Bringing Scotland’s wilderness ‘within the reach of the people’: William Eagle Clarke (1853-1938) and representations of place

William Eagle Clarke was on the staff of the Royal Scottish Museum, Edinburgh, (now incorporated into National Museums Scotland) from 1888 to 1921. This poster presents two related aspects of his construct of representations of Scotland’s landscape

Good guy or bad guy? The duality of wild-type p53 in hormone-dependent breast cancer origin, treatment, and recurrence

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. “Lactation is at one point perilously near becoming a cancerous process if it is at all arrested”, Beatson, 1896. Most breast cancers arise from the milk-producing cells that are characterized by aberrant cellular, molecular, and epigenetic translation. By understanding the underlying molecular disruptions leading to the origin of cancer, we might be able to design novel strategies for more efficacious treatments or, ambitiously, divert the cancerous process. It is an established reality that full-term pregnancy in a young woman provides a lifetime reduction in breast cancer risk, whereas delay in full-term pregnancy increases short-term breast cancer risk and the probability of latent breast cancer development. Hormonal activation of the p53 protein (encode by the TP53 gene) in the mammary gland at a critical time in pregnancy has been identified as one of the most important determinants of whether the mammary gland develops latent breast cancer. This review discusses what is known about the protective influence of female hormones in young parous women, with a specific focus on the opportune role of wild-type p53 reprogramming in mammary cell differentiation. The importance of p53 as a protector or perpetrator in hormone-dependent breast cancer, resistance to treatment, and recurrence is also explored

Organizational Influences on Interdisciplinary Interactions during Research and Design of Large-Scale Complex Engineered Systems

The design of large-scale complex engineered systems (LaCES) such as an aircraft is inherently interdisciplinary. Multiple engineering disciplines, drawing from a team of hundreds to thousands of engineers and scientists, are woven together throughout the research, development, and systems engineering processes to realize one system. Though research and development (R&D) is typically focused in single disciplines, the interdependencies involved in LaCES require interdisciplinary R&D efforts. This study investigates the interdisciplinary interactions that take place during the R&D and early conceptual design phases in the design of LaCES. Our theoretical framework is informed by both engineering practices and social science research on complex organizations. This paper provides preliminary perspective on some of the organizational influences on interdisciplinary interactions based on organization theory (specifically sensemaking), data from a survey of LaCES experts, and the authors experience in the research and design. The analysis reveals couplings between the engineered system and the organization that creates it. Survey respondents noted the importance of interdisciplinary interactions and their significant benefit to the engineered system, such as innovation and problem mitigation. Substantial obstacles to interdisciplinarity are uncovered beyond engineering that include communication and organizational challenges. Addressing these challenges may ultimately foster greater efficiencies in the design and development of LaCES and improved system performance by assisting with the collective integration of interdependent knowledge bases early in the R&D effort. This research suggests that organizational and human dynamics heavily influence and even constrain the engineering effort for large-scale complex systems

Differential hepatic features presenting in Wilson disease-associated cirrhosis and hepatitis B-associated cirrhosis

© The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved. BACKGROUND Cirrhosis is a chronic late stage liver disease associated with hepatitis viruses, alcoholism, and metabolic disorders, such as Wilson disease (WD). There are no clear markers or clinical features that define cirrhosis originating from these disparate origins. We hypothesized that cirrhosis is not one disease and cirrhosis of different etiology may have differential clinical hepatic features. AIM To delineate the liver features between WD-associated cirrhosis and hepatitis Bassociated cirrhosis in the Chinese population. METHODS In this observational study, we reviewed the medical data of consecutive inpatients who had WD-associated cirrhosis or hepatitis B-associated cirrhosis from January 2010 to August 2018, and excluded patients who had carcinoma, severe heart or pulmonary diseases, or other liver diseases. According to the etiology of cirrhosis, patients were divided into two groups: WD-associated cirrhosis group (60 patients) and hepatitis B-associated cirrhosis group (56 patients). The liver fibrosis degree, liver function indices, and portal hypertension features of these patients were compared between the two groups. RESULTS No inter-group differences were observed in the diagnostic liver fibrosis markers, however, clinical features clearly defined the origin of cirrhosis. WD-associated cirrhosis patients (16-29 years) had lower levels of alanine transaminase, aspartate transaminase, and bilirubin, lower prothrombin time, lower incidence of hepatic encephalopathy, and lower portal vein diameter (P < 0.05), compared to cirrhosis resulting from hepatitis B in older patients (45-62 years). Importantly, they had decreased risks of progression from Child-Pugh grade A to B (odds ratio = 0.046, 95% confidence interval: 0.006-0.387, P = 0.005) and of ascites (odds ratio = 0.08, 95% confidence interval: 0.01-0.48, P = 0.005). Conversely, WDassociated cirrhosis patients had a higher risk of splenomegaly (odds ratio = 4.15, 95% confidence interval: 1.38-12.45, P = 0.011). CONCLUSION WD-associated cirrhosis presents a higher risk of splenomegaly associated with leukopenia and thrombocytopenia, although revealing milder liver dysfunction and portal hypertension symptoms, which recommends WD patients to be monitored for associated complications

“Dicing and splicing” sphingosine kinase and relevance to cancer

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. Sphingosine kinase (SphK) is a lipid enzyme that maintains cellular lipid homeostasis. Two SphK isozymes, SphK1 and SphK2, are expressed from different chromosomes and several variant isoforms are expressed from each of the isozymes, allowing for the multi-faceted biological diversity of SphK activity. Historically, SphK1 is mainly associated with oncogenicity, however in reality, both SphK1 and SphK2 isozymes possess oncogenic properties and are recognized therapeutic targets. The absence of mutations of SphK in various cancer types has led to the theory that cancer cells develop a dependency on SphK signaling (hyper-SphK signaling) or “non-oncogenic addiction”. Here we discuss additional theories of SphK cellular mislocation and aberrant “dicing and splicing” as contributors to cancer cell biology and as key determinants of the success or failure of SphK/S1P (sphingosine 1 phosphate) based therapeutics

Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: Challenges for SphK as an oncotarget

Copyright: © Hatoum et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget

Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget.

The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget

MDO and Cross-Disciplinary Practice in R&D: A Portrait of Principles and Current Practice

For several decades, Multidisciplinary Design Optimization (MDO) has served an important role in aerospace engineering by incorporating physics based disciplinary models into integrated system or sub-system models for use in research, development, (R&D) and design. This paper examines MDO's role in facilitating the integration of the researchers from different single disciplines during R&D and early design of large-scale complex engineered systems (LaCES) such as aerospace systems. The findings in this paper are summarized from a larger study on interdisciplinary practices and perspectives that included considerable empirical data from surveys, interviews, and ethnography. The synthesized findings were derived by integrating the data with theories from organization science and engineering. The over-arching finding is that issues related to cognition, organization, and social interrelations mostly dominate interactions across disciplines. Engineering issues, such as the integration of hardware or physics-based models, are not as significant. Correspondingly, the data showed that MDO is not the primary integrator of researchers working across disciplines during R&D and early design of LaCES. Cognitive focus such as analysis versus design, organizational challenges such as incentives, and social opportunities such as personal networks often drove the human interactive practices among researchers from different disciplines. Facilitation of the inherent confusion, argument, and learning in crossdisciplinary research was identified as one of several needed elements of enabling successful research across disciplines