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JOURNAL/nrgr/04.03/01300535-202506000-00030/figure1/v/2024-08-05T133530Z/r/image-tiff Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors--NeuroD1, Ascl1, and Dlx2--in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore, we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4 (astrocyte endfeet signal), CX43 (gap junction signal), and S100ß. Importantly, none of these changes could be attributed to transgene leakage into pre-existing neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.
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INTRODUCTION: The purpose of this research was to determine how the P53/microRNA-34a (miR-34a)/survivin pathway contributes to oxaliplatin-induced (L-OHP) cell inhibition in gastric cancer. METHODS: The BGC-823 gastric cancer cells were selected, and we examined their viability following treatment with L-OHP at different concentrations and time periods. The expression levels of miR-34a, P53, and survivin in the cells were determined. RESULTS: In the 12- and 24-h groups, drug concentration of 15 µg/cm² (p < .005 in both) significantly lowered cell viability. In comparison to the control group, miR-34a mRNA expression, P53 mRNA expression, and protein expression were all significantly greater in the 24-h group (p = .0324, p = .0069, p = .0260, respectively), but survivin mRNA and protein expressions were significantly lower than those in the control group (p = .0338, p = .0032, respectively). There was a significant decrease in gastric cancer cells in the miR-34a overexpression group (p = .0020), a significant increase in P53 mRNA and protein expression compared to the control group (p = .0080, p = .0121, respectively), and a significant decrease in survivin mRNA and protein expression compared to the control group. (p = .0213, p = .0069, respectively). CONCLUSION: Oxaliplatin inhibits tumor growth, invasion, and metastasis by upregulating miR-34a, activating the expression of the upstream P53 gene, and driving the downregulation of survivin (P53/miR-34a/survivin axis) in BGC-823 gastric cancer cells.
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Regulação Neoplásica da Expressão Gênica , Proteínas Inibidoras de Apoptose , MicroRNAs , Oxaliplatina , Neoplasias Gástricas , Survivina , Proteína Supressora de Tumor p53 , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , MicroRNAs/genética , Humanos , Oxaliplatina/farmacologia , Survivina/metabolismo , Survivina/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da DoençaRESUMO
OBJECTIVE: The relationship between vitamin D3 and asthma remains controversial. However, previous studies have largely overlooked the impact of epi-25-(OH)-vitamin D3. This study aims to investigate the effects of different forms of vitamin D3 on asthma attack in adults. METHODS: In this cross-sectional study, a total of 3,873 eligible adult participants were extracted from the national health and nutrition examination survey (NHANES) database from 2007 to 2018. Based on quartiles method, different levels of vitamin D were divided into four groups (Quartile 1-4). Bivariate correlation analysis was performed for vitamin D and covariates to avoid multicollinearity. Multivariate logistic regression was used to investigate the association between serum levels of vitamin D3 (epi-25-(OH)-vitamin D3 and 25-(OH)-vitamin D3) and asthma attack, adjusting for covariates including age, gender, race, length of time in the U.S., house poverty income ratio (PIR), education level, smoking history, hypertension history, and diabetes history. The ratio of epi-25-(OH)-vitamin D3 to 25-(OH)-vitamin D3 was used for secondary analysis of its association with asthma attack. The outcomes were assessed by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the 3,873 eligible adults American with asthma, 1,508 (38.94%) had experienced at least one acute asthma attack in the past year. There was no significant correlation between vitamin D and covariates. After adjusting for covariates including age, gender, race, length of time in the U.S., house poverty income ratio (PIR), education level, smoking history, hypertension history and diabetes history, we found a positive correlation between the ratio of epi-25-(OH)-vitamin D3 to 25-(OH)-vitamin D3 and asthma attack. Additionally, a high ratio of epi-25-(OH)-vitamin D3 to 25-(OH)-vitamin D3 was more common among elder, male, of normal weight, non-Hispanic American, have a long time stay in the U.S., a high house PIR, and a history of hypertension individuals. CONCLUSION: Our findings suggest that attention should be given to asthma attack associated with a high ratio of epi-25-(OH)-vitamin D3 to 25-(OH)-vitamin D3 in American adults who are elderly, male, of normal weight, non-Hispanic Americans, have long-term residence in the U.S., a high house PIR, and a history of hypertension.
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Asma , Inquéritos Nutricionais , Humanos , Asma/epidemiologia , Asma/sangue , Masculino , Feminino , Estados Unidos/epidemiologia , Estudos Transversais , Adulto , Pessoa de Meia-Idade , Calcifediol/sangue , Fatores de Risco , Idoso , Adulto JovemRESUMO
Introduction: Antigen testing has been crucial in effectively managing the coronavirus disease 2019 (COVID-19) pandemic. This study evaluated the clinical performance of a nasopharyngeal swab (NPS)-based antigen rapid diagnostic test (Ag-RDT) compared to the gold standard real-time reverse transcription-polymerase chain reaction (RT-PCR) for early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We developed an IgM-based rapid antigen test for early detection of SARS-CoV-2 infection. Between July 2021 and January 2022, we analyzed 1,030 NPS samples from participants at three centers in different countries, using both antigen rapid diagnostic tests (Ag-RDT) and RT-PCR. Results: The Ag-RDT demonstrated minimal detection limits as low as 0.1 ng/mL for recombinant N antigen and 100 TCID50/mL for heat-inactivated SARS-CoV-2 virus. Specificity assessments involving four human coronaviruses and 13 other respiratory viruses showed no cross-reactivity. The Ag-RDT assay (ALLtest) exhibited high sensitivity (93.18%-100%) and specificity (99.67%-100%) across all centers. Factors such as cycle threshold (Ct) values and the timing of symptoms since onset were influential, with sensitivity increasing at lower Ct values (<30) and within the first week of symptoms. Conclusion: The ALLtest Ag-RDT demonstrated high reliability and significant potential for diagnosing suspected COVID-19 cases.
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Laminectomy is a commonly performed surgical procedure by orthopedic and neurosurgeons, aimed at alleviating nerve compression and reducing pain. However, in some cases, excessive proliferation of fibrous scar tissue in the epidural space post-surgery can lead to persistent and intractable lower back pain, a condition known as Failed Back Surgery Syndrome (FBSS). The persistent fibrous tissue causes both physical and emotional distress for patients and also makes follow-up surgeries more challenging due to reduced visibility and greater technical difficulty. It has been established that the application of biomaterials to prevent epidural fibrosis post-lumbar surgery is more beneficial than revision surgeries to relieve dural fibrosis. Hydrogel-based biomaterials, with their excellent biocompatibility, degradability, and injectability and tunable mechanical properties, have been increasingly introduced by clinicians and researchers. This paper, building on the foundation of epidural fibrosis, primarily discusses the strategies for the preparation of natural and polymeric biomaterials to prevent epidural fibrosis, their physicochemical properties, and their ability to mitigate the excessive proliferation of fibroblasts. It also emphasizes the challenges that need to be addressed to translate laboratory research into clinical practice and the latest advancements in this field.
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Diabetes mellitus (DM) is a chronic metabolic disease that is highly susceptible to kidney injury. Di'ao XinXueKang capsules (DXXK) is a novel Chinese herbal medicine that has been used in clinical trials for the therapy of DM and kidney disease, but the underlying pharmacological mechanism remains unclear. This study aims to integrate network pharmacology, molecular docking and in vivo experiments to explore the potential mechanisms of DXXK in the treatment of diabetic kidney injury. The chemical constituents of DXXK were extracted from the ETCM and Batman-TCM databases, and then evaluated for their pharmacological activity via the Swiss ADME platform. Multiple disease databases were searched and integrated for DM-related targets. Overlapping targets were then collected to construct a protein-protein interaction (PPI) network. KEGG and GO enrichment analyses were performed based on the Metascape database, and molecular docking was performed using AutoDock Vina software. The main components in DXXK were analyzed by HPLC. The results of network pharmacology and molecular docking were validated in an animal model of DM induced by the combination of a high-fat diet (HFD) and streptozotocin (STZ). We screened and obtained 7 ingredients and identified dioscin, protodioscin, and pseudoprotodioscin as the major components of DXXK by HPLC. A total of 2,216 DM-related pathogenic genes were obtained from DrugBank, GeneCards, OMIM, and DisGeNET databases. KEGG and GO enrichment analyses indicated that the TGF-beta signaling pathway is a critical pathway associated with DM therapy. Molecular docking revealed that the ingredients in DXXK bind to the pivotal targets TGFß1, Smad2, and Smad3. In diabetic mice, we found that DXXK alleviated diabetic symptoms, lowered blood glucose, improved insulin tolerance, and modulated lipid metabolism. Furthermore, DXXK attenuated renal lesions and fibrosis by downregulating TGFß1, Smad2, and Smad3. Collectively, our results suggest that DXXK has the potential to regulate glucolipid metabolism in DM, and it may serve as a viable therapeutic option for renoprotection by inhibiting of the TGF-ß1/Smad2/3 pathway.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Diabetes Mellitus Experimental/tratamento farmacológico , Mapas de Interação de Proteínas/efeitos dos fármacos , Camundongos , MasculinoRESUMO
Hypoxic stress, triggered by a multitude of factors, has inflicted significant economic repercussions on the aquaculture of Eriocheir sinensis. In this research, we sequenced a collective of 60 samples from both hypoxia-sensitive and hypoxia-resistant groups utilizing streamlined genome sequencing techniques. Subsequently, we delved into population evolution, scrutinized the selective sweep within these populations, and performed a genome-wide association study (GWAS) focused on the hypoxia tolerance traits within the population, all through the lens of SNPs molecular markers. This comprehensive analysis aimed to uncover the SNPs and pinpoint the pertinent candidate genes that influence the hypoxia tolerance capabilities of E. sinensis. The selective sweep analysis revealed that genes harboring potential genetic variations within the two populations were predominantly enriched in areas such as signaling molecules and interactions, energy metabolism, glycolipid metabolism, and immune response. In the genome-wide association study focusing on hypoxia tolerance traits, we identified four SNPs significantly associated with hypoxia resistance. Furthermore, one potential candidate gene, Dscam2, which is believed to influence hypoxia tolerance, was discovered within a 50 kb vicinity of these SNPs. These identified SNPs can serve as molecular markers for screening hypoxia tolerance, offering valuable insights for the genetic improvement of E. sinensis.
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BACKGROUND: Partial bladder outlet obstruction (pBOO) causes deposition of extracellular matrix (ECM), promotes bladder fibrosis, and decreases bladder compliance. METHODS: To investigate the effect of ß-adrenoceptor (ADRB) on the ECM deposition of pBOO rat model and explore its underlying mechanism, human bladder smooth muscle cells (hBSMCs) were exposed to the pathological hydrostatic pressure (100 cm H2O) for 6 h, reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were employed. Then the rats of sham operation and pBOO model were treated with vehicle or ADRB agonists for 3 weeks, and the alterations of the bladder were observed via Masson staining and immunohistochemical analysis. RESULTS: 100 cm H2O hydrostatic pressure significantly upregulated the expression of collagen I (COL1), collagen III (COL3) and fibronectin (FN), and downregulated the expression of ADRB2 and ADRB3 of hBSMCs at 6 h. The agonists of ADRB2 and ADRB3, Formoterol and BRL 37344, decreased COL1 and FN expression of hBSMCs under 100 cm H2O for 6 h compared with the cells exposed to hydrostatic pressure only. As the classic downstream pathways of ADRB, the EPAC pathway inhibited COL1 and FN expression of hBSMCs via regulating SMAD3 and SMAD2 activities, respectively. In pBOO rats, Procaterol (ADRB2 agonist), and Mirabegron (ADRB3 agonist) inhibited the formation of collagen and decreased the expression of FN and COL1 in the bladders of pBOO rats. CONCLUSIONS: The bladder fibrosis of pBOO and deposition of hBSMCs ECM under hydrostatic pressure were regulated by ADRB2, and ADRB3 via EPAC/SMAD2/FN and EPAC/SMAD3/COL1 pathways, these findings pave an avenue for effective treatment of pBOO.
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Matriz Extracelular , Fibrose , Transdução de Sinais , Obstrução do Colo da Bexiga Urinária , Bexiga Urinária , Obstrução do Colo da Bexiga Urinária/metabolismo , Obstrução do Colo da Bexiga Urinária/patologia , Animais , Matriz Extracelular/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/efeitos dos fármacos , Ratos , Humanos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Miócitos de Músculo Liso/metabolismo , Tiazóis/farmacologia , Fumarato de Formoterol/farmacologia , Acetanilidas/farmacologia , Etanolaminas/farmacologia , Etanolaminas/metabolismo , Fibronectinas/metabolismo , Fibronectinas/genética , Feminino , Agonistas Adrenérgicos beta/farmacologiaRESUMO
The inorganic matrices such as metal concentrates, steel, cement, glass, clay, coal, graphite, rocks and sediments, ores etc. play a pivotal role in infrastructure development, transportation, and energy. The presence of non-metallic elements particularly halogens influence their quality, processing cost, and environment dynamics. The analysis of non-metals in such matrices is critically challenging due to their hardness, rigidity, and non-digestibility. This comprehensive review provides a critical comparison of various sample preparation methods in conjunction with pros and cons of advanced techniques for the detection of non-metals in complex matrices, particularly focusing on ion chromatography. Moreover, the review also addresses the challenges related to the enrichment and automation of non-metals analysis. In addition, the previous literature on non-metals determination in diverse range of inorganic matrices has been tabulated for the first time. These insights are intended to guide researchers, quality control analysts, environmental scientists, and policymakers in enhancing pollution monitoring and control strategies.
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Halogênios , Halogênios/análise , Halogênios/química , Cromatografia por Troca Iônica/métodos , Monitoramento Ambiental/métodosRESUMO
In eukaryotes, the leading strand DNA is synthesized by Polε and the lagging strand by Polδ. These replicative polymerases have higher processivity when paired with the DNA clamp PCNA. While the structure of the yeast Polε catalytic domain has been determined, how Polε interacts with PCNA is unknown in any eukaryote, human or yeast. Here we report two cryo-EM structures of human Polε-PCNA-DNA complex, one in an incoming nucleotide bound state and the other in a nucleotide exchange state. The structures reveal an unexpected three-point interface between the Polε catalytic domain and PCNA, with the conserved PIP (PCNA interacting peptide)-motif, the unique P-domain, and the thumb domain each interacting with a different protomer of the PCNA trimer. We propose that the multi-point interface prevents other PIP-containing factors from recruiting to PCNA while PCNA functions with Polε. Comparison of the two states reveals that the finger domain pivots around the [4Fe-4S] cluster-containing tip of the P-domain to regulate nucleotide exchange and incoming nucleotide binding.
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Microscopia Crioeletrônica , Antígeno Nuclear de Célula em Proliferação , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/química , Humanos , Holoenzimas/química , Holoenzimas/metabolismo , Modelos Moleculares , DNA Polimerase II/metabolismo , DNA Polimerase II/química , DNA Polimerase II/genética , DNA/metabolismo , DNA/química , Ligação Proteica , Domínio Catalítico , Replicação do DNA , Proteínas de Ligação a Poli-ADP-RiboseRESUMO
OBJECTIVES: To study the risk factors and prognostic characteristics of pediatric silent lupus nephritis (SLN) with class â ¢ to V. METHODS: A retrospective study was conducted to collect clinical data from 30 children diagnosed with SLN at the Department of Pediatrics, Second Xiangya Hospital, Central South University, from May 2007 to April 2023. Based on renal pathological classification, the patients were divided into a class â ¡ group (12 cases) and a class â ¢ to â ¤ group (18 cases). The risk factors for the occurrence of class â ¢ to â ¤ SLN were analyzed, and the prognostic characteristics were summarized. RESULTS: Among the 30 SLN patients, the median follow-up time was 61.50 months. There were no statistically significant differences in the proportions of patients who discontinued glucocorticoids or achieved low disease activity status, nor in the annual decline rate of estimated glomerular filtration rate (eGFR) between the class â ¡ and class â ¢ to V groups (P>0.05). However, three patients in the class â ¡ group progressed to stage 1 chronic kidney disease (CKD), while eight patients in the class III to V group reached stage 1 CKD, and four patients reached stage 2 CKD. Among the 26 female SLN patients, serum complement C3 levels in the class III to V group were lower than those in the class â ¡ group (P<0.05). Serum C3 levels in SLN patients, as well as in female SLN patients, were negatively correlated with the fluorescence intensity of IgA, IgG, and C3 immune complexes in the kidneys (P<0.05). Additionally, serum C3 levels in female SLN patients were negatively correlated with the renal pathological activity index (P<0.05). Binary logistic regression analysis indicated that being female and having low serum complement C3 levels were risk factors for the occurrence of class â ¢ to V SLN in children (P<0.05). CONCLUSIONS: Class â ¢ to V SLN is not uncommon among SLN children, and there remains a risk of long-term renal function progression. Being female and having low serum complement C3 levels are identified as risk factors for class â ¢ to V SLN in children.
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Complemento C3 , Nefrite Lúpica , Humanos , Feminino , Masculino , Criança , Fatores de Risco , Estudos Retrospectivos , Prognóstico , Complemento C3/análise , Adolescente , Taxa de Filtração Glomerular , Pré-EscolarRESUMO
Glomerular filtration rate (GFR) is a critical indicator of renal function assessment, which exhibits age-dependency in children and may differ from adults under various disease conditions. In recent years, there has been a growing focus on GFR among scholars, with an increasing number of clinical studies dedicated to refining and optimizing GFR estimation to span all pediatric age groups. However, the methods and assessment equations for estimating GFR may vary under different disease conditions, affecting the accuracy and applicability of assessments. This article reviews the peculiarities of renal function in children, explores GFR measurement methods, and evaluates the application of various GFR assessment equations in pediatric clinical practice, providing a reference for clinical assessment of renal function in children.
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Taxa de Filtração Glomerular , Humanos , Criança , Creatinina/sangueRESUMO
Rabies is a highly lethal infectious disease with no existing treatment available, thus investigating effective antiviral compounds to control rabies virus (RABV) infection is of utmost importance. Resveratrol is a natural phenolic compound that, as a phytoalexin, exhibits several biological activities, including antiviral activity. In this study, we evaluated the inhibitory effect of resveratrol on RABV infection and investigated its molecular antiviral mechanism. We found that resveratrol significantly inhibited RABV infection, including the phases of adsorption, replication, and release, and also directly inactivated RABV and inhibited its infectivity. However, resveratrol had no significant effect on RABV internalization. Resveratrol also reduced RABV-induced oxidative stress, specifically reactive oxygen species and malondialdehyde levels. Western blotting analysis revealed that resveratrol enhanced antioxidant signaling via the SIRT1/Nrf2/HO-1 pathway and inhibited viral replication. Viral infection was enhanced after SIRT1 knockdown, which inhibited the SIRT1/Nrf2/HO-1 antioxidant signaling pathway, suggesting that this pathway plays an important role in RABV replication. Overall, resveratrol prevented the adsorption, replication, and release of RABV and directly inactivated RABV, but failed to inhibit RABV internalization. Furthermore, resveratrol activated the SIRT1/Nrf2/HO-1 pathway to inhibit RABV replication and suppressed RABV-induced oxidative stress. These findings highlight the therapeutic potential of resveratrol for fighting RABV infections.
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Background: Thyroid cancer (TC) prone to cervical lymph node (CLN) metastasis both before and after surgery. Ultrasonography (US) is the first-line imaging method for evaluating the thyroid gland and CLNs. However, this assessment relies mainly on the subjective judgment of the sonographer and is very much dependent on the sonographer's experience. This prospective study was designed to construct a machine learning model based on contrast-enhanced ultrasound (CEUS) videos of CLNs to predict the risk of CLN metastasis in patients with TC. Methods: Patients who were proposed for surgical treatment due to TC from August 2019 to May 2020 were prospectively included. All patients underwent US of CLNs suspected of metastasis, and a 2-minute imaging video was recorded. After target tracking, feature extraction, and feature selection through the lymph node imaging video, three machine learning models, namely, support vector machine, linear discriminant analysis (LDA), and decision tree (DT), were constructed, and the sensitivity, specificity, and accuracy of each model for diagnosing lymph nodes were calculated by leave-one-out cross-validation (LOOCV). Results: A total of 75 lymph nodes were included in the study, with 42 benign cases and 33 malignant cases. Among the machine learning models constructed, the support vector machine had the best diagnostic efficacy, with a sensitivity of 93.0%, a specificity of 93.8%, and an accuracy of 93.3%. Conclusions: The machine learning model based on US video is helpful for the diagnosis of whether metastasis occurs in the CLNs of TC patients.
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Microbial communities exhibit intricate interactions underpinned by metabolic dependencies. To elucidate these dependencies, we present a workflow utilizing random matrix theory on metagenome-assembled genomes to construct co-occurrence and metabolic complementarity networks. We apply this approach to a temperature gradient hot spring, unraveling the interplay between thermal stress and metabolic cooperation. Our analysis reveals an increase in the frequency of metabolic interactions with rising temperatures. Amino acids, coenzyme A derivatives, and carbohydrates emerge as key exchange metabolites, forming the foundation for syntrophic dependencies, in which commensalistic interactions take a greater proportion than mutualistic ones. These metabolic exchanges are most prevalent between phylogenetically distant species, especially archaea-bacteria collaborations, as a crucial adaptation to harsh environments. Furthermore, we identify a significant positive correlation between basal metabolite exchange and genome size disparity, potentially signifying a means for streamlined genomes to leverage cooperation with metabolically richer partners. This phenomenon is also confirmed by another composting system which has a similar wide range of temperature fluctuations. Our workflow provides a feasible way to decipher the metabolic complementarity mechanisms underlying microbial interactions, and our findings suggested environmental stress regulates the cooperative strategies of thermophiles, while these dependencies have been potentially hardwired into their genomes during co-evolutions.
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Archaea , Bactérias , Redes e Vias Metabólicas , Metagenoma , Microbiota , Redes e Vias Metabólicas/genética , Archaea/genética , Archaea/metabolismo , Bactérias/metabolismo , Bactérias/genética , Bactérias/classificação , Metagenoma/genética , Fontes Termais/microbiologia , Filogenia , Interações Microbianas , Temperatura AltaRESUMO
Path planning for multiple unmanned aerial vehicles (UAVs) is crucial in collaborative operations and is commonly regarded as a complicated, multi-objective optimization problem. However, traditional approaches have difficulty balancing convergence and diversity, as well as effectively handling constraints. In this study, a directional evolutionary non-dominated sorting dung beetle optimizer with adaptive stochastic ranking (DENSDBO-ASR) is developed to address these issues in collaborative multi-UAV path planning. Two objectives are initially formulated: the first one represents the total cost of length and altitude, while the second represents the total cost of threat and time. Additionally, an improved multi-objective dung beetle optimizer is introduced, which integrates a directional evolutionary strategy including directional mutation and crossover, thereby accelerating convergence and enhancing global search capability. Furthermore, an adaptive stochastic ranking mechanism is proposed to successfully handle different constraints by dynamically adjusting the comparison probability. The effectiveness and superiority of DENSDBO-ASR are demonstrated by the constrained problem functions (CF) test, the Wilcoxon rank sum test, and the Friedman test. Finally, three sets of simulated tests are carried out, each including different numbers of UAVs. In the most challenging scenario, DENSDBO-ASR successfully identifies feasible paths with average values of the two objective functions as low as 637.26 and 0. The comparative results demonstrate that DENSDBO-ASR outperforms the other five algorithms in terms of convergence accuracy and population diversity, making it an exceptional optimization approach to path planning challenges.
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OBJECTIVE: Thoracoscopy has gained extensive utilization in managing pleural disorders, and enhanced recovery after surgery (ERAS) can improve patients' prognosis and expedite post-surgical recovery. This study aimed to investigate the knowledge, attitudes, and practices (KAP) towards ERAS among patients underwent thoracoscopy surgery. METHODS: This cross-sectional study was conducted between September 2022 and August 2023, among patients underwent thoracoscopy surgery in 6 Secondary or Tertiary hospitals in the author's area. Demographic characteristics and KAP scores were collected by questionnaires, and clinical data were extracted from medical records. RESULTS: A total of 309 valid questionnaires were collected, with 165 (53.40%) males and 202 (65.37%) aged ≤65 years old. The mean scores for KAP were 28.92±7.21 (possible range: 9-45), 53.60±6.73 (possible range: 13-65), and 43.45±5.50 (possible range: 10-50), respectively. SEM confirmed the positive associations between knowledge and attitude (ß = 0.108, P = 0.019), knowledge and practice (ß = 0.096, P = 0.004), and attitude and practice (ß = 0.438, P<0.001). However, the KAP were found not associated with prognosis. CONCLUSION: Patients underwent thoracoscopy surgery showed moderate knowledge, positive attitude, and appropriate practice towards ERAS. Preoperative education, personalized counseling, peer support groups, peer support groups, and follow-up care were recommended in further clinical practice.
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Recuperação Pós-Cirúrgica Melhorada , Conhecimentos, Atitudes e Prática em Saúde , Toracoscopia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Toracoscopia/métodos , Adulto , Inquéritos e QuestionáriosRESUMO
2C is a highly conserved picornaviral non-structural protein with ATPase activity and plays a multifunctional role in the viral life cycle as a promising target for anti-picornavirus drug development. While the structure-function of enteroviral 2Cs have been well studied, cardioviral 2Cs remain largely uncharacterized. Here, an endogenous ATP molecule was identified in the crystal structure of 2C from encephalomyocarditis virus (EMCV, Cardiovirus A). The ATP is bound into the ATPase active site with a unique compact conformation. Notably, the γ-phosphate of ATP directly interacts with Arg311 (conserved in cardioviral 2Cs), and its mutation significantly inhibits the ATPase activity. Unexpectedly, this mutation remarkably promotes 2C self-oligomerization and viral replication efficiency. Molecular dynamic simulations showed that the Arg311 side chain is highly dynamic, indicating it may function as a switch between the activation state and the inhibition state of ATPase activity. A hexameric ring model of EMCV 2C full length indicated that the C-terminal helix may get close to the N-terminal amphipathic helices to form a continuous positive region for RNA binding. The RNA-binding studies of EMCV 2C revealed that the RNA length is closely associated with the RNA-binding affinities and indicated that the substrate may wrap around the outer surface of the hexamer. Our studies provide a biochemical framework to guide the characterization of EMCV 2C and the essential role of arginine in cardioviral 2C functions. IMPORTANCE: Encephalomyocarditis virus (Cardiovirus A) is the causative agent of the homonymous disease, which may induce myocarditis, encephalitis, and reproductive disorders in various mammals. 2C protein is functionally indispensable and a promising target for drug development involving broad-spectrum picornaviral inhibitors. Here, an endogenous ATP molecule with a unique conformation was discovered by a combination of protein crystallography and high-performance liquid chromatography in the encephalomyocarditis virus (EMCV) 2C structure. Biochemical and structural characterization analysis of EMCV 2C revealed the critical role of conserved Arg311 in ATPase activity and self-oligomerization of EMCV 2C. The viral replication kinetics and infectivity study suggested that the residue negatively regulated the infectivity titer and virus encapsulation efficiency of EMCV and is, therefore, crucial for 2C protein to promote viral replication. Our systemic structure-function analysis provides unique insights into the function and regulation mechanism of cardioviral 2C protein.
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Calcineurin is a serine/threonine protein phosphatase that is highly conserved from yeast to human and plays a critical role in many physiological processes. Regulators of calcineurin (RCANs) are a family of endogenous calcineurin regulators, which are capable of inhibiting the catalytic activity of calcineurin in vivo and in vitro. In this study, we first characterized the biochemical properties of yeast calcineurin and its endogenous regulator Rcn1, a yeast homolog of RCAN1. Our data show that Rcn1 inhibits yeast calcineurin toward pNPP substrate with a noncompetitive mode; and Rcn1 binds cooperatively to yeast calcineurin through multiple low-affinity interactions at several docking regions. Next, we reinvestigated the mechanism underlying the inhibition of mammalian calcineurin by RCAN1 using a combination of biochemical, biophysical, and computational methods. In contrast to previous observations, RCAN1 noncompetitively inhibits calcineurin phosphatase activity toward both pNPP and phospho-RII peptide substrates by targeting the enzyme active site in part. Re-analysis of previously reported kinetic data reveals that the RCAN1 concentrations used were too low to distinguish between the inhibition mechanisms [Chan B et al. (2005) Proc Natl Acad Sci USA 102, 13075]. The results presented in this study provide new insights into the interaction between calcineurin and RCAN1/Rcn1.
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BACKGROUND: Microbial anaerobic metabolism is a key driver of biogeochemical cycles, influencing ecosystem function and health of both natural and engineered environments. However, the temporal dynamics of the intricate interactions between microorganisms and the organic metabolites are still poorly understood. Leveraging metagenomic and metabolomic approaches, we unveiled the principles governing microbial metabolism during a 96-day anaerobic bioreactor experiment. RESULTS: During the turnover and assembly of metabolites, homogeneous selection was predominant, peaking at 84.05% on day 12. Consistent dynamic coordination between microbes and metabolites was observed regarding their composition and assembly processes. Our findings suggested that microbes drove deterministic metabolite turnover, leading to consistent molecular conversions across parallel reactors. Moreover, due to the more favorable thermodynamics of N-containing organic biotransformations, microbes preferentially carried out sequential degradations from N-containing to S-containing compounds. Similarly, the metabolic strategy of C18 lipid-like molecules could switch from synthesis to degradation due to nutrient exhaustion and thermodynamical disadvantage. This indicated that community biotransformation thermodynamics emerged as a key regulator of both catabolic and synthetic metabolisms, shaping metabolic strategy shifts at the community level. Furthermore, the co-occurrence network of microbes-metabolites was structured around microbial metabolic functions centered on methanogenesis, with CH4 as a network hub, connecting with 62.15% of total nodes as 1st and 2nd neighbors. Microbes aggregate molecules with different molecular traits and are modularized depending on their metabolic abilities. They established increasingly positive relationships with high-molecular-weight molecules, facilitating resource acquisition and energy utilization. This metabolic complementarity and substance exchange further underscored the cooperative nature of microbial interactions. CONCLUSIONS: All results revealed three key rules governing microbial anaerobic degradation. These rules indicate that microbes adapt to environmental conditions according to their community-level metabolic trade-offs and synergistic metabolic functions, further driving the deterministic dynamics of molecular composition. This research offers valuable insights for enhancing the prediction and regulation of microbial activities and carbon flow in anaerobic environments. Video Abstract.