Stress Hematopoiesis Is Regulated by the Krüppel‐Like Transcription Factor ZBP‐89

Previous studies have shown that ZBP‐89 (Zfp148) plays a critical role in erythroid lineage development, with its loss at the embryonic stage causing lethal anemia and thrombocytopenia. Its role in adult hematopoiesis has not been described. We now show that conditional deletion of ZBP‐89 in adult mouse hematopoietic stem/progenitor cells (HSPC) causes anemia and thrombocytopenia that are transient in the steady state, but readily uncovered following chemically induced erythro/megakaryopoietic stress. Unexpectedly, stress induced by bone marrow transplantation of ZBP89 − / − HSPC also resulted in a myeloid‐to‐B lymphoid lineage switch in bone marrow recipients. The erythroid and myeloid/B lymphoid lineage anomalies in ZBP89 − / − HSPC are reproduced in vitro in the ZBP‐89 ‐silenced multipotent hematopoietic cell line FDCP‐Mix A4, and are associated with the upregulation of PU.1 and downregulation of SCL/Tal1 and GATA‐1 in ZBP89‐deficient cells. Chromatin immunoprecipitation and luciferase reporter assays show that ZBP‐89 is a direct repressor of PU.1 and activator of SCL/Tal1 and GATA‐1 . These data identify an important role for ZBP‐89 in regulating stress hematopoiesis in adult mouse bone marrow. S tem C ells 2014;32:791–801Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106141/1/stem1598.pd

Somatic Variants in SVIL in Cerebral Aneurysms

Publisher Copyright: © American Academy of Neurology.Background and ObjectivesWhile somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms.MethodsWe performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results.ResultsSomatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway.DiscussionWe propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.Peer reviewe

Trait aggression affects the response inhibition to angry expressions: An event-related brain potential study

Response inhibition to angry expressions is impaired in individuals with high trait aggression. Yet, the underlying cognitive neural mechanism of it remains unclear. The present study aimed to investigate the underlying cognitive neural mechanisms of response inhibition to angry expressions in individuals with high trait aggression and whether there was emotion-specificity of response inhibition in individuals with high trait aggression. 58 individuals (29 participants with high trait aggression) completed an emotional Go/NoGo task, during which participants\u27 EEG were recorded. Results indicated that individuals with high trait aggression showed smaller NoGo P3 effect than individuals with low trait aggression, in particular facing angry or fearful expressions. These results suggest that individuals with high trait aggression show deficits in response inhibition, in particular facing angry expressions, and these deficits exist in the later stage of response inhibition, which is closely related to the actual inhibition of the motor system; there is no emotion-specificity of response inhibition in individuals with high trait aggression

Exploring the Individual Differences in Multidimensional Evolution of Knowledge States of Learners

The key to the effectiveness of Intelligent Tutoring Systems (ITSs) is to fit the uncertainty of each learner’s performance in performing different learning tasks. Throughout the tutoring and learning process, the uncertainty of learners’ performance can reflect their varying knowledge states, which can arise from individual differences in learning characteristics and capacities. In this investigation, we proposed a multidimensional representation of the evolution of knowledge states of learners to better understand individual differences among them. This assumption about this representation is verified using the Tensor Factorization (TF) based method, a modern state-of-the-art model for knowledge tracing. The accuracy of the Tensor-based method is evaluated by comparing it to other knowledge-tracing methods, to gain a deeper insight into individual differences among learners and their learning of diverse contents. The experimental data under focus in our investigation is derived from the AutoTutor lessons that were developed for the Center for the Study of Adult Literacy (CSAL), which employs a trialogue design comprising of a virtual tutor, a virtual companion and a human learner. A broader merit of our proposed approach lies in its capability to capture individual differences more accurately, without requiring any changes in the real-world implementation of ITSs

Impact of Virtual Simulation to Teach Concepts of Disaster Triage

Background: At a time when major disasters are occurring with increasing frequency, nurses must understand principles of disaster triage. The aim of this study was to determine the impact of a virtual simulation to teach nursing students concepts of triage using the Sort, Assess, Lifesaving Interventions, and Treatment/Transport model. Method: Using a mixed methods approach, six Bachelor of Science in Nursing students participated in a Web-based, virtual simulation of an earthquake. Students took a 20-item, multiple-choice test before and after the simulation and participated in a debriefing session. Results: A Wilcoxon signed rank test suggested no statistically significant improvement on the post-test (p = .168). Qualitative data revealed the following themes: (a) Fun, (b) Appreciation for Immediate Feedback, (c) Better than Reading, and (d) Technical Issues. Conclusions: With the improvement in technology and further educational research efforts, use of virtual simulation may be a teaching solution

Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU.1

Many types of acute myelogenous leukemia involve chromosomal translocations that target the C-terminus of Runx1/AML1 transcription factor, a master regulator of hematopoiesis. The C-terminus of Runx1/AML1 that includes the nuclear matrix targeting signal (NMTS) is essential for embryonic development, hematopoiesis, and target gene regulation. During the onset and normal progression of hematopoiesis, several lineage-specific factors such as C/EBPalpha and PU.1 interact with Runx1 to regulate transcription combinatorially. Here we addressed the functional interplay between subnuclear targeting of Runx1 and gene activation during hematopoiesis. Point mutations were generated in the NMTS of the human Runx1 protein and tested for their effect on transcriptional cooperativity with C/EBPalpha and PU.1 at myeloid-specific promoters. We characterized five mutants that do not alter nuclear import, DNA binding or C/EBPalpha-dependent synergistic activation of the target gene promoters. However a critical tyrosine in the NMTS is required for subnuclear targeting and activation of the granulocyte-macrophage colony stimulating factor (GM-CSF) promoter. Furthermore, this point mutation is defective for transcriptional synergism with PU.1 on the macrophage colony stimulating factor (MCSF) receptor c-FMS promoter. Our results indicate that the NMTS region of Runx1 is required for functional interactions with PU.1. Taken together, our findings establish that subnuclear targeting of Runx1 is a critical component of myeloid-specific transcriptional control

Understanding genetic breast cancer risk: Processing loci of the BRCA Gist Intelligent Tutoring System

The BRCA Gist Intelligent Tutoring System helps women understand and make decisions about genetic testing for breast cancer risk. BRCA Gist is guided by Fuzzy-Trace Theory, (FTT) and built using AutoTutor LITE. It responds differently to participants depending on what they say. Seven tutorial dialogues requiring explanation and argumentation are guided by three FTT concepts: forming gist explanations in one\u27s own words, emphasizing decision-relevant information, and deliberating the consequences of decision alternatives. Participants were randomly assigned to BRCA Gist, a control, or impoverished BRCA Gist conditions removing gist explanation dialogues, argumentation dialogues, or FTT images. All BRCA Gist conditions performed significantly better than controls on knowledge, comprehension, and risk assessment. Significant differences in knowledge, comprehension, and fine-grained dialogue analyses demonstrate the efficacy of gist explanation dialogues. FTT images significantly increased knowledge. Providing more elements in arguments against testing correlated with increased knowledge and comprehension

The development and analysis of tutorial dialogues in AutoTutor Lite

The goal of intelligent tutoring systems (ITS) that interact in natural language is to emulate the benefits that a well-trained human tutor provides to students, by interpreting student answers and appropriately responding in order to encourage elaboration. BRCA Gist is an ITS developed using AutoTutor Lite, a Web-based version of AutoTutor. Fuzzy-trace theory theoretically motivated the development of BRCA Gist, which engages people in tutorial dialogues to teach them about genetic breast cancer risk. We describe an empirical method to create tutorial dialogues and fine-tune the calibration of BRCA Gist\u27s semantic processing engine without a team of computer scientists. We created five interactive dialogues centered on pedagogic questions such as What should someone do if she receives a positive result for genetic risk of breast cancer? This method involved an iterative refinement process of repeated testing with different texts and successively making adjustments to the tutor\u27s expectations and settings in order to improve performance. The goal of this method was to enable BRCA Gist to interpret and respond to answers in a manner that best facilitated learning. We developed a method to analyze the efficacy of the tutor\u27s dialogues. We found that BRCA Gist\u27s assessment of participants\u27 answers was highly correlated with the quality of the answers found by trained human judges using a reliable rubric. The dialogue quality between users and BRCA Gist predicted performance on a breast cancer risk knowledge test completed after exposure to the tutor. The appropriateness of BRCA Gist\u27s feedback also predicted the quality of answers and breast cancer risk knowledge test scores. © 2013 Psychonomic Society, Inc