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Rotavirus causes severe diarrhea in infants. Although live attenuated rotavirus vaccines are available, vaccine-derived infections have been reported, which warrants development of next-generation rotavirus vaccines. A single-round infectious virus is a promising vaccine platform; however, this platform has not been studied extensively in the context of rotavirus. Here, we aimed to develop a single-round infectious rotavirus by impairing the function of the viral intermediate capsid protein VP6. Recombinant rotaviruses harboring mutations in VP6 were rescued using a reverse genetics system. Mutations were targeted at VP6 residues involved in virion assembly. Although the VP6-mutated rotavirus expressed viral proteins, it did not produce progeny virions in wild-type cells; however, the virus did produce progeny virions in VP6-expressing cells. This indicates that the VP6-mutated rotavirus is a single-round infectious rotavirus. Insertion of a foreign gene, and replacement of the VP7 gene segment with that of human rotavirus clinical isolates, was successful. No infectious virions were detected in mice infected with the single-round infectious rotavirus. Immunizing mice with the single-round infectious rotavirus induced neutralizing antibody titers as high as those induced by wild-type rotavirus. Taken together, the data suggest that this single-round infectious rotavirus has potential as a safe and effective rotavirus vaccine. This system is also applicable for generation of safe and orally administrable viral vectors.IMPORTANCERotavirus, a leading cause of acute gastroenteritis in infants, causes an annual estimated 128,500 infant deaths worldwide. Although live attenuated rotavirus vaccines are available, they are replicable and may cause vaccine-derived infections. Thus, development of safe and effective rotavirus vaccine is important. In this study, we report the development of a single-round infectious rotavirus that can replicate only in cells expressing viral VP6 protein. We demonstrated that (1) the single-round infectious rotavirus did not replicate in wild-type cells or in mice; (2) insertion of foreign genes and replacement of the outer capsid gene were possible; and (3) it was as immunogenic as the wild-type virus. Thus, the mutated virus shows promise as a next-generation rotavirus vaccine. The system is also applicable to orally administrable viral vectors, facilitating development of vaccines against other enteric pathogens.
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Antígenos Virais , Proteínas do Capsídeo , Mutação , Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Rotavirus/genética , Animais , Antígenos Virais/genética , Antígenos Virais/imunologia , Camundongos , Infecções por Rotavirus/virologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/genética , Vacinas contra Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Humanos , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Camundongos Endogâmicos BALB C , Linhagem Celular , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vírion/genética , FemininoRESUMO
Enhanced error monitoring, as indexed by increased amplitude of the error-related negativity (ERN) event-related potential (ERP) component, has been suggested to reflect a vulnerability neuro-marker of anxiety disorders. Another error-related ERP component is the error positivity (Pe), which reflects late-stage error processing. The associations between heightened ERN and Pe amplitudes and anxiety levels in the nonclinical population have been inconsistent. In this preregistered study, we examined the association between anxiety, ERN, and Pe, using different analytical methods (mass-univariate analyses, MUAs and conventional analyses), self-reported anxiety scales (STAI and STICSA), and trial numbers (all correct trials and equal numbers of correct and error trials). In a sample of 82 healthy adults, both conventional and MUAs demonstrated a robust enhancement of the ERN and Pe to errors relative to the correct-response ERPs. However, the mass-univariate approach additionally unveiled a wider array of electrodes and a longer effect duration for this error enhancement. Across the analytic methods, the results showed a lack of consistent correlation between trait anxiety and error-related ERPs. Findings were not modulated by trial numbers, analyses, or anxiety scales. The present results suggest a lack of enhancement of error monitoring by anxious traits in individuals with subclinical anxiety and those with clinical anxiety but without a clinical diagnosis. Importantly, the absence of such correlation questions the validity of the ERN as a neural marker for anxiety disorders. Future studies that investigate neuro-markers of anxiety may explore alternative task designs and employ robust statistics to provide a more comprehensive understanding of anxiety vulnerability.
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Glaucic acid isolated from the root of Lindera glauca, was investigated by the biotransformation methods via the endophytic fungi, resulting in the production of five new glausesquiterpenes AâE (1â5), along with a known analogue 6. Their structures were elucidated based on spectroscopic methods and electronic circular dichroism (ECD) calculations. In the bioassays, glausesquiterpene A (1) showed good inhibitory activity of NO production in LPS-activated RAW 264.7 macrophages with an IC50 value of 20.1 µM than positive control (Indomethacin, IC50 24.1 µM). Further in vitro studies demonstrated that glausesquiterpene A significantly suppressed the protein expression of iNOS and COX-2 at the concentration of 25.0 µM.
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Background: Complex surgical plans and consideration of risks and benefits often cause decisional conflicts for decision-makers in aortic dissection (AD) surgery, resulting in decision delay. Shared decision-making (SDM) improves decision readiness and reduces decisional conflicts. The purpose of this study was to investigate the impact of SDM on decision quality in AD. Methods: One hundred and sixty AD decision-makers were divided into two groups: control (n = 80) and intervention (n = 80). The surgical plan for the intervention group was determined using patient decision aids. The primary outcome was decisional conflict. Secondary outcomes included decision preparation, decision satisfaction, surgical method, postoperative complications, actual participation role, and duration of consultation. The data were analyzed with SPSS 26.0 (IBM Corp., Chicago, IL, USA). p < 0.05 was considered statistically significant. Results: The decisional conflict score was significantly lower in the intervention group than in the control group (p < 0.001). The decision preparation and decision satisfaction scores in the intervention group were significantly higher than those in the control group (p < 0.001). There were more SDM decision-makers in the intervention group (16 [20%] vs. 42 [52.50%]). There was no statistical significance in the choice of surgical, postoperative complications, duration of consultation, and hospital and post-operative intensive care unit stay time (p = 0.267, p = 0.130, p = 0.070, p = 0.397, p = 0.421, respectively). Income, education level, and residence were the influencing factors of decision-making conflict. Conclusions: SDM can reduce decisional conflict, improve decision preparation and satisfaction, and help decision-makers actively participate in the medical management of patients with AD without affecting the medical outcome.
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The dynamic behavior of droplets hitting a solid surface has received extensive attention due to its broad application prospects. Additionally, controlling the rebound behavior of impacting droplets is an important research topic. Current methods for investigating this behavior focus on the construction of a differentiated wettability surface, which is characterized by contact angle measurements, or a differentiated topography surface, which is represented by geometric height. This information allows one to obtain the nonuniform kinetic energy distribution of rebounding droplets and to realize control of rebounding droplet behavior. In this paper, femtosecond laser processing is proposed for the fabrication of an anisotropic surface with differences in adhesion, which allows for the control of impacting droplet rebound behavior. The experimental results show that the micro-nanostructure of the surface affects its adhesion. By changing the micro-nanostructure of the solid surface, the difference in surface adhesion can be controlled, thereby realizing precise control of impacting droplet rebound behavior. This study demonstrates that the micro-nanostructured surface formed by a femtosecond laser can be used to control a droplet rebound direction and landing site, which is of great significance to the development of liquid transport, microfluidic devices, and other fields.
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Vision is a key source of information input for humans, which involves various cognitive functions and a great range of neural networks inside and beyond the visual cortex. There has been increasing observation that the cognitive outcomes after a brain lesion cannot be well predicted by the attributes of the lesion itself but are influenced by the functional network plasticity. However, the mechanisms of impaired or preserved visual cognition have not been probed from direct function-execution conditions and few works have observed it on whole-brain dynamic networks. We used high-resolution electroencephalogram recordings from 25 patients with brain tumors to track the dynamical patterns of functional reorganization in visual processing tasks with multilevel complexity. By comparing with 24 healthy controls, increased cortical responsiveness as functional compensation was identified in the early phase of processing, which was highly localized to the visual cortex and functional networks and less relevant to the tumor position. Besides, a spreading wide enhancement in whole-brain functional connectivity was elicited by the visual word-recognition task. Enhanced early rapid-onset cortical compensation in the local functional networks may contribute to largely preserved basic vision functions, and higher-cognitive tasks are vulnerable to impairment but with high sensitivity of functional plasticity being elicited.
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Neoplasias Encefálicas , Córtex Visual , Encéfalo , Mapeamento Encefálico , Neoplasias Encefálicas/diagnóstico por imagem , Cognição , Humanos , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Vias Neurais , Percepção VisualRESUMO
It is vitally important to develop highly active, robust and low-cost transition metal-based electrocatalysts for overall water splitting in neutral solution especially at large current density. In this work, amorphous Mo-doped NiS0.5 Se0.5 nanosheets@crystalline NiS0.5 Se0.5 nanorods (Am-Mo-NiS0.5 Se0.5 ) was synthesized using a facil one-step strategy. In phosphate buffer saline solution, the Am-Mo-NiS0.5 Se0.5 shows tiny overpotentials of 48 and 209â mV for hydrogen evolution reaction (HER), 238 and 514â mV for oxygen evolution reaction (OER) at 10 and 1000â mA cm-2 , respectively. Moreover, Am-Mo-NiS0.5 Se0.5 delivers excellent stability for at least 300â h without obvious degradation. Theoretical calculations revealed that the Ni sites in the defect-rich amorphous structure of Am-Mo-NiS0.5 Se0.5 owns higher electron state density and strengthened the binding energy of H2 O, which will optimize H adsorption/desorption energy barriers and reduce the adsorption energy of OER determining step.
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Migratory birds spend several months in their breeding grounds in sympatry with local resident birds and relatively shorter periods of time at stopover sites. During migration, parasites may be transmitted between migratory and resident birds. However, to what extent they share these parasites remains unclear. In this study, we compared the assemblages of haemosporidian parasites in migratory, resident, and passing birds, as well as the correlations between parasite assemblages and host phylogeny. Compared with passing birds, migratory birds were more likely to share parasites with resident birds. Shared lineages showed significantly higher prevalence rates than other lineages, indicating that common parasites are more likely to spill over from the current host to other birds. For shared lineages, the prevalence was significantly higher in resident birds than in migratory birds, suggesting that migratory birds pick up parasites at their breeding ground. Among the shared lineages, almost two-thirds presented no phylogenetic signal in their prevalence, indicating that parasite transmission among host species is weakly or not correlated with host phylogeny. Moreover, similarities between parasite assemblages are not correlated with either migration status or the phylogeny of hosts. Our results show that the prevalence, rather than host phylogeny, plays a central role in parasite transmission between migratory and resident birds in breeding grounds.
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Doenças das Aves , Haemosporida , Parasitos , Plasmodium , Animais , Doenças das Aves/epidemiologia , Aves , Haemosporida/genética , Filogenia , Plasmodium/genética , PrevalênciaRESUMO
DHX15, a DEAH box containing RNA helicase, is a splicing factor required for the last step of splicing. Recent studies identified a recurrent mutational hotspot, R222G, in DHX15 in â¼ 6% of acute myeloid leukemia (AML) patients that carry the fusion protein RUNX1-RUNX1T1 produced by t (8;21) (q22;q22). Studies using yeast mutants showed that substitution of G for the residue equivalent to R222 leads to loss of its helicase function, suggesting that it is a loss-of-function mutation. To elucidate the role of DHX15 during development, we established the first vertebrate knockout model with CRISPR/Cas9 in zebrafish. Our data showed that dhx15 expression is enriched in the brain, eyes, pectoral fin primordia, liver and intestinal bulb during embryonic development. Dhx15 deficiency leads to pleiotropic morphological phenotypes in homozygous mutant embryos starting at 3 days post fertilization (dpf) that result in lethality by 7 dpf, revealing an essential role during embryonic development. RNA-seq analysis suggested important roles of Dhx15 in chromatin and nucleosome assembly and regulation of the Mdm2-p53 pathway. Interestingly, exons corresponding to the alternate transcriptional start sites for tp53 and mdm2 were preferentially expressed in the mutant embryos, leading to significant upregulation of their alternate isoforms, Δ113p53 (orthologous to Δ133p53 isoform in human) and mdm2-P2 (isoform using distal promoter P2), respectively. We speculate that these alterations in the Mdm2-p53 pathway contribute to the development of AML in patients with t(8;21) and somatically mutated DHX15.
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Proteínas Proto-Oncogênicas c-mdm2/genética , RNA Helicases/genética , Proteína Supressora de Tumor p53/genética , Proteínas de Peixe-Zebra/genética , Processamento Alternativo , Animais , Animais Geneticamente Modificados , Humanos , Regiões Promotoras Genéticas , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Helicases/metabolismo , Sítios de Splice de RNA , Splicing de RNA , Fatores de Processamento de RNA/genética , Sítio de Iniciação de Transcrição , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
The development of new type electrocatalysts with promising activity and antipoisoning ability is of great importance for electrocatalysis on alcohol oxidation. In this work, Pd nanowire (PdNW)/CuOx heterogeneous catalysts with different types of PdOCu interfaces (Pd/amorphous or crystalline CuOx ) are prepared via a two-step hydrothermal strategy followed by an air plasma treatment. Their interface-dependent performance on methanol and ethanol oxidation reaction (MOR and EOR) is clearly observed. The as-prepared PdNW/crystalline CuOx catalyst with 17.2 at% of Cu on the PdNW surface exhibits better MOR and EOR activity and stability, compared with that of PdNW/amorphous CuOx and pristine PdNW catalysts. Significantly, both the cycling tests and the chronoamperometric measurements reveal that the PdNW/crystalline CuOx catalyst yields excellent tolerance toward the possible intermediates including formaldehyde, formic acid, potassium carbonate, and carbon monoxide generated during the MOR process. The detailed analysis of their chemical state reveals that the enhanced activity and antipoison ability of the PdNW/crystalline CuOx catalyst originates from the electron-deficient Pdδ+ active sites which gradually turn into Pd5 O4 species during the MOR catalysis. The Pd5 O4 species can likely be stabilized by moderate crystalline CuOx decorated on the surface of PdNW due to the strong PdOCu interaction.
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Spinal cord injury (SCI) is a structural event with devastating consequences worldwide. Due to the limited intrinsic regenerative capacity of the spinal cord in adults, the neural restoration after SCI is difficult. Acupuncture is effective for SCI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve neural protection by the inhibition of inflammation, oxidation, and apoptosis. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating multiple cellular signal transduction pathways, such as the Wnt, Notch, and Rho/Rho kinase (ROCK) pathways. Several studies have demonstrated that the efficacy of combining acupuncture with mesenchymal stem cells (MSCs) transplantation is superior to either procedure alone. The advantage of the combined treatment is dependent on the ability of acupuncture to enhance the survival of MSCs, promote their differentiation into neurons, and facilitate targeted migration of MSCs to the spinal cord. Additionally, the differentiation of MSCs into neurons overcomes the problem of the shortage of endogenous neural stem cells (NSCs) in the acupuncture-treated SCI patients. Therefore, the combination of acupuncture and MSCs transplantation could become a novel and effective strategy for the treatment of SCI. Such a possibility needs to be verified by basic and clinical research.
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Terapia por Acupuntura , Transplante de Células-Tronco Mesenquimais , Neurônios/fisiologia , Traumatismos da Medula Espinal/prevenção & controle , Traumatismos da Medula Espinal/fisiopatologia , Animais , Humanos , Plasticidade Neuronal , Recuperação de Função FisiológicaRESUMO
Four new isocoumarin derivatives, botryospyrones A (1), B (2), C (3), and D (4), and a new natural tryptamine, (3aS, 8aS)-1-acetyl-1, 2, 3, 3a, 8, 8a-hexahydropyrrolo [2,3b] indol-3a-ol (5), were isolated from a marine mangrove endophytic fungus Botryosphaeria ramosa L29, obtained from the leaf of Myoporum bontioides. Their structures were elucidated using spectroscopic analysis. The absolute configurations of compounds 3, 4, and 5 were determined by comparison of their circular dichroism (CD) spectra with the calculated data. The inhibitory activities of compound 1 on Fusarium oxysporum, of compounds 2 and 3 on F. oxysporum and Fusarium graminearum, and of compound 5 on F. oxysporum, Penicillium italicum, and F. graminearum were higher than those of triadimefon, widely used as an agricultural fungicide. Compound 5 was produced after using the strategy we called "using inhibitory stress from components of the host" (UISCH), wherein (2R, 3R)-3, 5, 7-trihydroxyflavanone 3-acetate, a component of M. bontioides with weak growth inhibitory activity towards B. ramosa L29, was introduced into the culture medium.
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Antifúngicos/química , Ascomicetos/química , Fusarium/efeitos dos fármacos , Isocumarinas/química , Isocumarinas/farmacologia , Triptaminas/química , Triptaminas/farmacologia , Antifúngicos/farmacologia , Dicroísmo Circular , Endófitos/química , Espectroscopia de Ressonância Magnética , Myoporum , Penicillium/efeitos dos fármacos , Áreas AlagadasRESUMO
OBJECTIVE: As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism. DESIGN: A series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples. RESULTS: We have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients. CONCLUSIONS: A novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.
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Autofagia/efeitos dos fármacos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Corantes Fluorescentes/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mitocôndrias/enzimologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Fluorescência , Corantes Fluorescentes/uso terapêutico , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteínas de Transporte da Membrana Mitocondrial , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Fenômenos Ópticos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Cerebral edema, erupting simultaneously with severe ischemic stroke, might lead to increased intracranial pressure, cerebral herniation, and ultimately death. Studies conducted previously by our team have demonstrated the fact that bloodletting puncture at hand twelve Jing-well points (HTWP) could alleviate cerebral edema, which mainly results from the disruption of blood-brain barrier (BBB). The study, therefore, was first designed to demonstrate whether BBB-protection serves an important role in the edema-relief effect of HTWP bloodletting, based on which to research the molecular mechanism underlying. METHODS: The rats were made into model suffering from permanent middle cerebral artery occlusion (pMCAO) and then bloodletting puncture were treated at HTWP once a day. Wet and dry weight method was adopted to evaluate the degree of brain edema, evans blue extravasation and electron microscopy were used to evaluate the integrity of the BBB, and RT-qPCR was carried out to analyze the expression level of occludin, claudin-5, ICAM-1, and VEGF. RESULTS: Results revealed that bloodletting puncture treatment could reduce water content of brain and the permeability of BBB caused by ischemic stroke. In bloodletting puncture group, ameliorated tight junctions could be observed under electron microscopy. It was demonstrated in further study that, in bloodletting group, compared with pMCAO one, the expression levels of occludin and claudin-5 were up-regulated, while ICAM-1 and VEGF were down-regulated. CONCLUSIONS: In conclusion, bloodletting puncture at HTWP might play a significant role in protecting the tight junctions of BBB, thus alleviating cerebral edema induced by ischemic stroke. Therefore, the therapy of bloodletting puncture at HTWP may be a promising strategy for acute ischemic stroke in the future.
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Pontos de Acupuntura , Barreira Hematoencefálica/fisiologia , Sangria , Edema Encefálico/terapia , Infarto da Artéria Cerebral Média/terapia , Junções Íntimas/fisiologia , Animais , Masculino , Ratos , Ratos WistarRESUMO
Whole-genome shotgun assembly has been a long-standing issue for highly polymorphic genomes, and the advent of next-generation sequencing technologies has made the issue more challenging than ever. Here we present an automated pipeline, HaploMerger, for reconstructing allelic relationships in a diploid assembly. HaploMerger combines a LASTZ-ChainNet alignment approach with a novel graph-based structure, which helps to untangle allelic relationships between two haplotypes and guides the subsequent creation of reference haploid assemblies. The pipeline provides flexible parameters and schemes to improve the contiguity, continuity, and completeness of the reference assemblies. We show that HaploMerger produces efficient and accurate results in simulations and has advantages over manual curation when applied to real polymorphic assemblies (e.g., 4%-5% heterozygosity). We also used HaploMerger to analyze the diploid assembly of a single Chinese amphioxus (Branchiostoma belcheri) and compared the resulting haploid assemblies with EST sequences, which revealed that the two haplotypes are not only divergent but also highly complementary to each other. Taken together, we have demonstrated that HaploMerger is an effective tool for analyzing and exploiting polymorphic genome assemblies.
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Algoritmos , Alelos , Cordados não Vertebrados/genética , Diploide , Genômica/métodos , Alinhamento de Sequência/métodos , Animais , Gráficos por Computador , Simulação por Computador , Etiquetas de Sequências Expressas , Variação Genética , Genoma , Haplótipos , Heterozigoto , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
As a novel electrochemical energy conversion device, direct ethanol fuel cells are currently encountering two significant challenges: CO poisoning and the difficulty of C-C bond cleavage in ethanol. In this work, an amorphous PdS nanowires/ultrafine IrMnOx bimetallic oxides (denoted as a-PdS/IrMnOx NWs) catalyst with abundant oxide/metal (crystalline/amorphous) inverse heterogeneous interfaces was synthesized via a hydrothermal process succeeded by a nonthermal air-plasma treatment. This unique interfacial electronic structure along with the incorporation of oxyphilic metal has resulted in a significant enhancement in the electrocatalytic performance of a-PdS/IrMnOx NWs toward the ethanol oxidation reaction, achieving current densities of 12.45 mA·cm-2 and 3.68 A·mgPd-1. Moreover, the C1 pathway selectivity for ethanol oxidation has been elevated to 47%, exceeding that of other as-prepared Pd-based counterparts and commercial Pd/C catalysts. Density functional theory calculations have validated the findings that the decoration of IrMn species onto the amorphous PdS surface has induced a charge redistribution in the interface region. The redistribution of surface charges on the a-PdS/IrMnOx NWs catalyst results in a significant decrease in the activation energy required for C-C bond cleavage and a notable weakening of the CO binding strength at the Pd active sites. Consequently, it enhanced both the EOR C1 pathway selectivity and CO poisoning resistance to the a-PdS/IrMnOx NWs catalyst.
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BACKGROUND: Immune-checkpoint inhibitors (ICIs) against programmed death (PD)-1/PD-L1 pathway immunotherapy have been demonstrated to be effective in only a subset of patients with cancer, while the rest may exhibit low response or may develop drug resistance after initially responding. Previous studies have indicated that extensive collagen-rich stroma secreted by cancer-associated fibroblasts (CAFs) within the tumor microenvironment is one of the key obstructions of the immunotherapy for some tumors by decreasing the infiltrating cytotoxic T cells. However, there is still a lack of effective therapeutic strategies to control the extracellular matrix by targeting CAFs. METHODS: The enhanced uptake of IR-780 by CAFs was assessed by using in vivo or ex vivo nearinfrared fluorescence imaging, confocal NIR fluorescent imaging, and CAFs isolation testing. The fibrotic phenotype down-regulation effects and in vitro CAFs killing effect of IR-780 were tested by qPCR, western blot, and flow cytometry. The in vivo therapeutic enhancement of anti-PD-L1 by IR-780 was evaluated on EMT6 and MC38 subcutaneous xenograft mice models. RESULTS: IR-780 has been demonstrated to be preferentially taken up by CAFs and accumulate in the mitochondria. Further results identified low-dose IR-780 to downregulate the fibrotic phenotype, while high-dose IR-780 could directly kill both CAFs and EMT6 cells in vitro. Moreover, IR-780 significantly inhibited extracellular matrix (ECM) protein deposition in the peri-tumoral stroma on subcutaneous EMT6 and MC38 xenografts, which increased the proportion of tumor-infiltrating lymphocytes (TILs) in the deep tumor and further promoted anti-PD-L1 therapeutic efficacy. CONCLUSION: This work provides a unique strategy for the inhibition of ECM protein deposition in the tumor microenvironment by targeted regulating of CAFs, which destroys the T cell barrier and further promotes tumor response to PD-L1 monoclonal antibody. IR-780 has been proposed as a potential therapeutic small-molecule adjuvant to promote the effect of immunotherapy.
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Fibroblastos Associados a Câncer , Imunoterapia , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Camundongos , Humanos , Imunoterapia/métodos , Microambiente Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Indóis/farmacologia , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Sepsis is a condition that greatly impacts the brain, leading to neurological dysfunction and heightened mortality rates, making it one of the primary organs affected. Injury to the central nervous system can be attributed to dysfunction of various organs throughout the entire body and imbalances within the peripheral immune system. Furthermore, central nervous system injury can create a vicious circle with infection-induced peripheral immune disorders. We collate the pathogenesis of septic encephalopathy, which involves microglial activation, programmed cell death, mitochondrial dysfunction, endoplasmic reticulum stress, neurotransmitter imbalance, and blood-brain barrier disruption. We also spotlight the effects of intestinal flora and its metabolites, enterocyte-derived exosomes, cholinergic anti-inflammatory pathway, peripheral T cells and their cytokines on septic encephalopathy.
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Oil and gas exploitation introduces toxic contaminants such as hydrocarbons and heavy metals to the surrounding sediment, resulting in deleterious impacts on marine benthic communities. This study combines benthic monitoring data over a 30-year period in the North Sea with dietary information on >1400 taxa to quantify the effects of active oil and gas platforms on benthic food webs using a multiple before-after control-impact experiment. Contamination from oil and gas platforms caused declines in benthic food web complexity, community abundance, and biodiversity. Fewer trophic interactions and increased connectance indicated that the community became dominated by generalists adapting to alternative resources, leading to simpler but more connected food webs in contaminated environments. Decreased mean body mass, shorter food chains, and the dominance of small detritivores such as Capitella capitata near to structures suggested a disproportionate loss of larger organisms from higher trophic levels. These patterns were associated with concentrations of hydrocarbons and heavy metals that exceed OSPAR's guideline thresholds of sediment toxicity. This study provides new evidence to better quantify and manage the environmental consequences of oil and gas exploitation at sea.