Epigenetic regulation of gene silencing during stem cell commitment and differentiation

Imperial Users onl

Assessing Artificial Agent Response Time Effects on Human-Agent Teams in Variable Inter-Arrival Time Environments

Autonomous systems have gained an expanded presence within the Department of Defense (DoD). Furthermore, the DoD has clearly stated autonomous systems must extend the capabilities of their human operators. Thus, the exploration of strategies for effective pairing of humans and automation supports this vision. Previous research demonstrated that the time at which an automated agent assumes a task for its human teammate, or agent response time (ART), affects human-agent team performance, human engagement, and human workload. However, in this research environment, the time between subsequent tasks appearing to the human-agent team, or inter-arrival time (IAT), remained constant. Variable IAT environments more accurately reflect real-world operational environments. Previous research also maintained ART at a fixed level. Additionally, the effect of human understanding of automated teammate actions on human-agent team performance remains unknown. This thesis attempts to analyze the effect of an agent with adaptive ART that varies based on current IAT on human-agent team performance, human engagement, and human workload. Additionally, it seeks to determine the implication of agent predictability to the human. This thesis explores these issues in three phases. First, a method and development of a variable ART function for use in future phases is presented. Second, a study of a variable ART teammate against a fixed ART teammate highlights the significance of providing detailed agent instruction to the human. Third, analysis of instruction and type of agent teammate across an entire input IAT function and at different IAT levels is conducted. This work establishes key factors for adaptive ART function implementation. Based on specific IAT changes, the current research demonstrates that adaptive ART can boost human-agent team performance and manipulate human engagement. Furthermore, predictability of agent action in variable IAT environments is a desired system attribute

UNEARTHING ENTANGLEMENTS: HUMAN/MACHINE COLLABORATION IN THE WRITING CLASSROOM

This dissertation focuses on the dynamics between teachers and machines at the intersections of design, teaching labor, and pedagogy when automation is deployed in writing classrooms. The sites of analysis are Eli Review and Turnitin, two technologies that represent different design approaches that center around “informating” or “automating” data about student work. The exigence for this project emerges out of the labor crisis currently enveloping higher education. Traditionally, in times of labor crises, automation and machines are used to replace scarce or imperfect human labor. However, balanced and purposeful design of automated technology has the potential to enhance humans’ labor and protect workers. Using holistic and provisional coding, combined with object interviews, this dissertation analyzes data collected from a national survey distributed to composition instructors and nine interviews about their personal experiences with Eli Review and Turnitin. The data and findings from these methods suggests beneficial relationships between humans and machines are possible in the writing classroom through careful design, integration, and management of educational and learning technologies

Building instructor involement in a distance-learning setting

Distance learning (DL) is rapidly increasingly in education worldwide. DL courses are asynchronous; therefore, many students perceive them as disengaged and impersonal. DL instructors can dispel these perceptions by overseeing every aspect of student participation in the classroom. To help instructors develop DL pedagogies that compensate for the lack of face to face (f2f) interaction, this paper offers conceptual and practice advice about developing course content and teaching styles; these guidelines will support teachers who increasingly instructing in the virtual classroom and maximize student learning in that environment

Anxiety, Prenatal Attachment, and Depressive Symptoms in Women with Diabetes in Pregnancy

Abstract: The purpose of this study was to evaluate the relationship between anxiety, prenatal attachment, and depressive symptoms among women with diabetes in pregnancy. Participants were 131 consecutive pregnant women between the ages of 20 and 45 with a diagnosis of gestational or pregestational type 1 or type 2 diabetes. Data on previous psychiatric symptoms were obtained from the Anamnestic and Social Questionnaire and the Mini-International Neuropsychiatric Interview (MINI). Information on prenatal attachment was collected using The Prenatal Attachment Inventory (PAI), and The Edinburgh Postnatal Depression Scale (EPDS) assessed depressive symptoms in the third trimester of pregnancy (at a mean of 25 weeks). Results demonstrated that in women aected by diabetes in pregnancy, two facets of prenatal attachment (anticipation, interaction) were negatively correlated with depressive symptoms, and a history of anxiety, assessed with the MINI, moderated the relation between the prenatal attachment interaction factor and depressive symptoms during pregnancy

Job satisfaction mediates the association between perceived disability and work productivity in migraine headache patients

Migraine headache is the cause of an estimated 250,000,000 lost days from work or school every year and is often associated with decreased work productivity. The aim of this cross-sectional study was to assess the relationship between perceived disability, job satisfaction and work productivity in patients affected by chronic migraineurs. Participants were 98 consecutive adult outpatients admitted to the Regional Referral Headache Centre of the Sant’Andrea Hospital in Rome, Italy. Patients were administered the Italian Perceived Disability Scale, The Quality of Life Enjoyment and Satisfaction Questionnaire-Work Subscale and The EndicottWork Productivity Scale. Perceived disability is significantly associated with job satisfaction and work productivity. Job satisfaction is significantly related to work productivity and mediates the association between perceived disability and work productivity in patients affected by chronic migraineurs. Our results confirm that patients suffering from migraine headaches who have negative perceptions © 2019 by the authors. Licensee MDPI, Basel, Switzerland

Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome

Children with Down's syndrome (DS) have 20–50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid lineages during foetal haematopoiesis, contributing to the increased risk of both leukaemia types in DS

Down syndrome-recent progress and future prospects

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype-phenotype relationships in patients are likely to significantly contribute to the future understanding of DS

Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes

<p>Abstract</p> <p>Background</p> <p>Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown. Many different experimental techniques have been applied to analyse the effects of dosage imbalance at the molecular and phenotypical level, however, currently no integrative approach exists that attempts to extract the common information.</p> <p>Results</p> <p>We have performed a statistical meta-analysis from 45 heterogeneous publicly available DS data sets in order to identify consistent dosage effects from these studies. We identified 324 genes with significant genome-wide dosage effects, including well investigated genes like <it>SOD1</it>, <it>APP</it>, <it>RUNX1 </it>and <it>DYRK1A </it>as well as a large proportion of novel genes (N = 62). Furthermore, we characterized these genes using gene ontology, molecular interactions and promoter sequence analysis. In order to judge relevance of the 324 genes for more general cerebral pathologies we used independent publicly available microarry data from brain studies not related with DS and identified a subset of 79 genes with potential impact for neurocognitive processes. All results have been made available through a web server under <url>http://ds-geneminer.molgen.mpg.de/</url>.</p> <p>Conclusions</p> <p>Our study represents a comprehensive integrative analysis of heterogeneous data including genome-wide transcript levels in the domain of trisomy 21. The detected dosage effects build a resource for further studies of DS pathology and the development of new therapies.</p

Profile of down syndrome–associated malignancies: Epidemiology, clinical features and therapeutic aspects

Down syndrome (DS) is a congenital chromosomal abnormality caused by the presence of all or part of a third copy of chromosome 21 (+21). DS is frequently complicated by congenital heart or digestive tract diseases at birth. DS patients are prone to infections and have mental retardation, with dementia such as Alzheimer's disease showing in later life. Furthermore, malignancies with specific characteristics are also highly reported in DS patients compared with non-DS patients. Therefore, DS is believed to be a cancer predisposition syndrome due to the chromosomal instability. Acute myeloid leukemia (AML) and especially acute megakaryoblastic leukemia (AMKL) by French-American-British (FAB) classification are the most frequent hematological malignancies in DS patients, occurring at a rate that is 500 times higher than that in non-DS patients. Interestingly, transient abnormal myelopoiesis (TAM) is observed in approximately 10% of DS neonates with GATA1 mutations, and most TAM patients are asymptomatic and show spontaneous regression; however, about 10%–20% of TAM cases are fatal because of complications such as fetal effusion, liver fibrosis, and other complications.Acute lymphoblastic leukemia (ALL) is also associated with DS, occurring at a rate that is 20 times higher than that in non-DS patients. Furthermore, the prognosis of DS-ALL patients is poorer than that of non-DS-ALL patients. A recent genetic analysis revealed that more than half of DS-ALL cases have a mutation in the CRLF2–JAK pathway, indicating that JAK inhibitors might have a limited effect for DS-ALL patients.Notably, solid tumors such as neuroblastoma, Wilms tumor, and brain tumor, which are frequently observed in non-DS children, are rarely reported in DS children. The reason remains unknown, but it may be because of the triplication of the Down syndrome critical region 1 (DSCR1) gene on chromosome 21. In adult patients with DS, the expected age-adjusted incidence rates of solid tumors are low compared with age-matched euploid cohorts for most cancers except for testicular cancer. Although the average life expectancy of patients with DS will increase with advances in healthcare, the detailed health problems including cancer rates in older DS patients remain unknown. Therefore, these issues will be needed to be addressed in future studies