Unveiling the complexity of transcription factor networks in hematopoietic stem cells: implications for cell therapy and hematological malignancies

The functionality and longevity of hematopoietic tissue is ensured by a tightly controlled balance between self-renewal, quiescence, and differentiation of hematopoietic stem cells (HSCs) into the many different blood lineages. Cell fate determination in HSCs is influenced by signals from extrinsic factors (e.g., cytokines, irradiation, reactive oxygen species, O2 concentration) that are translated and integrated by intrinsic factors such as Transcription Factors (TFs) to establish specific gene regulatory programs. TFs also play a central role in the establishment and/or maintenance of hematological malignancies, highlighting the need to understand their functions in multiple contexts. TFs bind to specific DNA sequences and interact with each other to form transcriptional complexes that directly or indirectly control the expression of multiple genes. Over the past decades, significant research efforts have unraveled molecular programs that control HSC function. This, in turn, led to the identification of more than 50 TF proteins that influence HSC fate. However, much remains to be learned about how these proteins interact to form molecular networks in combination with cofactors (e.g. epigenetics factors) and how they control differentiation, expansion, and maintenance of cellular identity. Understanding these processes is critical for future applications particularly in the field of cell therapy, as this would allow for manipulation of cell fate and induction of expansion, differentiation, or reprogramming of HSCs using specific cocktails of TFs. Here, we review recent findings that have unraveled the complexity of molecular networks controlled by TFs in HSCs and point towards possible applications to obtain functional HSCs ex vivo for therapeutic purposes including hematological malignancies. Furthermore, we discuss the challenges and prospects for the derivation and expansion of functional adult HSCs in the near future

Rapamycin as an Adjunctive Therapy for NLRC4 Associated Macrophage Activation Syndrome

Gain of function (GOF) mutations affecting the inflammasome component NLRC4 are known to cause early-onset macrophage activation syndrome (MAS) and neonatal enterocolitis. Here we report a patient with a NLRC4 GOF mutation presenting with neonatal MAS efficiently treated with a combination of anakinra and rapamycin. Through in vitro studies, we show that rapamycin reduces both IL-1β and IL-18 secretion by the patient's phagocytic cells. The reduction of cytokine secretion is associated with a reduction of caspase-1 activation regardless of the pathogen- or danger-associated molecular patterns triggering the activation of the inflammasome. This study suggests that patients with inherited auto-inflammatory disorders could benefit from an adjunctive therapy with rapamycin

Etude des voies moléculaires modulées par le niveau d'expression du facteur de transcription SCL/TAL1 dans les cellules souches hémotopoïétiques humaines

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Prediction-based deadbeat control for grid-connected inverter with L-filter and LCL-filter

In this article, an improved deadbeat control algorithm suitable for digital signal processor-based circuit implementation is proposed. The control algorithm allows the derivation of a nearly sine wave output current with a fixed switching frequency of a current-controlled voltage source inverter. Two low-pass output filters configurations are considered in this study: a simple inductance filter and an LCL-filter. By taking advantage of prior knowledge of the state variables’ shape, the improved deadbeat control algorithm is based on a simple prediction model to derive the expected duty cycle needed to switch on and off the power switches. The control study of the grid-connected inverter with L and LCL output filters has been considered using a co-simulation approach with (Powersim Inc., Rockville, Maryland, USA) and MATLAB software (The MathWorks, Natick, Massachusetts, USA). The obtained results show the improvement of both shape quality and tracking accuracy of the output current quantified by low ripple content and a nearly unity power factor.Peer Reviewe

Prediction-based deadbeat control for grid-connected inverter with L-filter and LCL-filter

In this article, an improved deadbeat control algorithm suitable for digital signal processor-based circuit implementation is proposed. The control algorithm allows the derivation of a nearly sine wave output current with a fixed switching frequency of a current-controlled voltage source inverter. Two low-pass output filters configurations are considered in this study: a simple inductance filter and an LCL-filter. By taking advantage of prior knowledge of the state variables’ shape, the improved deadbeat control algorithm is based on a simple prediction model to derive the expected duty cycle needed to switch on and off the power switches. The control study of the grid-connected inverter with L and LCL output filters has been considered using a co-simulation approach with (Powersim Inc., Rockville, Maryland, USA) and MATLAB software (The MathWorks, Natick, Massachusetts, USA). The obtained results show the improvement of both shape quality and tracking accuracy of the output current quantified by low ripple content and a nearly unity power factor.Peer Reviewe

Wiltshire Fire Brigade Performance review inspection

SIGLEAvailable from British Library Document Supply Centre-DSC:m00/11650 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Artificial bee colony based algorithm for maximum power pointtracking (MPPT) for PV systems operating under partial shaded conditions

Artificial bee colony (ABC) algorithm has several characteristics that make it more attractive than other bio-inspired methods. Particularly, it is simple, it uses fewer control parameters and its convergence is independent of the initial conditions. In this paper, a novel artificial bee colony based maximum power point tracking algorithm (MPPT) is proposed. The developed algorithm, does not allow only overcoming the common drawback of the conventional MPPT methods, but it gives a simple and a robust MPPT scheme. A co-simulation methodology, combining Matlab/Simulink™ and Cadence/Pspice™, is used to verify the effectiveness of the proposed method and compare its performance, under dynamic weather conditions, with that of the Particle Swarm Optimization (PSO) based MPPT algorithm. Moreover, a laboratory setup has been realized and used to experimentally validate the proposed ABC-based MPPT algorithm. Simulation and experimental results have shown the satisfactory performance of the proposed approach.Peer Reviewe

Assessment of Human Multi-Potent Hematopoietic Stem/Progenitor Cell Potential Using a Single <em>In Vitro</em> Screening System

<div><p>Hematopoietic stem cells are responsible for the generation of the entire blood system through life. This characteristic relies on their ability to self renew and on their multi-potentiality. Thus quantification of the number of hematopoietic stem cells in a given cell population requires to show both properties in the studied cell populations. Although xenografts models that support human hematopoietic stem cells have been described, such <em>in vivo</em> experimental systems remain restrictive for high throughput screening purposes for example. In this work we developed a conditional tetracycline inducible system controlling the expression of the human NOTCH ligand Delta-like 1 in the murine stromal MS5 cells. We cultured hematopoietic immature cells enriched in progenitor/stem cells in contact with MS5 cells that conditionally express Delta-like 1, in conditions designed to generate multipotential lineage differentiation. We show that upon induction or repression of DL1 expression during co-culture, human immature CD34⁺CD38^−/low(CD45RA⁻CD90⁺) cells can express their B, T, NK, granulo/monocytic and erythroid potentials in a single well, and at the single cell level. We also document the interference of low NOTCH activation with human B and myelo/erythroid lymphoid differentiation. This system represents a novel tool to precisely quantify human hematopoietic immature cells with both lymphoid and myeloid potentials.</p> </div

Multi-lineage differentiation of human CD34⁺CD38^−/low cells in co-cultures with MS5 cell lines.

<p>Sorted cells (10×10³ cells/well) were cultured 21 days without DL1/expressing stromal cells (MS5 or MS5/DL1^ind100–doxycyclin). Cells were harvested and analysed by FACS for the presence of myeloid (CD14⁺/CD15⁺), lymphoid B (CD19⁺) and progenitor (CD34⁺) cells. Half of cells were plated with DL1/expressing stromal cells (MS5/DL1 or MS5/DL1^ind100+ doxycyclin). (A) Results of a representative experiment. % of expressing cells are indicated under the plots in case of quadrant stat or beside the gated population. (B) Summary results of 3 CB samples. (C) Levels of <i>Gata3</i>, <i>pT</i>α, <i>TCF7</i> and <i>Hes1</i> transcripts in the progeny of CD34⁺CD38^−/low cells before (MS5 or MS5/DL1^ind100–doxycyclin) and after (MS5/DL1 or MS5/DL1^ind100+doxycyclin) DL1 induction during culture. Results were normalized over ß2m transcript levels. M&W and K&W statistical analyses were respectively used in (B) and (C).</p