Endothelial Depletion of Acvrl1 in Mice Leads to Arteriovenous Malformations Associated with Reduced Endoglin Expression

Rare inherited cardiovascular diseases are frequently caused by mutations in genes that are essential for the formation and/ or function of the cardiovasculature. Hereditary Haemorrhagic Telangiectasia is a familial disease of this type. The majority of patients carry mutations in either Endoglin (ENG) or ACVRL1 (also known as ALK1) genes, and the disease is characterized by arteriovenous malformations and persistent haemorrhage. ENG and ACVRL1 encode receptors for the TGF beta superfamily of ligands, that are essential for angiogenesis in early development but their roles are not fully understood. Our goal was to examine the role of Acvrl1 in vascular endothelial cells during vascular development and to determine whether loss of endothelial Acvrl1 leads to arteriovenous malformations. Acvrl1 was depleted in endothelial cells either in early postnatal life or in adult mice. Using the neonatal retinal plexus to examine angiogenesis, we observed that loss of endothelial Acvrl1 led to venous enlargement, vascular hyperbranching and arteriovenous malformations. These phenotypes were associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity and increased endothelial cell proliferation. We found that Endoglin was markedly down-regulated in Acvrl1-depleted ECs showing endoglin expression to be downstream of Acvrl1 signalling in vivo. Endothelial-specific depletion of Acvrl1 in pups also led to pulmonary haemorrhage, but in adult mice resulted in caecal haemorrhage and fatal anaemia. We conclude that during development, endothelial Acvrl1 plays an essential role to regulate endothelial cell proliferation and arterial identity during angiogenesis, whilst in adult life endothelial Acvrl1 is required to maintain vascular integrity

Learning HCI Across Institutions, Disciplines and Countries: A Field Study of Cognitive Styles in Analytical and Creative Tasks

Human-computer interaction (HCI) is increasingly becoming a subject taught in universities around the world. However, little is known of the interactions of the HCI curriculum with students in different types of institutions and disciplines internationally. In order to explore these interactions, we studied the performance of HCI students in design, technology and business faculties in universities in UK, India, Namibia, Mexico and China who participated in a common set of design and evaluation tasks. We obtained participants’ cognitive style profiles based on Allinson and Hayes scale in order to gain further insights into their learning styles and explore any relation between these and performance. We found participants’ cognitive style preferences to be predominantly in the adaptive range, i.e. with combined analytical and intuitive traits, compared to normative data for software engineering, psychology and design professionals. We further identified significant relations between students’ cognitive styles and performance in analytical and creative tasks of a HCI professional individual. We discuss the findings in the context of the distinct backgrounds of the students and universities that participated in this study and the value of research that explores and promotes diversity in HCI education

Convergence in international business ethics? A comparative study of ethical philosophies, thinking style, and ethical decision-making between US and Korean managers

This study investigates the relationship among ethical philosophy, thinking style, and managerial ethical decision-making. Based on the premise that business ethics is a function of culture and time, we attempt to explore two important questions as to whether the national differences in managerial ethical philosophies remain over time and whether the relationship between thinking style and ethical decision-making is consistent across different national contexts. We conducted a survey on Korean managers’ ethical decision-making and thinking style and made a cross-cultural, cross-temporal comparison with the results presented by previous studies that surveyed Korean and US managers with the same questionnaire at different points in time. Our analysis revealed that Korean managers have become more reliant on rule utilitarianism for ethical decision-making over the last two decades, which is dominantly used by US managers, corroborating our convergence hypothesis built on social contracts theory. However, as opposed to previous research, we found that managers with a balanced linear and nonlinear thinking style do not necessarily make more ethical decisions compared to those with a predominantly linear or nonlinear thinking style. This study contributes to international business ethics literature by presenting a theoretical framework that may explain the convergence of ethical philosophies employed by managers in different national contexts over time, and that the relationship between thinking style and managerial ethical decision-making may not be universal, but contingent on contextual factors

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects

Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ40 and Aβ42, the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions

The Roots of Virtue: A Cross-Cultural Lexical Analysis

Although the notion of virtue is increasingly prominent in psychology, the way it has been studied and conceptualised has been relatively Western-centric, and does not fully account for variations in how it has been understood cross-culturally. As such, an enquiry was conducted into ideas relating to virtue found across the world’s cultures, focusing specifically on so-called untranslatable words. Through a quasi-systematic search of academic and grey literature, together with conceptual snowballing and crowd-sourced suggestions, over 200 relevant terms were located. An adapted grounded theory analysis identified five themes which together provide an insight into the “roots” of virtue (i.e., the main sources from which it appears to spring): virtue itself (the concept of it); considerateness (caring about it); wisdom (knowing what it consists of); agency (managing to be/do it); and skill (mastery of the preceding elements). The results help shed further light on the potential dynamics of this important phenomenon

Cognitive style and business process model understanding

Several factors influence the level of business process model understanding. In this paper, we investigate two personal factors that potentially relate to this level: a reader's cognitive style and theoretical knowledge on business process (BP) modeling. An experiment with 183 graduate students was conducted to explore their differences in cognitive styles using Cognitive Style Index (CSI) and how these relate to their scores in process model understandability. We used two real-life BPMN collaboration diagrams as our process models in our experiment. The results indicate a significant difference between intuitive and analytic students with respect to the level of BP model understandability. The relation between students' theoretical BP modeling and notation competency, and their level of model understanding is also found significant