Modelling severe paediatric aplastic anaemia using induced pluripotent stem cell technology

PhD ThesisAplastic anaemia (AA) is a disorder resulting in pancytopenia and hypocellular bone marrow. Although the immunological nature of AA pathogenesis is widely accepted, there is an increasing recognition that a significant number of AA patients might present dysfunctional haematopoietic stem or progenitor cells. In this study, induced pluripotent stem cell (iPSC) technology was used to reprogram fibroblasts from four paediatric severe AA (SAA) patients and three unaffected controls. SAA-iPSC lines were successfully differentiated into erythroid and myeloid progenitors and cells. Two key differences were observed in three of the four SAA patients: (1) SAA-iPSC generated a reduced number of erythroid and myeloid cells and (2) SAA-iPSC failed to elongate their telomeres during the reprogramming process. These deficiencies comprise two key features of AA and indicate that the iPSC model closely mimics the disease phenotype. These deficiencies also suggest that some (but not all SAA) may be characterised by an underlying genetic predisposition which impacts the proliferation and/or differentiation of erythroid and myeloid cells. A detailed flow cytometric analysis indicated a significant reduction in the fraction of proliferative iPSC-derived-haematopoietic progenitors in three SAA patients. Likewise, significant levels of replicative stress-associated DNA damage were observed in iPSC-derived-haematopoietic progenitors from one of the SAA patients, which may suggest an impaired DNA damage response in the face of replicative stress. Finally, thrombopoietin-receptor agonist eltrombopag was investigated in the iPSC model system and was shown to have no significant effect on the, proliferation, DNA repair and erythroid/myeloid colony-forming potential of SAA-iPSC derived haematopoietic progenitors under normal or stress conditions. In summary, the data generated from this study highlights the utility of patient specific iPSC in providing a disease model for SAA, in identifying likely constitutional cases for further genetic studies and predicting patient specific responses to available and future drugs

Comparative analysis of HESS (battery/supercapacitor) for power smoothing of PV/HKT, simulation and experimental analysis

Photovoltaic and hydrokinetic systems are increasing their penetration in electrical distribution systems. This leads to problems of power fluctuations due to the intermittence of renewable sources that could compromise the stability and quality of the power grid. To address this issue, this paper presents a feasibility study of three power smoothing methods for a photovoltaic-hydrokinetic system using laboratory equipment to optimally replicate the real behavior of this type of hybrid system. The proposed algorithms are based on a hybrid storage system with supercapacitors and lithium-ion batteries, several analyzes are presented based on technical and economic parameters. The results demonstrate the feasibility of power smoothing methods for real systems, the comparison between the algorithms highlights the characteristics of the Enhanced Linear Exponential Smoothing Method, reducing the energy cost and regulating the point of common coupling voltage. Moreover, the sensitivity studies show that the energy exchange with the utility grid is affected according to the variations in the capacity of the batteries and the response to power smoothing can decrease or improve depending on the size of the supercapacitors

Optimal energy management strategies to reduce diesel consumption for a hybrid off-grid system

Although climate change is a reality, many off-grid communities continue to use diesel generators for electricity supply. This document presents a strategy to reduce diesel consumption in an out-of-grid system formed by renewable sources (PV-HKT-WT-DG). Three energy dispatch strategies have been proposed to verify the impact on diesel consumption and generator operating hours. In addition, different energy storage technologies (acid lead, lithium-ion, vanadium redox flow, pump storage and supercapacitor) have been considered. The HOMER software has been used to calculate the optimal size of the systems through technical-economic indicators. The results show that it is possible to reduce diesel consumption progressively; however, the cost of energy increases. On the other hand, when using lithium-ion batteries under charge cycle control, the penetration of the diesel generator has been greatly reduced without affecting the cost of the system. Finally, sensitivity analyzes have shown that when demand increases, diesel consumption does not increase significantly by using redox vanadium flow batteries, whereas the diesel generator operating hours decrease significantly in all systems

ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export

The pluripotent state is not solely governed by the action of the core transcription factors OCT4, SOX2, and NANOG, but also by a series of co-transcriptional and post-transcriptional events, including alternative splicing (AS) and the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs. Zinc Finger Protein 207 (ZFP207) is an essential transcription factor for mammalian embryonic development. Here, we employ multiple functional analyses to characterize its role in mouse embryonic stem cells (ESCs). We find that ZFP207 plays a pivotal role in ESC maintenance, and silencing of Zfp207 leads to severe neuroectodermal differentiation defects. In striking contrast to human ESCs, mouse ZFP207 does not transcriptionally regulate neuronal and stem cell-related genes but exerts its effects by controlling AS networks and by acting as an RBP. Our study expands the role of ZFP207 in maintaining ESC identity, and underscores the functional versatility of ZFP207 in regulating neural fate commitment