Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia

Published first May 16, 2023Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance.Winnie L. Kan, Urmi Dhagat, Kerstin B. Kaufmann, Timothy R. Hercus, Tracy L. Nero, Andy G.X. Zeng, John Toubia, Emma F. Barry, Sophie E. Broughton, Guillermo A. Gomez, Brooks A. Benard, Mara Dottore, Karen S. Cheung Tung Shing, Héléna Boutzen, Saumya E. Samaraweera, Kaylene J. Simpson, Liqing Jin, Gregory J. Goodall, C. Glenn Begley, Daniel Thomas, Paul G. Ekert, Denis Tvorogov, Richard J. D, Andrea, John E. Dick, Michael W. Parker, and Angel F. Lope

Simulation of silicon dioxide LPCVD from teos

In this study, a model is constructed as a basis for an optimization tool for silicon dioxide low pressure chemica! vapor deposition (LPCVD) from the precursor gas tetra-ethyl-ortho-silicate (TEOS) in ASM International's A412, hot wall, vertical 300 mm multi-wafer reactor. The model consists of a chemistry model based on elementaryr reactions and a transport model for multi-component gas flow, heat and mass transfer. Model simulation results have been validated against experimental data on growth rate and uniformities. The model semi-quantitavely predicts the dependence of growth rate and uniformity on pressure, TEOS flow rate and temperature. It also provides a basis for understanding experimental observations, such as the importance of the interwafer distance, the need for the use of multiple inlets and the need for a wafer rotation. The developed simulation tool can be used in further optimization studies with respect to reactor design ansd process operation.Kramers Laboratorium voor Fysische TechnologieApplied Science

Simulation and validation of SiO2_2 LPCVD from TEOS in a vertical 300 mm multi-wafer reactor

Combining a slightly modified version of the chemical reaction mechanism for silicon-dioxide LPCVD from TEOS as proposed by Coltrin and coworkers, and the commercially available CFD program CFD-ACE+, a 21) model has been derived for gas flow, transport phenomena and deposition chemistry in the ASM A412 vertical 300mm multiwafer reactor. Silicon-dioxide deposition from TEOS is strongly influenced by gas-phase reactions, producing a reactive intermediate that is responsible for the majority of deposition. This phenomenon underlines the importance of the chemistry model in simulations. As a result of the gas phase intermediate, strong radial non-uniformities are observed. The simulation results have been validated against experimental growth rate data for various process conditions

A snapshot of the emerging tomato genome sequence

The genome of tomato (Solanum lycopersicum L.) is being sequenced by an international consortium of 10 countries (Korea, China, the United Kingdom, India, the Netherlands, France, Japan, Spain, Italy, and the United States) as part of the larger \u201cInternational Solanaceae Genome Project (SOL): Systems Approach to Diversity and Adaptation\u201d initiative. The tomato genome sequencing project uses an ordered bacterial artificial chromosome (BAC) approach to generate a high-quality tomato euchromatic genome sequence for use as a reference genome for the Solanaceae and euasterids. Sequence is deposited at GenBank and at the SOL Genomics Network (SGN). Currently, there are around 1000 BACs finished or in progress, representing more than a third of the projected euchromatic portion of the genome. An annotation effort is also underway by the International Tomato Annotation Group. The expected number of genes in the euchromatin is 3c40,000, based on an estimate from a preliminary annotation of 11% of finished sequence. Here, we present this first snapshot of the emerging tomato genome and its annotation, a short comparison with potato (Solanum tuberosum L.) sequence data, and the tools available for the researchers to exploit this new resource are also presented. In the future, whole-genome shotgun techniques will be combined with the BAC-by-BAC approach to cover the entire tomato genome. The high-quality reference euchromatic tomato sequence is expected to be near completion by 2010