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The biological function of RNA can be modulated by base modifications. Here, we unveiled the occurrence of N4-acetylation of cytidine in plant RNA, including mRNA, by employing LC-MS/MS and acRIP-seq. We identified 325 acetylated transcripts from the leaves of 4-week-old Arabidopsis (Arabidopsis thaliana) plants and determined that 2 partially redundant N-ACETYLTRANSFERASEs FOR CYTIDINE IN RNA (ACYR1 and ACYR2), which are homologous to mammalian NAT10, are required for acetylating RNA in vivo. A double-null mutant was embryo lethal, while eliminating 3 of the 4 ACYR alleles led to defects in leaf development. These phenotypes could be traced back to the reduced acetylation and concomitant destabilization of the transcript of TOUGH, which is required for miRNA processing. These findings indicate that N4-acetylation of cytidine is a modulator of RNA function with a critical role in plant development and likely many other processes.
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Arabidopsis , Citidina , Animais , RNA Mensageiro/genética , Acetilação , Citidina/genética , Citidina/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , RNA de Plantas , Arabidopsis/genética , Arabidopsis/metabolismo , Mamíferos/genética , Mamíferos/metabolismoRESUMO
5-Methylated cytosine is a frequent modification in eukaryotic RNA and DNA influencing mRNA stability and gene expression. Here we show that free 5-methylcytidine (5mC) and 5-methyl-2'-deoxycytidine are generated from nucleic acid turnover in Arabidopsis thaliana, and elucidate how these cytidines are degraded, which is unclear in eukaryotes. First CYTIDINE DEAMINASE produces 5-methyluridine (5mU) and thymidine which are subsequently hydrolyzed by NUCLEOSIDE HYDROLASE 1 (NSH1) to thymine and ribose or deoxyribose. Interestingly, far more thymine is generated from RNA than from DNA turnover, and most 5mU is directly released from RNA without a 5mC intermediate, since 5-methylated uridine (m5U) is an abundant RNA modification (m5U/U â¼1%) in Arabidopsis. We show that m5U is introduced mainly by tRNA-SPECIFIC METHYLTRANSFERASE 2A and 2B. Genetic disruption of 5mU degradation in the NSH1 mutant causes m5U to occur in mRNA and results in reduced seedling growth, which is aggravated by external 5mU supplementation, also leading to more m5U in all RNA species. Given the similarities between pyrimidine catabolism in plants, mammals and other eukaryotes, we hypothesize that the removal of 5mU is an important function of pyrimidine degradation in many organisms, which in plants serves to protect RNA from stochastic m5U modification.
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Arabidopsis , RNA , Animais , Timina , Uridina/metabolismo , Pirimidinas/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , DNA , Mamíferos/genéticaRESUMO
Although intravenous bevacizumab (IVBEV) is the most promising treatment for cerebral radiation necrosis (CRN), there is no conclusion on the optimal dosage. Our retrospective study aimed to compare the efficacy and safety of high-dose with low-dose IVBEV in treating CRN associated with radiotherapy for brain metastases (BMs). This paper describes 75 patients who were diagnosed with CRN secondary to radiotherapy for BMs, treated with low-dose or high-dose IVBEV and followed up for a minimum of 6 months. The clinical data collected for this study include changes in brain MRI, clinical symptoms, and corticosteroid usage before, during, and after IVBEV treatment. At the 3-month mark following administration of IVBEV, a comparison of two groups revealed that the median percentage decreases in CRN volume on T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium contrast-enhanced image (T1CE), as well as the signal ratio reduction on T1CE, were 65.8% versus 64.8% (p = 0.860), 41.2% versus 51.9% (p = 0.396), and 37.4% versus 35.1% (p = 0.271), respectively. Similarly, at 6 months post-IVBEV, the median percentage reductions of the aforementioned parameters were 59.5% versus 62.0% (p = 0.757), 39.1% versus 31.3% (p = 0.851), and 35.4% versus 28.2% (p = 0.083), respectively. Notably, the incidence of grade ≥3 adverse events was higher in the high-dose group (n = 4, 9.8%) than in the low-dose group (n = 0). Among patients with CRN secondary to radiotherapy for BMs, the administration of high-dose IVBEV did not demonstrate superiority over low-dose IVBEV. Moreover, the use of high-dose IVBEV was associated with a higher incidence of grade ≥3 adverse events compared with low-dose IVBEV.
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Neoplasias Encefálicas , Humanos , Bevacizumab/efeitos adversos , Estudos Retrospectivos , Necrose/etiologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologiaRESUMO
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Evasão Tumoral/imunologia , Animais , Apolipoproteínas E/metabolismo , Arginase/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Movimento Celular , Proliferação de Células , Feminino , Humanos , Tolerância Imunológica/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores Imunológicos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Objective: Investigating the application effectiveness of using loop-mediated isothermal amplification (LAMP) on a microfluidic chip to detect the pathogens associated with ventilator-associated pneumonia (VAP). Methods: Eighty samples of bronchoalveolar lavage fluid from patients with ventilator-associated pneumonia (VAP) were collected at The First Hospital of Hebei Medical University from July 2022 to July 2023. The bacterial culture technique and the LAMP method were used to detect the nucleic acid of the pathogens in the patient samples. The positivity rates of bacterial culture and LAMP method in detecting VAP pathogens were analyzed. Results: A total of 80 specimens were examined, with 73 positive specimens detected using the LAMP method (positivity rate of 91.25%) and 60 positive specimens detected using bacterial culture (positivity rate of 75.00%). The LAMP method exhibited a higher number of positive detections compared to bacterial culture. Both methods showed a high level of concordance and were virtually identical in detecting methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Haemophilus influenzae, and Streptococcus pneumoniae. Conclusion: The LAMP method demonstrates significantly improved performance in the detection of pathogens for VAP, with a higher pathogen positivity rate compared to bacterial culture. This method holds promising prospects for clinical application.
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Garnet Li7La3Zr2O12 (LLZO)-based solid-state electrolytes (SSEs) hold promise for realizing next-generation lithium metal batteries with high energy density. However, the high stiffness of high-temperature sintered LLZO makes it brittle and susceptible to strain during the fabrication of solid-state batteries. Cold-pressed LLZO exhibits improved ductility but suffers from insufficient Li+ conductivity. Here, we report cold-pressed Ta-doped LLZO (Ta-LZ) particles integrated with ductile Li6PS5Cl (LPSC) via a Li+ conductive Li-containing Ta-Cl structure. This configuration creates a continuous Li+ conduction network by enhancing the Li+ exchange at the Ta-LZ/LPSC interface. The resulting Ta-LZ/LPSC SSE exhibits Li+ conductivity of 4.42 × 10-4 S cm-1 and a low activation energy of 0.31 eV. Li symmetric cells with Ta-LZ/LPSC SSE demonstrate excellent Li dendrite suppression ability, with an improved critical current density of 5.0 mA cm-2 and a prolonged cycle life exceeding 600 h at 1 mA cm-2. Our finding provides valuable insights into developing cold-pressed ceramic powder electrolytes for high-performance all-solid-state batteries.
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PURPOSE: Side overlap with fundoplication by Yamashita (SOFY) is an anti-reflux form of esophagogastrostomy. We compared the safety and efficacy of laparoscopic proximal gastrectomy (PG) with SOFY to that of laparoscopic total gastrectomy (TG) with Roux-en-Y for treating cT1-2 Siewert II/III adenocarcinoma of the esophagogastric junction. METHODS: Fifty-two patients who underwent PG (n = 28) or TG (n = 24), without conversion to laparotomy, were included. Surgical outcomes, complications, reflux symptoms, quality of life, and nutritional status of both groups were compared. RESULTS: Significant differences between PG and TG groups regarding operative time (245.7 versus 294.6 min, P = 0.005), reconstruction time (22.1 versus 28.5 min, P < 0.001), time to pass gas (3 versus 4 days, P = 0.021), time to oral intake (4.5 versus 5 days, P = 0.043), and gastroesophageal reflux (60.7% versus 4.2%, P < 0.001) were observed. Reflux esophagitis for the PG group was 42.9% (12/28). The incidence of Los Angeles grade B and above was 10.7%. Between-group differences in terms of global health status, diarrhea, reflux, and eating were observed. Body weight maintenance was better in the PG group than in the TG group 6 months and 1 year postoperatively. CONCLUSION: SOFY is simple and more advantageous than TG in terms of postoperative recovery, body weight, eating, and diarrhea. However, the occurrence of postoperative reflux after SOFY was high. The limitations of this study are the significant differences in pathological T stage of patients in the two groups and the small sample size.
Assuntos
Adenocarcinoma , Refluxo Gastroesofágico , Laparoscopia , Neoplasias Gástricas , Humanos , Fundoplicatura , Qualidade de Vida , Estudos Prospectivos , Neoplasias Gástricas/patologia , Junção Esofagogástrica/cirurgia , Junção Esofagogástrica/patologia , Gastrectomia/efeitos adversos , Refluxo Gastroesofágico/cirurgia , Refluxo Gastroesofágico/etiologia , Laparoscopia/efeitos adversos , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Estudos Retrospectivos , Resultado do Tratamento , Complicações Pós-Operatórias/cirurgiaRESUMO
PURPOSE: This study aimed to evaluate the safety and efficacy of augmented-rectangle technique (ART) versus delta-shaped anastomosis (DA) for treating gastric cancer in total laparoscopic distal gastrectomy. METHODS: In total, 99 patients with distal gastric cancer who underwent ART (n = 60) or DA (n = 39) were considered. Operative data, postoperative recovery, complications, quality of life, and endoscopic findings of both groups were compared. RESULTS: The ART group had faster postoperative recovery than the DA group, and was better than DA regarding complications. The mode of reconstruction remained an independent predictor of complications, but not postoperative recovery. Dumping syndrome occurred in 3 (5.0%) and 2 patients (5.1%) of ART and DA groups within 30 days after surgery, and 3 (5.0%) and 2 patients (5.1%) 1 year after surgery. Regarding global health status on the EORTC-QLQ-C30 scale, the ART group had better outcomes than the DA group. Gastritis occurred in 38 (63.3%) and 27 (69.3%) patients of ART and DA groups, respectively. Residual food occurred in 8 (13.3%) and 11 (28.2%) patients of ART and DA groups. Reflux esophagitis occurred in 5 (8.3%) and 4 (10.3%) patients of ART and DA groups. Further, bile reflux occurred in 8 (13.3%) and 4 (10.3%) patients of ART and DA groups. CONCLUSIONS: ART has similar advantages to DA for total laparoscopic reconstruction and is superior to DA regarding the incidence of complications, complication grade, and global health status. Furthermore, ART may have potential advantages in postoperative recovery and anastomotic stenosis.
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Laparoscopia , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Qualidade de Vida , Anastomose Cirúrgica/efeitos adversos , Gastrectomia/efeitos adversos , Laparoscopia/efeitos adversosRESUMO
Common carp (Cyprinus carpio L.) is one of the most widely cultivated fish in China. Spring viraemia of carp virus (SVCV) is a highly pathogenic virus and has often caused excessive losses in carp pond fisheries. Innate immune play important roles against virus infection. To better understand the immune response of common carp against SVCV infection, transcriptome analysis was performed using the Illumina Novaseq 6000 platform. It was showed that a total of 3953 differentially expressed unigenes were identified, and the RLR signaling pathway were significantly enriched after SVCV infection. Subsequently, the role of RLR signaling pathway in SVCV infection was studied. The results showed that common carp RIG-I (CcRIG-I) and TRIM25 (CcTRIM25) significantly decreased the replication of SVCV by inducing the phosphorylation of TBK1, IRF3 and p65 and the expression of ifn-1, viperin, isg15 and mx. Further studies illustrated that CcTRIM25 could positive regulate CcRIG-I mediated downstream signaling pathway. Finally, the mechanism of CcTRIM25 promoting CcRIG-I-mediated signaling was investigated. CcTRIM25 could interact with the caspase activation and recruitment domain (CARD) of CcRIG-I and promoted K63-linked polyubiquitination of CcRIG-I. Altogether, the study revealed a mechanism of CcTRIM25 regulating CcRIG-I mediated immune response in SVCV infection.
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Carpas , Doenças dos Peixes , Infecções por Rhabdoviridae , Rhabdoviridae , Animais , Carpas/genética , Rhabdoviridae/fisiologia , Transdução de Sinais , ViremiaRESUMO
To solve the insufficient ability of the current Thermal InfraRed (TIR) tracking methods to resist occlusion and interference from similar targets, we propose a TIR tracking method based on efficient global information perception. In order to efficiently obtain the global semantic information of images, we use the Transformer structure for feature extraction and fusion. In the feature extraction process, the Focal Transformer structure is used to improve the efficiency of remote information modeling, which is highly similar to the human attention mechanism. The feature fusion process supplements the relative position encoding to the standard Transformer structure, which allows the model to continuously consider the influence of positional relationships during the learning process. It can also generalize to capture the different positional information for different input sequences. Thus, it makes the Transformer structure model the semantic information contained in images more efficiently. To further improve the tracking accuracy and robustness, the heterogeneous bi-prediction head is utilized in the object prediction process. The fully connected sub-network is responsible for the classification prediction of the foreground or background. The convolutional sub-network is responsible for the regression prediction of the object bounding box. In order to alleviate the contradiction between the vast demand for training data of the Transformer model and the insufficient scale of the TIR tracking dataset, the LaSOT-TIR dataset is generated with the generative adversarial network for network training. Our method achieves the best performance compared with other state-of-the-art trackers on the VOT2015-TIR, VOT2017-TIR, PTB-TIR and LSOTB-TIR datasets, and performs outstandingly especially when dealing with severe occlusion or interference from similar objects.
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Percepção , Semântica , HumanosRESUMO
INTRODUCTION: Although the traditional bilateral surgical approach to treat hiatal hernia (HH) with gastroesophageal reflux disease (GERD) can provide local protection of the vagus nerve, the integrity of the entire vagus nerve cannot be evaluated. Therefore, we developed and described the total left-side surgical approach (TLSA), which theoretically reduces injury to the vagus nerve, and described the detailed surgical procedure. METHODS: Initially, we performed a cadaver study to explore the characteristics of the vagus nerve. Then, we prospectively evaluated the TLSA in 5 patients with HH and GERD between June 2020 and September 2020. Demographic characteristics, surgical parameters, perioperative outcomes, and follow-up findings were analyzed. RESULTS: The TLSA was successfully used in five patients (40-64 years old), and no major complications were noted. The median total operative time was 114 min, median blood loss was 50 mL, and median postoperative hospital stay was 3.8 days. Gastrointestinal function recovered within 4 days of surgery in all the patients. The 6-month follow-up gastroscopy examination showed well-established gastroesophageal flap valves. Compared with the baseline results, the 6-month follow-up results showed lower values for the total GerdQ score (12.4 vs. 6.2) and the total esophageal acid exposure time (3.48% vs. 0.38%). Based on the European Organization for Research and Treatment of Cancer quality of life questionnaire-stomach module 52 results, the incidence of dysphagia and flatulence decreased over time after the TLSA. CONCLUSIONS: The TLSA provides a clear and broad surgical field, less trauma, and rapid recovery; moreover, it is technically simple. Although our results suggest that the TLSA provides safety and short-term efficacy and is feasible for patients with HH and GERD, long-term results from a larger clinical trial are needed to validate these findings. Trial registration ChiCTR2000034028, registration date is June 21, 2020. The study was registered prospectively.
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Refluxo Gastroesofágico , Hérnia Hiatal , Laparoscopia , Adulto , Refluxo Gastroesofágico/cirurgia , Hérnia Hiatal/cirurgia , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do TratamentoRESUMO
The rapid emergence of bacterial coinfection caused by cytosolic bacteria has become a huge threat to public health worldwide. Past efforts have been devoted to discover the broad-spectrum antibiotics, while the emergence of antibiotic resistance encourages the development of antibacterial agents. In essence, bacterial virulence is a factor in antibiotic tolerance. However, the discovery and development of new antibacterial drugs and special antitoxin drugs is much more difficult in the antibiotic resistance era. Herein, we hypothesize that antitoxin hemolytic activity can serve as a screening principle to select antibacterial drugs to combat coinfection from natural products. Being the most abundant natural drug of plant origins, flavonoids were selected to assess the ability of antibacterial coinfections in this paper. Firstly, we note that four flavonoids, namely, baicalin, catechin, kaempferol, and quercetin, have previously exhibited antibacterial abilities. Then, we found that baicalin, kaempferol, and quercetin have better inhibitions of hemolytic activity of Hla than catechin. In addition, kaempferol and quercetin, have therapeutic effectivity for the coinfections of Staphylococcus aureus and Pseudomonas aeruginosa in vitro and in vivo. Finally, our results indicated that kaempferol and quercetin therapied the bacterial coinfection by inhibiting S. aureus α-hemolysin (Hla) and reduced the host inflammatory response. These results suggest that antitoxins may play a promising role as a potential target for screening flavonoids to combat bacterial coinfection.
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Antibacterianos , Proteínas de Bactérias , Flavonoides , Proteínas Hemolisinas , Pseudomonas aeruginosa/metabolismo , Staphylococcus aureus/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Avaliação Pré-Clínica de Medicamentos , Flavonoides/química , Flavonoides/farmacologia , Proteínas Hemolisinas/antagonistas & inibidores , Proteínas Hemolisinas/metabolismoRESUMO
Bacillus cereus is an opportunistic pathogen that often causes foodborne infectious diseases and food poisoning. Non-hemolytic enterotoxin (Nhe) is the major toxin found in almost all enteropathogenic B. cereus and B. thuringiensis isolates. However, little is known about the cellular response after Nhe triggered pore formation on cell membrane. Here, we demonstrate that Nhe induced cell cycle arrest at G0 /G1 phase and provoked apoptosis in Vero cells, most likely associated with mitogen-activated protein kinase (MAPK) and death receptor pathways. The influx of extracellular calcium ions and increased level of reactive oxygen species in cytoplasm were sensed by apoptosis signal-regulating kinase 1 (ASK1) and p38 MAPK. Extrinsic death receptor Fas could also promote the activation of p38 MAPK. Subsequently, ASK1 and p38 MAPK triggered downstream caspase-8 and 3 to initiate apoptosis. Our results clearly demonstrate that ASK1, and Fas-p38 MAPK-mediated caspase-8 dependent pathways are involved in apoptotic cell death provoked by the pore-forming enterotoxin Nhe.
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Apoptose/imunologia , Bacillus cereus/fisiologia , Enterotoxinas/fisiologia , Animais , Toxinas Bacterianas/farmacologia , Sinalização do Cálcio , Chlorocebus aethiops , Enterotoxinas/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular , Estresse Oxidativo , Receptores de Morte Celular/metabolismo , Transdução de Sinais , Células VeroRESUMO
Targeting leukemia initiating cells is considered to be an effective way to cure leukemia, for which it is critical to identify novel therapeutic targets. Herein, we demonstrate that CD244, which was initially reported as a key regulator for natural killer cells, is highly expressed on both mouse and human leukemia initiating cells. Upon CD244 knockdown, human leukemia cell lines and primary leukemia cells have markedly impaired proliferation abilities both in vitro and in vivo Interestingly, the repopulation ability of both mouse and human hematopoietic stem cells is not impaired upon CD244 knockdown. Using an MLL-AF9-induced murine acute myeloid leukemia model, we show that leukemogenesis is dramatically delayed upon CD244 deletion, together with remarkably reduced Mac1+/c-Kit+ leukemia cells (enriched for leukemia initiating cells). Mechanistically, we reveal that CD244 is associated with c-Kit and p27 except for SHP-2 as previously reported. CD244 co-operates with c-Kit to activate SHP-2 signaling to dephosphorylate p27 and maintain its stability to promote leukemia development. Collectively, we provide intriguing evidence that the surface immune molecule CD244 plays an important role in the maintenance of stemness of leukemia initiating cells, but not in hematopoietic stem cells. CD244 may represent a novel therapeutic target for the treatment of acute myeloid leukemia.
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Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Leucemia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Humanos , Imunofenotipagem , Leucemia/genética , Camundongos , Camundongos Knockout , Modelos Biológicos , Fenótipo , Ligação Proteica , Estabilidade Proteica , Família de Moléculas de Sinalização da Ativação Linfocitária/genéticaRESUMO
How stem cells interact with the microenvironment to regulate their cell fates and metabolism is largely unknown. Here we demonstrated that the deletion of the cytoskeleton-modulating protein profilin 1 (pfn1) in hematopoietic stem cell (HSCs) led to bone marrow failure, loss of quiescence, and mobilization and apoptosis of HSCs in vivo. A switch from glycolysis to mitochondrial respiration with increased reactive oxygen species (ROS) level was also observed in HSCs on pfn1 deletion. Importantly, treatment of pfn1-deficient mice with the antioxidant N-acetyl-l-cysteine reversed the ROS level and loss of quiescence of HSCs, suggesting that the metabolism is mechanistically linked to the cell cycle quiescence of stem cells. The actin-binding and proline-binding activities of pfn1 are required for its function in HSCs. Our study provided evidence that pfn1 at least partially acts through the axis of pfn1/Gα13/EGR1 to regulate stem cell retention and metabolism in the bone marrow.
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Medula Óssea , Movimento Celular/genética , Glicólise/genética , Células-Tronco Hematopoéticas/fisiologia , Profilinas/fisiologia , Animais , Medula Óssea/fisiologia , Sobrevivência Celular/genética , Células Cultivadas , Mobilização de Células-Tronco Hematopoéticas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nicho de Células-Tronco/genéticaRESUMO
Murine paired immunoglobulin-like receptors B (PIRB), as the ortholog of human leukocyte immunoglobulin-like receptor B2 (LILRB2), is involved in a variety of biological functions. Here, we found that PIRB and LILRB2 were expressed in mouse and human platelets, respectively. PIRB intracellular domain deletion (PIRB-TM) mice had thrombocythemia and significantly higher proportions of megakaryocytes in bone marrow. Agonist-induced aggregation and spreading on immobilized fibrinogen were facilitated in PIRB-TM platelets. The rate of clot retraction in platelet-rich plasma containing PIRB-TM platelets was also increased. Characterization of signaling confirmed that PIRB associated with phosphatases Shp1/2 in platelets. The phosphorylation of Shp1/2 was significantly downregulated in PIRB-TM platelets stimulated with collagen-related peptide (CRP) or on spreading. The results further revealed that the phosphorylation levels of the linker for activation of T cells, SH2 domain-containing leukocyte protein of 76kDa, and phospholipase C were enhanced in PIRB-TM platelets stimulated with CRP. The phosphorylation levels of FAK Y397 and integrin ß3 Y759 were also enhanced in PIRB-TM platelet spread on fibrinogen. The PIRB/LILRB2 ligand angiopoietin-like-protein 2 (ANGPTL2) was expressed and stored in platelet α-granules. ANGPTL2 inhibited agonist-induced platelet aggregation and spreading on fibrinogen. The data presented here reveal that PIRB and its ligand ANGPTL2 possess an antithrombotic function by suppressing collagen receptor glycoprotein VI and integrin αIIbß3-mediated signaling.
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Glicoproteínas de Membrana/metabolismo , Ativação Plaquetária , Receptores Imunológicos/metabolismo , Proteína 2 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Angiopoietinas/metabolismo , Animais , Plaquetas/metabolismo , Proteínas de Transporte/farmacologia , Humanos , Ligantes , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Estrutura Terciária de Proteína , Receptores Imunológicos/química , Deleção de Sequência , Transdução de Sinais/efeitos dos fármacos , Trombocitose/genéticaRESUMO
Sulfate-rich wastewater is an indirect threat to the environment especially at low pH. Sulfate reducing bacteria (SRB) could use sulfate as the terminal electron acceptor for the degradation of organic compounds and hydrogen transferring SO(4)(2-) to H2S. However their acute sensitivity to acidity leads to a greatest limitation of SRB applied in such wastewater treatment. With the addition of iron shavings SRB could adapt to such an acidic environment, and 57.97, 55.05 and 14.35% of SO(4)(2-) was reduced at pH 5, pH 4 and pH 3, respectively. Nevertheless it would be inhibited in too acidic an environment. The behavior of SRB after inoculation in acidic synthetic wastewater with and without iron shavings is presented, and some glutinous substances were generated in the experiments at pH 4 with SRB culture and iron shavings.
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Ferro/química , Bactérias Redutoras de Enxofre/metabolismo , Águas Residuárias/química , Purificação da Água/métodos , Concentração de Íons de Hidrogênio , OxirreduçãoRESUMO
OBJECTIVE: With the improvement of medical level, the number of elderly patients is increasing, and the postoperative outcome of the patients cannot be ignored. However, there have been no studies on the relationship between preoperative heart rate variability (HRV) and Perioperative Neurocognitive Disorders (PND). The purpose of this study was to explore the correlation between (HRV) and (PND), postoperative intensive care unit (ICU), and hospital stay in patients undergoing non-cardiac surgery. METHOD: This retrospective analysis included 687 inpatients who underwent 24-hour dynamic electrocardiogram examination in our six departments from January 2021 to January 2022. Patients were divided into two groups based on heart rate variability (HRV): high and low. Possible risk factors of perioperative outcomes were screened using univariate analysis, and risk factors were included in multivariate logistic regression to screen for independent risk factors. The subgroup analysis was carried out to evaluate the robustness of the results. The nomogram of PND multi-factor logistic prediction model was constructed. The receiver operating characteristic (ROC) curve was drawn, and the calibration curve was drawn by bootstrap resampling 1000 times for internal verification to evaluate the prediction ability of nomogram. RESULT: A total of 687 eligible patients were included. The incidence of low HRV was 36.7% and the incidence of PND was 7.6%. The incidence of PND in the low HRV group was higher than that in the high HRV group (11.8% vs 5.2%), the postoperative ICU transfer rate was higher (15.9% than 9.3%P = 0.009), and the hospital stay was longer [15 (11, 19) vs (13), 0.015]. The multivariable logistic regression analysis showed that after adjusting for other factors, decreased low HRV was identified as an independent risk factor for the occurrence of PND (Adjusted Odds Ratio = 2.095; 95% Confidence Interval: 1.160-3.784; P = 0.014) and postoperative ICU admission (Adjusted Odds Ratio = 1.925; 95% Confidence Interval: 1.128-3.286; P = 0.016). This study drew a nomogram column chart for a multivariate logistic regression model, incorporating age and HRV. The calibration curve shows that the predicted value of the model for the occurrence of cardio-cerebrovascular events is in good agreement with the actual observed value, with C-index of 0.696 (95% CI: 0.626 ~ 0.766). Subgroup analysis showed that low HRV was an independent risk factor for PND in patients with gastrointestinal surgery and ASA â ¢, aged ≥ 65 years. CONCLUSION: In patients undergoing non-cardiac surgery, the low HRV was an independent risk factor for PND and postoperative transfer to the ICU, and the hospitalization time of patients with low HRV was prolonged. Through establishing a risk prediction model for the occurrence of PND, high-risk patients can be identified during the perioperative period for early intervention.
Assuntos
Transtornos Neurocognitivos , Nomogramas , Idoso , Humanos , Estudos Retrospectivos , Frequência Cardíaca , Fatores de RiscoRESUMO
The endothelial barrier plays a critical role in immune defense against bacterial infection. Efficient interactions between neutrophils and endothelial cells facilitate the activation of both cell types. However, neutrophil activation can have dual effects, promoting bacterial clearance on one hand while triggering inflammation on the other. In this review, we provide a detailed overview of the cellular defense progression when neutrophils encounter bacteria, focusing specifically on neutrophil-endothelial interactions and endothelial activation or dysfunction. By elucidating the underlying mechanisms of inflammatory pathways, potential therapeutic targets for inflammation caused by endothelial dysfunction may be identified. Overall, our comprehensive understanding of neutrophil-endothelial interactions in modulating innate immunity provides deeper insights into therapeutic strategies for infectious diseases and further promotes the development of antibacterial and anti-inflammatory drugs.