319 research outputs found
ZMYM2 inhibits NANOG-mediated reprogramming [version 1; peer review: 2 approved, 1 approved with reservations]
A Comparative Study of Tool-Pin Profile on Process Response of Friction Stir Welding of AA6082-T6 Aluminium Alloy
This paper presents research work conducted to experimentally establish the process response of two diverse shaped tool-pin profiles for friction stir welding (FSW) AA6082-T6 aluminium. The dwell time was optimised by plunging each tool-pin into a plate sample until the spindle torque stabilised thus ensuring sufficient plasticised material in contact with tool shoulder and the tool-pins. The welds were conducted by employing the optimised dwell time, which in turn revealed a minimised process response time and distance to reach weld stability with respect to (1) the force exerted on the tool-pin in the welding direction, Fx , and (2) the spindle torque, T, during the welding process. Both Fx and T stabilised well within the set (pre-determined) ramp-up distance of 20 mm, indicating that the effective (useful) weld length is maximised. The macrographs also revealed good dynamic material flow within the nugget zone regions and more evident in the nugget zone of the flared tool
TRES predicts transcription control in embryonic stem cells.
SUMMARY: Unraveling transcriptional circuits controlling embryonic stem cell maintenance and fate has great potential for improving our understanding of normal development as well as disease. To facilitate this, we have developed a novel web tool called 'TRES' that predicts the likely upstream regulators for a given gene list. This is achieved by integrating transcription factor (TF) binding events from 187 ChIP-sequencing and ChIP-on-chip datasets in murine and human embryonic stem (ES) cells with over 1000 mammalian TF sequence motifs. Using 114 TF perturbation gene sets, as well as 115 co-expression clusters in ES cells, we validate the utility of this approach. AVAILABILITY AND IMPLEMENTATION: TRES is freely available at http://www.tres.roslin.ed.ac.uk. CONTACT: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.This work was supported by a University of Edinburgh Chancellors Fellowship awarded to AJ and strategic funding from the BBSRC. CP was
funded by the Scottish Government through the Strategic Partnership for
Animal Science Excellence (SPASE). The Gottgens’ lab is supported by
LLR, the MRC, BBSRC, Cancer Research UK, and Wellcome Trust core
support to the Cambridge Institute for Medical Research and Wellcome
Trust–MRC Cambridge Stem Cell Institute.This version is the author accepted manuscript. The published advanced access version can be viewed on the journals website at: http://bioinformatics.oxfordjournals.org/content/early/2014/06/23/bioinformatics.btu399.full.pdf+htm
Recommended from our members
ZMYM2 inhibits NANOG-mediated reprogramming.
Background: NANOG is a homeodomain-containing transcription factor which forms one of the hubs in the pluripotency network and plays a key role in the reprogramming of somatic cells and epiblast stem cells to naïve pluripotency. Studies have found that NANOG has many interacting partners and some of these were shown to play a role in its ability to mediate reprogramming. In this study, we set out to analyse the effect of NANOG interactors on the reprogramming process. Methods: Epiblast stem cells and somatic cells were reprogrammed to naïve pluripotency using MEK/ERK inhibitor PD0325901, GSK3β inhibitor CHIR99021 and Leukaemia Inhibitory Factor (together termed 2i Plus LIF). Zmym2 was knocked out using the CRISPR/Cas9 system or overexpressed using the PiggyBac system. Reprogramming was quantified after ZMYM2 deletion or overexpression, in diverse reprogramming systems. In addition, embryonic stem cell self renewal was quantified in differentiation assays after ZMYM2 removal or overexpression. Results: In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells. In addition, ZMYM2 impairs the self renewal of embryonic stem cells and its overexpression promotes differentiation. Conclusions: We propose that ZMYM2 curtails NANOG's actions during the reprogramming of both somatic cells and epiblast stem cells and impedes embryonic stem cell self renewal, promoting differentiation.This study was supported by the Wellcome Trust through
a Wellcome Trust Fellowship to J.C.R.S. [101861], Wellcome
Trust Studentship to M.L. [079249], and a core funding
grant jointly with the Medical Research Council (MRC) to the
Wellcome-MRC Cambridge Stem Cell Institute [079249]
CO2 Injectivity in geological storages: an overview of program and results of the GeoCarbone-Injectivity Project
International audienceThe objective of the GeoCarbone-Injectivity project was to develop a methodology to study the complex phenomena involved in the near wellbore region during CO2 injection. This paper presents an overview of the program and results of the project, and some further necessary developments. The proposed methodology is based on experiments and simulations at the core scale, in order to understand (physical modelling and definition of constitutive laws) and quantify (calibration of simulation tools) the mechanisms involved in injectivity variations: fluid/rock interactions, transport mechanisms, geomechanical effects. These mechanisms and the associated parameters have then to be integrated in the models at the wellbore scale. The methodology has been applied for the study of a potential injection of CO2 in the Dogger geological formation of the Paris Basin, in collaboration with the other ANR GeoCarbone projects
The methyl binding domain 3/nucleosome remodelling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex.
BACKGROUND: Chromatin-modifying complexes have key roles in regulating various aspects of neural stem cell biology, including self-renewal and neurogenesis. The methyl binding domain 3/nucleosome remodelling and deacetylation (MBD3/NuRD) co-repressor complex facilitates lineage commitment of pluripotent cells in early mouse embryos and is important for stem cell homeostasis in blood and skin, but its function in neurogenesis had not been described. Here, we show for the first time that MBD3/NuRD function is essential for normal neurogenesis in mice. RESULTS: Deletion of MBD3, a structural component of the NuRD complex, in the developing mouse central nervous system resulted in reduced cortical thickness, defects in the proper specification of cortical projection neuron subtypes and neonatal lethality. These phenotypes are due to alterations in PAX6+ apical progenitor cell outputs, as well as aberrant terminal neuronal differentiation programmes of cortical plate neurons. Normal numbers of PAX6+ apical neural progenitor cells were generated in the MBD3/NuRD-mutant cortex; however, the PAX6+ apical progenitor cells generate EOMES+ basal progenitor cells in reduced numbers. Cortical progenitor cells lacking MBD3/NuRD activity generate neurons that express both deep- and upper-layer markers. Using laser capture microdissection, gene expression profiling and chromatin immunoprecipitation, we provide evidence that MBD3/NuRD functions to control gene expression patterns during neural development. CONCLUSIONS: Our data suggest that although MBD3/NuRD is not required for neural stem cell lineage commitment, it is required to repress inappropriate transcription in both progenitor cells and neurons to facilitate appropriate cell lineage choice and differentiation programmes.We wish to thank Nicola Reynolds for the help with figures; Aoife O’Shaughnessy for the critical reading of the manuscript; Peter Humphreys, the SCI Biofacility staff and Margaret McLeish for technical assistance; Stephanie Hall and Gerard Evan for access to the Laser Capture Microscope and Nathalie Saurat and members of the BH lab for useful discussions. This work was supported by a Wellcome Trust Senior Fellowship in the Basic Biomedical Sciences awarded to BH and a bourse de formation from the Fonds de la Recherche en Santé Québec awarded to EK.This is the final published version of the article. It was originally published in Neural Development (Knock E, et al., Neural Development, 2015, 10:13, doi:10.1186/s13064-015-0040-z). The final version is available at http://dx.doi.org/10.1186/s13064-015-0040-
Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis.
Naive pluripotency is manifest in the preimplantation mammalian embryo. Here we determine transcriptome dynamics of mouse development from the eight-cell stage to postimplantation using lineage-specific RNA sequencing. This method combines high sensitivity and reporter-based fate assignment to acquire the full spectrum of gene expression from discrete embryonic cell types. We define expression modules indicative of developmental state and temporal regulatory patterns marking the establishment and dissolution of naive pluripotency in vivo. Analysis of embryonic stem cells and diapaused embryos reveals near-complete conservation of the core transcriptional circuitry operative in the preimplantation epiblast. Comparison to inner cell masses of marmoset primate blastocysts identifies a similar complement of pluripotency factors but use of alternative signaling pathways. Embryo culture experiments further indicate that marmoset embryos utilize WNT signaling during early lineage segregation, unlike rodents. These findings support a conserved transcription factor foundation for naive pluripotency while revealing species-specific regulatory features of lineage segregation.We thank Peter Humphreys for assistance with imaging, and Samuel Jameson and staff for mouse husbandry. We are grateful to Charis Drummer, Ayako Sedohara, Akiko Shimada, Yuko Yamada, Ryo Oiwa, and Takeshi Kuge for technical support with marmoset embryo recovery. Illumina sequencing was provided by Bettina Haase and Dinko Pavlinic at the EMBL Genomics Core Facility. This work was supported by funding from the Wellcome Trust, the Genome Biology Unit of the European Molecular Biology Laboratory, BBSRC grants BB/G015678/1 and BB/M004023/1, an MRC Centenary Award, and the Louis Jeantet Foundation. A.S. is a Medical Research Council Professor.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.devcel.2015.10.01
Interferon-gamma release assays versus tuberculin skin testing for detection of latent tuberculosis in chronic haemodialysis patients
Background. End stage renal disease increases the risk of reactivating latent tuberculosis (LTBI). Interferon-γ release assays (IGRA) are an alternative to the tuberculin skin test (TST) for detecting LTBI. Methods. Sixty-two hemodialysis patients (46 male, 16 female, aged 65 ± 15 years) from 3 hemodialysis facilities in the Geneva area were submitted to a TST, 2 IGRA (T-SPOT.TB and QuantiFERON Gold in tube: QFT), a chest radiography, and a questionnaire to record social status, country of birth, history of prior TST, tuberculosis (TB), BCG (Bacillus of Calmette-Guérin vaccine), and any cause of immuno-suppression. LTBI was defined as prior "at risk” contact with a case of contagious TB and/or a chest X-ray suggestive of prior TB infection. Results. Positivity rate was 19% for TST, 21% for QFT and 29% for T-SPOT-TB; 8% of QFT and 11% of T-SPOT-TB were indeterminate. Agreement between IGRA was fair (κ= 0.60). After adjusting for age and BCG, OR (Odds Ratio) of having a positive QFT was 4.6-fold (p = 0.029) higher in patients with LTBI vs. those without LTBI. In contrast, no association was found between LTBI and having a positive T-SPOT.TB or a positive TST. As expected, there was a strong association between prior BCG vaccination and having a positive TST (OR 5.3, p = 0.017). QFT was the only test with a significant OR of having LTBI (adjusted OR: 4.4; 95%CI: 1.1 − 17.6; p = 0.034). Among 5 patients with definite prior TB, TST and T-SPOT.TB were positive in 1 and QFT, in 2. Conclusions. In this population, QFT was superior to TST for detecting LTBI, but both IGRAs and TST have important limitations, and are unreliable for screening for LTB
Recommended from our members
Complementary Activity of ETV5, RBPJ, and TCF3 Drives Formative Transition from Naive Pluripotency.
The gene regulatory network (GRN) of naive mouse embryonic stem cells (ESCs) must be reconfigured to enable lineage commitment. TCF3 sanctions rewiring by suppressing components of the ESC transcription factor circuitry. However, TCF3 depletion only delays and does not prevent transition to formative pluripotency. Here, we delineate additional contributions of the ETS-family transcription factor ETV5 and the repressor RBPJ. In response to ERK signaling, ETV5 switches activity from supporting self-renewal and undergoes genome relocation linked to commissioning of enhancers activated in formative epiblast. Independent upregulation of RBPJ prevents re-expression of potent naive factors, TBX3 and NANOG, to secure exit from the naive state. Triple deletion of Etv5, Rbpj, and Tcf3 disables ESCs, such that they remain largely undifferentiated and locked in self-renewal, even in the presence of differentiation stimuli. Thus, genetic elimination of three complementary drivers of network transition stalls developmental progression, emulating environmental insulation by small-molecule inhibitors.This research was funded by the Wellcome
Trust, the Biotechnology and Biological Sciences Research Council, European Commission
(contract no. 200720, EuroSyStem) and the Louis Jeantet Foundation. The Cambridge Stem
Cell Institute receives core support from the Wellcome Trust and the Medical Research
Council. AS is a Medical Research Council Professor
- …