A novel role for Lyl1 in primitive erythropoiesis

© 2018. Published by The Company of Biologists Ltd. Stem cell leukemia (Scl or Tal1) and lymphoblastic leukemia 1 (Lyl1) encode highly related members of the basic helix-loop-helix family of transcription factors that are co-expressed in the erythroid lineage. Previous studies have suggested that Scl is essential for primitive erythropoiesis. However, analysis of single-cell RNA-seq data of early embryos showed that primitive erythroid cells express both Scl and Lyl1. Therefore, to determine whether Lyl1 can function in primitive erythropoiesis, we crossed conditional Scl knockout mice with mice expressing a Cre recombinase under the control of the Epo receptor, active in erythroid progenitors. Embryos with 20% expression of Scl from E9.5 survived to adulthood. However, mice with reduced expression of Scl and absence of Lyl1 (double knockout; DKO) died at E10.5 because of progressive loss of erythropoiesis. Gene expression profiling of DKO yolk sacs revealed loss of Gata1 and many of the known target genes of the SCL-GATA1 complex. ChIP-seq analyses in a human erythroleukemia cell line showed that LYL1 exclusively bound a small subset of SCL targets including GATA1. Together, these data show for the first time that Lyl1 can maintain primitive erythropoiesis

When the going gets tough the beautiful get going: aesthetic appeal facilitates task performance.

The current studies examined the effect of aesthetic appeal on performance. According to one hypothesis, appeal would lead to overall decrements or enhancements in performance [e.g. Sonderegger & Sauer, (Applied Ergonomics, 41, 403-410, 2010)]. Alternatively, appeal might influence performance only in problem situations, such as when the task is difficult [e.g. Norman, (2004)]. The predictions of these hypotheses were examined in the context of an icon search-and-localisation task. Icons were used because they are well-defined stimuli and pervasive to modern everyday life. When search was made difficult using visually complex stimuli (Experiment 1), or abstract and unfamiliar stimuli (Experiment 2), icons that were appealing were found more quickly than their unappealing counterparts. These findings show that in a low-level visual processing task, with demand characteristics related to appeal eliminated, appeal can influence performance, especially under duress

Allergen Uptake, Activation, and IL-23 Production by Pulmonary Myeloid DCs Drives Airway Hyperresponsiveness in Asthma-Susceptible Mice

Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs “pro-asthmatic”, and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness

Author Correction: Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells (Nature Communications, (2020), 11, 1, (6211), 10.1038/s41467-020-20091-6)

In the original version of this Article, contributions from Jennifer R. Baker and Cecilia C. Russell from the University of Newcastle for synthesizing batches of Dynole 34-2 were not acknowledged. This error has now been corrected in both the PDF and HTML versions of the Article

Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance

Ancient ruins of the future

The Herculea Telesina in the region of Campania is certainly not a fragment but an almost continuous defensive wall. The strong point of this particular project for siege defense being geometric criteria that have remained practically unchanged even when the weapons themselves evolved. The ruins offer a vast repertory of useful signs: the contemporary scholar can not only acquire the teachings of a culture that was much advanced compared to the Roman world, but by observing the angles and vectors can ponder the absence of any changes in the measurements that were subordinated to tactics and thus to human needs. Decisive factors that elevate the walls of Telesia to the level of a cultural testament still to be discovered