RESUMO

OBJECTIVES: To establish a nomogram for differentiating malignant and benign focal liver lesions (FLLs) using ultrasomics features derived from contrast-enhanced ultrasound (CEUS). METHODS: 527 patients were retrospectively enrolled. On the training cohort, ultrasomics features were extracted from CEUS and b-mode ultrasound (BUS). Automatic feature selection and model development were performed using the Ultrasomics-Platform software, outputting the corresponding ultrasomics scores. A nomogram based on the ultrasomics scores from artery phase (AP), portal venous phase (PVP) and delayed phase (DP) of CEUS, and clinical factors were established. On the validation cohort, the diagnostic performance of the nomogram was assessed and compared with seniorexpert and resident radiologists. RESULTS: In the training cohort, the AP, PVP and DP scores exhibited better differential performance than BUS score, with area under the curve (AUC) of 84.1-85.1% compared with the BUS (74.6%, P < 0.05). In the validation cohort, the AUC of combined nomogram and expert was significantly higher than that of the resident (91.4% vs. 89.5% vs. 79.3%, P < 0.05). The combined nomogram had a comparable sensitivity with the expert and resident (95.2% vs. 98.4% vs. 97.6%), while the expert had a higher specificity than the nomogram and the resident (80.6% vs. 72.2% vs. 61.1%, P = 0.205). CONCLUSIONS: A CEUS ultrasomics based nomogram had an expert level performance in FLL characterization.

Assuntos

Meios de Contraste , Neoplasias Hepáticas , Nomogramas , Ultrassonografia , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Ultrassonografia/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Estudos Retrospectivos , Diagnóstico Diferencial , Adulto , Idoso , Sensibilidade e Especificidade , Fígado/diagnóstico por imagem

RESUMO

BACKGROUND: Exploring effect biomarkers that monitor tumor progression and predict the prognosis could benefit the clinical management of bladder cancer and improve the postoperative life of patients. This study aimed to estimate the function of long non-coding (lnc)RNA RHPN1-AS1 (RHPN1-AS1) in bladder cancer and the potential molecular mechanism. METHODS: The expression of RHPN1-AS1 was evaluated in bladder cancer tissues from 115 patients and cells by polymerase chain reaction. The clinical significance of RHPN1-AS1 was assessed and its effect was also estimated in cell proliferation, migration, and invasion. The underlying molecular mechanism was explored by the dual-luciferase reporter assay. RESULTS: The expression of RHPN1-AS1 was 2.91-fold elevated in bladder cancer, which showed a close correlation with advanced tumor node metastasis stage (P = 0.013) and the presence of lymph node metastasis (P = 0.018). RHPN1-AS1 also served as a poor prognostic indicator (hazard ratio = 2.563) for bladder cancer. The knockdown of RHPN1-AS1 significantly suppressed the proliferation and metastasis ability of bladder cancer cells. Moreover, miR-485-5p was found to mediate the function of RHPN1-AS1 in bladder cancer, which was considered the underlying regulatory mechanism. CONCLUSIONS: RHPN1-AS1 serves as a prognostic biomarker and tumor promoter in bladder cancer via modulating miR-485-5p, which might be a reliable target of bladder cancer therapy.

RESUMO

Joint toxicity of organic-metal co-contamination can vary depending on organisms, toxicants, and even the sequence of exposure. This study examines how the combined toxicity of aniline (An) and cadmium (Cd) to soil bacteria in microcosms changes when the order of contaminant introduction is altered. Through analyzing biodiversity, molecular ecological network, functional redundancy, functional genes and pathways, we find the treatment of Cd followed by An brings about the strongest adverse impact to the bacterial consortium, followed by the reverse-ordered exposure and the simple mixture of the two chemicals. On the level of individual organisms, exposure sequence also affects the bacteria that are otherwise resistant to the standalone toxicity of both An and Cd. The dynamic behavior of aniline-cadmium composite is interpreted by considering the tolerance of organisms to individual chemicals, the interactions of the two toxicants, the recovery time, as well as the priority effect. The overall effect of the composite contamination is conceptualized by treating the chemicals as environmental filters screening the growth of the community.

Assuntos

Compostos de Anilina , Bactérias , Cádmio , Microbiologia do Solo , Poluentes do Solo , Compostos de Anilina/toxicidade , Cádmio/toxicidade , Poluentes do Solo/toxicidade , Bactérias/efeitos dos fármacos , Bactérias/genética , Biodiversidade

RESUMO

Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acids─Gly, Pro, and Lys─as the ligand to recruit the corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs, to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC. We found that the extent of EML4-ALK and EGFR reduction can be easily fine-tuned by using different degradation signals. These amino acid-based PROTACs, termed AATacs, hindered proliferation and induced cell cycle arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs, AATacs are small, interchangeable but with different degradation efficiency. Our study further expands the repertoire of E3 ligases and their ligands for PROTAC application, improving the versatility and utility of targeted protein degradation for therapeutic purposes.

Assuntos

Aminoácidos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteólise , Ubiquitina-Proteína Ligases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteólise/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Aminoácidos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Quimera de Direcionamento de Proteólise

RESUMO

Methanogenic archaea are main contributors to methane emissions, and have a crucial role in carbon cycling and global warming. Until recently, methanogens were confined to Euryarchaeota, but metagenomic studies revealed the presence of genes encoding the methyl coenzyme M reductase complex in other archaeal clades1-4, thereby opening up the premise that methanogenesis is taxonomically more widespread. Nevertheless, laboratory cultivation of these non-euryarchaeal methanogens was lacking to corroborate their potential methanogenic ability and physiology. Here we report the isolation of a thermophilic archaeon LWZ-6 from an oil field. This archaeon belongs to the class Methanosuratincolia (originally affiliated with 'Candidatus Verstraetearchaeota') in the phylum Thermoproteota. Methanosuratincola petrocarbonis LWZ-6 is a strict hydrogen-dependent methylotrophic methanogen. Although previous metagenomic studies speculated on the fermentative potential of Methanosuratincolia members, strain LWZ-6 does not ferment sugars, peptides or amino acids. Its energy metabolism is linked only to methanogenesis, with methanol and monomethylamine as electron acceptors and hydrogen as an electron donor. Comparative (meta)genome analysis confirmed that hydrogen-dependent methylotrophic methanogenesis is a widespread trait among Methanosuratincolia. Our findings confirm that the diversity of methanogens expands beyond the classical Euryarchaeota and imply the importance of hydrogen-dependent methylotrophic methanogenesis in global methane emissions and carbon cycle.

Assuntos

Archaea , Euryarchaeota , Metano , Archaea/metabolismo , Archaea/genética , Archaea/classificação , Archaea/isolamento & purificação , Metabolismo Energético , Euryarchaeota/classificação , Euryarchaeota/metabolismo , Genoma Arqueal , Hidrogênio/metabolismo , Metano/biossíntese , Metano/metabolismo , Metanol/metabolismo , Campos de Petróleo e Gás/microbiologia , Oxirredução , Oxirredutases/metabolismo , Oxirredutases/genética , Filogenia , Ciclo do Carbono

RESUMO

BACKGROUND: Prostate cancer, characterized by its insidious onset and short overall survival, and has seen a rise in incidence over recent decades. This study aims to investigate the expression and molecular mechanism of lncRNA PTCSC3 (PTCSC3) in prostate cancer in order to develop new prognostic and therapeutic biomarkers. METHODS: The level of PTCSC3 in serum and cell samples of prostate cancer was quantitatively measured using RT-qPCR assays. The correlation between the variation in PTCSC3 levels and clinical indicators of patients was evaluated. The survival status of the prostate cancer patients included in the study was evaluated using Kaplan-Meier curve and multivariable Cox analysis. The impact of PTCSC3 overexpression on cell growth and activity was revealed by CCK-8 and Transwell assays. The targeting relationship between PTCSC3 and miR-182-5p was determined by bioinformatics prediction and luciferase activity. RESULTS: PTCSC3 was found to be downregulated in prostate cancer, and its low levels were associated with short overall survival in patients. It influenced the progression of prostate cancer by targeting miR-182-5p. Increasing PTCSC3 levels suppressed the proliferation, migration and invasion levels of cells, and miR-182-5p mimic counteracted PTCSC3's effects on cells. CONCLUSIONS: As a potential prognostic biological factor for prostate cancer, PTCSC3 may regulate the progression of prostate cancer by sponging miR-182-5p and affect the prognosis of patients.

Assuntos

MicroRNAs , Neoplasias da Próstata , RNA Longo não Codificante , Masculino , Humanos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , MicroRNAs/genética , MicroRNAs/sangue , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/sangue , Pessoa de Meia-Idade , Idoso , Taxa de Sobrevida , Regulação para Baixo

RESUMO

Introduction: This study aims to investigate the clinical efficacy of V-Y advanced flap pedicled with freestyle perforator flap for repairing small range defects in the anterior knee region. Methods: 8 patients with skin and soft tissue defect/necrosis in the anterior knee area admitted to the Changshu No.1 People's Hospital from January 2021 to January 2022 were selected, with a defect range of 4 cm × 3 cm-9 cm × 6 cm, designed a V-Y advanced flap pedicled with freestyle perforator flap to repair the wound in the anterior knee area. Adjust the size and position of the flap according to the number and position of perforating branches found during the surgery, with a cutting area of 6 cm × 5 cm-14 cm × 10 cm and the supply area was directly pulled and sutured. Results: 4 patients were repaired by flaps pedicled with 2 perforating branches, 2 patients were repaired by flaps pedicled with 1 perforating branch and 2 patients were repaired by flaps pedicled with 3 perforating branches. 4 patients were repaired by flaps pedicled with 2 perforating branches, 2 patients were repaired by flaps pedicled with 1 perforating branch and 2 patients were repaired by flaps pedicled with 3 perforating branches. All flaps survived and following up for 6-15 months, the blood supply, appearance, and color of the flap were satisfactory, and the functions of knee joint flexion and extension were well preserved. Discussion: The V-Y advancement flap pedicled with freestyle perforator flap has the advantages of reliable blood supply, simple surgical operation, texture and thickness similar to the skin of the anterior knee area, and direct suture of the donor area. It is a perforator flap with good repair effect for small scale defects in the anterior knee area.

RESUMO

BACKGROUND: The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure. METHODS AND RESULTS: Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, P=0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity. CONCLUSIONS: Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.

Assuntos

Autofagia , Cardiotoxicidade , Colchicina , Doxorrubicina , Lisossomos , Miócitos Cardíacos , Colchicina/toxicidade , Colchicina/farmacologia , Doxorrubicina/toxicidade , Cardiotoxicidade/prevenção & controle , Autofagia/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Animais , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Modelos Animais de Doenças , Masculino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Antibióticos Antineoplásicos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Função Ventricular Esquerda/efeitos dos fármacos

RESUMO

BACKGROUND: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling. METHODS: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine -modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH. RESULTS: This modification occurs at the position 5 of the tRF-1-AspGTC (5o8G tRF). Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH. CONCLUSIONS: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.

Assuntos

Biomarcadores , Receptores de Proteínas Morfogenéticas Ósseas Tipo II , Hipertensão Pulmonar , Artéria Pulmonar , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/etiologia , Humanos , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Animais , Biomarcadores/metabolismo , Biomarcadores/sangue , Artéria Pulmonar/metabolismo , Proteína Wnt-5a/metabolismo , Proteína Wnt-5a/genética , Guanina/análogos & derivados , Guanina/metabolismo , Masculino , Estresse Oxidativo , Caspase 3/metabolismo , Miócitos de Músculo Liso/metabolismo , Proliferação de Células , Apoptose , Células Cultivadas , Remodelação Vascular , Feminino , Ratos , Espécies Reativas de Oxigênio/metabolismo , Músculo Liso Vascular/metabolismo

RESUMO

Metalenses are typically designed for a fixed focal length, restricting their functionality to static scenarios. Various methods have been introduced to achieve the zoom function in metalenses. These methods, however, have a very limited zoom range, or they require additional lenses to achieve direct imaging. Here, we demonstrate a zoom metalens based on axial movement that performs both the imaging and the zoom function. The key innovation is the use of a polynomial phase profile that mimics an aspheric lens, which allows an extended depth of focus, enabling a large zoom range. Experimental results show that this focal length variation, combined with the extended depth of focus, translates into an impressive zoom range of 11.9× while maintaining good imaging quality. We see applications for such a zoom metalens in surveillance cameras of drones or microrobots to reduce their weight and volume, thus enabling more flexible application scenarios.

RESUMO

PURPOSE: The purpose of this study was to investigate the role of lncRNA DSCAM-AS1 in prostate cancer to find new therapeutic targets and promote the research progress of prostate cancer. METHODS: RT-qPCR was used to detect DSCAM-AS1 expression in prostate cancer tissues, normal tissues, human normal prostate epithelial cells (RWPE), and four prostate cancer cell lines. The clinical and prognostic role of DSCAM-AS1 was evaluated by the Kaplan-Meier curve and chi-square test. Secondly, a dual luciferase reporter gene assay was used to study the regulatory mechanism between miR-338-3p and DSCAM-AS1. Finally, the roles of DSCAM-AS1 and miR-338-3p in prostate cancer cell proliferation and metastasis were explored by CCK-8 and Transwell assays. RESULTS: It was found that DSCAM-AS1 upregulation could serve as a warning of deterioration and poor prognosis in prostate cancer patients, and that knockdown of DSCAM-AS1 expression inhibited the progression of prostate cancer cells. In addition, miR-338-3p, a target of DSCAM-AS1, was found to be down-regulated in prostate cancer cells and miR-338-3p knockdown could reverse the inhibitory effect of DSCAM-AS1 silencing on prostate cancer. CONCLUSION: DSCAM-AS1 is up-regulated in prostate cancer and regulates the progression of prostate cancer cells by targeting miR-338-3p.

RESUMO

Pleckstrin homology domain-containing family M member 2 (PLEKHM2) is an essential adaptor for lysosomal trafficking and its homozygous truncation have been reported to cause early onset dilated cardiomyopathy (DCM). However, the molecular mechanism of PLEKHM2 deficiency in DCM pathogenesis and progression is poorly understood. Here, we generated an in vitro model of PLEKHM2 knockout (KO) induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the potential pathogenic mechanism of PLEKHM2-deficient cardiomyopathy. PLEKHM2-KO hiPSC-CMs developed disease phenotypes with reduced contractility and impaired calcium handling. Subsequent RNA sequencing (RNA-seq) analysis revealed altered expression of genes involved in mitochondrial function, autophagy and apoptosis in PLEKHM2-KO hiPSC-CMs. Further molecular experiments confirmed PLEKHM2 deficiency impaired autophagy and resulted in accumulation of damaged mitochondria, which triggered increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential (Δψm). Importantly, the elevated ROS levels caused oxidative stress-induced damage to nearby healthy mitochondria, resulting in extensive Δψm destabilization, and ultimately leading to impaired mitochondrial function and myocardial contractility. Moreover, ROS inhibition attenuated oxidative stress-induced mitochondrial damage, thereby partially rescued PLEKHM2 deficiency-induced disease phenotypes. Remarkably, PLEKHM2-WT overexpression restored autophagic flux and rescued mitochondrial function and myocardial contractility in PLEKHM2-KO hiPSC-CMs. Taken together, these results suggested that impaired mitochondrial clearance and increased ROS levels play important roles in PLEKHM2-deficient cardiomyopathy, and PLEKHM2-WT overexpression can improve mitochondrial function and rescue PLEKHM2-deficient cardiomyopathy.

RESUMO

The emerging roles of O-GlcNAcylation, a distinctive post-translational modification, are increasingly recognized for their involvement in the intricate processes of protein trafficking and secretion. This modification exerts its influence on both conventional and unconventional secretory pathways. Under healthy and stress conditions, such as during diseases, it orchestrates the transport of proteins within cells, ensuring timely delivery to their intended destinations. O-GlcNAcylation occurs on key factors, like coat protein complexes (COPI and COPII), clathrin, SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors), and GRASP55 (Golgi reassembly stacking protein of 55 kDa) that control vesicle budding and fusion in anterograde and retrograde trafficking and unconventional secretion. The understanding of O-GlcNAcylation offers valuable insights into its critical functions in cellular physiology and the progression of diseases, including neurodegeneration, cancer, and metabolic disorders. In this review, we summarize and discuss the latest findings elucidating the involvement of O-GlcNAc in protein trafficking and its significance in various human disorders.

Assuntos

Clatrina , Proteínas SNARE , Humanos , Acetilglucosamina/metabolismo , Clatrina/metabolismo , Processamento de Proteína Pós-Traducional , Transporte Proteico/fisiologia , Proteínas SNARE/metabolismo , Animais , Acetilação , Glucose/metabolismo

RESUMO

Rhizosphere is a soil volume of high spatio-temporal heterogeneity and intensive plant-soil-microbial interactions, for which visualization and process quantification is of highest scientific and applied relevance, but still very challenging. A novel methodology for quick assessment of two-dimensional distribution of available phosphorus (P) in rhizosphere was suggested, tested, and development up to the application platform. Available P was firstly trapped by an in-situ diffusive gradients in thin-films (DGT) sampler with precipitated zirconia as the binding gel, and subsequently, the loaded gel was analyzed with an optimized colorimetric imaging densitometry (CID). The imaging platform was established linking: i) DGT, ii) planar optode, and iii) soil zymography techniques to simultaneously determine available P, oxygen, and acid phosphatase in rhizosphere at sub-millimeter spatial scales. The DGT identified available P level in rice rhizosphere were spatially overlapping to the localized redox hotspots and phosphatase activity. The spatial relationship between available P and acid phosphatase activity was dependent on root development. The root radial oxygen loss (ROL) remained active during the experimental observations (2-3 days), while a flux of available P of 10 pg cm-2 s-1 was visualized within 2-3 mm of roots, confirming the correlative response of rice roots to oxygen secretion and P uptake. Summarizing, the established imaging platform is suitable to capture spatial heterogeneity and temporal dynamics of root activities, nutrient bioavailability, ROL and enzyme activities in rhizosphere.

Assuntos

Oryza , Fósforo , Fósforo/metabolismo , Rizosfera , Solo , Oxigênio/metabolismo , Fosfatase Ácida/metabolismo , Raízes de Plantas/metabolismo

RESUMO

Coastal wetlands contribute to the mitigation of climate change through the sequestration of "blue carbon". Microbial necromass, lignin, and glycoproteins (i.e., glomalin-related soil proteins (GRSP)), as important components of soil organic carbon (SOC), are sensitive to environmental change. However, their contributions to blue carbon formation and the underlying factors remain largely unresolved. To address this paucity of knowledge, we investigated their contributions to blue carbon formation along a salinity gradient in coastal marshes. Our results revealed decreasing contributions of microbial necromass and lignin to blue carbon as the salinity increased, while GRSP showed an opposite trend. Using random forest models, we showed that their contributions to SOC were dependent on microbial biomass and resource stoichiometry. In N-limited saline soils, contributions of microbial necromass to SOC decreased due to increased N-acquisition enzyme activity. Decreases in lignin contributions were linked to reduced mineral protection offered by short-range-ordered Fe (FeSRO). Partial least-squares path modeling (PLS-PM) further indicated that GRSP could increase microbial necromass and lignin formation by enhancing mineral protection. Our findings have implications for improving the accumulation of refractory and mineral-bound organic matter in coastal wetlands, considering the current scenario of heightened nutrient discharge and sea-level rise.

Assuntos

Carbono , Solo , Lignina , Glicoproteínas , Proteínas Fúngicas , Minerais

RESUMO

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is frequently caused by mutations in the ß-cardiac myosin heavy chain gene (MYH7). Abnormal calcium handling and diastolic dysfunction are archetypical features of HCM caused by MYH7 gene mutations. However, the mechanism of how MYH7 mutations leads to these features remains unclear, which inhibits the development of effective therapies. Initially, cardiomyocytes were generated from induced pluripotent stem cells from an eight-year-old girl diagnosed with HCM carrying a MYH7(C.1063 G>A) heterozygous mutation(mutant-iPSC-CMs) and mutation-corrected isogenic iPSCs(control-iPSC-CMs) in the present study. Next, we compared phenotype of mutant-iPSC-CMs to that of control-iPSC-CMs, by assessing their morphology, hypertrophy-related genes expression, calcium handling, diastolic function and myofilament calcium sensitivity at days 15 and 40 respectively. Finally, to better understand increased myofilament Ca2+ sensitivity as a central mechanism of central pathogenicity in HCM, inhibition of calcium sensitivity with mavacamten can improveed cardiomyocyte hypertrophy. Mutant-iPSC-CMs exhibited enlarged areas, increased sarcomere disarray, enhanced expression of hypertrophy-related genes proteins, abnormal calcium handling, diastolic dysfunction and increased myofilament calcium sensitivity at day 40, but only significant increase in calcium sensitivity and mild diastolic dysfunction at day 15. Increased calcium sensitivity by levosimendan aggravates cardiomyocyte hypertrophy phenotypes such as expression of hypertrophy-related genes, abnormal calcium handling and diastolic dysfunction, while inhibition of calcium sensitivity significantly improves cardiomyocyte hypertrophy phenotypes in mutant-iPSC-CMs, suggesting increased myofilament calcium sensitivity is the primary mechanisms for MYH7 mutations pathogenesis. Our studies have uncovered a pathogenic mechanism of HCM caused by MYH7 gene mutations through which enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction. Correction of the myofilament calcium sensitivity was found to be an effective method for treating the development of HCM phenotype in vitro.

Assuntos

Cardiomiopatias , Cardiomiopatia Hipertrófica , Células-Tronco Pluripotentes Induzidas , Criança , Feminino , Humanos , Cálcio/metabolismo , Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Hipertrofia/metabolismo , Hipertrofia/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Miofibrilas/patologia , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo

RESUMO

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

RESUMO

Passive wireless surface acoustic wave (SAW) resonant sensors are widely used in measuring pressure, temperature, and torque, typically detecting sensing parameters by measuring the echo signal frequency of SAW resonators. Therefore, the accuracy of echo signal frequency estimation directly affects the performance index of the sensor. Due to the exponential attenuation trend of the echo signal, the duration is generally approximately 10 µs, with conventional frequency domain analysis methods limited by the sampling frequency and data points. Thus, the resolution of frequency estimation is limited. Here, signal time-domain fitting combined with a genetic algorithm is used to estimate SAW echo signal frequency. To address the problem of slow estimation speed and poor timeliness caused by a conventional genetic algorithm, which needs to simultaneously estimate multiple parameters, such as signal amplitude, phase, frequency, and envelope, the Hilbert transform is proposed to remove the signal envelope and estimate its amplitude, and the fast Fourier transform subsection method is used to analyze the initial phase of the signal. The genetic algorithm is thereby optimized to realize the frequency estimation of SAW echo signals under a single parameter. The developed digital signal processing frequency detection system was monitored in real time to estimate the frequency of an SAW echo signal lasting 10 µs and found to have only 100 sampling points. The proposed method has a frequency estimation error within 3 kHz and a frequency estimation time of less than 1 s, which is eight times faster than the conventional genetic algorithm.

RESUMO

BACKGROUND: Plants show developmental plasticity with variations in environmental nutrients. Considering low-cost rock dust has been identified as a potential alternative to artificial fertilizers for more sustainable agriculture, the growth responses of Arabidopsis seedlings on three rock meals (basalt, granite, and marlstone) were examined for the different foraging behavior, biomass accumulation, and root architecture. RESULTS: Compared to ½ MS medium, basalt and granite meal increased primary root length by 13% and 38%, respectively, but marlstone caused a 66% decrease, and they all drastically reduced initiation and elongation of lateral roots but lengthened root hairs. Simultaneous supply of organic nutrients and trace elements increased fresh weight due to the increased length of primary roots and root hairs. When nitrogen (N), phosphorus (P), and potassium (K) were supplied individually, N proved most effective in improving fresh weight of seedlings growing on basalt and granite, whereas K, followed by P, was most effective for those growing on marlstone. Unexpectedly, the addition of N to marlstone negatively affected seedling growth, which was associated with repressed auxin biosynthesis in roots. CONCLUSIONS: Our data indicate that plants can recognize and adapt to complex mineral deficiency by adjusting hormonal homeostasis to achieve environmental sensitivity and developmental plasticity, which provide a basis for ecologically sound and sustainable strategies to maximize the use of natural resources and reduce the production of artificial fertilizers.

Assuntos

Proteínas de Arabidopsis , Arabidopsis , Plântula , Ácidos Indolacéticos , Fertilizantes , Raízes de Plantas , Homeostase , Nutrientes