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BACKGROUND: Overlapping clinical manifestations of irritable bowel syndrome (IBS) and IBS-like symptoms in patients with inflammatory bowel disease (IBD-IBS) present challenges in diagnosis and management. Both conditions are associated with alterations in metabolites, but few studies have described the lipid profiles. Our aim was to pinpoint specific lipids that contribute to the pathogenesis of IBS and IBD-IBS by analyzing multiple biologic samples. METHODS: Diarrhea-predominant IBS (IBS-D) patients (n = 39), ulcerative colitis in remission with IBS-like symptoms patients (UCR-IBS) (n = 21), and healthy volunteers (n = 35) were recruited. IBS-D patients meet the Rome IV diagnostic criteria, and UCR-IBS patients matched mayo scores ≤ two points and Rome IV diagnostic criteria. Serum, feces, and mucosa were collected for further analysis. Lipid extraction was carried out by ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). RESULTS: Lipidomics of mucosa and serum samples significantly differed among the three groups. Feces showed the most altered lipid species, and the enrichment analysis of 347 differentially abundant metabolites via KEGG pathway analysis revealed that alpha-linolenic acid metabolism was significantly altered in the two groups (P < 0.01). The ratio of omega-6/omega-3 fatty acid were imbalance in serum samples. CONCLUSIONS: This study revealed a comprehensive lipid composition pattern between IBS-D patients and UCR-IBS patients. We found several distinctive lipids involved in alpha-linolenic acid metabolism, reflecting an imbalance in the omega-6/omega-3 fatty acid ratio. Compared to mucosa and serum samples, fecal samples might have more advantages in lipidomics studies due to the convenience of sample collection and effectiveness in reflecting metabolic information.
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The treatment of chronic diabetic wounds is a major challenge due to oxidative stress, persistent hyperglycemia, and susceptibility to bacterial infection. In this study, multifunctional sandwich-structured nanofiber dressings (SNDs) are prepared via electrospinning. The SNDs consisted of an outer layer of hydrophobic polylactic acid (PLA) fibers encapsulating MgB2 nanosheets (MgB2 NSs), a middle layer of PLA and polyvinylpyrrolidone (PVP) fibers encapsulating the MgB2 NSs and metformin hydrochloride complex (MgB2-Met), and an inner layer of water-soluble PVP fibers encapsulating MgB2-Met. Because of their special sandwich structure, SNDs have high photothermal conversion efficiency (24.13%) and photothermal cycle performance. SNDs also exhibit a photothermal effect, bacteria-targeting effect of MgB2, electrostatic attraction ability of metformin hydrochloride (Met), and strong antibacterial activity against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA). SNDs can eliminate intracellular reactive oxygen species (ROS) by regulating the hydrogen release from MgB2. In addition, SNDs have good biocompatibility, can effectively inhibit the inflammatory factor Interleukin-6 (IL-6), and promote granulation tissue formation, collagen deposition, and diabetic wound healing. These findings offer a promising approach for clinical treatment of diabetic wounds.
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The occupancy of the binding pocket by the substrate ultimately determines the outcome of enzyme catalysis. Previous engineering and substrate scope of phenylalanine aminomutase from Taxus chinensis (TcPAM) has generated valuable knowledge about the regioselectivity with biocatalytic potentials for the preparation of α- and ß-phenylalanine and their derivatives. However, the significantly different regioselectivity during the amination of cinnamates by TcPAM is not fully understood. In this study, we take a reconstruction approach to change the whole binding pocket of TcPAM for probing the factors affecting the regioselectivity, resulting in variant C107S/Q319M/I431V reaching a 25.5-fold enhancement of the ß/α product ratio toward trans-cinnamate acid. Furthermore, when substituted cinnamates were used as substrates, the regioselectivity was strongly correlated with various changes in the binding pocket, and value-added 2-Cl-α-Phe (100% α-selectivity) and 4-CH3-ß-Phe (98% ß-selectivity) were individually verified by the mutants L104A and Q319M at a preparative scale, exemplifying the application feasibility of our engineering strategy. The present study uncovered the cooperative connection between aromatic binding and carboxylate binding to affect the regioselectivity, which provides new insights into the determinants of the regioselectivity possessed by TcPAM and paves the way for its biocatalytic applications on phenylalanine derivatives.
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BACKGROUND: Hemiptera is the fifth species-rich order of insects and the most species-rich order of hemimetabolous insects, including numerous insect species that are of agricultural or medical significance. Despite much effort and recent advance in inferring the Hemiptera phylogeny, some high-level relationships among superfamilies remain controversial. RESULTS: We sequenced the genomes of 64 hemipteran species from 15 superfamilies and the transcriptomes of two additional scale insect species, integrating them with existing genomic and transcriptomic data to conduct a comprehensive phylogenetic analysis of Hemiptera. Our datasets comprise an average of 1625 nuclear loci of 315 species across 27 superfamilies of Hemiptera. Our analyses supported Cicadoidea and Cercopoidea as sister groups, with Membracoidea typically positioned as the sister to Cicadoidea + Cercopoidea. In most analyses, Aleyrodoidea was recovered as the sister group of all other Sternorrhyncha. A sister-group relationship was supported between Coccoidea and Aphidoidea + Phylloxeroidea. These relationships were further supported by four-cluster likelihood mapping analyses across diverse datasets. Our ancestral state reconstruction indicates phytophagy as the primary feeding strategy for Hemiptera as a whole. However, predation likely represents an ancestral state for Heteroptera, with several phytophagous lineages having evolved from predatory ancestors. Certain lineages, like Lygaeoidea, have undergone a reversal transition from phytophagy to predation. Our divergence time estimation placed the diversification of hemipterans to be between 60 and 150 million years ago. CONCLUSIONS: By expanding phylogenomic taxon sampling, we clarified the superfamily relationships within the infraorder Cicadomorpha. Our phylogenetic analyses supported the sister-group relationship between the superfamilies Cicadoidea and Cercopoidea, and the superfamily Membracoidea as the sister to Cicadoidea + Cercopoidea. Our divergence time estimation supported the close association of hemipteran diversification with the evolutionary success and adaptive radiation of angiosperms during the Cretaceous period.
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Genoma de los Insectos , Hemípteros , Filogenia , Transcriptoma , Animales , Hemípteros/genética , Hemípteros/clasificación , Genómica , Evolución Molecular , Evolución BiológicaRESUMEN
Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.
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OBJECTIVE: Few studies have examined the relationship between systemic oxidative stress and prostate cancer (PCa) risk. This study aimed to explore potential correlations between PCa and oxidative balance score (OBS), which measures systemic oxidative stress. DESIGN: A cross-sectional study. SETTING: The National Health and Nutrition Examination Survey. PARTICIPANTS: A total of 8156 individuals were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Weighted logistic regression with multivariable adjustment and restricted cubic splines (RCS) were used to assess the correlation between PCa and OBS. A sensitivity analysis was conducted specifically on patients with PCa to verify the results. RESULTS: The prevalence of PCa was 2.55%. The multivariable logistic regression model revealed no correlation between OBS, dietary OBS, lifestyle OBS and PCa. Compared with the lowest quartile of OBS, the adjusted ORs for the highest quartile of OBS, dietary OBS and lifestyle OBS were 1.852 (95% CI 1.028-3.339), 1.565 (95% CI 0.841-2.913) and 1.575 (95% CI 0.915-2.710), respectively. Additionally, all p values for trend were greater than 0.05. Subgroup analysis revealed a consistent lack of association between OBS and PCa across various population settings. Furthermore, analysis using RCS confirmed this absence of association, indicating no significant relationship in either a linear or non-linear context. A sensitivity analysis focusing exclusively on patients with PCa showed a strong association (OR=2.737, p=0.008). CONCLUSION: This cross-sectional study reveals no significant association between systemic oxidative stress, measured by OBS, and PCa risk. Notably, a sensitivity analysis focusing solely on PCa patients suggested a potential link, warranting further investigation.
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Encuestas Nutricionales , Estrés Oxidativo , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/epidemiología , Estudios Transversales , Persona de Mediana Edad , Anciano , Modelos Logísticos , Estados Unidos/epidemiología , Adulto , Factores de Riesgo , Estilo de Vida , Dieta/estadística & datos numéricosRESUMEN
Background: Emerging evidence indicated that depression is currently one of the most burdensome diseases worldwide, and it can lead to a variety of functional physical impairments. However, the studies estimated the association between depression and thyroid function remain sparse. We aimed to investigate the association between depression and thyroid function in the American population. Methods: A cross-sectional analysis was performed using the data from the National Health and Nutrition Examination Survey conducted from 2007 to 2012. In the 12,502 adults aged 20-80 years, weighted linear regression models and multiple logistic regression models were applied to evaluate the association between depression and thyroid function indicators. The thyroid indicators investigated were mainly free thyroxine (FT4), total T4 (TT4), free triiodothyronine (FT3), total T3 (TT3), thyroid-stimulating hormone (TSH), and antithyroperoxidase antibody (TPOAb), thyroglobulin (Tg) and antithyroglobulin antibody (TgAb). Results: The final results were reached after adjusting for various confounding factors. In the stratification analysis of subgroups divided by age, depression was significantly negatively correlated with FT4, FT3, and TT3 in both younger adults (p = 0.00122, p < 0.00001, and p = 0.00003) and older adults (p = 0.00001, p = 0.00004, and p < 0.00001). In contrast, depression was significantly negatively correlated with TT4 and Tg in older adults (p = 0.00054, p = 0.00695) and positively correlated in younger adults (p = 0.01352, p < 0.00001). The subgroup analysis by gender revealed that depression was significantly negatively correlated with FT4, FT3, and TT3 in both adult males (p = 0.0164, p = 0.0204, and p = 0.0050) and adult females (p ≤ 0.0001, p < 0.0001, and p < 0.0001), which was more prominent in females. The positive correlation between depression symptoms and TPOAb was only found in adult females (p = 0.0282) and younger adults (p = 0.00488). Conclusion: This study confirmed a significant correlation between depressive and thyroid function and it varied among different genders or age. In the future, more prospective studies are needed to reveal these findings and confirm a causal relationship between them.
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Depresión , Encuestas Nutricionales , Pruebas de Función de la Tiroides , Glándula Tiroides , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Estudios Transversales , Anciano , Depresión/epidemiología , Depresión/sangre , Anciano de 80 o más Años , Glándula Tiroides/fisiopatología , Adulto Joven , Tiroxina/sangre , Tirotropina/sangre , Triyodotironina/sangreRESUMEN
Background: Life's Essential 8 (LE8), an indicator of cardiovascular health (CVH), can predict overall and cardiovascular mortality in the general population. Considering that cancer survivors have a higher risk of cardiovascular disease (CVD), our study aimed to investigate the association between LE8 and the prognosis of cancer survivors. Methods: A total of 2191 cancer survivors were included from the National Health and Nutrition Examination Survey (2005-2018). LE8 scores, derived from eight individual metrics, were categorized into three groups: low (0-49), moderate (50-79), and high (80-100). Cox regression analysis, nonlinear analysis, sensitivity analysis, and subgroup analysis were conducted to explore the association between LE8 scores and mortality risks, adjusting for potential confounders. Results: During a median follow-up of six years, 479 deaths were recorded, including 118 CVD events and 156 cancer events. LE8 scores showed an inverse linear relationship with all-cause and cardiovascular mortality. A 10-point increase in LE8 scores was associated with a 25 % reduction in all-cause mortality (hazard ratio [HR], 0.75; 95 % CI, 0.66-0.85) and a 29 % reduction in cardiovascular mortality (HR, 0.71; 95 % CI, 0.57-0.89). Additionally, moderate CVH was linked to a lower risk of all-cause mortality (HR, 0.55; 95 % CI, 0.37-0.81), while high CVH was associated with an even lower risk (HR, 0.35; 95 % CI, 0.19-0.68). Similarly, moderate CVH demonstrated a decreased risk of cardiovascular mortality (HR, 0.31; 95 % CI, 0.15-0.63), with high CVH showing an even lower risk (HR, 0.23; 95 % CI, 0.09-0.58). However, LE8 scores was not associated with cancer-specific mortality. Conclusions: A higher LE8 score was independently associated with a decreased risk of both all-cause and cardiovascular mortality in cancer survivors, underscoring the significance of optimizing CVH during the survivorship phase of cancer care.
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Introduction: The relationships among microelements and soil microbial communities are essential for understanding the maintenance of soil's ecological functions and their effects on fruit quality in orchards. However, these relationships have not been adequately studied, despite the importance of microelements for the growth of microorganisms and plants. Methods: To address this research gap, we investigated the relationships among microelements (K, Ca, Na, Mg, Fe, Mn, Zn, and Cu), the diversity and composition of soil microbiomes, and fruit quality in loquat orchards. Results: We found that microelements explained more variations in microbial community structures than geographic position, basic soil properties, and macroelements, with 19.6-42.6% of bacterial, 4.3-27.7% of fungal, and 5.9-18.8% of protistan genera significantly correlated with microelements. Among the microelements, AMg and ACu were the most influential in determining the soil microbiome. The soil microbes exhibited varied threshold values for environmental breadth among the microelements, with the broadest range for AMg and the narrowest for AZn. Additionally, the microbes showed significant phylogenetic signals for all microelements, with an increasing divergence of soil microelements. The dominant community assembly shifted from homogeneous selection to stochastic, and then to heterogeneous selection. Moreover, microelements and the microbiome were the top two factors individually explaining 11.0 and 11.4% of fruit quality variation, respectively. Discussion: These results highlight the importance of microelement fertilization in orchard management and provide scientific guidance for improving fruit quality.
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The Omicron subvariants of SARS-CoV-2, especially for BA.2.86 and JN.1, have rapidly spread across multiple countries, posing a significant threat in the ongoing COVID-19 pandemic. Distinguished by 34 additional mutations on the Spike (S) protein compared to its BA.2 predecessor, the implications of BA.2.86 and its evolved descendant, JN.1 with additional L455S mutation in receptor-binding domains (RBDs), are of paramount concern. In this work, we systematically examine the neutralization susceptibilities of SARS-CoV-2 Omicron subvariants and reveal the enhanced antibody evasion of BA.2.86 and JN.1. We also determine the cryo-EM structures of the trimeric S proteins from BA.2.86 and JN.1 in complex with the host receptor ACE2, respectively. The mutations within the RBDs of BA.2.86 and JN.1 induce a remodeling of the interaction network between the RBD and ACE2. The L455S mutation of JN.1 further induces a notable shift of the RBD-ACE2 interface, suggesting the notably reduced binding affinity of JN.1 than BA.2.86. An analysis of the broadly neutralizing antibodies possessing core neutralizing epitopes reveals the antibody evasion mechanism underlying the evolution of Omicron BA.2.86 subvariant. In general, we construct a landscape of evolution in virus-receptor of the circulating Omicron subvariants.
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Enzima Convertidora de Angiotensina 2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Microscopía por Crioelectrón , Evasión Inmune , Mutación , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Humanos , COVID-19/inmunología , COVID-19/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/inmunología , Enzima Convertidora de Angiotensina 2/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/química , Evolución Molecular , Unión Proteica , Modelos MolecularesRESUMEN
Factor XII (FXII) is the zymogen of the plasma protease FXIIa that activates the intrinsic coagulation pathway and the kallikrein kinin-system. The role of FXII in inflammation has been obscure. Here, we report a single-domain antibody (nanobody, Nb) fused to the Fc region of a human immunoglobulin (Nb-Fc) that recognizes FXII in a conformation-dependent manner and interferes with FXIIa formation. Nb-Fc treatment inhibited arterial thrombosis in male mice without affecting hemostasis. In a mouse model of extracorporeal membrane oxygenation (ECMO), FXII inhibition or knockout reduced thrombus deposition on oxygenator membranes and systemic microvascular thrombi. ECMO increased circulating levels of D-dimer, alkaline phosphatase, creatinine and TNF-α and triggered microvascular neutrophil adherence, platelet aggregation and their interaction, which were substantially attenuated by FXII blockade. Both Nb-Fc treatment and FXII knockout markedly ameliorated immune complex-induced local vasculitis and anti-neutrophil cytoplasmic antibody-induced systemic vasculitis, consistent with selectively suppressed neutrophil migration. In human blood microfluidic analysis, Nb-Fc treatment prevented collagen-induced fibrin deposition and neutrophil adhesion/activation. Thus, FXII is an important mediator of inflammatory responses in vasculitis and ECMO, and Nb-Fc provides a promising approach to alleviate thrombo-inflammatory disorders.
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Factor XII , Inflamación , Ratones Noqueados , Neutrófilos , Anticuerpos de Dominio Único , Trombosis , Animales , Humanos , Trombosis/inmunología , Trombosis/metabolismo , Anticuerpos de Dominio Único/farmacología , Anticuerpos de Dominio Único/inmunología , Masculino , Factor XII/metabolismo , Factor XII/antagonistas & inhibidores , Inflamación/metabolismo , Ratones , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Agregación Plaquetaria/efectos de los fármacos , Factor XIIa/metabolismo , Factor XIIa/antagonistas & inhibidores , Fibrina/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/metabolismoRESUMEN
In this work, a highly efficient rongalite/iodine-mediated oxime formation reaction for the preparation of thiohydroximic acids from methyl ketones by employing copper nitrate as the [NO] reagent has been developed. Notably, copper nitrate participated as both a catalyst and the mild oximation reagent in the transformation. This reaction is highly efficient and facile, with a broad substrate scope, especially for fused ring skeleton substrates, heterocyclic skeleton substrates, and acetyl-substituted natural products. Mechanistic studies revealed that copper nitrate might be converted into a NO2 radical or the NO2 radical dimeric forms as an ion-pair equivalent to participate in the transformation.
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In light of the escalating global warming and the escalating frequency of extreme weather events, the agricultural sector, being a fundamental and pivotal industry worldwide, is encountering substantial challenges due to climate change. Using Chinese provincial panel data for 2000-2021, this paper utilizes a two-way fixed-effect model to investigate the impact of Climate Risk (CR) on green total factor productivity in agriculture (AGTFP), with China's climate policy uncertainty (CPU) being introduced as a moderating variable within the research framework to scrutinize its influence in this context. The findings reveal a noteworthy adverse effect of CR on AGTFP, further exacerbated by CPU. Heterogeneity analysis results show that there is a clear regional variation in the effect of CR on AGTFP across different Chinese regions, with CR significantly inhibiting AGTFP development in the northern regions and provinces in major grain producing regions. Consequently, there is a pressing necessity to bolster the establishment of climate change monitoring infrastructures, devise tailored climate adaptation strategies at a regional level, and enhance the clarity and predictability of climate policies to fortify the resilience and sustainability of agricultural production systems.
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To elucidate the microstructure and charge transfer behavior at the interface of Pd/metal oxide semiconductor (MOS) catalysts and systematically explore the crucial role of the Mott-Schottky effect in the oxygen reduction reaction (ORR) electrocatalysis process, this study established a testing system for spatially identifying Mott-Schottky effects and electronic properties at Pd/MOS interfaces, leveraging highly sensitive Kelvin probe force microscopy (KPFM). This system enabled visualization and quantification of the surface potential difference and Mott-Schottky barrier height (ΦSBH) at the Pd/MOS heterojunction interfaces. Furthermore, a series of Pd/MOS Mott-Schottky catalysts were constructed based on differences in work functions between Pd and n-type MOS. The abundant oxygen vacancies in these catalysts facilitated the adsorption and activation of oxygen molecules. Notably, the intensity of the built-in electric field in the Pd/MOS Mott-Schottky catalysts was calculated through surface potential and zeta potential analysis, systematically correlating the Mott-Schottky effect at the heterojunction interface of Pd/MOS with ORR activity and kinetics. By comprehensively exploring the correlation between the Mott-Schottky effect and ORR performance in Pd/MOS catalysts using the KPFM testing system, this study provides necessary tools and approaches for a deep understanding of heterogeneous interface charge transfer mechanisms, as well as for optimizing catalyst design and enhancing ORR performance.
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Background Tissue engineering based on whole-organ perfusion decellularization has successfully generated small-animal organs, including the heart and limbs. Herein, we aimed to use angiosome-guided perfusion decellularization to generate an acellular fasciocutaneous flap matrix with an intact vascular network. Method Abdominal flaps of rats were harvested, and the vascular pedicle (iliac artery and vein) was dissected and injected with methylene blue to identify the angiosome region and determine the flap dimension for harvesting. To decellularize flaps, the iliac artery was perfused sequentially with 1% sodium dodecyl sulfate, deionized water, and 1% Triton-X100. Gross morphology, histology, and DNA quantity of flaps were then obtained. Flaps were also subjected to glycosaminoglycan and hydroxyproline content assays, as well as computer tomography angiography. Results Histological assessment indicated that cellular content was completely removed in all flap layers following 10-h perfusion in sodium dodecyl sulfate. DNA quantification confirmed 81% DNA removal. Based on biochemical assays, decellularized flaps had hydroxyproline content comparable with that of native flaps, although significantly fewer glycosaminoglycans (p = 0.0019). Histology and computed tomography angiography illustrated the integrity and perfusability of the vascular system. Conclusion The proposed angiosome-guided perfusion decellularization protocol could effectively remove cellular content from rat fasciocutaneous flaps and preserve the integrity of innate vascular networks.
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Why lower low-density lipoprotein cholesterol (LDL-C) was associated with a decreased atherosclerotic cardiovascular disease (ASCVD) risk but an increased hemorrhagic stroke (HS) risk in hypertensive adults remains unclear. We examined whether the inverse LDL-C-HS association partly arises from its effect on ASCVD. We estimated separable effects of LDL-C on HS outside (i.e., separable direct effect) or only through its effect on ASCVD (i.e., separable indirect effect) in hypertensive adults from the Chinese Multi-provincial Cohort Study. We quantified such effects using numbers needed to treat (NNT) to prevent or cause an extra HS based on the restricted mean event-free time till a 25-year follow-up. LDL-C $<$ 70 mg/dL was not associated with an increased HS risk compared to LDL-C $\ge$ 70 mg/dL regarding total and separable direct effects. However, a small separable indirect effect (i.e., NNT to harm: 9722 participants) was noted and validated via a series of sensitivity analyses. Moreover, modified effects were observed, particularly in the 35-49-year age group, men, and those with SBP $\ge$ 140 mm Hg. These results suggest the inverse LDL-C-HS association in hypertensive adults is partly due to its effect on ASCVD. A better understanding of such associations would provide more enlightening into stroke prevention.
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Candesartan cilexetil (CC) is one of well-tolerated antihypertensive drugs, while its poor solubility and low bioavailability limit its use. Herein, two mesoporous silica (Syloid XDP 3150 and Syloid AL-1 FP) and the corresponding amino-modified products (N-XDP 3150 and N-AL-1 FP) have been selected as the carriers of Candesartan cilexetil to prepare solid dispersion through solvent immersion, and characterized through using powder X-ray diffraction analysis, infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance spectroscopy, etc. The state of CC changed from crystalline to amorphous after loading onto the silica carriers, in which no interactions between CC and silica existed. Then, the dissolution behaviors in vitro were studied through using flow-through cell dissolution method. CC-XDP 3150 sample exhibited the most extensive dissolution, and the cumulative release of CC from it was 1.88-fold larger than that of CC. Moreover, the pharmacokinetic results in rats revealed that the relative bioavailability of CC-XDP 3150 and CC-N-XDP 3150 solid dispersions were estimated to be 326 % % and 238 % % in comparison with CC, respectively. Clearly, pore size, pore volume, and surface properties of silica carrier have remarkable effect on loading, dissolution and bioavailability of CC. In brief, this work will provide valuable information in construction of mesoporous silica-based delivery system toward poorly water-soluble drugs.
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In the aquatic farming industry, understanding the factors affecting fish behavior is crucial, particularly in response to infections that compromise welfare and productivity. Swimming performance is a key life history trait critical to their ecology. This study explores the swimming behavior imbalance in Nile tilapia (Oreochromis niloticus, GIFT) post-infection with Streptococcus agalactiae (GBS), a common pathogen responsible for significant losses in aquaculture. We focused on how the microbiota-gut-brain axis influences the behavioral response of tilapia to GBS infection. Behavioral changes were quantified by measuring collision times and swimming speeds, which decreased significantly following infection. This behavioral downturn is mediated by alterations in the microbiota-gut-brain axis, evidenced by increased levels of monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) in the brain and intestinal tissues. The study utilized pharmacological agents, the 5-HT1A receptor agonist (8-OH-DPAT) and antagonist (WAY-100635), to investigate their efficacy in mitigating these behavioral and biochemical changes. Both agents partially restored normal behavior by adjusting neurotransmitter concentrations disrupted by GBS infection. Additionally, a notable increase in the relative abundance of Streptococcus within the gut microbiota of infected fish highlights the potential role of specific bacterial populations in influencing host behavior. This research provides novel insights into the complex interactions between pathogen-induced gut microbiota changes and Nile tilapia's behavioral outcomes, highlighting potential avenues for improving fish health management through microbiota-targeted interventions.
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Conducta Animal , Cíclidos , Enfermedades de los Peces , Microbioma Gastrointestinal , Infecciones Estreptocócicas , Streptococcus agalactiae , Animales , Cíclidos/microbiología , Cíclidos/fisiología , Infecciones Estreptocócicas/veterinaria , Infecciones Estreptocócicas/microbiología , Streptococcus agalactiae/fisiología , Microbioma Gastrointestinal/fisiología , Enfermedades de los Peces/microbiología , Eje Cerebro-Intestino/fisiología , Encéfalo/metabolismo , NataciónRESUMEN
The bacterium Pseudomonas aeruginosa is an exceptionally resilient opportunistic pathogen, presenting formidable challenges for treatment due to its proclivity for developing drug resistance. To address this predicament, we have devised a self-assembled supramolecular antibiotic known as dHTSN1@pHPplus, which can circumvent the drug resistance mechanism of Pseudomonas aeruginosa and effectively combat Pseudomonas aeruginosa infection by impeding the secretion of key virulence factors through the inhibition of the type III secretion system while simultaneously mobilizing immune cells to eradicate Pseudomonas aeruginosa. Furthermore, dHTSN1@pHPplus was ingeniously engineered with infection-targeting capabilities, enabling it to selectively concentrate precisely at the site of infection. As anticipated, the administration of dHTSN1@pHPplus exhibited a remarkable therapeutic efficacy in combating dual resistance to Meropenem and imipenem in a mouse model of P. aeruginosa lung infection. The results obtained from metagenomic detection further confirmed these findings, demonstrating a significant reduction in the proportion of Pseudomonas aeruginosa compared to untreated mice with Pseudomonas aeruginosa-infected lungs. Additionally, no notable acute toxicity was observed in the acute toxicity experiments. The present study concludes that the remarkable efficacy of dHTSN1@pHPplus in treating drug-resistant P. aeruginosa infection confirms its immense potential as a groundbreaking antibiotic agent for combating drug-resistant P. aeruginosa.