The transcriptional co‐activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD‐family co‐activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP‐TEAD cooperates with the RAS‐induced AP‐1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF‐SRF to promote (...) activation of cancer‐associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2‐LATS1/2) pathway and the key upstream activators are mechanically induced Integrin‐SRC and E‐cadherin‐AJUBA/TRIP6/LIMD1, growth factor induced PI3K‐AKT, and inflammation‐induced G‐protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy. (shrink)

The YAP/TAZ family of transcriptional co‐activators drives cell proliferation in epithelial tissues and cancers. Yet, how YAP and TAZ are physiologically regulated remains unclear. Here we review recent reports that YAP and TAZ act primarily as sensors of epithelial cell polarity, being inhibited when cells differentiate an apical membrane domain, and being activated when cells contact the extracellular matrix via their basal membrane domain. Apical signalling occurs via the canonical Crumbs/CRB‐Hippo/MST‐Warts/LATS kinase cascade to phosphorylate and inhibit YAP/TAZ. Basal signalling occurs (...) via Integrins and Src family kinases to phosphorylate and activate YAP/TAZ. Thus, YAP/TAZ is localised to the nucleus in basal stem/progenitor cells and cytoplasm in differentiated squamous cells or columnar cells. In addition, other signals such as mechanical forces, tissue damage and possibly receptor tyrosine kinases (RTKs) can influence MST‐LATS or Src family kinase activity to modulate YAP/TAZ activity. (shrink)

In light of growing concerns in the public and recent mandates from business program accrediting bodies and curricular task forces, the importance of teaching ethical topics in information systems programs is discussed. Innovative strategies used for teaching the application of ethical criteria to common situations are reviewed. Results of a survey of information systems faculty members in the US are presented and are compared to previous studies that related primarily to computer science and software engineering programs. Insight is provided into (...) the topics, techniques, degree of coverage, and assessment techniques currently used when teaching ethics in computing-related programs. Key concerns and future work is also outlined. (shrink)

The Embodied Mind provides a unique, sophisticated treatment of the spontaneous and reflective dimension of human experience.

Volume 20, Issue 2, February 2020, Page 51-53.

Understanding spoken words involves a rapid mapping from speech to conceptual representations. One distributed feature-based conceptual account assumes that the statistical characteristics of concepts’ features—the number of concepts they occur in and likelihood of co-occurrence —determine conceptual activation. To test these claims, we investigated the role of distinctiveness/sharedness and correlational strength in speech-to-meaning mapping, using a lexical decision task and computational simulations. Responses were faster for concepts with higher sharedness, suggesting that shared features are facilitatory in tasks like lexical decision (...) that require access to them. Correlational strength facilitated responses for slower participants, suggesting a time-sensitive co-occurrence-driven settling mechanism. The computational simulation showed similar effects, with early effects of shared features and later effects of correlational strength. These results support a general-to-specific account of conceptual processing, whereby early activation of shared features is followed by the gradual emergence of a specific target representation. (shrink)

Working through Esme Johnson’s case brings to light many of the elements that make for a rich and impactful clinical ethics consultation. The health and well-being of a young person, whether a fami...

Journal of Philosophy of Education, EarlyView.

It’s a familiar fact that there is something it is like to see red, eat chocolate or feel pain. More recently philosophers have insisted that in addition to this objectual phenomenology there is something it is like for me to eat chocolate, and this for-me-ness is no less there than the chocolatishness. Recognizing this subjective feature of consciousness helps shape certain theories of consciousness, introspection and the self. Though it does this heavy philosophical work, and it is supposed to be (...) relatively obvious to anyone who introspects, it is rather difficult to see just what this phenomenal me-ness is supposed to be; indeed, many philosophers deny it exists. In this paper we try to provide a clear sense of what phenomenal me-ness involves, and then then consider some arguments for the existence of phenomenal me-ness experience as well as some accounts of what gives rise to it. In the end, we argue that the plausible senses of me-ness are a good deal thinner than what often seems to be claimed. (shrink)

Codes of conduct are a conspicuous feature of modern business organization, but doubts have been raised regarding their efficacy in ensuring high standards of behavior. Although some of the issues involved have been discussed at some length in the business ethics literature, the amount of systematic empirical evidence on the impact of codes is very limited. This paper seeks to make a contribution to that body of knowledge by studying the policies and procedures of a sample of banks which have (...) signed a statement on banking and the environment promulgated by the United Nations Development Programme. Although some differences are found when compared with a sample of banks which did not sign the Statement, they are not extensive. The implications of the findings, for codes of conduct and for future empirical studies, are then discussed. (shrink)

Several lines of evidence have underscored the remarkable neuroplasticity of the primate sensorimotor cortex, characterizing these cortical areas as dynamic constructs that are modelled in a use-dependent manner by behaviourally significant experiences. Their plasticity likely provides a neural substrate that may contribute to the dynamic systems paradigm argued by Shanker & King (S&K) as crucial for development of communication skills.

This commentary focusses on MacNeilage's arguments and evidence that the development of cerebral cortical controls over cyclic ingestive movements has provided substrates for the evolution of speech production. It outlines evidence from experimental approaches using cortical stimulation, inactivation, and single neuron recording in primates that lateral frontal cortical regions are indeed crucial for the generation and guidance of cyclic orofacial movements.

This discussion paper aims to explore potential ethical and moral implications of (patient) centredness in nursing and healthcare. Healthcare is experiencing a philosophical shift from a perspective where the health professional is positioned as the expert to one that re‐centres care and service provision central to the needs and desires of the persons served. This centred approach to healthcare delivery has gained a moral authority as the right thing to do. However, little attention has been given to its moral and (...) ethical theoretical grounding and potential implications for nurses, persons served and the healthcare system. Based upon a review of academic and grey literature, centredness is proposed as a value‐laden concept in nursing inquiry. Potential moral and ethical implications of centredness on nurses/healthcare providers, persons served and the healthcare system are discussed. These challenges are then considered within the context of normative and relational ethical theories. These perspectives may offer guidance relative to how one should act in those circumstances as well as an understanding as to how interdependency and engagement with the other person(s) can help navigate the challenges of a centred care approach. Viewing centredness through an ethical theoretical lens provides a valuable discourse to nursing in efforts to expand the knowledge base and integrate centred approaches into practice and policy. (shrink)

Ephesians 1:14 and 1:22, 23 as a scriptural maximum-minimum for ecclesiology. Against the background of a membership decline in mainstream churches in South Africa and abroad, and conscious of the theological debate in which a missional ecclesiology is presented as at least part of the modern-day solution to the problem, this article points in the direction of a Christological ecclesiology as an important ecclesiological point of departure. The article gives an exegetical outline of Ephesians 1:14 and 1:22, 23 as a (...) critical maximum-minimum for a Christological ecclesiology and as a means of making missional ecclesiology more acceptable. (shrink)

A tolerant treatment of church order and the law of usance: This article discusses the recent decline of church polity in the Netherdutch Reformed Church which is obvious in different areas of the Church with special reference to the liturgy practised in sermons of some congregations. This decline is also observed in other churches in South Africa and abroad. The article is a reaction to the reason for this situation and indicates that it should not be found in a collegialistic (...) concept of church, but rather due to congregationalism or independentism in modern form. The article’s viewpoint is that the above-mentioned church polity decline is a result of the fact that church order is not valued as an order with a Scriptural and therefore an ecclesiological basis. (shrink)

Health regulators must carefully monitor the real-world safety and effectiveness of marketed vaccines through post-market monitoring in order to protect the public’s health and promote those vaccines that best achieve public health goals. Yet, despite the fact that vaccines used in collective immunization programmes should be assessed in the context of a public health response, post-market effectiveness monitoring is often limited to assessing immunogenicity or limited programmatic features, rather than assessing effectiveness across populations. We argue that post-market monitoring ought to (...) be expanded in two ways to reflect a ‘public health notion of post-market effectiveness’, which incorporates normative public health considerations: effectiveness monitoring should yield higher quality data and grant special attention to underrepresented and vulnerable populations; and the scope of effectiveness should be expanded to include a consideration of the various social factors that maximize a vaccine’s effectiveness at the population level, paying particular attention to how immunization programmes impact related health gradients. We use the case of the human papillomavirus vaccine in Canada to elucidate how expanding post-market effectiveness monitoring is necessary to close the gap between clinical practice and public health, and to ensure that vaccines are effective in a morally relevant sense. (shrink)