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The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.
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Astrócitos/metabolismo , Carcinogênese/metabolismo , Transdiferenciação Celular , Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Comunicação Parácrina , Animais , Linhagem da Célula , Neoplasias Cerebelares/patologia , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/metabolismo , Xenoenxertos , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Microambiente TumoralRESUMO
Acinetobacter baumannii, an opportunistic pathogen, poses a significant threat in intensive care units, leading to severe nosocomial infections. The rise of multi-drug-resistant strains, particularly carbapenem-resistant A. baumannii, has created formidable challenges for effective treatment. Given the prolonged development cycle and high costs associated with antibiotics, phages have garnered clinical attention as an alternative for combating infections caused by drug-resistant bacteria. However, the utilization of phage therapy encounters notable challenges, including the narrow host spectrum, where each phage targets a limited subset of bacteria, increasing the risk of phage resistance development. Additionally, uncertainties in immune system dynamics during treatment hinder tailoring symptomatic interventions based on patient-specific states. In this study, we isolated two A. baumannii phages from wastewater and conducted a comprehensive assessment of their potential applications. This evaluation included sequencing analysis, genome classification, pH and temperature stability assessments, and in vitro bacterial inhibition assays. Further investigations involved analyzing histological and cytokine alterations in rats undergoing phage cocktail treatment for pneumonia. The therapeutic efficacy of the phages was validated, and transcriptomic studies of rat lung tissue during phage treatment revealed crucial changes in the immune system. The findings from our study underscore the potential of phages for future development as a treatment strategy and offer compelling evidence regarding immune system dynamics throughout the treatment process.IMPORTANCEDue to the growing problem of multi-drug-resistant bacteria, the use of phages is being considered as an alternative to antibiotics, and the genetic safety and application stability of phages determine the potential of phage application. The absence of drug resistance genes and virulence genes in the phage genome can ensure the safety of phage application, and the fact that phage can remain active in a wide range of temperatures and pH is also necessary for application. In addition, the effect evaluation of preclinical studies is especially important for clinical application. By simulating the immune response situation during the treatment process through mammalian models, the changes in animal immunity can be observed, and the effect of phage therapy can be further evaluated. Our study provides compelling evidence that phages hold promise for further development as therapeutic agents for Acinetobacter baumannii infections.
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Infecções por Acinetobacter , Acinetobacter baumannii , Bacteriófagos , Carbapenêmicos , Modelos Animais de Doenças , Terapia por Fagos , Acinetobacter baumannii/virologia , Acinetobacter baumannii/efeitos dos fármacos , Animais , Infecções por Acinetobacter/terapia , Infecções por Acinetobacter/microbiologia , Ratos , Terapia por Fagos/métodos , Carbapenêmicos/farmacologia , Bacteriófagos/fisiologia , Bacteriófagos/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Masculino , Genoma Viral , Águas Residuárias , Pneumonia/terapia , Pneumonia/microbiologia , Pneumonia/virologiaRESUMO
Inorganic fullerene clusters have attracted widespread attention due to their highly symmetrical geometric structures and intrinsic electronic properties. However, cage-like clusters composed of heavy metal elements with high symmetry are rarely reported, and their synthesis is also highly challenging. In this study, we present the synthesis of a [K2(Bi@Pd12@Bi20)]4- cluster that incorporates a {Bi20} cage with pseudo-Ih symmetry, making it the largest main group metal cluster compound composed of the bismuth element to date. Magnetic characterization and theoretical calculations suggest that the spin state of the overall cluster is a quartet. Quantum chemical calculations reveal that the [Bi20]3- cluster has a similar electronic configuration to C606- and the [Bi@Pd12@Bi20]6- cluster exhibits a unique open-shell aromatic character.
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Achieving accurate detection of different speciations of heavy metal ions (HMIs) in an aqueous solution is an urgent problem due to the different bioavailabilities and physiological toxicity. Herein, we nominated a novel strategy to detect HCrO4- and Cr(OH)2+ at a trace level via the electrochemical sensitive surface constructed by Co3O4-rGO modified with amino and carboxyl groups, which revealed that the interactions between distinct functional groups and different oxygen-containing groups of target ions are conducive to the susceptible and anti-interference detection. The detection sensitivities of 19.46 counts µg-1 L for HCrO4- and 13.44 counts µg-1 L for Cr(OH)2+ were obtained under optimal conditions, while the limits of detection were 0.10 and 0.12 µg L-1, respectively. Satisfactory anti-interference and actual water sample analysis results were obtained. A series of advanced optical techniques like X-ray photoelectron spectroscopy, X-ray absorption near-edge structure technology, and density functional theory calculations under an electric field demonstrated that chemical interactions between groups contribute more to the fixation of target ions than electrical attraction alone. The presence of oxygen-containing groups distinct from simple ionic forms was a critical factor in the selectivity and anti-interference detection. Furthermore, the valence cycle of Co(II)/(III) synergistically boosted the detection performance. This research provides a promising tactic from the microscopic perspective of groups' interactions to accomplish the precise speciation analysis of HMIs in the water environment.
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Cytoplasmic dynein participates in transport functions and is essential in spermatogenesis. KM23 belongs to the dynein light chain family. The TGFß signaling pathway is indispensable in spermatogenesis, and Smad2 is an important member of this pathway. We cloned PTKM23 and PTSMAD2 from Portunus trituberculatus and measured their expression during spermatogenesis. PTKM23 may be related to cell division, acrosome formation and nuclear remodeling, and PTSMAD2 may participate in regulating the expression of genes related to spermatogenesis. We assessed the localization of PTKM23 with PTDHC and α-Tubulin, and the results suggested that PTKM23 functions in intracellular transport during spermatogenesis. We knocked down PTKM23 in vivo, and the expression of p53, B-CATAENIN and CYCLIN B decreased significantly, further suggesting a role of PTKM23 in transport and cell division. The localization of PTDIC with α-Tubulin and that of PTSMAD2 with PTDHC changed after PTKM23 knockdown. We transfected PTKM23 and PTSMAD2 into HEK-293 T cells and verified their colocalization. These results indicate that PTKM23 is involved in the assembly of cytoplasmic dynein and microtubules during spermatogenesis and that PTKM23 mediates the participation of cytoplasmic dynein in the transport of PTSMAD2 during spermatogenesis. This study provides a theoretical molecular biological basis for the breeding of P. trituberculatus.
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We investigate theoretically the photoelectron momentum distributions (PMDs) of the helium atom in the few-cycle nonlinear chirped laser pulse. The numerical results show that the direction of the spider-like interference structure in PMDs exhibits periodic variations with the increase of the chirp parameter. It is illustrated that the direction of the spider-like interference structure is related to the direction of the electron motion by tracking the trajectories of the electrons. We also demonstrate that the carrier-envelope phase can precisely control the opening of the ionization channel. In addition, we investigate the PMDs when a chirp-free second harmonic (SH) laser pulse is added to the chirped laser field, the numerical results show that the interference patterns can change from only spider-like interference structure to both spider-like and ring-like interference structures.
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Diabetic cardiomyopathy (DCM) represents a distinct myocardial disorder elicited by diabetes mellitus, characterized by aberrations in myocardial function and structural integrity. This pathological condition predominantly manifests in individuals with diabetes who do not have concurrent coronary artery disease or hypertension. An escalating body of scientific evidence substantiates the pivotal role of programmed cell death (PCD)-encompassing apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis-in the pathogenic progression of DCM, thereby emerging as a prospective therapeutic target. Additionally, numerous non-coding RNAs (ncRNAs) have been empirically verified to modulate the biological processes underlying programmed cell death, consequently influencing the evolution of DCM. This review systematically encapsulates prevalent types of PCD manifest in DCM as well as nascent discoveries regarding the regulatory influence of ncRNAs on programmed cell death in the pathogenesis of DCM, with the aim of furnishing novel insights for the furtherance of research in PCD-associated disorders relevant to DCM.
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Apoptose , Cardiomiopatias Diabéticas , RNA não Traduzido , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/genética , Humanos , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Animais , Autofagia , Necroptose/genética , Piroptose/genéticaRESUMO
Inadequate reference databases in RNA-seq analysis can hinder data utilization and interpretation. In this study, we have successfully constructed a high-quality reference transcript dataset, ZjRTD1.0, for Zoysia japonica, a widely-used turfgrass with exceptional tolerance to various abiotic stress, including low temperatures and salinity. This dataset comprises 113,089 transcripts from 57,143 genes. BUSCO analysis demonstrates exceptional completeness (92.4%) in ZjRTD1.0, with reduced proportions of fragmented (3.3%) and missing (4.3%) orthologs compared to prior datasets. ZjRTD1.0 enables more precise analyses, including transcript quantification and alternative splicing assessments using public datasets, which identified a substantial number of differentially expressed transcripts (DETs) and differential alternative splicing (DAS) events, leading to several novel findings on Z. japonica's responses to abiotic stresses. First, spliceosome gene expression influenced alternative splicing significantly under abiotic stress, with a greater impact observed during low-temperature stress. Then, a significant positive correlation was found between the number of differentially expressed genes (DEGs) encoding protein kinases and the frequency of DAS events, suggesting the role of protein phosphorylation in regulating alternative splicing. Additionally, our results suggest possible involvement of serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in generating inclusion/exclusion isoforms under low-temperature stress. Furthermore, our investigation revealed a significantly enhanced overlap between DEGs and differentially alternatively spliced genes (DASGs) in response to low-temperature stress, suggesting a unique co-regulatory mechanism governing transcription and splicing in the context of low-temperature response. In conclusion, we have proven that ZjRTD1.0 will serve as a reliable and useful resource for future transcriptomic analyses in Z. japonica.
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Processamento Alternativo , Temperatura Baixa , Poaceae , Processamento Alternativo/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Poaceae/genética , Estresse Fisiológico/genética , Transcriptoma/genéticaRESUMO
Catalytic hydrogenation of nitrobenzene (Ph-NO2) to aniline (Ph-NH2) is a model reaction in the field of catalysis, in which the development of efficient catalysts remains a great challenge due to the lack of strategies to solve activity and selectivity problems. In this work, the mechanism of Ph-NO2 hydrogenation over Pt1 supported on phosphomolybdic acid (α-PMA) was proposed by density functional theory (DFT) calculations. The results show that the dissociation of the first and second N-O bonds is triggered by single H-induced and double H-induced mechanisms, respectively. The limiting potential of the reaction process is -0.19 V, which is the smallest potential in the field of Ph-NO2 reduction reaction to date. In the whole reaction process, the catalytic active site is the Pt atom, and polyoxometalate plays the role of an electronic sponge in the reaction. Additionally, based on experimentally confirmed Pt1/Na3PMA, the reduction capacity of Pd1/Na3PMA toward Ph-NO2 was predicted by DFT calculation. The distinctive adsorption patterns of Ph-NO2 on Pt1/Na3PMA and Pd1/Na3PMA were elucidated using the DOS diagram and fragment molecular orbital analysis. We anticipate that our theoretical calculations can provide novel perspectives for experimental researchers.
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Carbon dioxide (CO2) coupled with epoxide to generate cyclic carbonate stands out in carbon neutrality due to its 100% atom utilization. In this work, the mechanism of CO2 cycloaddition with propylene oxide (PO) cocatalyzed by windmill-shaped polyoxovanadate, [(C2N2H8)4(CH3O)4VIV4VV4O16]·4CH3OH (V8-1), and n-Bu4NX (X = Br, I) was thoroughly investigated using density functional theory (DFT) calculations. The ring-opening, CO2-insertion, and ring-closing steps of the process were extensively studied. Our work emphasizes the synergistic effect between V8-1 and n-Bu4NX (X = Br, I). Through the analysis of an independent gradient model based on Hirshfeld partition (IGMH), it was found that the attack of n-Bu4NX (X = Br, I) on Cß of PO triggers a distinct attractive interaction between the active fragment and the surrounding framework, serving as the primary driving force for the ring opening of PO. Furthermore, the effect of different cocatalysts was explored, with n-Bu4NI being more favorable than n-Bu4NBr. Moreover, the role of V8-1 in the CO2 cycloaddition reaction was clarified as not only acting as Lewis acid active sites but also serving as "electron sponges". This work is expected to advance the development of novel catalysts for organic carbonate formation.
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Although the treatment of ovarian cancer has made great progress, there are still many patients who are not timely detected and given targeted therapy due to unknown pathogenesis. Recent studies have found that hsa_circ_0015326 is upregulated in ovarian cancer and is involved in the proliferation, invasion, and migration of ovarian cancer cells. However, whether hsa_circ_0015326 can be used as a new target of ovarian cancer needs further investigation. Therefore, the effect of hsa_circ_0015326 on epithelial ovarian cancer was investigated in this study. At first, si-hsa_circ_0015326 lentivirus was transfected into epithelial ovarian cancer cells. Then real-time fluorescence quantitative PCR (qRT-PCR) was used to detect hsa_circ_0015326 level. The proliferation of ovarian cancer cells was detected by CCK-8 assay. The horizontal and vertical migration abilities of the cells were detected by wound-healing assay and Transwell assay, respectively. Transwell assay was also used to determine the invasion rate. As for the apoptosis rate, it was assessed by flow cytometry. As a result, the expression level of hsa_circ_0015326 in A2780 and SKOV3 was found to be higher than that in IOSE-80. However, after transfecting si-hsa_circ_0015326 and si-NC into the cells, the proliferation, migration, and invasion abilities of A2780 and SKOV3 cells in the si-hsa_circ_0015326 group were significantly reduced in comparison to those in the si-NC and mock groups, while their apoptosis rates were elevated. Collectively, silencing hsa_circ_0015326 bears the capability of inhibiting the proliferation, migration, and invasion of ovarian cancer cells while increasing apoptosis rate. It can be concluded that hsa_circ_0015326 promotes the malignant biological activities of epithelial ovarian cancer cells.
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MicroRNAs , Neoplasias Ovarianas , Humanos , Feminino , RNA/metabolismo , Carcinoma Epitelial do Ovário/genética , RNA Circular/genética , RNA Circular/metabolismo , Linhagem Celular Tumoral , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proliferação de Células , Apoptose , MicroRNAs/metabolismo , Movimento CelularRESUMO
To recover methane from waste activated sludge through anaerobic digestion (AD) is one promising alternative to achieve carbon neutrality for wastewater treatment plants. However, humic acids (HAs) are one of the major compositions in waste activated sludge, and their accumulation performs inhibition effects on AD. This study investigated the potentials of biochar (BC) in alleviating inhibition effects of HAs on AD. Results showed that although the accumulated HAs reduced methane yield by 9.37% compared to control, the highest methane yield, 132.6 mL CH4/g VSS, was obtained after adding BC, which was 45.9% higher than that in HA group. Mechanism analysis showed that BC promoted the activities of hydrolase such as protease and α-glucosidase, which were 69.7% and 29.7% higher than those in HA group, respectively. The conversion of short-chain fatty acids was accelerated. In addition, the evolutions of electroactive microorganisms like Clostridium_sensu_stricto_13 and Methanosaeta were consistent with the activitiies of electron transfer and the contents of cytochrome c. Furthermore, parts of HAs rather than all of them were adsorbed by BC, and the remaining free HAs and BC formed synergistic effects on methanogenesis, then both CO2 reduction and acetoclastic methanogenesis pathways were improved. The findings may provide some solutions to alleviate inhibition effects of HAs on AD.
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Biochar produced from bio-wastes has been widely used to promote the performance of anaerobic digestion. Waste activated sludge (WAS) is considered as a kind of popular precursor for biochar preparation, but the abundant resources in WAS were neglected previously. In this study, the roles of biochar prepared from raw, pretreated, and fermented sludge on anaerobic digestion were investigated. That is, parts of carbon sources and nutrients like polysaccharides, proteins, and phosphorus were firstly recovered after sludge pretreatment or fermentation, and then the sludge residuals were used as raw material to prepare biochar. The methane yield improved by 22.1% with adding the biochar (AK-BC) prepared by sludge residual obtained from alkaline pretreatment. Mechanism study suggested that the characteristics of AK-BC like specific surface area and defect levels were updated. Then, the conversion performance of intermediate metabolites and electro-activities of extracellular polymeric substances were up-regulated. As a result, the activity of electron transfer was increased with the presence of AK-BC, with increase ratio of 21.4%. In addition, the electroactive microorganisms like Anaerolineaceae and Methanosaeta were enriched with the presence of AK-BC, and the potential direct interspecies electron transfer was possibly established. Moreover, both aceticlastic and CO2-reducing methanogenesis pathways were improved by up-regulating related enzymes. Therefore, the proposed strategy can not only obtain preferred biochar but also recover abundant resources like carbon source, nutrients, and bioenergy.
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Carvão Vegetal , Metano , Esgotos , Carvão Vegetal/química , Esgotos/química , Esgotos/microbiologia , Anaerobiose , Metano/metabolismo , Eliminação de Resíduos Líquidos/métodos , Álcalis/química , Reatores BiológicosRESUMO
Acinetobacter baumannii, which is resistant to multiple drugs, is an opportunistic pathogen responsible for severe nosocomial infections. With no antibiotics available, phages have obtained clinical attention. However, since immunocompromised patients are often susceptible to infection, the appropriate timing of administration is particularly important. During this research, we obtained a lytic phage vB_AbaM_P1 that specifically targets A. baumannii. We then assessed its potential as a prophylactic treatment for lung infections caused by clinical strains. The virus experiences a period of inactivity lasting 30 min and produces approximately 788 particles during an outbreak. Transmission electron microscopy shows that vB_AbaM_P1 was similar to the Saclayvirus. Based on the analysis of high-throughput sequencing and bioinformatics, vB_AbaM_P1 consists of 107537 bases with a G + C content of 37.68%. It contains a total of 177 open reading frames and 14 tRNAs. No antibiotic genes were detected. In vivo experiments, using a cyclophosphamide-induced neutrophil deficiency model, tested the protective effect of phage on neutrophil-deficient rats by prophylactic application of phage. The use of phages resulted in a decrease in rat mortality caused by A. baumannii and a reduction in the bacterial burden in the lungs. Histologic examination of lung tissue revealed a decrease in the presence of immune cells. The presence of phage vB_AbaM_P1 had a notable impact on preventing A. baumannii infection, as evidenced by the decrease in oxidative stress in lung tissue and cytokine levels in serum. Our research offers more robust evidence for the early utilization of bacteriophages to mitigate A. baumannii infection. KEY POINTS: â¢A novel Saclayvirus phage infecting A. baumannii was isolated from sewage. â¢The whole genome was determined, analyzed, and compared to other phages. â¢Assaying the effect of phage in preventing infection in neutrophil-deficient models.
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Infecções por Acinetobacter , Acinetobacter baumannii , Bacteriófagos , Genoma Viral , Acinetobacter baumannii/virologia , Acinetobacter baumannii/genética , Animais , Infecções por Acinetobacter/prevenção & controle , Infecções por Acinetobacter/microbiologia , Bacteriófagos/genética , Bacteriófagos/isolamento & purificação , Bacteriófagos/fisiologia , Ratos , Terapia por Fagos/métodos , Composição de Bases , Modelos Animais de Doenças , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Pulmão/virologia , Pulmão/microbiologia , Pneumonia/prevenção & controle , Pneumonia/microbiologia , Pneumonia/virologia , MasculinoRESUMO
Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca2+-activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. Then, we found that TMEM16A activation induces tubular mitochondrial dysfunction in in vivo and in vitro models, with the evidence of the TMEM16A inhibition with specific inhibitor. Mechanically, TMEM16A mediated tubular mitochondrial dysfunction through inhibiting PGC-1α, whereas overexpression of PGC-1α could rescue the changes. In addition, TMEM16A-induced fibrogenesis was dependent on increased intracellular Cl-, and reducing intracellular Cl- significantly blunted high glucose-induced PGC-1α and profibrotic factors expression. Taken together, our studies demonstrated that tubular TMEM16A promotes TIF by suppressing PGC-1α-mediated mitochondrial homeostasis in DKD. Blockade of TMEM16A may serve as a novel therapeutic approach to ameliorate TIF.
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Diabetes Mellitus , Nefropatias Diabéticas , Animais , Camundongos , Nefropatias Diabéticas/genética , Homeostase , Mitocôndrias , FibroseRESUMO
Two previously undescribed coumarins (1-2) were isolated from the root of Notopterygium incisum. The structures of new findings were elucidated by analyses of spectral evidences in HRESIMS, NMR, as well as ICD. The absolute configurations were further confirmed by chemical calculations. 1-2 exhibits obviously anti-inflammatory activity by inhibiting the expression of inflammatory mediators (COX-2, iNOS), as well as reducing the release of NO and the accumulation of ROS in cells. Western blotting analysis revealed that 2 could inhibit the PI3K/AKT pathway by reducing the expression of p-PI3K and p-AKT.
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Biochar has been used to enhance methane generation from anaerobic digestion through establishing direct interspecific electron transfer between microorganisms. However, the microbial communication is still inadequate, thereby limiting further methane production improvement contributed by biochar. This study investigated the roles of quorum-sensing molecules, acylated homoserine lactone (AHL), in anaerobic digestion of waste activated sludge aided by biochar. Results showed that the co-addition of separated biochar and AHL achieved best methane production performance, with the maximal methane yield of 154.7 mL/g volatile suspended solids, which increased by 51.9%, 47.2%, 17.9%, and 39.4% respectively compared to that of control, AHL-loaded biochar, sole AHL, and sole biochar groups. The reason was that the co-addition of separated biochar and AHL promoted the stages of hydrolysis and acidification, promoting the conversion of organic matters and short-chain fatty acids, and optimizing the accumulation of acetate acid. Moreover, the methanogenesis stage also performed best among experimental groups. Correspondingly, the highest activities of electron transfer and coenzyme F420 were obtained, with increase ratios of 33.2% and 27.2% respectively compared to that of control. Furthermore, biochar did more significant effects on the evolution of microbial communities than AHL, and the direct interspecific electron transfer between fermentative bacteria and methanogens were possibly promoted.
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Carvão Vegetal , Metano , Percepção de Quorum , Metano/metabolismo , Anaerobiose , Esgotos , Ácidos Graxos Voláteis/metabolismo , Acil-Butirolactonas/metabolismoRESUMO
PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.
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Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Humanos , Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estudos de Coortes , Estudos Retrospectivos , MutaçãoRESUMO
Traditional nanomodified electrodes have made great achievements in electrochemical stripping voltammetry of sensing materials for As(III) detection. Moreover, the intermediate states are complicated to probe because of the ultrashort lifetime and complex reaction conditions of the electron transfer process in electroanalysis, which seriously hinder the identification of the actual active site. Herein, the intrinsic interaction of highly sensitive analytical behavior of nanomaterials is elucidated from the perspective of electronic structure through density functional theory (DFT) and gradient boosting regression (GBR). It is revealed that the atomic radius, d-band center (εd), and the largest coordinative TM-N bond length play a crucial role in regulating the arsenic reduction reaction (ARR) performance by the established ARR process for 27 sets of transition-metal single atoms supported on N-doped graphene. Furthermore, the database composed of filtered intrinsic electronic structural properties and the calculated descriptors of the central metal atom in TM-N4-Gra were also successfully extended to oxygen evolution reaction (OER) systems, which effectively verified the reliability of the whole approach. Generally, a multistep workflow is developed through GBR models combined with DFT for valid screening of sensing materials, which will effectively upgrade the traditional trial-and-error mode for electrochemical interface designing.
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Significant progress has been made in nanomaterial-modified electrodes for highly efficient electroanalysis of arsenic(III) (As(III)). However, the modifiers prepared using some physical methods may easily fall off, and active sites are not uniform, causing the potential instability of the modified electrode. This work first reports a promising practical strategy without any modifiers via utilizing only soluble Fe3+ as a trigger to detect trace-level As(III) in natural water. This method reaches an actual detection limit of 1 ppb on bare glassy carbon electrodes and a sensitivity of 0.296 µA ppb-1 with excellent stability. Kinetic simulations and experimental evidence confirm the codeposition mechanism that Fe3+ is preferentially deposited as Fe0, which are active sites to adsorb As(III) and H+ on the electrode surface. This facilitates the formation of AsH3, which could further react with Fe2+ to produce more As0 and Fe0. Meanwhile, the produced Fe0 can also accelerate the efficient enrichment of As0. Remarkably, the proposed sensing mechanism is a general rule for the electroanalysis of As(III) that is triggered by iron group ions (Fe2+, Fe3+, Co2+, and Ni2+). The interference analysis of coexisting ions (Cu2+, Zn2+, Al3+, Hg2+, Cd2+, Pb2+, SO42-, NO3-, Cl-, and F-) indicates that only Cu2+, Pb2+, and F- showed inhibitory effects on As(III) due to the competition of active sites. Surprisingly, adding iron power effectively eliminates the interference of Cu2+ in natural water, achieving a higher sensitivity for 1-15 ppb As(III) (0.487 µA ppb-1). This study provides effective solutions to overcome the potential instability of modified electrodes and offers a practical sensing platform for analyzing other heavy-metal anions.