clinical application of SD-4 and offers an effective strategy for the identification of bioactive substances in traditional Chinese medicine formulas and the study of their potential mechanisms.
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Artrite Reumatoide , Medicamentos de Ervas Chinesas , Farmacologia em Rede , Animais , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Cromatografia Líquida de Alta Pressão/métodos , Masculino , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/sangue , Espectrometria de Massas em Tandem/métodos , Ratos Sprague-Dawley , Artrite Experimental/tratamento farmacológico , Artrite Experimental/sangue , Artrite Experimental/metabolismo , Transcriptoma/efeitos dos fármacos , Simulação de Acoplamento Molecular , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Aging and regeneration are heavily linked processes. While it is generally accepted that regenerative capacity declines with age, some vertebrates, such as newts, can bypass the deleterious effects of aging and successfully regenerate a lens throughout their lifetime. RESULTS: Here, we used Spectral-Domain Optical Coherence Tomography (SD-OCT) to monitor the lens regeneration process of larvae, juvenile, and adult newts. While all three life stages were able to regenerate a lens through transdifferentiation of the dorsal iris pigment epithelial cells (iPECs), an age-related change in the kinetics of the regeneration process was observed. Consistent with these findings, iPECs from older animals exhibited a delay in cell cycle re-entry. Furthermore, it was observed that clearance of the extracellular matrix (ECM) was delayed in older organisms. CONCLUSIONS: Collectively, our results suggest that although lens regeneration capacity does not decline throughout the lifespan of newts, the intrinsic and extrinsic cellular changes associated with aging alter the kinetics of this process. By understanding how these changes affect lens regeneration in newts, we can gain important insights for restoring the age-related regeneration decline observed in most vertebrates.
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Cristalino , Pleurodeles , Animais , Salamandridae , Matriz Extracelular , Divisão CelularRESUMO
Dengue is a significant health problem due to the high burden of critical infections during outbreaks. In 1997, the World Health Organization (WHO) classified dengue as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). It was revised in 2009 (updated in 2015), and the new guidelines recommended classifying patients as dengue without warning signs (DNS), dengue with warning signs (DWS), and severe dengue (SD). Although the utility of the revised 2009 classification for clinical studies is accepted, for immunological studies it needs to be clarified. We determined the usefulness of the 2009 classification for pediatric studies that analyze the circulating interleukin (IL)-6 and IL-8, two inflammatory cytokines. Plasma levels of IL-6 and IL-8 were evaluated in the acute and convalescent phases by flow cytometry in children with dengue classified using the 1997 and 2009 WHO guidelines. The plasma levels of IL-6 and IL-8 were elevated during the acute and decreased during convalescence, and both cytokines served as a good marker of acute dengue illness compared to convalescence. There were no differences in the plasma level of the evaluated cytokines among children with different clinical severity with any classification, except for the IL-8, which was higher in DWS than DNS. Based on the levels of IL-8, the 2009 classification identified DWS plus SD (hospital-treated children) compared to the DNS group [area under the curve (AUC): 0.7, p = 0.028]. These results support the utility of the revised 2009 (updated in 2015) classification in studies of immune markers in pediatric dengue.
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Dengue , Interleucina-6 , Interleucina-8 , Organização Mundial da Saúde , Humanos , Dengue/imunologia , Dengue/diagnóstico , Criança , Masculino , Feminino , Interleucina-6/sangue , Pré-Escolar , Interleucina-8/sangue , Dengue Grave/diagnóstico , Dengue Grave/imunologia , Dengue Grave/sangue , Adolescente , Índice de Gravidade de Doença , Biomarcadores/sangue , Vírus da Dengue/imunologia , Guias de Prática Clínica como Assunto , Citometria de Fluxo , Lactente , Citocinas/sangueRESUMO
The reliability of the communication link is quite common and challenging to handle as the topology changes frequently in vehicular ad hoc networks (VANETs). Another problem with VANETs is that the vehicles are from different manufacturers. Hence, the heterogeneity of hardware is obvious. These heterogeneity and reliability problems affect the message dissemination in VANETs. This paper aims to address these challenges by proposing a robust routing protocol capable of ensuring reliable, scalable, and heterogeneity-tolerant message dissemination in VANETs. We first introduced a hybrid hierarchical architecture based on software-defined networking (SDN) principles for VANETs, leveraging SDN's inherent scalability and adaptability to heterogeneity. Further, a road-side unit (RSU)-assisted cloud-based location-aware hybrid routing for software-defined VANETs (SD-VANETs) that we call RC-LAHR was proposed. RC-LAHR was rigorously tested and analyzed for its performance in terms of packet delivery ratio (PDR) and end-to-end delay (EED), along with a comprehensive assessment of network traffic and load impacts on cloud infrastructure and RSUs. The routing protocol is compared with state-of-the-art protocols, Greedy Perimeter Stateless Routing (GPSR) and Opportunistic and Position-Based Routing (OPBR). The proposed routing protocol performs well as compared to GPSR and OPBR. The result shows that the EED is reduced to 20% and the PDR is increased to 30%. The network reliability is also increased up to 5% as compared to the OPBR and GPSR.
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BACKGROUND: Falling on stairs is a major health hazard for older people. Risk factors for stair falls have been identified, but these are mostly examined in controlled biomechanics/gait laboratory environments, on experimental stairs with a given set of step dimensions. It remains unknown whether the conclusions drawn from these controlled environments would apply to the negotiation of other domestic staircases with different dimensions in real houses where people live. OBJECTIVES: The aim of this paper is to investigate whether selected biomechanical stepping behavior determined through stair gait parameters such as foot clearance, foot contact length and cadence are maintained when the staircase dimensions are different in real houses. METHODS: Twenty-five older adults (>65 years) walked on a custom-made seven-step laboratory staircase. Older adults were classified into two groups (fallers and non-fallers) based on recent fall history. Among the 25 participants, 13 people had at least one fall, trip, or slip in the last six months and they were assigned to the fallers group; 12 people did not experience any fall in the last six months, so they were assigned to the non-fallers group. In addition, these participants walked on the stairs in three different real exemplar houses wearing a novel instrumented shoe sensor system that could measure the above stair gait parameters. MATLAB was used to extract fall risk parameters from the collected data. One-way ANOVA was used to compare fall risk parameters on the different staircases. In addition, the laboratory-based fall risk parameters were compared to those derived from the real house stairs. RESULTS: There was a significant difference in selected stair-fall biomechanical risk factors among the house and laboratory staircases. The fall risk group comparisons suggest that high-risk fallers implemented a biomechanically riskier strategy that could increase overall falling risk. CONCLUSIONS: The significant differences due to the main effects of the fallers and non-fallers groups were obtained. For example, when ascending, the fallers group had less foot clearance on the entry (p = 0.016) and middle steps (p = 0.003); in addition, they had more foot clearance variability on the entry steps (p = 0.003). This suggests that the fallers group in this present study did not adopt more conservative stepping strategies during stair ascent compared to low-risk older adults. By showing less foot clearance and more variability in foot clearance, the risk for a trip would be increased.
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Marcha , Caminhada , Humanos , Idoso , Estudos Prospectivos , Pé , Ambiente ControladoRESUMO
In most cases, the number of honeybee stings received by the body is generally small, but honeybee stings can still cause serious allergic reactions. This study fully simulated bee stings under natural conditions and used 1H Nuclear Magnetic Resonance (1H NMR) to analyze the changes in the serum metabolome of Sprague-Dawley (SD) rats stung once or twice by honeybees to verify the impact of this mild sting on the body and its underlying mechanism. The differentially abundant metabolites between the blank control rats and the rats stung by honeybees included four amino acids (aspartate, glutamate, glutamine, and valine) and four organic acids (ascorbic acid, lactate, malate, and pyruvate). There was no separation between the sting groups, indicating that the impact of stinging once or twice on the serum metabolome was similar. Using the Principal Component Discriminant Analysis ( PCA-DA) and Variable Importance in Projection (VIP) methods, glucose, lactate, and pyruvate were identified to help distinguish between sting groups and non-sting groups. Metabolic pathway analysis revealed that four metabolic pathways, namely, the tricarboxylic acid cycle, pyruvate metabolism, glutamate metabolism, and alanine, aspartate, and glutamate metabolism, were significantly affected by bee stings. The above results can provide a theoretical basis for future epidemiological studies of bee stings and medical treatment of patients stung by honeybees.
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Mordeduras e Picadas de Insetos , Metaboloma , Ratos Sprague-Dawley , Animais , Abelhas/metabolismo , Ratos , Mordeduras e Picadas de Insetos/sangue , Masculino , Redes e Vias Metabólicas , Análise de Componente PrincipalRESUMO
The accumulation of ginsenosides (triterpenic saponins) was determined in Panax quinquefolium hairy root cultures subjected to an elicitation process using carvacrol at 5, 10, 25, 50, 100, 250, and 500 µM concentrations during 24 and 72 h exposure. This study was the first one in which carvacrol was applied as an elicitor. The content of eight ginsenosides, Rb1, Rb2, Rb3, Rc, Rd, Rg1, Rg2, and Re, was determined using HPLC analysis. Moreover, the quantitative RT-PCR method was applied to assess the relative expression level of farnesyl diphosphate synthase, squalene synthase, and dammarenediol synthase genes in the studied cultures. The addition of carvacrol (100 µM) was an effective approach to increase the production of ginsenosides. The highest content and productivity of all detected saponins were, respectively, 20.01 mgâg-1 d.w. and 5.74 mgâL-1âday-1 after 72 h elicitation. The production profile of individual metabolites in P. quinquefolium cultures changed under the influence of carvacrol. The biosynthesis of most examined protopanaxadiol derivatives was reduced under carvacrol treatment. In contrast, the levels of ginsenosides belonging to the Rg group increased. The strongest effect of carvacrol was noticed for Re metabolites, achieving a 7.72-fold increase in comparison to the control. Saponin Rg2, not detected in untreated samples, was accumulated after carvacrol stimulation, reaching its maximum concentration after 72 h exposure to 10 µM elicitor.
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Ginsenosídeos , Panax , Saponinas , Panax/genética , Saponinas/farmacologia , Cimenos , Fármacos do Sistema Nervoso CentralRESUMO
In Alzheimer's disease (AD), transgenic mouse models have established links between abnormalities in the retina and those in the brain. APPNL-F/NL-F is a murine, humanized AD model that replicates several pathological features observed in patients with AD. Research has focused on obtaining quantitative parameters from optical coherence tomography (OCT) in AD. The aim of this study was to analyze, in a transversal case-control study using manual retinal segmentation via SD-OCT, the changes occurring in the retinal layers of the APPNL/F-NF/L AD model in comparison to C57BL/6J mice (WT) at 6, 9, 12, 15, 17, and 20 months of age. The analysis focused on retinal thickness in RNFL-GCL, IPL, INL, OPL, and ONL based on the Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. Both APPNL-F/NL-F-model and WT animals exhibited thickness changes at the time points studied. While WT showed significant changes in INL, OPL, and ONL, the AD model showed changes in all retinal layers analyzed. The APPNL-F/NL-F displayed significant thickness variations in the analyzed layers except for the IPL compared to related WT. These thickness changes closely resembled those found in humans during preclinical stages, as well as during mild and moderate AD stages, making this AD model behave more similarly to the disease in humans.
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Doença de Alzheimer , Modelos Animais de Doenças , Camundongos Transgênicos , Retina , Tomografia de Coerência Óptica , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Tomografia de Coerência Óptica/métodos , Retina/patologia , Retina/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Humanos , Envelhecimento/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Masculino , Feminino , Estudos de Casos e ControlesRESUMO
BACKGROUND: Obesity induces insulin resistance and chronic inflammation, impacting human health. The relationship between obesity, gut microbiota, and regulatory mechanisms has been studied extensively. Dendrobium officinale polysaccharide (DOP), a traditional Chinese herbal medicine, potentially reduces insulin resistance. However, the mechanism through which DOP affects gut microbiota and alleviates obesity-induced insulin resistance in rats requires further investigation. RESULTS: The current study aimed to assess the impact of DOP on gut microbiota and insulin resistance in rats on a high-fat diet. The results revealed that DOP effectively reduced blood lipids, glucose disorders, oxidative stress, and inflammatory infiltration in the liver of obese Sprague Dawley rats. This was achieved by downregulating SOCS3 expression and upregulating insulin receptor substrate-1 (IRS-1) by regulating the JAK/STAT/SOCS3 signaling pathway. Notably, DOP intervention enhanced the abundance of beneficial gut microbiota and reduced harmful microbiota. Correlation analysis demonstrated significant associations among intestinal microbiota, SOCS3-mediated IRS-1 expression, and inflammatory factors. CONCLUSION: Dendrobium officinale polysaccharide regulated the gut microbiota, enhanced IRS-1 expression, and mitigated liver injury and insulin resistance due to a high-fat diet. These findings depict the potential anti-insulin resistance properties of DOP and offer further evidence for addressing obesity and its complications. © 2023 Society of Chemical Industry.
Assuntos
Dendrobium , Microbioma Gastrointestinal , Resistência à Insulina , Ratos , Humanos , Animais , Dendrobium/química , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Ratos Sprague-Dawley , Polissacarídeos/química , Transdução de Sinais , Obesidade/tratamento farmacológico , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismoRESUMO
A mechanized direct seeding of rice with less labor and water usage, has been widely adopted. However, this approach requires varieties that exhibit uniform seedling emergence. Mesocotyl elongation (ME) offers the main drive of fast emergence of rice seedlings from soils; nevertheless, its genetic basis remains unknown. Here, we identify a major rice quantitative trait locus Mesocotyl Elongation1 (qME1), an allele of the Green Revolution gene Semi-Dwarf1 (SD1), encoding GA20-oxidase for gibberellin (GA) biosynthesis. ME1 expression is strongly induced by soil depth and ethylene. When rice grains are direct-seeded in soils, the ethylene core signaling factor OsEIL1 directly promotes ME1 transcription, accelerating bioactive GA biosynthesis. The GAs further degrade the DELLA protein SLENDER RICE 1 (SLR1), alleviating its inhibition of rice PHYTOCHROME-INTERACTING FACTOR-LIKE13 (OsPIL13) to activate the downstream expansion gene OsEXPA4 and ultimately promote rice seedling ME and emergence. The ancient traits of long mesocotyl and strong emergence ability in wild rice and landrace were gradually lost in company with the Green Revolution dwarf breeding process, and an elite ME1-R allele (D349H) is found in some modern Geng varieties (long mesocotyl lengths) in northern China, which can be used in the direct seeding and dwarf breeding of Geng varieties. Furthermore, the ectopic and high expression of ME1 driven by mesocotyl-specific promoters resulted in rice plants that could be direct-seeded without obvious plant architecture or yield penalties. Collectively, we reveal the molecular mechanism of rice ME, and provide useful information for breeding new Green Revolution varieties with long mesocotyl suitable for direct-seeding practice.