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The hematopoietic stem cells (HSCs) that produce blood for the lifetime of an animal arise from RUNX1+ hemogenic endothelial cells (HECs) in the embryonic vasculature through a process of endothelial-to-hematopoietic transition (EHT). Studies have identified inflammatory mediators and fluid shear forces as critical environmental stimuli for EHT, raising the question of how such diverse inputs are integrated to drive HEC specification. Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid shear forces and inflammatory mediators, and it plays roles in cardiovascular development and disease that have been linked to both stimuli. Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for the specification of RUNX1+ HECs in both the yolk sac and dorsal aorta of the mouse embryo and for their transition to intraaortic hematopoietic cluster (IAHC) cells. The inflammatory mediators lipopolysaccharide and interferon-γ increase RUNX1+ HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis.
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Subunidade alfa 2 de Fator de Ligação ao Core , Hemangioblastos , Hematopoese , Animais , Diferenciação Celular , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Endotélio/metabolismo , Hemangioblastos/citologia , Hemangioblastos/metabolismo , Hemodinâmica , Mediadores da Inflamação/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , CamundongosRESUMO
In this work, N-doped and oxygen vacancy-rich NiCo2O4/NiO/Co3O4composites are synthesized by the direct calcination method. Noticeably, by changing the additive concentrations of urea dissolved in DMF (N-N dimethylformamide), the electromagnetic wave (EMW) absorption abilities of NiCo2O4/NiO/Co3O4composite effectively. A maximum reflection loss (RLmax) value at 12.94 GHz for a 2.8 mm thick sheet is -29.76 dB, while its effective absorption bandwidth (RL < -10 dB) reaches 4.21 GHz. In-depth research of possible mechanisms of EMW absorption enhancement. Owing to its simple preparation method and superb EMW absorption properties, the NiCo2O4/NiO/Co3O4composites have a chance to be suitable candidates for high-property EMW absorbers.
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Type 2 diabetes mellitus (T2DM) patients exhibit greater susceptibility to vascular calcification (VC), which has a higher risk of death and disability. However, there is no specific drug for VC therapy. NLRP3 inflammasome activation as a hallmark event of medial calcification leads to arterial stiffness, causing vasoconstrictive dysfunction in T2DM. Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), restrains hyperglycemia with definite cardiovascular benefits. Given the anti-inflammatory activity of EMPA, herein we investigated whether EMPA protected against VC in the aorta of T2DM mice by inhibiting NLRP3 inflammasome activation. Since db/db mice receiving a normal diet developed VC at the age of about 20 weeks, we administered EMPA (5, 10, 20 mg·kg-1·d-1, i.g) to 8 week-old db/db mice for 12 weeks. We showed that EMPA intervention dose-dependently ameliorated the calcium deposition, accompanied by reduced expression of RUNX2 and BMP2 proteins in the aortas. We found that EMPA (10 mg·kg-1·d-1 for 6 weeks) also protected against VC in vitamin D3-overloaded mice, suggesting the protective effects independent of metabolism. We showed that EMPA (10 mg·kg-1·d-1) inhibited the abnormal activation of NLRP3 inflammasome in aortic smooth muscle layer of db/db mice. Knockout (KO) of NLRP3 significantly alleviated VC in STZ-induced diabetic mice. The protective effects of EMPA were verified in high glucose (HG)-treated mouse aortic smooth muscle cells (MOVASs). In HG-treated NLRP3 KO MOVASs, EMPA (1 µM) did not cause further improvement. Bioinformatics and Western blot analysis revealed that EMPA significantly increased the expression levels of basic helix-loop-helix family transcription factor e40 (Bhlhe40) in HG-treated MOVASs, which served as a negative transcription factor directly binding to the promotor of Nlrp3. We conclude that EMPA ameliorates VC by inhibiting Bhlhe40-dpendent NLRP3 inflammasome activation. These results might provide potential significance for EMPA in VC therapy of T2DM patients.
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Compostos Benzidrílicos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Glucosídeos , Calcificação Vascular , Animais , Humanos , Lactente , Camundongos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Proteínas de Homeodomínio , Inflamassomos/metabolismo , Camundongos Endogâmicos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fatores de Transcrição , Calcificação Vascular/tratamento farmacológicoRESUMO
Indoor cases of Tetranychus cinnabarinus displaying resistance have been documented, but the resistance level in field populations remains unexplored in China. This study delves into the resistance dynamics of T. cinnabarinus to fenpropathrin in various field populations across China, a pressing concern in contemporary agricultural pest control. The conventional bioassay and amplicon sequencing reveal a notable absence of significant fenpropathrin resistance in field populations, contrasting with known resistance in indoor cases. Current study highlights the limitations of traditional bioassays in detecting early-stage resistance and underscores the nuanced capabilities and constraints of amplicon sequencing in resistance gene frequency analysis. By employing an integrated approach, we combined dose-response bioassays, amplicon sequencing, and statistical modeling to assess resistance levels and investigate underlying genetic factors. The model with empirical data indicates that a 5% mutation frequency represents the threshold before resistance emerges. However, the detection of the kdr mutation in certain populations ranging from 0 to 1.2%, signals an early looming threat of future resistance emergence. Additionally, we further assessed a specific dsRNA targeting VGSC genes at two concentrations (10 ng/µL and 100 ng/µL), both inducing substantial mortality by silencing target genes effectively. The exploration of RNA interference (RNAi) as a novel, more environmentally friendly pest control measure opens new avenues, despite the ongoing challenge of resistance evolution. Overall, this study underscores the necessity for evolving pest management strategies, integrating advanced biotechnological approaches with traditional methods, to effectively counter pesticide resistance and ensure sustainable agricultural productivity.
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Resistência a Inseticidas , Piretrinas , Interferência de RNA , Tetranychidae , Animais , Tetranychidae/genética , Tetranychidae/efeitos dos fármacos , Piretrinas/farmacologia , Resistência a Inseticidas/genética , Inseticidas/farmacologiaRESUMO
This study examines the possible consequence of elder mistreatment on resilience and whether social support moderates this posited association, using a rural sample of 432 community-dwelling older Chinese adults aged 60 to 79 years. Elder abuse included verbal abuse, physical abuse, or financial exploitation. Social support was measured by The Multidimensional Scale of Perceived Social Support (MSPSS). Resilience was represented by a seven-item scale. Hierarchical regression models indicated that mistreatment is significantly related to low levels of resilience when confounding factors are adjusted. A significant interaction term (abuse × social support) was also detected. Mistreated respondents who reported higher levels of social support were less likely to experience low resilience compared to those with lower levels of social support. Social support buffers against the undesirable effect of mistreatment on resilience, especially for those who were abused.
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Metabolic reprogramming is the survival rule of tumor cells, and tumor cells can meet their high metabolic requirements by changing the energy metabolism mode. Metabolic reprogramming of tumor cells is an important biochemical basis of tumor malignant phenotypes. Ras-related C3 botulinum toxin substrate 1 (Rac1) is abnormally expressed in a variety of tumors and plays an important role in the proliferation, invasion, and migration of tumor cells. However, the role of Rac1 in tumor metabolic reprogramming is still unclear. Herein, we revealed that Rac1 was highly expressed in colon cancer tissues and cell lines. Rac1 promotes the proliferation, migration, and invasion of colon cancer cells by upregulating SOX9, which as a transcription factor can directly bind to the promoters of HK2 and G6PD genes and regulate their transcriptional activity. Rac1 upregulates the expression of SOX9 through the PI3K/AKT signaling pathway. Moreover, Rac1 can promote glycolysis and the activation of the pentose phosphate pathway in colon cancer cells by mediating the axis of SOX9/HK2/G6PD. These findings reveal novel regulatory axes involving Rac1/SOX9/HK2/G6PD in the development and progression of colon cancer, providing novel promising therapeutic targets.
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Neoplasias do Colo , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Neoplasias do Colo/genética , Proliferação de Células/fisiologia , Linhagem Celular Tumoral , Glucose/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Fatores de Transcrição SOX9/metabolismoRESUMO
Cancer cells prefer glycolysis to support their proliferation. Our previous studies have shown that the long palate, lung, and nasal epithelial cell clone 1 (LPLUNC1) can upregulate prohibitin 1 (PHB1) expression to inhibit the proliferation of nasopharyngeal carcinoma (NPC) cells. Given that PHB1 is an important regulator of cell energy metabolism, we explored whether and how LPLUNC1 regulated glucose glycolysis in NPC cells. LPLUNC1 or PHB1 overexpression decreased glycolysis and increased oxidative phosphorylation (OXPHOS)-related protein expression in NPC cells, promoting phosphorylated PHB1 nuclear translocation through 14-3-3σ. LPLUNC1 overexpression also increased p53 but decreased c-Myc expression in NPC cells, which were crucial for the decrease in glycolysis and increase in OXPHOS-related protein expression induced by LPLUNC1 overexpression. Finally, we found that treatment with all-trans retinoic acid (ATRA) reduced the viability and clonogenicity of NPC cells, decreased glycolysis, and increased OXPHOS-related protein expression by enhancing LPLUNC1 expression in NPC cells. Therefore, the LPLUNC1-PHB1-p53/c-Myc axis decreased glycolysis in NPC cells, and ATRA upregulated LPLUNC1 expression, ATRA maybe a promising drug for the treatment of NPC.
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Neoplasias Nasofaríngeas , Proteína Supressora de Tumor p53 , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Glicólise , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/patologia , Tretinoína/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Autoantígenos/metabolismoRESUMO
The cellular transcription factors are known to play important roles in virus infection. The present study cloned and characterized a transcription factor CCAAT/Enhancer-binding protein homolog from the shrimp Penaeus vannamei (designates as PvCEBP), and explored its potential functions in white spot syndrome virus (WSSV) infection. PvCEBP has an open reading frame (ORF) of 864 bp encoding a putative protein of 287 amino acids, which contained a highly C-terminal conserved bZIP domain. Phylogenetic tree analysis showed that PvCEBP was evolutionarily clustered with invertebrate CEBPs and closely related to the CEBP of Homarus americanus. Quantitative real-time PCR (qPCR) analysis revealed that PvCEBP was expressed in all examined shrimp tissues, with transcript levels increased in shrimp hemocytes and gill upon WSSV challenge. Furthermore, knockdown of PvCEBP mediated by RNA interference significantly decreased the expression of WSSV genes and viral loads, while enhanced the shrimp survival rate under WSSV challenge. In silico prediction and reporter gene assays demonstrated that PvCEBP could activate the promoter activity of the viral immediate-early gene ie1. Collectively, our findings suggest that PvCEBP is annexed by WSSV to promote its propagation by enhancing the expression of viral immediate-early genes.
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Penaeidae , Vírus da Síndrome da Mancha Branca 1 , Animais , Fatores de Transcrição/genética , Penaeidae/genética , Vírus da Síndrome da Mancha Branca 1/fisiologia , Filogenia , Sequência de Aminoácidos , Proteínas de Artrópodes/genéticaRESUMO
BACKGROUND: Intraoperative intravenous fluid administration proves to be associated with surgical patients' postoperative outcomes. Few studies reported the relationship between intraoperative crystalloid-colloid infusion ratio and early surgical complications after ileal pouch-anal anastomosis (IPAA) in ulcerative colitis (UC). METHODS: Data on patients with underwent IPAA from January 2008 to March 2022 at our three inflammatory bowel disease (IBD) surgery centers were retrospectively collected. Intraoperative anesthetic data were recorded and later evaluated by our team anesthesiologist. RESULTS: A total of 140 eligible patients with a median follow-up time of 6.0 years [interquartile range (IQR): 2.0-8.0] were enrolled. Among all enrolled patients, 34 (24.3%) developed early surgical complications after IPAA. Greater blood loss and lower crystalloid-colloid infusion ratio were observed in patients with early surgical complications. Crystalloid-colloid infusion ratio < 2 and blood loss ≥ 200 ml had the most significant area under the receiver-operating characteristic curve (AUC) of 0.664 and 0.674 in predicting early surgical complications. Crystalloid-colloid infusion ratio < 2 [odds ratio (OR), 2.571; 95% confidence intervals (CI), 1.067-6.195, p = 0.035] and blood loss ≥ 200 ml (OR, 3.165; 95% CI, 1.288-7.777, p = 0.012) were independent risk factors for the development of early post-IPAA complications. CONCLUSION: Intraoperative crystalloid-colloid infusion ratio < 2 and blood loss volume over 200 ml during IPAA contribute to the occurrence of early surgical complications. Early attentions and necessary interventions are warranted to avoid these risk factors during the IPAA surgery in order to prevent the development of early surgical complications.
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Colite Ulcerativa , Bolsas Cólicas , Proctocolectomia Restauradora , Humanos , Colite Ulcerativa/cirurgia , Colite Ulcerativa/complicações , Seguimentos , Estudos Retrospectivos , Soluções Cristaloides , Proctocolectomia Restauradora/efeitos adversos , Anastomose Cirúrgica/efeitos adversos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Bolsas Cólicas/efeitos adversos , Resultado do TratamentoRESUMO
Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.
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Microbioma Gastrointestinal/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Imunidade Inata , Receptor 4 Toll-Like/imunologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Suscetibilidade a Doenças , Células Endoteliais/metabolismo , Feminino , Vida Livre de Germes , Bactérias Gram-Negativas/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/microbiologia , Humanos , Injeções Intravenosas , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Transdução de Sinais , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genéticaRESUMO
Thaumatin-like proteins (TLPs), which are defined as pathogenesis-related protein family 5 (PR5) members, are common plant proteins involved in defense responses and confer antifungal activity against many plant pathogens. Our earlier studies have reported that the TaTLP1 gene was isolated from wheat and proved to be involved in wheat defense in response to leaf rust attack. The present study aims to identify the interacting proteins of TaTLP1 and characterize the role of the interaction between wheat and Puccinia triticina (Pt). Pull-down experiments designed to isolate the molecular target of TaTLP1 in tobacco resulted in the identification of TaPR1, a pathogenesis-related protein of family 1, and the interaction between TaTLP1 and TaPR1 was confirmed by yeast two-hybrid experiments (Y2H), bimolecular fluorescence complementation (BiFC), and co-immunoprecipitation (Co-IP). In vitro, TaTLP1 and TaPR1 together increased antifungal activity against Pt. In vivo, the disease resistance phenotype, histological observations of fungal growth and host responses, and accumulation of H2O2 in TaTLP1-TaPR1 in co-silenced plants indicated that co-silencing significantly enhanced wheat susceptibility compared to single knockdown TaTLP1 or TaPR1 plants. The accumulation of reactive oxygen species (ROS) was significantly reduced in co-silenced plants compared to controls during Pt infection, which suggested that the TaTLP1-TaPR1 interaction positively modulates wheat resistance to Pt in an ROS-dependent manner. Our findings provide new insights for understanding the roles of two different PRs, TaTLP1 and TaPR1, in wheat resistance to leaf rust.
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Antígenos de Plantas/genética , Resistência à Doença/genética , Doenças das Plantas/genética , Proteínas de Plantas/genética , Triticum/genética , Basidiomycota/genética , Basidiomycota/patogenicidade , Doenças das Plantas/microbiologia , Folhas de Planta/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Triticum/crescimento & desenvolvimento , Triticum/microbiologiaRESUMO
Biosupercapacitors (BSCs) that can harvest and store chemical energy show great promise for power delivery of biological applications. However, low power density still limits their applications, especially as miniaturized implants. Here, we report an implantable fiber BSC with maximal power density of 22.6â mW cm-2 , superior to the previous reports. The fiber BSC was fabricated by integrating anode and cathode fibers of biofuel cell with supercapacitor fibers through multi-strand twisting. This twisting structure endowed many channels inside and high electrochemical active area for efficient mass diffusion and charge transfer among different fibers, benefiting high power output. The obtained thin and flexible fiber BSC operated stably under deformations and performed high biocompatibility after implantation. Eventually, the fiber BSC was implanted subcutaneously in rats and successfully realized electrical stimulation of sciatic nerve, showing promise as a power source in vivo.
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Fontes de Energia Bioelétrica , Ratos , Animais , Eletrodos , Glucose/química , Próteses e ImplantesRESUMO
Prohibitins (PHBs) are a class of highly evolutionarily conserved proteins that widely distribute in prokaryotes and eukaryotes. PHBs function in cell growth and proliferation or differentiation, regulating metabolism and signaling pathways. PHBs have different subcellular localization in eukaryotes, but they are mainly located in mitochondria. In the mitochondria, PHBs stabilize the structure of the mitochondrial membrane and regulate mitochondrial autophagy, mitochondrial dynamics, mitochondrial biogenesis and quality control, and mitochondrial unfolded protein response. PHBs has shown to be associated with many diseases, such as mitochondria diseases, cancers, infectious diseases, and so on. Some molecule targets of PHBs can interfere with the occurrence and development of diseases. Therefore, this review clarifies the functions of PHBs in mitochondria, and provides a summary of the potential values in clinics.
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The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , NAD(P)H Desidrogenase (Quinona)/efeitos dos fármacos , Quinolonas/farmacologia , Proteína Supressora de Tumor p53/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética , Regulação para CimaRESUMO
Atrial fibrillation (AF) represents the most common type of sustained cardiac arrhythmia in humans and confers a significantly increased risk for thromboembolic stroke, congestive heart failure and premature death. Aggregating evidence emphasizes the predominant genetic defects underpinning AF and an increasing number of deleterious variations in more than 50 genes have been involved in the pathogenesis of AF. Nevertheless, the genetic basis underlying AF remains incompletely understood. In the current research, by whole-exome sequencing and Sanger sequencing analysis in a family with autosomal-dominant AF and congenital patent ductus arteriosus (PDA), a novel heterozygous variation in the PRRX1 gene encoding a homeobox transcription factor critical for cardiovascular development, NM_022716.4:c.373G>T;p.(Glu125*), was identified to be in co-segregation with AF and PDA in the whole family. The truncating variation was not detected in 306 unrelated healthy individuals employed as controls. Quantitative biological measurements with a reporter gene analysis system revealed that the Glu125*-mutant PRRX1 protein failed to transactivate its downstream target genes SHOX2 and ISL1, two genes that have been causally linked to AF. Conclusively, the present study firstly links PRRX1 loss-of-function variation to AF and PDA, suggesting that AF and PDA share a common abnormal developmental basis in a proportion of cases.
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The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.
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Suscetibilidade a Doenças , Metabolismo Energético , Imunidade , Neoplasias/etiologia , Neoplasias/metabolismo , Imunidade Adaptativa , Biomarcadores , Biomarcadores Tumorais , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata , Redes e Vias Metabólicas , Neoplasias/patologia , Nutrientes/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder with the disorders of estrogen(E2) and progesterone(P) secretion. The purpose of this study was to evaluate the association between the progesterone level or progesterone/estradiol(P/E2) ratio on human chorionic gonadotropin (hCG) trigger day and the outcome of in vitro fertilization in PCOS patients and explore the value of progesterone and P/E2 ratio for predicting the clinical pregnancy. METHODS: The clinical data of 1254 PCOS patients who satisfied the inclusion criteria were retrospectively analyzed, including baseline characteristics such as age, body mass index, basal sex hormone levels, et al., as well as ovarian stimulation data and clinic outcome. RESULTS: The number of follicles larger than 14 mm in diameter (P < 0.001) and retrieved oocytes (P < 0.001) was greater in the high progesterone group (progesterone ≥ 0.92 ng/mL). In the high P/E2 group(P/E2 ratio ≥ 0.3), the number of follicles larger than 14 mm in diameter (P < 0.001) and retrieved oocytes (P < 0.001), as well as the rate of high-quality embryos (P = 0.040) were significantly decreased. In ultralong GnRH agonist protocol, the implantation rate(P < 0.001), hCG positive rate (P < 0.001), clinical pregnancy rate (P < 0.001) and live birth rate (P < 0.001) were all significantly higher than long GnRH agonist protocol and GnRH antagonist protocol. The clinical pregnancy rate of high progesterone group was significantly lower than that of low progesterone group in ultralong GnRH agonist (P = 0.008). The progesterone level could be used as an indicator to predict the positive clinical pregnancy (long GnRH agonist: P = 0.001; ultralong GnRH agonist: P < 0.001) except in cycles using GnRH antagonist (P = 0.169). In the ultralong GnRH agonist, the value of progesterone level in the prediction of clinical pregnancy was significantly higher than that of the P/E2 ratio (P = 0.021). CONCLUSIONS: In PCOS patients, the progesterone level is associated with clinical pregnancy rate while P/E2 ratio is not. In subgroup analysis using three different COS protocols, a significant association between progesterone level and clinical pregnancy rate can be observed in the long GnRH agonist protocol and ultralong GnRH agonist protocol. The progesterone level is significantly better than the P/E2 ratio in predicting the pregnancy outcome of PCOS patients, especially in ultralong GnRH agonist cycles.
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Estradiol/sangue , Fármacos para a Fertilidade Feminina/administração & dosagem , Indução da Ovulação/métodos , Progesterona/sangue , Gonadotropina Coriônica/administração & dosagem , Feminino , Fertilização in vitro , Humanos , Leuprolida/administração & dosagem , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos Retrospectivos , Injeções de Esperma IntracitoplásmicasRESUMO
OBJECTIVES: Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive. METHODS: Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system. RESULTS: A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM. CONCLUSIONS: The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.
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Cardiomiopatia Dilatada , Cardiomiopatia Dilatada/genética , Análise Mutacional de DNA , Heterozigoto , Humanos , Proteínas com Homeodomínio LIM , Fatores de Transcrição MEF2/genética , Proteínas Musculares , Linhagem , Fatores de TranscriçãoRESUMO
Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode ß-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.
Assuntos
Hipertensão Arterial Pulmonar/genética , Fatores de Transcrição SOXF/genética , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Mutação com Perda de Função , MasculinoRESUMO
Little research has considered all children while investigating adult children's role in their older parents' health and well-being. In this study, we examine the effect of filial piety across all children on parental depressive symptoms. A sample of 432 older parents with 1,223 adult children in a rural county in northern China rated the filial piety level for each child individually. Ratings were then combined across multiple children and organized into an ordinal variable of filial piety including three levels: all children being filial, some of the children being filial, and none of the children being filial. Ordinary least squares linear regression analyses were performed. The results reveal a significant and negative relationship between adult children's filial piety levels and older parents' depressive symptoms after controlling for age, gender, marital status, financial strain, chronic conditions, and social support from family and friends, respectively. That is, one level lower in the adult children's filial piety corresponds to increase in level of older parents' depressive symptoms. Filial piety seems to benefit older Chinese parents' mental health net of social support from family and friends in this sample. Including information from all children in the analyses is informative for better understanding the psychological significance of filial piety for healthy aging in China.