HES1 in immunity and cancer

Hairy and enhancer of split homolog-1 (HES1) is a part of an extensive family of basic helix-loop-helix (bHLH) proteins and plays a crucial role in the control and regulation of cell cycle, proliferation, cell differentiation, survival and apoptosis in neuronal, endocrine, T-lymphocyte progenitors as well as various cancers. HES1 is a transcription factor which is regulated by the NOTCH, Hedgehog and Wnt signalling pathways. Aberrant expression of these pathways is a common feature of cancerous cells. There appears to be a fine and complicated crosstalk at the molecular level between the various signalling pathways and HES1, which contributes to its effects on the immune response and cancers such as leukaemia. Several mechanisms have been proposed, including an enhanced invasiveness and metastasis by inducing epithelial mesenchymal transition (EMT), in addition to its strict requirement for tumour cell survival. In this review, we summarize the current biology and molecular mechanisms as well as its use as a clinical target in cancer therapeutics

The Kepler Science Data Processing Pipeline Source Code Road Map

We give an overview of the operational concepts and architecture of the Kepler Science Processing Pipeline. Designed, developed, operated, and maintained by the Kepler Science Operations Center (SOC) at NASA Ames Research Center, the Science Processing Pipeline is a central element of the Kepler Ground Data System. The SOC consists of an office at Ames Research Center, software development and operations departments, and a data center which hosts the computers required to perform data analysis. The SOC's charter is to analyze stellar photometric data from the Kepler spacecraft and report results to the Kepler Science Office for further analysis. We describe how this is accomplished via the Kepler Science Processing Pipeline, including, the software algorithms. We present the high-performance, parallel computing software modules of the pipeline that perform transit photometry, pixel-level calibration, systematic error correction, attitude determination, stellar target management, and instrument characterization

Current and emerging developments in subseasonal to decadal prediction

Weather and climate variations of subseasonal to decadal timescales can have enormous social, economic and environmental impacts, making skillful predictions on these timescales a valuable tool for decision makers. As such, there is a growing interest in the scientific, operational and applications communities in developing forecasts to improve our foreknowledge of extreme events. On subseasonal to seasonal (S2S) timescales, these include high-impact meteorological events such as tropical cyclones, extratropical storms, floods, droughts, and heat and cold waves. On seasonal to decadal (S2D) timescales, while the focus remains broadly similar (e.g., on precipitation, surface and upper ocean temperatures and their effects on the probabilities of high-impact meteorological events), understanding the roles of internal and externally-forced variability such as anthropogenic warming in forecasts also becomes important. The S2S and S2D communities share common scientific and technical challenges. These include forecast initialization and ensemble generation; initialization shock and drift; understanding the onset of model systematic errors; bias correct, calibration and forecast quality assessment; model resolution; atmosphere-ocean coupling; sources and expectations for predictability; and linking research, operational forecasting, and end user needs. In September 2018 a coordinated pair of international conferences, framed by the above challenges, was organized jointly by the World Climate Research Programme (WCRP) and the World Weather Research Prograame (WWRP). These conferences surveyed the state of S2S and S2D prediction, ongoing research, and future needs, providing an ideal basis for synthesizing current and emerging developments in these areas that promise to enhance future operational services. This article provides such a synthesis

Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells.

The production of autologous T cells expressing a chimaeric antigen receptor (CAR) is time-consuming, costly and occasionally unsuccessful. T-cell-derived induced pluripotent stem cells (TiPS) are a promising source for the generation of off-the-shelf CAR T cells, but the in vitro differentiation of TiPS often yields T cells with suboptimal features. Here we show that the premature expression of the T-cell receptor (TCR) or a constitutively expressed CAR in TiPS promotes the acquisition of an innate phenotype, which can be averted by disabling the TCR and relying on the CAR to drive differentiation. Delaying CAR expression and calibrating its signalling strength in TiPS enabled the generation of human TCR- CD8αβ+ CAR T cells that perform similarly to CD8αβ+ CAR T cells from peripheral blood, achieving effective tumour control on systemic administration in a mouse model of leukaemia and without causing graft-versus-host disease. Driving T-cell maturation in TiPS in the absence of a TCR by taking advantage of a CAR may facilitate the large-scale development of potent allogeneic CD8αβ+ T cells for a broad range of immunotherapies

Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells

The production of autologous T cells expressing a chimaeric antigen receptor (CAR) is time-consuming, costly and occasionally unsuccessful. T-cell-derived induced pluripotent stem cells (TiPS) are a promising source for the generation of ‘off-the-shelf’ CAR T cells, but the in vitro differentiation of TiPS often yields T cells with suboptimal features. Here we show that the premature expression of the T-cell receptor (TCR) or a constitutively expressed CAR in TiPS promotes the acquisition of an innate phenotype, which can be averted by disabling the TCR and relying on the CAR to drive differentiation. Delaying CAR expression and calibrating its signalling strength in TiPS enabled the generation of human TCR– CD8αβ+ CAR T cells that perform similarly to CD8αβ+ CAR T cells from peripheral blood, achieving effective tumour control on systemic administration in a mouse model of leukaemia and without causing graft-versus-host disease. Driving T-cell maturation in TiPS in the absence of a TCR by taking advantage of a CAR may facilitate the large-scale development of potent allogeneic CD8αβ+ T cells for a broad range of immunotherapies