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JOURNAL/nrgr/04.03/01300535-202502000-00029/figure1/v/2024-05-28T214302Z/r/image-tiff Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis. Human-induced pluripotent stem cell-derived neural stem cell exosomes (hiPSC-NSC-Exos) have shown potential for brain injury repair in central nervous system diseases. In this study, we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism. Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits, enhanced blood-brain barrier integrity, and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage. Additionally, hiPSC-NSC-Exos decreased immune cell infiltration, activated astrocytes, and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α post-intracerebral hemorrhage, thereby improving the inflammatory microenvironment. RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion, thereby improving blood-brain barrier integrity. Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects. In summary, our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity, in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.
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Parkinson's disease (PD) pathology speculates that neuromelanin (NM) and iron ions play a significant role in physiological and pathological conditions of PD. Because the difficult accessibility of NM has limited targeted research, synthetic melanin-like nanoparticles have been used to instead. In this report, the eumelanin and pheomelanin-like polydopamine (PDA) nanoparticles are prepared that can be used to simulate natural NM with or without chelating iron ion and studied the redox effects in vitro and in vivo on neuronal cells and PD. The synthetic pheomelanin-like PDA nanoparticles have much stronger redox activity than eumelanin-like PDA nanoparticles without or with iron ion. They can protect neurons by scavenging reactive oxygen species (ROS), while cause neuronal cell death and PD due to excessive binding of iron ions. This work provides new evidence for the relationship among two structural components of NM and iron in PD as well as displays the different effects on the roles of eumelanin and pheomelanin in redox activity under physiological or pathological conditions, which provide a new effective choice for cellular and animal models of PD and offer theoretical guidance for targeted treatment and mechanism research on PD.
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Dynamic ADP-ribosylation signalling is a crucial pathway that controls fundamental cellular processes, in particular, the response to cellular stresses such as DNA damage, reactive oxygen species and infection. In some pathogenic microbes the response to oxidative stress is controlled by a SirTM/zinc-containing macrodomain (Zn-Macro) pair responsible for establishment and removal of the modification, respectively. Targeting this defence mechanism against the host's innate immune response may lead to novel approaches to support the fight against emerging antimicrobial resistance. Earlier studies suggested that Zn-Macros play a key role in the activation of this defence. Therefore, we used phylogenetic, biochemical, and structural approaches to elucidate the functional properties of these enzymes. Using the substrate mimetic asparagine-ADP-ribose as well as the ADP-ribose product, we characterise the catalytic role of the zinc ion in the removal of the ADP-ribosyl modification. Furthermore, we determined structural properties that contribute to substrate selectivity within the different Zn-Macro branches. Together, our data not only give new insights into the Zn-Macro family but also highlight their distinct features that may be exploited for the development of future therapies.
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Dragonflies are some of the most stable and maneuverable flying organisms. To explore the mechanism of how dragonfly leading edges enhance flight lift, this article conducts a detailed study on the leading edge veins and the microstructures on them of dragonfly wings. Observations have discovered the special leading edge vein and the regularly distributed microstructures on the leading edge vein. A biomimetic model has been established, and computational fluid dynamics (CFD) simulation analysis has been conducted on the biomimetic model. The analysis explores the effects of microstructure characteristics, distribution patterns, and positions on the aerodynamic characteristics of dragonfly gliding. The analysis shows that the leading edge structure influences the incoming flow, simultaneously promotes the formation of the leading edge vortex (LEV), and increases the lift-to-drag ratio by up to 4%. A wing prototype featuring biomimetic microstructures is subsequently fabricated and tested in wind tunnel experiments. Compared with a control group without leading edge structures, the airflow passing through the biomimetic structures is influenced by the shape and arrangement of these structures. The smoother transition of the leading edge vein's shape facilitates the flow of air. The microstructures primarily filter and accelerate the airflow. The spacing of the microstructures affects the stability of the airflow, thereby influencing aerodynamic performance. Additionally, the middle-row arrangement of microstructures is more beneficial for gliding conditions, while the upper-row arrangement is more advantageous for flapping conditions. These findings enhance our understanding of insect wings and advance micro aerial vehicle applications. RESEARCH HIGHLIGHTS: This study observed the leading-edge veins and microstructures of dragonfly wings in detail. Using a biomimetic model and computational fluid dynamics (CFD) simulations, it was found that these leading-edge structures promote the formation of leading-edge vortices (LEV), increasing the lift-to-drag ratio by up to 4%. Wind tunnel experiments demonstrated that wings with biomimetic microstructures significantly improved airflow smoothness and lift compared with control wings. Additionally, the arrangement of microstructures greatly affects airflow stability and aerodynamic performance, with middle-row arrangements being more beneficial for gliding and upper-row arrangements for flapping conditions. These findings enhance our understanding of insect wings and provide innovative guidance for designing efficient micro aerial vehicles.
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Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.
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Antígeno B7-H1 , Imunoterapia , Receptor de Morte Celular Programada 1 , Neoplasias Urológicas , Humanos , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Imunoterapia/métodos , Neoplasias Urológicas/terapia , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/imunologia , Neoplasias Urológicas/etiologia , Neoplasias Urológicas/patologia , Animais , Transdução de Sinais/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Evasão TumoralRESUMO
Background: Radiation-induced intestinal injuries are common in patients with pelvic or abdominal cancer. However, these injuries are currently not managed effectively. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been extensively used in regenerative medicine. However, the results of MSC-EVs in the repair of radiation-induced intestinal damage have been unsatisfactory. We here investigated the nanotherapeutic functions of MSC-EVs in radiation-induced intestinal injury. Methods: We visualized the biodistribution and trend of MSC-EVs through in vivo imaging. A radiation-induced intestinal injury model was constructed, and the therapeutic effect of MSC-EVs was explored through in vivo and in vitro experiments. Immunofluorescence and qRT-PCR assays were conducted to explore the underlying mechanisms. Results: MSC-EVs exhibited a dose-dependent tendency to target radiation-injured intestines while providing spatiotemporal information for the early diagnosis of the injury by quantifying the amount of MSC-EVs in the injured intestines through molecular imaging. Meanwhile, MSC-EVs displayed superior nanotherapeutic functions by alleviating apoptosis, improving angiogenesis, and ameliorating the intestinal inflammatory environment. Moreover, MSC-EVs-derived miRNA-455-5p negatively regulated SOCS3 expression, and the activated downstream Stat3 signaling pathway was involved in the therapeutic efficacy of MSC-EVs in radiation-induced intestinal injuries. Conclusion: MSC-EVs can dose-dependently target radiation-injured intestinal tissues, allow a spatiotemporal diagnosis in different degrees of damage to help guide personalized therapy, offer data for designing EV-based theranostic strategies for promoting recovery from radiation-induced intestinal injury, and provide cell-free treatment for radiation therapy.
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Vesículas Extracelulares , Intestinos , Células-Tronco Mesenquimais , Vesículas Extracelulares/metabolismo , Animais , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/metabolismo , MicroRNAs/genética , Apoptose/efeitos da radiação , Humanos , Lesões por Radiação/terapia , Lesões por Radiação/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Transdução de Sinais , Fator de Transcrição STAT3/metabolismoRESUMO
PURPOSE: To develop and evaluate a new pulse sequence for highly accelerated distortion-free diffusion MRI (dMRI) by inserting an additional echo without prolonging TR, when generalized slice dithered enhanced resolution (gSlider) radiofrequency encoding is used for volumetric acquisition. METHODS: A phase-reversed interleaved multi-echo acquisition (PRIME) was developed for rapid, high-resolution, and distortion-free dMRI, which includes two echoes where the first echo is for target diffusion-weighted imaging (DWI) acquisition with high-resolution and the second echo is acquired with either 1) lower-resolution for high-fidelity field map estimation, or 2) matching resolution to enable efficient diffusion relaxometry acquisitions. The sequence was evaluated on in vivo data acquired from healthy volunteers on clinical and Connectome 2.0 scanners. RESULTS: In vivo experiments demonstrated that 1) high in-plane acceleration (Rin-plane of 5-fold with 2D partial Fourier) was achieved using the high-fidelity field maps estimated from the second echo, which was made at a lower resolution/acceleration to increase its SNR while matching the effective echo spacing of the first readout, 2) high-resolution diffusion relaxometry parameters were estimated from dual-echo PRIME data using a white matter model of multi-TE spherical mean technique (MTE-SMT), and 3) high-fidelity mesoscale DWI at 550 um isotropic resolution could be obtained in vivo by capitalizing on the high-performance gradients of the Connectome 2.0 scanner. CONCLUSION: The proposed PRIME sequence enabled highly accelerated, high-resolution, and distortion-free dMRI using an additional echo without prolonging scan time when gSlider encoding is utilized.
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Biochar modification is an effective approach to enhance its ability to promote anaerobic digestion (AD). Focusing on the physical properties of biochar, the impact of different particle sizes of biochar on AD of food waste (FW) at high organic loading rate (OLR) was investigated. Four biochar with different sizes (40-200 mesh) were prepared and used in AD systems at OLR 30 g VS/L. The research results found that biochar with a volume particle size of 102 µm (RBC-P140) had top-performance in promoting cumulative methane production, increasing by 13.20% compared to the control group. The analysis results of the variety in volatile acids and alkalinity in the system did not show a correlation with the size of biochar, but small size has the potential to improve the environmental tolerance of the system to high acidity. Microbial community analysis showed that the abundance of aceticlastic methanogen and the composition of zoogloea were optimized through relatively small-sized biochar. Through revealing the effect of biochar particle size on AD system at high OLR, this work provided theoretical guidance for regulating fermentation systems using biochar.
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The use of bio-based composites to enhance the methane production in anaerobic digestion has attracted considerable attention. Nevertheless, the study of electron transfer mechanisms and the applications of biochar/MnO2 (MBC) in complex systems remains largely unexplored. Biochar composited with MnO2 at 10:1 mass ratio (MBC10) increased the content of volatile fatty acids by 9.09 % during acidogenic phase. During the methanogenic experiments using acetate, cumulative methane production (CMP) rose by 5.83 %, and in the methanogenic experiments using food waste, CMP increased by 24.32 %. Microbial community analysis indicated an enrichment of Syntrophomonas, Bacilli, and Methanosaetaceae in the MBC10 group. This enrichment occurred mainly due to the redox capability of MnO2 enhancing MBC capacitance, thereby facilitating microbial electron transfer processes. Additionally, under 2 g/L ammonia nitrogen concentration and 30 g/L organic load, the CMP of MBC10 increased by 12.74 % and 9.44 %, respectively, compared to the BC600 group. This study illuminates MBC's electron transfer mechanisms and applications, facilitating its wider practical adoption and fostering future innovations.
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The ligated boryl radical (LBR) has emerged as a potent tool for activating alkyl halides in radical transformations through halogen-atom transfer (XAT). However, unactivated alkyl chlorides still present an open challenge for this strategy. We herein describe a new activation mode of the LBR for the activation of unactivated alkyl chlorides to construct a C(sp3)-C(sp3) bond. Mechanistic studies reveal that the success of the protocol relies on a radical replacement process between the LBR and unactivated alkyl chloride, forming an alkyl borane intermediate as the alkyl radical precursor. Aided with the additive K3PO4, the alkyl borane then undergoes one-electron oxidation, generating an alkyl radical. The incorporation of the radical replacement activation model to activate unactivated alkyl chlorides significantly enriches LBR chemistry, which has been applied to activate alkyl iodides, alkyl bromides, and activated alkyl chlorides via XAT.
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Riptortus pedestris (Hemiptera: Alydidae), a common agricultural pest, is the major causative agent of "soybean staygreen." However, the interactions between chemosensory proteins (CSPs) in R. pedestris and host plant volatiles have yet to be comprehensively studied. In this study, we performed real-time fluorescence quantitative polymerase chain reaction (PCR) to analyze the antennal expression of RpedCSP22 and subsequently analyzed the interactions between 21 soybean volatiles, five aggregation pheromones, and RpedCSP22 protein in vitro using a protein expression system, molecular docking, site-directed mutagenesis, and fluorescence competitive binding experiments. The RpedCSP22 protein showed binding affinity to three soybean volatiles (benzaldehyde, 4-ethylbenzaldehyde, and 1-octene-3-ol), with optimal binding observed under neutral pH conditions, and lost binding ability after site-directed mutagenesis. In subsequent RNA interference (RNAi) studies, gene silencing was more than 90 %, and in silenced insects, electroantennographic responses were reduced by more than 75 % compared to non-silenced insects. Moreover, Y-tube olfactory behavioral assessments revealed that the attraction of R. pedestris to the three soybean volatiles was significantly attenuated. These findings suggest that RpedCSP22 plays an important role in the recognition of host plant volatiles by R. pedestris andprovides a theoretical basis for the development of novel inhibitors targeting pest behavior.
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Glycine max , Proteínas de Insetos , Compostos Orgânicos Voláteis , Animais , Glycine max/metabolismo , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/química , Compostos Orgânicos Voláteis/metabolismo , Mutagênese Sítio-Dirigida , Simulação de Acoplamento Molecular , Hemípteros/metabolismo , Hemípteros/genética , Antenas de Artrópodes/metabolismo , Feromônios/metabolismo , Heterópteros/metabolismo , Heterópteros/genéticaRESUMO
The soil-water characteristic curve (SWCC) is an important basis for describing hydraulic properties, which is closely related to environmental problems such as the migration of toxic substances from groundwater and soil. The SWCC models vary considerably with respect to the void ratio or bulk density. However, the void ratio and bulk density of the same soil change at different depths or positions within a flat space. Accurate simulation or calculation requires a precise SWCC, but measuring every SWCC under each density or void ratio condition is difficult. In this study, two particle packing models, the Kwan model and the modified linear packing density model (MLPDM), were introduced into the van Genuchten (VG) model to predict the SWCC for soil at the minimum void ratio (the maximum dry density). Then, the prediction method of the SWCCs for the same soil with different densities or void ratios was given. A series of laboratory tests using quartz sand mixtures were conducted to verify the accuracy of two extended models (the K-VG model and the M-VG model). For the K-VG model, the average RMSE was 0.020. For the M-VG model, the average RMSE was 0.017. In general, the SWCCs predicted by the two extended models were consistent with the measured values.
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Cryptorchidism, commonly known as undescended testis, affects 1%-9% of male newborns, posing infertility and testis tumor risks. Despite its prevalence, the detailed pathophysiology underlying male infertility within cryptorchidism remains unclear. Here, we profile and analyze 46,644 single-cell transcriptomes from individual testicular cells obtained from adult males diagnosed with cryptorchidism and healthy controls. Spermatogenesis compromise in cryptorchidism links primarily to spermatogonium self-renewal and differentiation dysfunctions. We illuminate the involvement of testicular somatic cells, including immune cells, thereby unveiling the activation and degranulation of mast cells in cryptorchidism. Mast cells are identified as contributors to interstitial fibrosis via transforming growth factor ß1 (TGF-ß1) and cathepsin G secretion. Furthermore, significantly increased levels of secretory proteins indicate mast cell activation and testicular fibrosis in the seminal plasma of individuals with cryptorchidism compared to controls. These insights serve as valuable translational references, enriching our comprehension of testicular pathogenesis and informing more precise diagnosis and targeted therapeutic strategies for cryptorchidism.
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Criptorquidismo , Perfilação da Expressão Gênica , Análise de Célula Única , Espermatogênese , Transcriptoma , Criptorquidismo/genética , Criptorquidismo/patologia , Criptorquidismo/metabolismo , Masculino , Humanos , Análise de Célula Única/métodos , Espermatogênese/genética , Transcriptoma/genética , Testículo/metabolismo , Testículo/patologia , Mastócitos/metabolismo , Mastócitos/patologia , Adulto , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Fibrose , Espermatogônias/metabolismo , Espermatogônias/patologiaRESUMO
Age-related cognitive decline and dementia are significant manifestations of brain aging. As the elderly population grows rapidly, the health and socio-economic impacts of cognitive dysfunction have become increasingly significant. Although clinical treatment of dementia has faced considerable challenges over the past few decades, with limited breakthroughs in slowing its progression, there has been substantial progress in understanding the molecular mechanisms and hallmarks of age-related dementia (ARD). This progress brings new hope for the intervention and treatment of this disease. In this review, we categorize the latest findings in ARD biomarkers into four stages based on disease progression: healthy brain, pre-clinical, mild cognitive impairment, and dementia. We then systematically summarize the most promising therapeutic approaches to prevent or slow ARD at four levels: genome and epigenome, organelle, cell, and organ and organism. We emphasize the importance of early prevention and detection, along with the implementation of combined treatments as multimodal intervention strategies, to address brain aging and ARD in the future.
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Indole and skatole (3-methylindole, C9H9N) are common nitrogen-containing heterocyclic pollutants found in waste, wastewater treatment plants, and public restrooms and are the most notorious compounds in animal feces. Biodegradation was considered a feasible method for the removal of indole and skatole, but a comprehensive understanding of the metabolic pathways under both aerobic and anaerobic conditions was lacking, and the functional genes responsible for skatole biodegradation remained a mystery. Through metagenomic and gene cluster functional analysis, Acinetobacter piscicola p38 (NCBI: CP167896), genes 1650 (styrene monooxygenase: ACDW34_08180), and 1687 (styrene monooxygenase: ACDW34_08350) were identified as having the potential to degrade indole and skatole. The heterologous expression results demonstrate that the genes 1650 and 1651 (flavin reductase: ACDW34_08185), when combined, are capable of degrading indole, while the genes 1687 and 1688 (flavin reductase: ACDW34_08355), in combination, can degrade indole as well as skatole. These reactions necessitate the involvement of flavin reductase and NAD(P)H to catalyze the oxygenation process. This work aimed to provide new experimental evidence for the biodegradation of indole and skatole. This study offered new insights into our understanding of skatole degradation. The Acinetobacter_piscicola p38 strain provided an effective bacterial resource for the bioremediation of fecal indole and skatole.
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To investigate the effect of 5-aminolevulinic acid (5-ALA) on in vitro rumen gas production, fermentation characteristics, and bacterial community profiles, five levels of 5-ALA (0, 100, 500, 1000, and 5000 mg/kg DM) were supplemented into a total mixed ration (concentrate/forage = 40:60) as substrate in an in vitro experiment. Results showed that as the supplementation level of 5-ALA increased, asymptotic gas production (b) decreased linearly and quadratically (p < 0.01) while the dry matter degradation rate increased quadratically (p < 0.01). Meanwhile, the propionate concentration of 72 h incubation fluid increased linearly (p = 0.03) and pH value increased linearly and quadratically (p < 0.01), while the concentrations of butyrate, isobutyrate, valerate, isovalerate, and NH3-N and the ratio of acetate/propionate (A/P) decreased linearly and quadratically (p < 0.05). There was no significant difference in any alpha diversity indices of bacterial communities among the various 5-ALA levels (p < 0.05). PCoA and PERMANOVA analysis revealed that the bacterial profiles showed a statistical difference between the treatment 5-ALA at 1000 mg/kg DM and the other levels except for 5000 mg/kg DM (p < 0.05). Taxonomic classification revealed a total of 18 and 173 bacterial taxa at the phylum and genus level with relative abundances higher than 0.01% in at least half of the samples, respectively. LEfse analysis revealed that 19 bacterial taxa were affected by 5-ALA levels. Correlation analysis showed that Actinobacteriota was positively correlated with the gas production parameter b, the ratio of A/P, and the concentration of butyrate, isovalerate, and NH3-N (p < 0.05) and negatively correlated with pH (p < 0.05). WPS-2 exhibited a negative correlation with the gas production parameter b, the ratio of A/P, and the concentration of butyrate, valerate, isobutyrate, isovalerate, and NH3-N (p < 0.05), along with a weaker positive correlation with pH (p = 0.04). The Bacteroidales BS11 gut group was negatively correlated with the concentration of propionate but positively correlated with gas production parameter b and the concentration of butyrate and NH3-N (p < 0.05). The Lachnospiraceae NK3A20 group was found to have a positive correlation with gas production parameter b, the ratio of A/P, and the concentration of butyrate, isobutyrate, isovalerate, valerate, total VFA, and NH3-N (p < 0.05), but a highly negative correlation with pH (p < 0.01). Differential metabolic pathways analysis suggested that metabolic pathways related to crude protein utilization, such as L-glutamate degradation VIII (to propanoate), L-tryptophan degradation IX, and urea cycle, increased with 5-ALA levels. In summary, including 5-ALA in the diet might improve energy and protein utilization by reducing the abundance of Actinobacteriota, the Bacteroidales BS11 gut group, the Lachnospiraceae NK3A20 group, and certain pathogenic bacteria and increasing the abundance of WPS-2.
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PURPOSE: This study aimed to investigate the clinical significance of combining peripheral blood miR-21 and miR-486 with CT for the early cancer diagnosis in pulmonary nodules. METHODS: A total of 215 patients diagnosed with isolated pulmonary nodules with a history of smoking were selected as researchsubjects. 30 healthy volunteers with a history of smoking were recruitedas the control group.The selection of subjectswas based on the presence of isolated pulmonary nodules detected on chest CT scans. The training set consisted of 65 patients with lung nodules and 30 healthy smokers, while the verification setincluded 150 patients with lung nodules. RESULTS: Compared with the control group, the plasma expression level of miR-210 was significantly higher in the group of patients with benign pulmonary nodules (P < 0.05). The level of miR-486-5p was lower in patients with malignant pulmonary nodules compared to those with benign pulmonary nodules (P < 0.05). Moreover, the plasma level of miR-210was higher in patients with malignant pulmonary nodules compared to those with benign pulmonary nodules and healthy smokers (P < 0.05). The combination of miR-21 and miR-486 yielded an AUC of 0.865, which was significantly higher than any other gene combination (95%CI: 0.653-0.764, P < 0.05). CONCLUSIONS: This study offered preliminary evidence supporting the use of peripheral blood miR-21 and miR-486, combined with CT scans, as potential biomarkers for the early cancer diagnosis in lung nodules.
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Neoplasias Pulmonares , MicroRNAs , Tomografia Computadorizada por Raios X , Humanos , MicroRNAs/sangue , Masculino , Feminino , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagem , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/sangue , Detecção Precoce de Câncer/métodos , Idoso , AdultoRESUMO
Metal-ligand cooperation (MLC) has emerged as a pivotal strategy for the catalytic activation of small molecules within both synthetic and biological arenas. Leveraging this approach, a suite of potent catalytic reactionsâencompassing hydrogenation, hydroelementation, and dehydrogenative processesâhave been realized, with notable advances in manganese catalysis in recent years. However, the activation of alkyl halides by Mn complexes, which typically requires strong reductants to form Mn(-I) complexes that are incompatible with standard cross-coupling conditions, remains a significant challenge. This limitation underscores the urgent need to investigate alternative methods for activating C(sp3)-X bonds using higher valence state Mn complexes. In response to this challenge, we present the synthesis, characterization, and reactivity of a new anionic Mn(I) complex featuring a redox-active dianionic ligand that induces multiple MLC functionalities. We have discovered an innovative mechanism of MLC, characterized by a single ligand transferring two electrons to the metal center. This novel process facilitates an orbital-symmetry-allowed nucleophilic attack on C(sp3)-X bonds, preserving manganese's oxidative state at +1. To the best of our knowledge, this is the first instance where the MLC strategy via a two-electron transfer process has been utilized to execute an SN2 nucleophilic attack at a C(sp3)-X bond by a relatively electron-deficient metal center like Mn(I). Additionally, the dianionic ligand of the anionic Mn(I) complex exhibits ambident nucleophilicity by reacting with different electrophiles, further highlighting its versatile reactivity.
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Silymarin, an antioxidant, is locally used for kidney and heart ailments. However, its limited water solubility and less oral bioavailability limit its therapeutic efficiency. The present study investigated the enhancement of solubility and bioavailability of silymarin by loading it in Cordia myxa plant extract-coated zeolitic imidazole framework (CME@ZIF-8) against carbon tetrachloride (CCl4)-induced nephrotoxicity and cardiac toxicity in albino rats. The synthesized PEG-coated silymarin drug-loaded CME@ZIF-8 MOFs (PEG-Sily@CME@ZIF-8) were characterized by scanning electron microscopy, transmission electron microscopy, high-resolution transmission electron microscopy, energy dispersive X-ray spectroscopy, UV-visible spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, and zeta potential. The average crystal size of CME@ZIF-8 and PEG-Sily@CME@ZIF-8 was 12.69 and 16.81 nm, respectively. The silymarin drug loading percentage in PEG-Sily@CME@ZIF-8 was 33.05% (w/w). In the animal model with CCl4 treatment, different parameters like serum profile, enzymatic level, genotoxicity, and histopathology were assessed. Treatment with PEG-Sily@CME@ZIF-8 with different doses of 500, 1000, and 1500 µg/kg body weight efficiently ameliorated the alterations in the antioxidant defenses, biochemical parameters, and histopathological alterations and DNA damage in comparison to silymarin drug in a CCl4-induced toxicity rat model via alleviating the cellular abnormalities and attenuation of normal antioxidant enzymes levels. Moreover, the molecular mechanism of drug-silymarin interaction with the target protein was investigated. It involves the binding pockets of silymarin molecules with VEGFR, TNF-α, NLRP3, AT1R, NOX1, RIPK1, Caspase-3, CHOP, and MMP-9 proteins, elucidating the silymarin-protein interactions by the formation of hydrogen bonds and hydrophobic interactions. This study suggests that the nanodrug PEG-Sily@CME@ZIF-8 MOFs protect the kidneys and heart possibly by mitigating oxidative stress more efficiently than the conventional drug silymarin.
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In environments teeming with distractions, the ability to selectively focus on relevant information is crucial for advanced cognitive processing. Existing research using event-related potential (ERP) technology has shown active suppression of irrelevant stimuli during the consolidation phase of visual working memory (VWM). In previous studies, participants have always been given sufficient time to consolidate VWM, while suppressing distracting information. However, it remains unclear whether the suppression of irrelevant distractors requires continuous effort throughout their presence or whether this suppression is only necessary after the consolidation of task-relevant information. To address this question, our study examines whether distractor suppression is necessary in scenarios where consolidation time is limited. This research investigates the effect of varying presentation durations on the filtering of distractors in VWM. We tasked participants with memorizing two color stimuli and ignoring four distractors, presented for either 50 ms or 200 ms. Using ERP technology, we discovered that the distractor-induced distractor positivity (PD) amplitude is larger during longer presentation durations compared to shorter ones. These findings underscore the significant impact of presentation duration on the efficacy of distractor suppression in VWM, as prolonged exposure results in a stronger suppression effect on distractors. This study sheds light on the temporal dynamics of attention and memory, emphasizing the critical role of stimulus timing in cognitive tasks. These findings provide valuable insights into the mechanisms underlying VWM and have significant implications for models of attention and memory.