Transcriptomic characterization of CRISPR/Cas9-edited THP1 cells to test the effect of disrupting the 3q23 genomic region containing TB-risk associated variants marking a putative monocyte-specific enhancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE134419 | GEO | 2019/07/18
REPOSITORIES: GEO
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Project description:Transcriptomic characterization of CRISPR/Cas9-edited THP1 cells to test the effect of disrupting the 3q23 genomic region containing TB-risk associated variants marking a putative monocyte-specific enhancer
| PRJNA555107 | ENA
Project description:The goal of these experiments were to test the on-target and target-adjacent editing efficiencies of different single-nucleobase editing systems. Previous studies have shown that tethering DNA mutating enzymes to Cas9-nickase-UGI complexes results in editing of chromosomal DNA. However, these editing events encompass undesirable target-adjacent nucleobase edits. Here, we characterize a novel approach that reduces the frequency of target-adjacent editing while maintaining a high level of on-target editing.
2020-02-23 | E-MTAB-8742 | biostudies-arrayexpress
Project description:ObjectiveWe assessed the long-term outcomes of the loop technique with the ink-dot marking test, an alternative to the ink test for aligning the mitral valve (MV) leaflet height, during MV repair.MethodsWe retrospectively reviewed 351 patients who underwent MV repair with the loop technique via median sternotomy or right mini-thoracotomy. The ink-dot marking test involves creation of a dotted line between the rough and clear zones in the anterior leaflet and the center of the posterior leaflet by gentian violet. According to this marking, we adjusted the fixing position of the loops with or without the loop-in-loop technique and additional neochordal repair.ResultsThis study involved 141 women and 210 men (mean age, 63.7 ± 13.0 years). Forty-one patients required additional adjustment after the ink-dot marking test. No significant differences were found in the need for second arrest between patients who did and did not require additional adjustment after the ink-dot marking test (3 vs 32 patients, P = .782). Predischarge transthoracic echocardiography showed trivial residual MV regurgitation (MR) in 285 patients, mild in 64, and moderate in 2. Ten patients needed reoperations (9 MV replacements and 1 MV re-repair) because of recurrent MR during postoperative follow-up. The 3-, 5-, and 10-year postoperative cumulative incidence of moderate to severe recurrent MR was 3.6%, 6.0%, and 19.8%, respectively.ConclusionsThe loop technique with the ink-dot marking test provided good early and long-term results. This test may help to decrease residual MR, especially when using the loop technique.
| S-EPMC8302930 | biostudies-literature
Project description:This dataset aims to dissect the whole blood transcriptional signature by determining if elements of the whole blood signature are still present in purified cell subpopulations. We aimed to characterise the transcriptional response during TB and identify if cell subsets drove changes in whole blood cellular composition. The aim of the experiment was to define transcriptional signatures in neutrophils, monocytes, CD4+ and CD8+ cells from blood of active TB patients and healthy controls to distinguish the signature of active TB patients from each other and from healthy controls. This will help in the diagnosis of active tuberculosis, which normally relies on culture of the bacilli, which can take up to 6 weeks, sometimes the bacilli cannot be obtained from sputum thus requiring invasive techniques obtaining bronchoalveolar lavage (BAL). In some cases the bacill cannot be grown from sputum or BAL.
2010-08-11 | GSE19443 | GEO
Project description:This dataset aims to validate and confirm the signature identified in the training set. The aim of the experiment was to define transcriptional signatures in whole blood of TB patients (before drug treatment) and healthy controls to distinguish the signature of Latent and Active TB patients from each other and from healthy controls. This will help in diagnosis of active tuberculosis which normally relies on culture of the bacilli, which can take up to 6 wks, and sometimes the bacilli cannot be obtained from sputum thus requiring invasive techniques obtaining bronchoalveolar lavage (BAL). In some cases the bacill cannot be grown from sputum or BAL. Secondly the aim was to determine whether Latent patients have a homogeneous or heterogeneous signature, one may expect the latter since it is not possible to determine by the present tests (Tuberculin skin test - TST - or MTb antigen responsiveness of blood cells to produce IFN-gamma - IGRA assay) whether the mycobacteria has been cleared, is still present but is controlled, or if patients are recently infected or reactivated and will develop active TB.
2010-08-11 | GSE19444 | GEO
Project description:To determine if there is a physical interaction between the FOXF1 promoter and putative enhancer sequences ~250kb upstream of the promoter chromosome conformation capture-on-chip (4C) analysis was performed. An unanticipated and tremendous amount of the non-coding sequences of the human genome are transcribed. Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides and their functions remain enigmatic. We demonstrate that deletions of lncRNA genes cause a lethal lung developmental disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV), with parent of origin effects. We identify non-coding overlapping deletions 250 kb upstream to FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete a fetal lung-specific EST, part of an lncRNA. These deletions define distant cis-regulatory region that harbors a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter, consistent with the absence of the fetal lung-transcribed lncRNA perturbing FOXF1 regulation. LncRNA-mediated chromatin interactions may be responsible for position effect phenomenon and potentially cause many disorders of human development.
2012-07-11 | GSE39256 | GEO
Project description:Thymic stromal lymphopoietin (TSLP) is a key player in atopic diseases, which has sparked great interest in therapeutically targeting TSLP. Yet, no small-molecule TSLP inhibitors exist due to the challenges of disrupting the protein-protein interaction between TSLP and its receptor. Here, we report the development of small-molecule TSLP receptor inhibitors using virtual screening and docking of >1,000,000 compounds followed by iterative chemical synthesis. BP79 emerged as our lead compound that effectively abrogates TSLP-triggered cytokines at low micromolar concentrations. For in-depth analysis, we developed a human atopic disease drug discovery platform using multi-organ chips. Here, topical BP79 application of BP79 onto atopic skin models that were co-cultivated with lung models and Th2 cells effectively suppressed immune cell infiltration and along IL-13, IL-4, TSLP, and periostin, while upregulating skin barrier proteins. RNA-Seq analysis corroborate these findings and indicate protective downstream effects on the lungs. To the best of our knowledge, this represents the first report of a potent putative small molecule TSLPR inhibitor which has the potential to expand the therapeutic and preventive options in atopic diseases.
| S-SCDT-10_1038-S44321-024-00085-3 | biostudies-other
Project description:To determine if there is a physical interaction between the FOXF1 promoter and putative enhancer sequences ~250kb upstream of the promoter chromosome conformation capture-on-chip (4C) analysis was performed. An unanticipated and tremendous amount of the non-coding sequences of the human genome are transcribed. Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides and their functions remain enigmatic. We demonstrate that deletions of lncRNA genes cause a lethal lung developmental disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV), with parent of origin effects. We identify non-coding overlapping deletions 250 kb upstream to FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete a fetal lung-specific EST, part of an lncRNA. These deletions define distant cis-regulatory region that harbors a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter, consistent with the absence of the fetal lung-transcribed lncRNA perturbing FOXF1 regulation. LncRNA-mediated chromatin interactions may be responsible for position effect phenomenon and potentially cause many disorders of human development. 4C analysis using 16q24.1 specific 3x720K arrays demonstrated physical interaction between the FOXF1 promoter and distant putative regulatory sequences, about 250 kb upstream in human pulomonary microvascular endothelial cells; 2 biological replicates performed; this chromatin looping was not detected in lymphoblasts that do not express FOXF1 and hence serve as a negative control.
2012-07-10 | E-GEOD-39256 | biostudies-arrayexpress
Project description:This dataset aims to dissect the whole blood transcriptional signature by determining if elements of the whole blood signature are still present in purified cell subpopulations. We aimed to characterise the transcriptional response during TB and identify if cell subsets drove changes in whole blood cellular composition. The aim of the experiment was to define transcriptional signatures in neutrophils, monocytes, CD4+ and CD8+ cells from blood of active TB patients and healthy controls to distinguish the signature of active TB patients from each other and from healthy controls. This will help in the diagnosis of active tuberculosis, which normally relies on culture of the bacilli, which can take up to 6 weeks, sometimes the bacilli cannot be obtained from sputum thus requiring invasive techniques obtaining bronchoalveolar lavage (BAL). In some cases the bacill cannot be grown from sputum or BAL. Experimental design : Whole blood collected in EDTA tubes from patients with active TB disease and healthy controls. Blood was then processed or separated sequentially into neutrophil, monocyte, CD4+ or CD8+ populations and then processed. All patients were sampled prior to the initiation of any antimycobacterial therapy. Active pulmonary TB: PTB - all patients confirmed by isolation of Mycobacterium tuberculosis on culture of sputum or bronchoalvelolar lavage fluid. Healthy controls - these were volunteers without exposure to TB who were negative by both tuberculin skin test (<15mm if BCG vaccinated, <6mm if unvaccinated); who were also negative by IGRA (as described above). This dataset: PTB, n = 7 patients (whole blood, neutrophils, monocytes, CD4+ or CD8+). BCG+, n = 4 patients (whole blood, neutrophils, monocytes, CD4+ or CD8+). Experimental variables : Patient group: Active PTB; Healthy controls (BCG vaccinated only) and Cell populations: Neutrophils, Monocytes, CD4+, CD8+. Ethnicity - a range of ethnic groups is represented.
2010-08-11 | E-GEOD-19443 | biostudies-arrayexpress
Project description:Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining repair pathways, but many precise edits that correct disease-causing mutations in vivo require homology-directed repair (HDR) templates. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs to produce segmental deletions, or a single sgRNA with an HDR template. We also examine the utility of Nme2Cas9 target sites in the vector for self-inactivation. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice. These results will enable single-vector AAVs to achieve diverse therapeutic genome editing outcomes.
2020-10-19 | GSE159356 | GEO