RESUMO
PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited disorder that involves epistaxis, mucocutaneous telangiectases, and visceral arteriovenous malformations (AVMs). This study aims to investigate the genetic causes in a Chinese family with HHT. METHODS: HHT was confirmed according to Curaçao's diagnostic criteria. Three patients diagnosed with HHT and healthy members were recruited. Whole-exome sequencing (WES) and sanger sequencing were performed to define the patient's genetically pathogenic factor. RESULTS: The proband presented with recurrent epistaxis, hepatopulmonary arteriovenous malformation, and adenocarcinoma. A novel frameshift mutation (c.1376_1377delAC, p.H459Lfs*41) of the ENG gene was revealed in affected individuals by WES. There was no report of this variant and predicted to be highly damaging by causing truncation of the ENG protein. CONCLUSION: We report a novel variant in the ENG gene in Chinese that extends the mutational and phenotypic spectra of the ENG gene, and also demonstrates the feasibility of WES in the application of genetic diagnosis of HHT.
Assuntos
Mutação da Fase de Leitura , Telangiectasia Hemorrágica Hereditária , Humanos , Endoglina/genética , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/genética , Epistaxe , Mutação , ChinaRESUMO
Long non-coding RNAs (lncRNAs) have been highlighted as attractive markers for diagnosis and prognosis as well as new therapeutic targets in multiple cancers, including nasopharyngeal carcinoma (NPC). Here, we attempted to investigate the underlying regulatory role of the lncRNA maternally expressed gene 3 (MEG3) in NPC development. As determined by RT-qPCR, MEG3 expression was down-regulated in NPC cells. Online RNA crosstalk analysis predicted the binding of miR-21 to MEG3 and PTEN, respectively. MEG3 was validated to bind to miR-21 while PTEN was identified as a target of miR-21 by dual-luciferase reporter gene assay. Exogenous transfection was done to change the levels of MEG3, miR-21 and PTEN in HK-1 cells to investigate their effects on the autophagy and apoptosis of NPC cells. The results suggested that MEG3 overexpression in HK-1 cells up-regulated PTEN and down-regulated miR-21, by which MEG3 further inhibited autophagy and apoptosis ability of NPC cells. The tumour formation ability was tested after injecting the HK-1 cells into nude, mice and tumour growth was monitored. Consistently, MEG3 overexpression inhibited the tumour formation in vivo. Collectively, MEG3 promotes the autophagy and apoptosis of NPC cells via enhancing PTEN expression by binding to miR-21.
Assuntos
Apoptose/genética , Autofagia/genética , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , PTEN Fosfo-Hidrolase/genética , RNA Longo não Codificante/metabolismo , Regulação para Cima/genética , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Modelos Biológicos , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Ligação Proteica , RNA Longo não Codificante/genéticaRESUMO
The development of efficient models for predicting specific properties through machine learning is of great importance for the innovation of chemistry and material science. However, predicting global electronic structure properties like Frontier molecular orbital highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels and their HOMO-LUMO gaps from the small-sized molecule data to larger molecules remains a challenge. Here, we develop a multilevel attention neural network, named DeepMoleNet, to enable chemical interpretable insights being fused into multitask learning through (1) weighting contributions from various atoms and (2) taking the atom-centered symmetry functions (ACSFs) as the teacher descriptor. The efficient prediction of 12 properties including dipole moment, HOMO, and Gibbs free energy within chemical accuracy is achieved by using multiple benchmarks, both at the equilibrium and nonequilibrium geometries, including up to 110,000 records of data in QM9, 400,000 records in MD17, and 280,000 records in ANI-1ccx for random split evaluation. The good transferability for predicting larger molecules outside the training set is demonstrated in both equilibrium QM9 and Alchemy data sets at the density functional theory (DFT) level. Additional tests on nonequilibrium molecular conformations from DFT-based MD17 data set and ANI-1ccx data set with coupled cluster accuracy as well as the public test sets of singlet fission molecules, biomolecules, long oligomers, and protein with up to 140 atoms show reasonable predictions for thermodynamics and electronic structure properties. The proposed multilevel attention neural network is applicable to high-throughput screening of numerous chemical species in both equilibrium and nonequilibrium molecular spaces to accelerate rational designs of drug-like molecules, material candidates, and chemical reactions.
Assuntos
Aprendizado de Máquina , Redes Neurais de Computação , Atenção , Proteínas , TermodinâmicaRESUMO
Towards understanding the bulk material response in nanocomposites, an interfacial zone model was proposed to define a variety of material interface behaviors (e.g. brittle, ductile, rubber-like, elastic-perfectly plastic behavior etc.). It also has the capability to predict bulk material response though independently control of the interface properties (e.g. stiffness, strength, toughness). The mechanical response of granular nanocomposite (i.e. nacre) was investigated through modeling the "relatively soft" organic interface as an interfacial zone among "hard" mineral tablets and simulation results were compared with experimental measurements of stress-strain curves in tension and compression tests. Through modeling varies material interfaces, we found out that the bulk material response of granular nanocomposite was regulated by the interfacial behaviors. This interfacial zone model provides a possible numerical tool for qualitatively understanding of structure-property relationships through material interface design.
RESUMO
An improved interfacial bonding model was proposed from potential function point of view to investigate interfacial interactions in polycrystalline materials. It characterizes both attractive and repulsive interfacial interactions and can be applied to model different material interfaces. The path dependence of work-of-separation study indicates that the transformation of separation work is smooth in normal and tangential direction and the proposed model guarantees the consistency of the cohesive constitutive model. The improved interfacial bonding model was verified through a simple compression test in a standard hexagonal structure. The error between analytical solutions and numerical results from the proposed model is reasonable in linear elastic region. Ultimately, we investigated the mechanical behavior of extrafibrillar matrix in bone and the simulation results agreed well with experimental observations of bone fracture.
RESUMO
The focus of this work is to investigate spall fracture in polycrystalline materials under high-speed impact loading by using an atomistic-based interfacial zone model. We illustrate that for polycrystalline materials, increases in the potential energy ratio between grain boundaries and grains could cause a fracture transition from intergranular to transgranular mode. We also found out that the spall strength increases when there is a fracture transition from intergranular to transgranular. In addition, analysis of grain size, crystal lattice orientation and impact speed reveals that the spall strength increases as grain size or impact speed increases.
RESUMO
Congenital midline sinus of the upper lip are rare congenital malformations. We recently identified a case featuring a congenital midline sinus of the upper lip. The punctate opening was positioned at the midline of the philtrum, immediately below the base of the columella. Surgical removal of the sinus tract was conducted through an intraoral approach. Up to now, fewer than 70 cases have been reported. Several postulates, including the fusion theory, merging theory, and invagination theory, have been proposed to explain the formation of the congenital midline sinus of the upper lip. Nevertheless, the etiology of this uncommon abnormality remains unclear. This report details a case of a congenital upper lip sinus presenting as a congenital midline sinus of the upper lip and reviews the current literature on this condition.
RESUMO
Objective: Evidence shows that allergic rhinitis (AR) may increase the risk of erectile dysfunction (ED). This study aims to investigate whether there is a causal relationship between AAR and ED by Mendelian randomization (MR) analysis. Methods: We performed a two-sample MR analysis using genome-wide association studies (GWAS) summary data. Single nucleotide polymorphisms (SNPs) associated with AR and ED were obtained from the GWAS database. The MR analysis primarily employed the inverse variance weighted (IVW), MR Egger, and weighted median (WM) methods. We assessed pleiotropy using the MR-PRESSO global test and MR-Egger regression. Cochran's Q test was used to evaluate heterogeneity, and a leave-one-out analysis was performed to verify the robustness and reliability of the results. Results: The IVW analysis demonstrated a positive association between genetic susceptibility to AR and an elevated relative risk of ED (IVW OR = 1.40, p = 0.01, 95% CI 1.08-1.80). The results obtained from MR-Egger regression and WM methods exhibited a consistent trend with the results of the IVW method. Sensitivity analyses showed no evidence of heterogeneity nor horizontal pleiotropy. The leave-one-out analysis showed that the findings remained robust and were unaffected by any instrumental variables. Conclusion: This study presents genetic evidence that indicates a causal association between AR and ED.
RESUMO
Cancer stem cells (CSCs) are responsible for tumor initiation, relapse, and metastasis. Thus, residual CSCs after chemotherapy may result in poor prognosis for nasopharyngeal carcinoma (NPC). Emerging evidence suggests that differentially expressed microRNAs (miRNAs) regulate genes that carry out important functions in CSCs. Here we investigate the interaction of microRNA-873 (miR-873) with the Zic family member 2 (ZIC2) and the effects on downstream serine-threonine protein kinase (AKT) signaling pathway in CSCs in the context of NPC. Initially, microarray-based gene expression profiling identified ZIC2 as a key differentially expressed gene in NPC, which was subsequently confirmed to be upregulated in clinical NPC tissue samples. NPC cells were subjected to sphere-formation conditions in low-attachment plates, followed by sorting of CD133+ cells, which were selected as NPC stem cells after further characterization of stem cell biomarkers. ZIC2 was then shown to be enriched in NPC stem cells at both mRNA and protein levels. However, loss of ZIC2 was associated with the self-renewal, proliferative and tumorigenic properties of NPC stem cells. Next, miRNAs potentially able to target ZIC2 were predicted by the intersection of mirDIP and TargetScan database results, and miRNA miR-873 was found to be downregulated in NPC tissues in general but especially in NPC stem cells. Upregulation of miR-873 inhibited the stem-like properties and tumorigenicity of NPC stem cells, which was found to take place through downregulation of ZIC2 and disruption of the AKT signaling pathway. Collectively, the results obtained suggest that overexpression of miR-873 could aid NPC tumor suppression through reduction of the malignant potential of CSCs.
Assuntos
MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Regulação para Baixo , Feminino , Genes Supressores de Tumor , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Transdução de SinaisRESUMO
Bone ultrastructure at sub-lamellar length scale is a key structural unit in bone that bridges nano- and microscale hierarchies of the tissue. Despite its influence on bulk response of bone, the mechanical behavior of bone at ultrastructural level remains poorly understood. To fill this gap, in this study, a two-dimensional cohesive finite element model of bone at sub-lamellar level was proposed and analyzed under tensile and compressive loading conditions. In the model, ultrastructural bone was considered as a composite of mineralized collagen fibrils (MCFs) embedded in an extrafibrillar matrix (EFM) that is comprised of hydroxyapatite (HA) polycrystals bounded via thin organic interfaces of non-collagenous proteins (NCPs). The simulation results indicated that in compression, EFM dictated the pre-yield deformation of the model, then damage was initiated via relative sliding of HA polycrystals along the organic interfaces, and finally shear bands were formed followed by delamination between MCF and EFM and local buckling of MCF. In tension, EFM carried the most of load in pre-yield deformation, and then an array of opening-mode nano-cracks began to form within EFM after yielding, thus gradually transferring the load to MCF until failure, which acted as crack bridging filament. The failure modes, stress-strain curves, and in situ mineral strain of ultrastructural bone predicted by the model were in good agreement with the experimental observations reported in the literature, thus suggesting that this model can provide new insights into sub-microscale mechanical behavior of bone.
Assuntos
Osso e Ossos/ultraestrutura , Simulação por Computador , Análise de Elementos Finitos , Colágeno/metabolismo , Minerais/metabolismo , Estresse MecânicoAssuntos
Surdez/genética , Adolescente , Adulto , Criança , Surdez/diagnóstico , Feminino , Humanos , Masculino , Linhagem , Adulto JovemRESUMO
During collective cell migration, the intercellular forces will significantly affect the collective migratory behaviors. However, the measurement of mechanical stresses exerted at cell-cell junctions is very challenging. A recent experimental observation indicated that the intercellular adhesion sites within a migrating monolayer are subjected to both normal stress exerted perpendicular to cell-cell junction surface and shear stress exerted tangent to cell-cell junction surface. In this study, an interfacial interaction model was proposed to model the intercellular interactions for the first time. The intercellular interaction model-based study of collective epithelial migration revealed that the direction of cell migration velocity has better alignment with the orientation of local principal stress at higher maximum shear stress locations in an epithelial monolayer sheet. Parametric study of the effects of adhesion strength indicated that normal adhesion strength at the cell-cell junction surface has dominated effect on local alignment between the direction of cell velocity vector and the principal stress orientation, while the shear adhesion strength has little effect, which provides compelling evidence to help explain the force transmission via cell-cell junctions between adjacent cells in collective cell motion and provides new insights into "adhesive belt" effects at cell-cell junction.
Assuntos
Comunicação Celular , Movimento Celular , Células Epiteliais/citologia , Junções Intercelulares/metabolismo , Análise Numérica Assistida por Computador , Fenômenos Biomecânicos , Células Epiteliais/metabolismo , Modelos Biológicos , Estresse MecânicoRESUMO
OBJECTIVE: To establish the fingerprint spectrum of Loquat Leaf of Fujian authentic medicinal herbs by HPCE. METHODS: The HPLC fingerprints of Loquat Leaf were obtained from instrument HP1100. The HPLC separation was performed on a Eclipse XDB-C18 (4.6 mm x 150 mm, 5 microm) analytical column diluted with methanol-l% glacial acetic acid (90:10) at the flow rate of 1.0 ml/min. The temperature of column was room temperature. The UV detection wavelength was 215 nm. RESULTS: Detected 12 batches samples of different species Lopuat Leaf Fingerprint by the method of HPLC. Eight peaks in the chromatogram were common. All the similarity were above 0.9, the fingerprints integer feature were coincident essentially. CONCLUSION: The method is convenient, quick and exact, and its reproducibility is good. It will be a scientific reference for qualitation identification and quality evaluation of Loquat Leaf.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Eriobotrya/química , Plantas Medicinais/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/normas , Eriobotrya/classificação , Folhas de Planta/química , Controle de Qualidade , Reprodutibilidade dos Testes , Triterpenos/análise , Ácido UrsólicoRESUMO
Tethering and rolling of circulating leukocytes on the surface of endothelium are critical steps during an inflammatory response. A soft solid cell model was proposed to study monocytes tethering and rolling behaviors on substrate surface in shear flow. The interactions between monocytes and micro-channel surface were modeled by a coarse-grained molecular adhesive potential. The computational model was implemented in a Lagrange-type meshfree Galerkin formulation to investigate the monocyte tethering and rolling process with different flow rates. From the simulation results, it was found that the flow rate has profound effects on the rolling velocity, contact area and effective stress of monocytes. As the flow rate increased, the rolling velocity would increase linearly, whereas the contact area and average effective stress in monocyte showed nonlinear increase.
Assuntos
Simulação por Computador , Migração e Rolagem de Leucócitos/fisiologia , Reologia , Aceleração , Algoritmos , Adesão Celular , Humanos , Leucócitos/citologia , Monócitos/citologia , Análise Numérica Assistida por ComputadorRESUMO
The mechanical behavior of bone is determined at all hierarchical levels, including lamellae (the basic building block of bone) that are comprised of mineralized collagen fibrils and extrafibrillar matrix. The mechanical behavior of mineralized collagen fibrils has been investigated intensively using both experimental and computational approaches. Yet, the contribution of the extrafibrillar matrix to bone mechanical properties is poorly documented. In this study, we intended to address this issue using a novel cohesive finite element (FE) model, in conjunction with the experimental observations reported in the literature. In the FE model, the extrafibrillar matrix was considered as a nanocomposite of hydroxyapatite (HA) crystals bounded through a thin organic interface modeled as a cohesive interfacial zone. The parameters required by the cohesive FE model were defined based on the experimental data reported in the literature. This hybrid nanocomposite model was tested in two loading modes (i.e. tension and compression) and under two hydration conditions (i.e. wet and dry). The simulation results indicated that (1) the failure modes of the extrafibrillar matrix predicted using the cohesive FE model were closely coincided with those experimentally observed in tension and compression tests; (2) the pre-yield deformation (i.e. internal strain) of HA crystals with respect to the applied strain was consistent with that obtained from the synchrotron X-ray scattering measurements irrespective of the loading modes and hydration status; and (3) the mechanical behavior of the extrafibrillar matrix was dictated by the properties of the organic interface between the HA crystals. Taken together, we postulate that the extrafibrillar matrix plays a major role in the pre-yield deformation and the failure mode of bone, thus, giving rise to important insights in the ultrastructural origins of bone fragility.