RESUMO
Estimation of heritability and genetic covariance is crucial for quantifying and understanding complex trait genetic architecture and is employed in almost all recent genome-wide association studies (GWAS). However, many existing approaches for heritability estimation and almost all methods for estimating genetic correlation ignore the presence of indirect genetic effects, i.e., genotype-phenotype associations confounded by the parental genome and family environment, and may thus lead to incorrect interpretation especially for human sociobehavioral phenotypes. In this work, we introduce a statistical framework to decompose heritability and genetic covariance into multiple components representing direct and indirect effect paths. Applied to five traits in UK Biobank, we found substantial involvement of indirect genetic components in shared genetic architecture across traits. These results demonstrate the effectiveness of our approach and highlight the importance of accounting for indirect effects in variance component analysis of complex traits.
Assuntos
Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Herança Multifatorial/genética , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único , Modelos GenéticosRESUMO
Sorbitol is a critical photosynthate and storage substance in the Rosaceae family. Sorbitol transporters (SOTs) play a vital role in facilitating sorbitol allocation from source to sink organs and sugar accumulation in sink organs. While prior research has addressed gene duplications within the SOT gene family in Rosaceae, the precise origin and evolutionary dynamics of these duplications remain unclear, largely due to the complicated interplay of whole genome duplications and tandem duplications. Here, we investigated the synteny relationships among all identified Polyol/Monosaccharide Transporter (PLT) genes in 61 angiosperm genomes and SOT genes in representative genomes within the Rosaceae family. By integrating phylogenetic analyses, we elucidated the lineage-specific expansion and syntenic conservation of PLTs and SOTs across diverse plant lineages. We found that Rosaceae SOTs, as PLT family members, originated from a pair of tandemly duplicated PLT genes within Class III-A. Furthermore, our investigation highlights the role of lineage-specific and synergistic duplications in Amygdaloideae in contributing to the expansion of SOTs in Rosaceae plants. Collectively, our findings provide insights into the genomic origins, duplication events, and subsequent divergence of SOT gene family members. Such insights lay a crucial foundation for comprehensive functional characterizations in future studies.
Assuntos
Magnoliopsida , Rosaceae , Rosaceae/genética , Filogenia , Magnoliopsida/genética , Genoma de Planta/genética , Sorbitol , Evolução Molecular , Duplicação GênicaRESUMO
Optical emitters in hexagonal boron nitride (hBN) are promising probes for single-molecule sensing platforms. When engineered in nanoparticle form, they can be integrated as detectors in nanodevices, yet positional control at the nanoscale is lacking. Here we demonstrate the functionalization of DNA origami nanopores with optically active hBN nanoparticles (NPs) with nanometer precision. The NPs are active under three wavelengths of visible illumination and display both stable and blinking emission, enabling their accurate localization by using wide-field optical nanoscopy. Correlative opto-structural characterization reveals deterministic binding of bright, multicolor hBN NPs at the pore rim due to π-π stacking interactions at site-specific locations on the DNA origami. Our work provides a scalable, bottom-up approach toward deterministic assembly of solid-state emitters on arbitrary structural elements based on DNA origami. Such a nanoscale arrangement of optically active components can advance the development of single-molecule platforms, including optical nanopores and nanochannel sensors.
Assuntos
Compostos de Boro , DNA , Nanoporos , Compostos de Boro/química , DNA/química , Nanotecnologia/métodos , Nanopartículas/químicaRESUMO
Reactive oxygen species (ROS) is a chemically reactive chemical substance containing oxygen and a natural by-product of normal oxygen metabolism. Excessive ROS affect the growth process of crops, which will lead to the decrease of yield. Nitrogen, as a critical nutrient element in plants and plays a vital role in plant growth and crop production. Nitrate is the primary nitrogen source available to plants in agricultural soil and various natural environments. However, the molecular mechanism of ROS-nitrate crosstalk is still unclear. In this study, we used the foxtail millet (Setaria italica L.) as the material to figure it out. Here, we show that excessive NaCl inhibits nitrate-promoted plant growth and nitrogen use efficiency (NUE). NaCl induces ROS accumulation in roots, and ROS inhibits nitrate-induced gene expression in a short time. Surprisingly, low concentration ROS slight promotes and high concentration of ROS inhibits foxtail millet growth under long-term H2O2 treatment. These results may open a new perspective for further exploration of ROS-nitrate signaling pathway in plants.
Assuntos
Nitratos , Setaria (Planta) , Espécies Reativas de Oxigênio , Nitratos/farmacologia , Setaria (Planta)/genética , Peróxido de Hidrogênio , Cloreto de Sódio , Oxigênio , Transdução de Sinais , Perfilação da Expressão Gênica , NitrogênioRESUMO
Accurate diagnosis and effective treatment of tumors remain significant clinical challenges. While fluorescence imaging is essential for tumor detection, it has limitations in terms of specificity, penetration depth, and emission wavelength. Here, we report a novel glutathione (GSH)-responsive peptide self-assembly excimer probe (pSE) that optimizes two-photon tumor imaging and self-assisted counteraction of the cisplatin resistance in cancer cells. The GSH-responsive self-assembly of pSE induces a monomer-excimer transition of coumarin, promoting a near-infrared redshift of fluorescence emission under two-photon excitation. This process enhances penetration depth and minimizes interference from biological autofluorescence. Moreover, the intracellular self-assembly of pSE impacts GSH homeostasis, modulates relevant signaling pathways, and significantly reduces GSTP1 expression, resulting in decreased cisplatin efflux in cisplatin-resistant cancer cells. The proposed self-assembled excimer probe not only distinguishes cancer cells from normal cells but also enhances the efficacy of cisplatin chemotherapy, offering significant potential in tumor diagnosis and overcoming cisplatin-resistant tumors.
Assuntos
Antineoplásicos , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Glutationa , Peptídeos , Cisplatino/farmacologia , Cisplatino/química , Humanos , Peptídeos/química , Peptídeos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Glutationa/metabolismo , Glutationa/química , Fótons , Imagem Óptica , Corantes Fluorescentes/química , Cumarínicos/química , Cumarínicos/farmacologia , Linhagem Celular TumoralRESUMO
PURPOSE: This study aimed to apply a newly developed semi-automatic phantom-less QCT (PL-QCT) to measure proximal humerus trabecular bone density based on chest CT and verify its accuracy and precision. METHODS: Subcutaneous fat of the shoulder joint and trapezius muscle were used as calibration references for PL-QCT BMD measurement. A self-developed algorithm based on a convolution map was utilized in PL-QCT for semi-automatic BMD measurements. CT values of ROIs used in PL-QCT measurements were directly used for phantom-based quantitative computed tomography (PB-QCT) BMD assessment. The study included 376 proximal humerus for comparison between PB-QCT and PL-QCT. Two sports medicine doctors measured the proximal humerus with PB-QCT and PL-QCT without knowing each other's results. Among them, 100 proximal humerus were included in the inter-operative and intra-operative BMD measurements for evaluating the repeatability and reproducibility of PL-QCT and PB-QCT. RESULTS: A total of 188 patients with 376 shoulders were involved in this study. The consistency analysis indicated that the average bias between proximal humerus BMDs measured by PB-QCT and PL-QCT was 1.0 mg/cc (agreement range - 9.4 to 11.4; P > 0.05, no significant difference). Regression analysis between PB-QCT and PL-QCT indicated a good correlation (R-square is 0.9723). Short-term repeatability and reproducibility of proximal humerus BMDs measured by PB-QCT (CV: 5.10% and 3.41%) were slightly better than those of PL-QCT (CV: 6.17% and 5.64%). CONCLUSIONS: We evaluated the bone quality of the proximal humeral using chest CT through the semi-automatic PL-QCT system for the first time. Comparison between it and PB-QCT indicated that it could be a reliable shoulder BMD assessment tool with acceptable accuracy and precision. This study developed and verify a semi-automatic PL-QCT for assessment of proximal humeral bone density based on CT to assist in the assessment of proximal humeral osteoporosis and development of individualized treatment plans for shoulders.
Assuntos
Densidade Óssea , Osso Esponjoso , Úmero , Tomografia Computadorizada por Raios X , Humanos , Densidade Óssea/fisiologia , Masculino , Feminino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Idoso , Reprodutibilidade dos Testes , Úmero/diagnóstico por imagem , Úmero/fisiologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/fisiopatologia , Osso Esponjoso/fisiologia , Algoritmos , Imagens de Fantasmas , Adulto , Osteoporose/fisiopatologia , Osteoporose/diagnóstico por imagem , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Numerous genome-wide association studies revealed that SNPs (single nucleotide polymorphisms) at the PHACTR1 (phosphatase and actin regulator 1) locus strongly correlate with coronary artery disease. However, the biological function of PHACTR1 remains poorly understood. Here, we identified the proatherosclerotic effect of endothelial PHACTR1, contrary to macrophage PHACTR1. METHODS: We generated global (Phactr1-/-) and endothelial cell (EC)-specific (Phactr1ECKO) Phactr1 KO (knockout) mice and crossed these mice with apolipoprotein E-deficient (Apoe-/-) mice. Atherosclerosis was induced by feeding the high-fat/high-cholesterol diet for 12 weeks or partially ligating carotid arteries combined with a 2-week high-fat/high-cholesterol diet. PHACTR1 localization was identified by immunostaining of overexpressed PHACTR1 in human umbilical vein ECs exposed to different types of flow. The molecular function of endothelial PHACTR1 was explored by RNA sequencing using EC-enriched mRNA from global or EC-specific Phactr1 KO mice. Endothelial activation was evaluated in human umbilical vein ECs transfected with siRNA targeting PHACTR1 and in Phactr1ECKO mice after partial carotid ligation. RESULTS: Global or EC-specific Phactr1 deficiency significantly inhibited atherosclerosis in regions of disturbed flow. PHACTR1 was enriched in ECs and located in the nucleus of disturbed flow areas but shuttled to cytoplasm under laminar flow in vitro. RNA sequencing showed that endothelial Phactr1 depletion affected vascular function, and PPARγ (peroxisome proliferator-activated receptor gamma) was the top transcription factor regulating differentially expressed genes. PHACTR1 functioned as a PPARγ transcriptional corepressor by binding to PPARγ through the corepressor motifs. PPARγ activation protects against atherosclerosis by inhibiting endothelial activation. Consistently, PHACTR1 deficiency remarkably reduced endothelial activation induced by disturbed flow in vivo and in vitro. PPARγ antagonist GW9662 abolished the protective effects of Phactr1 KO on EC activation and atherosclerosis in vivo. CONCLUSIONS: Our results identified endothelial PHACTR1 as a novel PPARγ corepressor to promote atherosclerosis in disturbed flow regions. Endothelial PHACTR1 is a potential therapeutic target for atherosclerosis treatment.
Assuntos
Aterosclerose , PPAR gama , Animais , Humanos , Camundongos , Aterosclerose/metabolismo , Colesterol , Estudo de Associação Genômica Ampla , Camundongos Knockout , PPAR gama/genéticaRESUMO
BACKGROUND AND AIM: Patients with type 2 diabetes mellitus (T2DM) have a higher risk of colorectal cancer (CRC), and those with diagnosed CRC have a poorer prognosis compared with individuals with normal glucose levels. The inhibition of sodium-glucose cotransporter 2 (SGLT2) channels has been associated with a reduction in tumor proliferation in preclinical studies. We aimed to investigate the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcome of T2DM patients with colorectal cancer. METHODS: We performed a retrospective cohort study comprising adult patients with T2DM and colorectal adenocarcinoma. SGLT2i recipients were matched to non-SGLT2i recipients in a 1:1 ratio based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with SGLT2i. RESULTS: We identified 1347 patients with T2DM and colorectal adenocarcinoma, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of 5-year OS (86.2% [95% CI: 72.0-93.5] vs 62.3% [95% CI: 50.9-71.8], P = 0.013) and 5-year PFS (76.6% [95% CI: 60.7-86.7] vs 57.0% [95% CI: 46.2-66.4], P = 0.021). In Cox proportional hazard analyses, SGLT2i were associated with a 50-70% reduction in all-cause mortality and disease progression. SGLT2i were not associated with an increased risk of serious adverse events. CONCLUSION: SGLT2i were associated with a higher rate of survival in T2DM patients with colorectal cancer.
Assuntos
Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Resultado do Tratamento , Taxa de Sobrevida , Estudos de CoortesRESUMO
OBJECTIVE: Gastric cancer (GC) is believed to be one of the most common digestive tract malignant tumors. However, mounting evidence indicates a link between the glycolysis and tumorigenesis, including gastric cancer. METHODS: Our research identified 5508 differently expressed mRNAs in gastric cancer. Then, the genes highly associated with tumorigenesis were identified through weighted correlation network analysis (WGCNA). Bioinformatics analysis observed that these hub genes were significantly linked to the regulation of cell cycle, drug metabolism, and glycolysis. Among these hub genes, there is a critical gene involved in glycolysis regulation, namely fructose-bisphosphate B (ALDOB). RESULTS: Analysis based on The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets revealed that ALDOB was significantly downregulated in GC compared with normal tissues. In addition, cell viability assay confirmed that ALDOB acted as a tumor suppressor. Finally, drug sensitivity analysis revealed that ALDOB increased the sensitivity of gastric cancer cells to most antitumor drugs, especially talazoparib, XAV939, and FTI-277. Our results showed that the expression of ALDOB was significantly lower in GC tissues than in normal tissues. And ALDOB significantly inhibited proliferation and migration, delayed glycolysis in GC cells. Consequently, our study suggests that ALDOB may be a potential target for the clinical treatment of gastric cancer.
RESUMO
Numerous applications at the photon-starved regime require a free-space coupling single-photon detector with a large active area, low dark count rate (DCR), and superior time resolutions. Here, we developed a superconducting microstrip single-photon detector (SMSPD), with a large active area of 260 µm in diameter, a DCR of â¼5k c p s, and a low time jitter of â¼171p s, operated at a near-infrared of 1550 nm and a temperature of â¼2.0K. As a demonstration, we applied the detector to a single-pixel galvanometer scanning system and successfully reconstructed the object information in depth and intensity using a time-correlated photon counting technology.
RESUMO
BACKGROUND: Being one of the most widespread, pervasive, and troublesome illnesses in the world, depression causes dysfunction in various spheres of individual and social life. Regrettably, despite obtaining evidence-based antidepressant medication, up to 70% of people are going to continue to experience troublesome symptoms. Quetiapine, as one of the most commonly prescribed antipsychotic medication worldwide, has been reported as an effective augmentation strategy to antidepressants. The right quetiapine dose and personalized quetiapine treatment are frequently challenging for clinicians. This study aimed to identify important influencing variables for quetiapine dose by maximizing the use of data from real world, and develop a predictive model of quetiapine dose through machine learning techniques to support selections for treatment regimens. METHODS: The study comprised 308 depressed patients who were medicated with quetiapine and hospitalized in the First Hospital of Hebei Medical University, from November 1, 2019, to August 31, 2022. To identify the important variables influencing the dose of quetiapine, a univariate analysis was applied. The prediction abilities of nine machine learning models (XGBoost, LightGBM, RF, GBDT, SVM, LR, ANN, DT) were compared. Algorithm with the optimal model performance was chosen to develop the prediction model. RESULTS: Four predictors were selected from 38 variables by the univariate analysis (p < 0.05), including quetiapine TDM value, age, mean corpuscular hemoglobin concentration, and total bile acid. Ultimately, the XGBoost algorithm was used to create a prediction model for quetiapine dose that had the greatest predictive performance (accuracy = 0.69) out of nine models. In the testing cohort (62 cases), a total of 43 cases were correctly predicted of the quetiapine dose regimen. In dose subgroup analysis, AUROC for patients with daily dose of 100 mg, 200 mg, 300 mg and 400 mg were 0.99, 0.75, 0.93 and 0.86, respectively. CONCLUSIONS: In this work, machine learning techniques are used for the first time to estimate the dose of quetiapine for patients with depression, which is valuable for the clinical drug recommendations.
RESUMO
Curcumae Radix (CuR) is a traditional Chinese medicine that has been used in China for more than 1,000â years. It has the traditional efficacy of activating blood and relieving pain, promoting qi and relieving depression, clearing heart and cooling blood, and promoting gallbladder and removing jaundice. Based on this, many domestic and foreign scholars have conducted systematic studies on its chemical composition, pharmacological effects, toxicity and quality control. Currently, 250 compounds, mainly including terpenoids and curcuminoids, have been isolated and identified from CuR, which has pharmacological activities, including antitumor, anti-inflammatory and analgesic, antidepressant, hepatoprotective, hemostatic, hematopoietic, and treatment of diabetes mellitus. In modern clinical practice, CuR is widely used in the treatment of tumors, breast hyperplasia, hepatitis, and stroke. However, the generation of toxicity and clinical application of CuR and Caryophylli Flos, the determination of the concoction process of artifacts, the determination of specific Quality Marker, and the establishment of the quality control system of CuR, are problems that need to be solved urgently at present.
Assuntos
Curcuma , Controle de Qualidade , Humanos , Curcuma/química , Medicina Tradicional Chinesa , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Animais , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificaçãoRESUMO
Epimedium genus is a traditional Chinese medicine, which has functions of tonifying kidney and yang, strengthening tendons and bones, dispelling wind and emoving dampness. It is mainly used for the treatment of impotence and spermatorrhea, osteoporosis, Parkinson's, Alzheimer's, and cardiovascular diseases. The aim of this review is to provide a systematic summary of the phytochemistry, pharmacology, and clinical applications of the Epimedium Linn. In this paper, the relevant literature on Epimedium Linn. was collected from 1987 to the present day, and more than 274 chemical constituents, including flavonoids, phenylpropanoids, lignans, phenanthrenes, and others, were isolated from this genus. Modern pharmacological studies have shown that Epimedium Linn. has osteoprotective, neuroprotective, cardiovascular protective, and immune enhancing pharmacological effects. In addition, Epimedium Linn. has been commonly used to treat osteoporosis, erectile dysfunction, hypertension and cardiovascular disease. In this paper, the distribution of resources, chemical compositions, pharmacological effects, clinical applications and quality control of Epimedium Linn. are progressed to provide a reference for further research and development of the resources of this genus.
Assuntos
Epimedium , Epimedium/química , Humanos , Controle de Qualidade , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Animais , Medicina Tradicional Chinesa , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificaçãoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.
Assuntos
Apoptose , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Receptor Tirosina Quinase Axl , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Movimento Celular/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Return to play (RTP) and functional outcomes are critical to treatment success for acute Achilles tendon rupture (AATR). This systematic review and meta-analysis explored treatment superiority essential in optimal treatment selection concerning individual patients and their expectations regarding RTP and functional outcomes. This study was in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. The included studies were assessed regarding the level and quality of evidence. Fixed-effects models were employed for I2 < 25% and random-effects models for I2 ≥ 25%. The RTP rate meta-analysis of surgical vs conservative treatment revealed no significant difference. This was similar to the subgroup analysis of open repair and conservative treatment. The RTP rate and Achilles Tendon Total Rupture Score (ATRS) meta-analysis of open repair + earlier rehabilitation (ER) vs + later rehabilitation (LR) also revealed no significant differences. The mean time to RTP meta-analysis of open repair + ER vs + LR showed that open repair + ER was significantly favored (-4.19 weeks; p = .002). The ATRS meta-analysis of conservative treatment with ER vs with LR revealed no significant difference. This meta-analysis has revealed that the RTP rates following treatment of AATR are high. Therefore, the decision for surgical vs conservative treatment or open repair + ER vs + LR for AATR should not be selected based on the expectation of RTP. However, open repair + ER can be advocated over + LR for reduced mean time to RTP.
Assuntos
Tendão do Calcâneo , Volta ao Esporte , Traumatismos dos Tendões , Humanos , Tendão do Calcâneo/lesões , Tendão do Calcâneo/cirurgia , Ruptura/cirurgia , Traumatismos dos Tendões/cirurgia , Traumatismos dos Tendões/reabilitação , Traumatismos dos Tendões/terapia , Recuperação de Função Fisiológica , Resultado do Tratamento , Tratamento Conservador/métodos , Procedimentos Ortopédicos/métodosRESUMO
Organic materials with room-temperature phosphorescence (RTP) are in high demand for optoelectronics and bioelectronics. Developing RTP materials highly relies on expert experience and costly excited-state calculations. It is a challenge to find a tool for effectively screening RTP materials. Herein we first establish ground-state orbital descriptors (πFMOs ) derived from the π-electron component of the frontier molecular orbitals to characterize the RTP lifetime (τp ), achieving a balance in screening efficiency and accuracy. Using the πFMOs , a data-driven machine learning model gains a high accuracy in classifying long τp , filtering out 836 candidates with long-lived RTP from a virtual library of 19,295 molecules. With the aid of the excited-state calculations, 287 compounds are predicted with high RTP efficiency. Impressively, experiments further confirm the reliability of this workflow, opening a novel avenue for designing high-performance RTP materials for potential applications.
RESUMO
The transient receptor potential melastatin 4 (TRPM4) channel contributes extensively to cardiac electrical activity, especially cardiomyocyte action potential formation. Mechanical stretch can induce changes in heart rate and rhythm, and the mechanosensitive channel Piezo1 is expressed in many cell types within the myocardium. Our previous study showed that TRPM4 and Piezo1 are closely co-localized in the t-tubules of ventricular cardiomyocytes and contribute to the Ca2+ -dependent signalling cascade that underlies hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. In the present study, we employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate whether Piezo1-TRPM4 coupling can affect action potential properties. We used the small molecule Piezo1 agonist, Yoda1, as a surrogate for mechanical stretch to activate Piezo1 and detected the action potential changes in HL-1 cells using FluoVolt, a fluorescent voltage sensitive dye. Our results demonstrate that Yoda1-induced activation of Piezo1 changes the action potential frequency in HL-1 cells. This change in action potential frequency is reduced by Piezo1 knockdown using small intefering RNA. Importantly knockdown or pharmacological inhibition of TRPM4 significantly affected the degree to which Yoda1-evoked Piezo1 activation influenced action potential frequency. Thus, the present study provides in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+ -activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction. KEY POINTS: The transient receptor potential melastatin 4 (TRPM4) and Piezo1 channels have been confirmed to contribute to the Ca2+ -dependent signalling cascade that underlies cardiac hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. We employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate the effect of Piezo1-TRPM4 coupling on cardiac electrical properties. The results show that both pharmacological and genetic inhibition of TRPM4 significantly affected the degree to which Piezo1 activation influenced action potential frequency in HL-1 cells. Our findings provide in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+ -activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction in various (patho)physiological processes.
RESUMO
For decades, numerous experimental animal models have been developed to examine the pathophysiologic mechanisms and potential treatments for abdominal aortic aneurysms (AAAs) in diverse species with varying chemical or surgical approaches. This study aimed to create an AAA mouse model by the periarterial incubation with papain, which can mimic human AAA with advantages such as simplicity, convenience, and high efficiency. Eighty C57BL/6J male mice were randomly assigned to 1 of the 4 groups: papain (1.0 or 2.0 mg), porcine pancreatic elastase, and phosphate-buffered solution. The aortic segment was wrapped for 20 minutes, and the diameter was measured using ultrasound preoperatively and postoperative days 7 and 14. Then, the mice were killed for histomorphometric and immunohistochemical analyses. According to ultrasound measurements and histomorphometric analyses, on postoperative day 7, 65% of mice in the 1.0-mg papain group and 60% of mice in the 2.0-mg papain group developed AAA. In both papain groups, 100% of mice developed AAA, and 65% of mice in the porcine pancreatic elastase group developed AAA on postoperative day 14. Furthermore, hematoxylin/eosin, elastin van Gieson, and Masson staining of tissues from the papain group revealed thickened media and intimal hyperplasia, collagen sediments, and elastin destruction, indicating that AAA histochemical alteration was similar to that of humans. In addition, the immunohistochemical analysis was conducted to detect infiltrated inflammatory cells, such as macrophages and leukocytes, in the aortic wall and hyperplasic adventitia. The expression of matrix metalloproteinase 2 and 9 was significantly upregulated in papain and human AAA tissues. Periarterial incubation with 1.0 mg of papain for 20 minutes can successfully create an experimental AAA model in mice for 14 days, which can be used to explore the mechanism and treatment of human AAA.
Assuntos
Aorta Abdominal , Aneurisma da Aorta Abdominal , Masculino , Camundongos , Humanos , Animais , Suínos , Aorta Abdominal/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Elastina/efeitos adversos , Elastina/metabolismo , Papaína/efeitos adversos , Papaína/metabolismo , Camundongos Endogâmicos C57BL , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Modelos Animais de Doenças , Elastase Pancreática/efeitos adversos , Elastase Pancreática/metabolismoRESUMO
ATP-binding cassette (ABC) transporters are involved in transporting multiple substrates, such as toxins, and may be important for the survival of Trichoderma when encountering biotic toxins. In this study, genome searching revealed that there are 44 ABC transporters encoded in the genome of Trichoderma asperellum. These ABC transporters were divided into six types based on three-dimensional (3D) structure prediction, of which four, represented by 39 ABCs, are involved in transport and the remaining two, represented by 5 ABCs, are involved in regulating translation. The characteristics of nucleotide-binding domain (NBD) are important in the identification of ABC proteins. Even though the 3D structures of the 79 NBDs in the 44 ABCs are similar, multiple sequence alignment showed they can be divided into three classes. In total, 794 motifs were found in the promoter regions of the 44 ABC genes, of which 541 were cis-regulators related to stress responses. To characterize how their ABCs respond when T. asperellum interact with fungi or plants, T. asperellum was cultivated in either minimal media (MM) control, C-hungry, N-hungry, or poplar medium (PdPap) to simulate normal conditions, competition with pathogens, interaction with pathogens, and interaction with plants, respectively. The results show that 17 of 39 transport ABCs are highly expressed in at least one condition, whereas four of the five translation-regulating ABCs are highly expressed in at least one condition. Of these 21 highly expressed ABCs, 6 were chosen for RT-qPCR expression under the toxin stress of phytopathogen Alternaria alternata, and the results show ABC01, ABC04, ABC05, and ABC31 were highly expressed and may be involved in pathogen interaction and detoxifying toxins from A. alternata.
RESUMO
The effective and convenient detection of single photons via advanced detectors with a large active area is becoming significant for quantum and classical applications. This work demonstrates the fabrication of a superconducting microstrip single-photon detector (SMSPD) with a millimeter-scale active area via the use of ultraviolet (UV) photolithography. The performances of NbN SMSPDs with different active areas and strip widths are characterized. SMSPDs fabricated by UV photolithography and electron beam lithography with small active areas are also compared from the aspects of the switching current density and line edge roughness. Furthermore, an SMSPD with an active area of 1 mm × 1 mm is obtained via UV photolithography, and during operation at 0.85â K, it exhibits near-saturated internal detection efficiency at wavelengths up to 800â nm. At a wavelength of 1550â nm, the detector exhibits a system detection efficiency of â¼5% (7%) and a timing jitter of 102 (144) ps, when illuminated with a light spot of â¼18 (600) µm in diameter, respectively.