Similar Datasets
Project description:Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression. We designed DEMs to target two human genes, CCR5 and CXCR4, with the aim of epigenetically silencing their expression in primary human T lymphocytes. We observed robust and sustained target gene silencing associated with reduced chromatin accessibility, increased promoter methylation at the target sites and undetectable changes in global gene expression. Our results demonstrate that DEMs can be successfully used to silence target gene expression in primary human cells with remarkably high specificity, paving the way for the establishment of a potential new class of therapeutics.
| S-EPMC5961145 | biostudies-literature
Project description:Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression. We designed DEMs to target two human genes, CCR5 and CXCR4, with the aim of epigenetically silencing their expression in primary human T lymphocytes. We observed robust and sustained target gene silencing associated with reduced chromatin accessibility, increased promoter methylation at the target sites and undetectable changes in global gene expression. Our results demonstrate that DEMs can be successfully used to silence target gene expression in primary human cells with remarkable high specificity, paving the way for the establishment of a potential new class of therapeutics.
2018-02-27 | GSE108024 | GEO
Project description:Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression. We designed DEMs to target two human genes, CCR5 and CXCR4, with the aim of epigenetically silencing their expression in primary human T lymphocytes. We observed robust and sustained target gene silencing associated with reduced chromatin accessibility, increased promoter methylation at the target sites and undetectable changes in global gene expression. Our results demonstrate that DEMs can be successfully used to silence target gene expression in primary human cells with remarkable high specificity, paving the way for the establishment of a potential new class of therapeutics.
2018-02-27 | GSE108029 | GEO
Project description:Designer epigenome modifiers enable robust and sustained gene silencing in clinically relevant human cells
| PRJNA422251 | ENA
Project description:Designer epigenome modifiers enable robust and sustained gene silencing in clinically relevant human cells [RNA-seq]
| PRJNA422254 | ENA
Project description:Designer epigenome modifiers enable robust and sustained gene silencing in clinically relevant human cells [ATAC-seq]
| PRJNA422250 | ENA
Project description:Phosphatidylcholine lipid bilayers or liposomes at interfaces in aqueous environments can provide extremely efficient lubrication. This is attributed to the hydration lubrication mechanism acting at the highly hydrated phosphocholine-headgroup layers exposed at the outer surface of each bilayer. Micelles exposing such phosphocholine groups could be an attractive alternative to liposomes due to their much easier preparation and structure control, but all studies to date of surfactant micelles have revealed that at relatively low normal stresses the surface layers rupture and friction increases abruptly. Here, we examine surface interactions between three kinds of phosphocholine-exposing micelles with different designed structures: single-tail surfactant micelles, homo-oligomeric micelles, and block copolymer micelles. Normal and shear forces between mica surfaces immersed in solutions of these micelles were measured using a surface force balance. The adsorbed layers on the mica were imaged using atomic force microscope, revealing surface structures ranging from wormlike to spherical micelles. The block copolymer micelles showed relatively low coverage arising from their stabilizing corona and consequently poor lubrication (? ? 10-1). In contrast, the surfactant and homo-oligomeric micelles fully covered the mica surface and demonstrated excellent lubrication (? ? O(10-3)). However, while the boundary layer of single-tailed surfactant micelles degraded under moderate pressure, the homo-oligomeric micellar boundary layer was robust at all applied contact pressures in our study (up to about 5 MPa). We attribute the difference to the much greater energy required to remove a homo-oligomeric molecule from its micelle, resulting in far greater stability under pressure and shear.
| S-EPMC7315629 | biostudies-literature
Project description:Head and neck cancer is the fifth most common type of cancer worldwide and remains challenging for effective treatment due to the proximity to critical anatomical structures in the head and neck region, which increases the probability of toxicity from surgery and radiotherapy, and therefore emphasizes the importance of maximizing the targeted ablation. We have assessed the effectiveness of porphysome nanoparticles to enhance fluorescence and photoacoustic imaging of head and neck tumors in rabbit and hamster models. In addition, we evaluated the effectiveness of this agent for localized photothermal ablative therapy of head and neck tumors. We have demonstrated that porphysomes not only enabled fluorescence and photoacoustic imaging of buccal and tongue carcinomas, but also allowed for complete targeted ablation of these tumors. The supremacy of porphysome-enabled photothermal therapy over surgery to completely eradicate primary tumors and metastatic regional lymph node while sparing the adjacent critical structures' function has been demonstrated for the first time. This study represents a novel breakthrough that has the potential to revolutionize our approach to tumor diagnosis and treatment in head and neck cancer and beyond.
| S-EPMC4672023 | biostudies-literature
Project description:The assessment of language lateralization has become widely used when planning neurosurgery close to language areas, due to individual specificities and potential influence of brain pathology. Functional magnetic resonance imaging (fMRI) allows non-invasive and quantitative assessment of language lateralization for presurgical planning using a laterality index (LI). However, the conventional method is limited by the dependence of the LI on the chosen activation threshold. To overcome this limitation, different threshold-independent LI calculations have been reported. The purpose of this study was to propose a simplified approach to threshold-independent LI calculation and compare it with three previously reported methods on the same cohort of subjects. Fifteen healthy subjects, who performed picture naming, verb generation, and word fluency tasks, were scanned. LI values were calculated for all subjects using four methods, and considering either the whole hemisphere or an atlas-defined language area. For each method, the subjects were ranked according to the calculated LI values, and the obtained rankings were compared. All LI calculation methods agreed in differentiating strong from weak lateralization on both hemispheric and regional scales (Spearman's correlation coefficients 0.59-1.00). In general, a more lateralized activation was found in the language area than in the whole hemisphere. The new method is well suited for application in the clinical practice as it is simple to implement, fast, and robust. The good agreement between LI calculation methods suggests that the choice of method is not key. Nevertheless, it should be consistent to allow a relative comparison of language lateralization between subjects.
| S-EPMC7067428 | biostudies-literature
Project description:The human DNA base excision repair enzyme MUTYH (MutY homolog DNA glycosylase) excises undamaged adenine that has been misincorporated opposite the oxidatively damaged 8-oxoG, preventing transversion mutations and serving as an important defense against the deleterious effects of this damage. Mutations in the MUTYH gene predispose patients to MUTYH-associated polyposis and colorectal cancer, and MUTYH expression has been documented as a biomarker for pancreatic cancer. Measuring MUTYH activity is therefore critical for evaluating and diagnosing disease states as well as for testing this enzyme as a potential therapeutic target. However, current methods for measuring MUTYH activity rely on indirect electrophoresis and radioactivity assays, which are difficult to implement in biological and clinical settings. Herein, we synthesize and identify novel fluorescent adenine derivatives that can act as direct substrates for excision by MUTYH as well as bacterial MutY. When incorporated into synthetic DNAs, the resulting fluorescently modified adenine-release turn-on (FMART) probes report on enzymatic base excision activity in real time, both in vitro and in mammalian cells and human blood. We also employ the probes to identify several promising small-molecule modulators of MUTYH by employing FMART probes for in vitro screening.
| S-EPMC7596860 | biostudies-literature