HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α

Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic

The AIQ Meta-Testbed: Pragmatically Bridging Academic AI Testing and Industrial Q Needs

AI solutions seem to appear in any and all application domains. As AI becomes more pervasive, the importance of quality assurance increases. Unfortunately, there is no consensus on what artificial intelligence means and interpretations range from simple statistical analysis to sentient humanoid robots. On top of that, quality is a notoriously hard concept to pinpoint. What does this mean for AI quality? In this paper, we share our working definition and a pragmatic approach to address the corresponding quality assurance with a focus on testing. Finally, we present our ongoing work on establishing the AIQ Meta-Testbed.Comment: Accepted for publication in the Proc. of the Software Quality Days 2021, Vienna, Austri

TESOL Teachers’ Engagement with the Native Speaker Model: How Does Teacher Education Impact on Their Beliefs?

© 2017, © The Author(s) 2017. This research investigates non-native English teachers’ engagement with the native speaker model, i.e. whether they agree/disagree with measuring English teaching and learning performance against native speaker standards. More importantly, it aims to unearth the impact of teacher education on teachers’ attitudes and beliefs about “native-speakerness”. Data were gathered from an online survey delivered to 85 Vietnamese TESOL teachers who had completed one of 19 Master’s level TESOL programmes offered overseas and in Vietnam, followed by in-depth interviews with 20 participants. The results revealed that teacher education strengthened the teachers’ beliefs about the linguistic diversity of English and led them to question the native and non-native divide by providing relevant input and opportunities to engage in critical discussion on nativeness, as well as fruitful learning experience. However, language proficiency is an area where “native-speakerness” still dominates, and where teacher education did not exert much influence. These findings shed light on the role of TESOL teacher training in influencing teacher beliefs about the native speaker model, and suggest that teacher education programmes dedicate more space for teachers to critically explore the construct of language teacher proficiency

Conflicts Targeting Epigenetic Systems and Their Resolution by Cell Death: Novel Concepts for Methyl-Specific and Other Restriction Systems

Epigenetic modification of genomic DNA by methylation is important for defining the epigenome and the transcriptome in eukaryotes as well as in prokaryotes. In prokaryotes, the DNA methyltransferase genes often vary, are mobile, and are paired with the gene for a restriction enzyme. Decrease in a certain epigenetic methylation may lead to chromosome cleavage by the partner restriction enzyme, leading to eventual cell death. Thus, the pairing of a DNA methyltransferase and a restriction enzyme forces an epigenetic state to be maintained within the genome. Although restriction enzymes were originally discovered for their ability to attack invading DNAs, it may be understood because such DNAs show deviation from this epigenetic status. DNAs with epigenetic methylation, by a methyltransferase linked or unlinked with a restriction enzyme, can also be the target of DNases, such as McrBC of Escherichia coli, which was discovered because of its methyl-specific restriction. McrBC responds to specific genome methylation systems by killing the host bacterial cell through chromosome cleavage. Evolutionary and genomic analysis of McrBC homologues revealed their mobility and wide distribution in prokaryotes similar to restriction–modification systems. These findings support the hypothesis that this family of methyl-specific DNases evolved as mobile elements competing with specific genome methylation systems through host killing. These restriction systems clearly demonstrate the presence of conflicts between epigenetic systems