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Enrichment analysis from TCGA RNA-seq and RPPA data comparing CREBBPaltered versus wild-type patients.

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Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model in vivo–like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population.Significance:This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.

Supplementary Materials and Methods

Throughout the coronavirus disease 2019 (COVID-19) pandemic the Queen's University Belfast Connections (QUB Connections) project has provided online well-being support to nursing students and student midwives. The project, which was co-designed and led by students and academic staff, provided an online well-being service for students who took on front-line roles during the early part of the pandemic and for those who had to pause their studies. Insights gained from responses to an evaluation of the support sessions suggested that some students felt stigmatised, frightened, lost, isolated and abandoned during this period, but that QUB Connections gave them a sense of 'being held' and 'attended to' in a time of uncertainty. The evaluation findings are a reminder of the need to continue to help nursing and midwifery students and newly qualified staff develop self-care and support mechanisms. QUB Connections is now embedded in the university's school of nursing and midwifery pre-registration programmes to support students and those new to nursing and midwifery practice.

In this chapter, the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) is placed in a broader context. It is argued that Article 12 of the UNCRPD makes sense when viewed against the backdrop of developments across a range of disciplines that have been silently evolving over the past two decades or more. These new theories are about the nature, function, and outer boundaries of personhood. They debunk the idea that cognitive capacity is a central or ‘essentialist’ criterion of personhood. It is suggested that it is these changes that convert the seemingly utopian ideal of Article 12 into a valid legislative and policy goal for states into the future. The UNCRPD encapsulates a new approach to law reform, in terms of how received understandings of personhood have in fact changed in a variety of disciplines in recent times. Finally, it is argued that we need to move away from a traditional human rights default that aims to police how we limit rights (as in guardianship) to a human rights perch that explores how to give life to rights (through appropriate supports). This entails a completely different policy imagination.

Generation of transcriptional data has dramatically increased in the past decade, driving the development of analytical algorithms that enable interrogation of the biology underpinning the profiled samples. However, these resources require users to have expertise in data wrangling and analytics, reducing opportunities for biological discovery by ‘wet-lab’ users with a limited programming skillset. Although commercial solutions exist, costs for software access can be prohibitive for academic research groups. To address these challenges, we have developed an open source and user-friendly data analysis platform for on-the-fly bioinformatic interrogation of transcriptional data derived from human or mouse tissue, called Molecular Subtyping Resource (MouSR). This internet-accessible analytical tool, https://mousr.qub.ac.uk/, enables users to easily interrogate their data using an intuitive ‘point-and-click’ interface, which includes a suite of molecular characterisation options including quality control, differential gene expression, gene set enrichment and microenvironmental cell population analyses from RNA sequencing. The MouSR online tool provides a unique freely available option for users to perform rapid transcriptomic analyses and comprehensive interrogation of the signalling underpinning transcriptional datasets, which alleviates a major bottleneck for biological discovery. This article has an associated First Person interview with the first author of the paper.

The COVID-19 crisis has revealed systemic inequities that uniquely impact persons with disabilities. Although governments have purportedly adopted a human rights framework in providing for persons with disabilities, the immediate policy responses to COVID-19 expose how governments have yet to internalize human rights-based commitments. As a result, the diverse needs of persons with disabilities have been neglected, and persons with disabilities have disproportionately been put at risk of homelessness, domestic abuse, unequal medical treatment, and, in extreme cases, complete abandonment. This chapter explores the differences between the traditional paradigm of welfare-based treatment versus the human rights-based treatment of persons with disabilities. It examines the ways in which the traditional paradigm appears to have dominated COVID-19 policy responses and the adverse impacts to persons with disabilities. In particular, unequal treatment was most pronounced in the delivery of medical care and in group home settings – institutions where persons with disabilities are disproportionality represented. This chapter suggests that policymakers must avoid anachronistic frameworks and provide greater support for persons with disabilities in subsequent crises. Ultimately, the human rights of persons with disabilities can be better protected by making their rights central to policymaking, encouraging greater civil society participation in the policymaking process, and deinstitutionalization.

Experimentally, mutually coupled quantum dot lasers demonstrate a greatly reduced modal linewidth when mutually phase-locked. The authors investigate this phenomenon theoretically. Specifically, they examine a delay differential equation coupled phase model and use it to find the laser linewidth in several configurations. The numerical results are in excellent agreement with previously reported experimental findings. They show that while the model predicts a restoring force on the phase difference of the coupled lasers, this translates to an effective restoring force on the individual laser phases. The phenomenon should be robust to changes in device type and in particular for modern, integrated coupled lasers.

Accessible summary • The UN Convention on Rights for Persons with Disabilities explains the rights that people with disabilities should have. • These rights are for all people with disabilities, wherever they are in the world. • You can find an easy to read copy of the Convention at this website:http://www.fedvol.ie/UN_Convention_on_the_Rights_of_Persons_with_Disabilities__easy_to_read_reports/Default.403.htl • Countries that say in writing that they will do what the Convention says have to do the work to make this happen. • Countries that say in writing that they will do what the Convention says have to report to the UN Committee about what they have done. Ireland still has to fully agree to the Convention. This is very important. Summary This article provides an account of the UN Convention on the Rights of Persons with Disabilities. It describes why the Convention is important in asserting and safeguarding the rights of persons with disabilities and outlines its core values. It explores the nature of rights in the Convention with an account of the Convention as a blueprint for reference and research. The importance of ratification of the Convention is emphasised.

‘What is needed nowadays is that as against an abstract and unreal theory of State omnipotence on the one hand, and an atomistic and artificial view of individual independence on the other, the facts of the world with its innumerable bonds of association and the naturalness of social authority should be generally recognized, and become the basis of our laws, as it is of our life.’ Recovering the human ‘Human rights’ – here are two words expressing two different normative domains. Most simply assume that the two are mutually reinforcing, mutually implicated by each other, coterminous and coeval. Everywhere in the world, first-year law students are routinely told that we enjoy human rights simply because we are human. The question of whether there are any essential criteria of being human or of ‘personhood’ and, if so, what they are, is left dangling as if solved by the conjuncture of ‘human’ with ‘rights’. That is, rights-talk tends to cloud our view of what it means to be human. And rights tend to impute a certain view of humanity – one that is not necessarily tied to observable reality. Another result is the absence of any clear toeholds in the slippery debate about whether there are any non-human ‘persons’ (e.g. animals or even the earth) and, if so, whether they are the proper subject of rights.

This chapter explores the implementation and monitoring process put in place by the disability Convention. It is predicated on the vital need to gain traction between international monitoring and implementation to facilitate 'persuasion' and 'socialisation' to occur. The chapter explores how and why political failure occurs in the disability context. It also focuses on thorny issue of reservations to the Convention which, unless adequately policed, could delay forever the introduction of a positive dynamic of change at the domestic level. The chapter finally analyses the implementation and monitoring regime of the disability Convention and concludes by assessing its potential to trigger real political change where it matters most - within the States Parties themselves. Keywords: CRPD; persuasion; socialisation; States Parties

Member States are generally taking a civil rights approach to disability: from seeing people with disabilities as the passive recipients of benefits, they acknowledge the legitimate demands of people with disabilities for equal rights. Accordingly, they are making efforts to develop policies that aim at the full participation of people with disabilities into the economy and society. It implies equal opportunities, empowerment and active citizenship in mainstream society. Introduction – the emergence of the rights-based approach to disability in the EU The main purpose of this chapter is to assess the significance and future potential of the Framework Employment Directive in the specific context of disability. A recent report by the European Foundation for the Improvement of Living and Working Conditions on the status of persons with disabilities in Europe makes for sober reading. It recalls that disability (which it combines with chronic illness) affects 17 per cent of Europe's general population and about 15 per cent of the working population. Disabled people are reported to have twice the rate for non-participation in the labour market as compared to persons without disabilities. The unemployment rate for persons with a severe disability is about three times the level for non-disabled persons. Workers with disabilities typically receive a lower wage than others and segregation is reported to begin at an early age ‘with children often pushed into parallel education networks or otherwise excluded from mainstream society’.

Clustering of related or similar objects has long been regarded as a potentially useful contribution to helping users navigate an information space such as a document collection. When documents are related by virtue of being about the same or similar topics, then this is often a good indicator that they will be relevant to the same queries and this can be used during the retrieval operation. Many clustering algorithms and techniques have been developed and implemented since the earliest days of computational information retrieval but as the sizes of document collections have grown these techniques have not been scaled to large collections because of their computational overhead. In this paper we describe a technique for clustering a collection of documents such as a collection of online newspapers which uses a number of short-cuts to make the process computable for large collections. Furthermore, our design is extensible in that it caters for a dynamic collection of documents which would be periodically, perhaps nightly, updated, amended or have deletions. An implementation of the clustering on an archive of the Irish Times newspaper is reported here.

In this paper we describe Taiscealai, a web-based system which provides content-based retrieval on an up-to-date archive of RTE radio news bulletins. Taiscealai automatically records and indexes news bulletins twice daily using a stream of phones recognised from the raw audio data. A user's typed query is matched against fixed length windows from the broadcasts. A user interface allows the news bulletins most likely to be relevant to be presented and the user to select sub-parts of the bulletins to be played. Many of the parameters we have chosen to use such as the size and amount of overlap of windows and the weighting of phones within those windows, have been determined within the framework of the TREC Spoken Document Retrieval track and are thus well-founded. We conclude the paper with a walkthrough of a worked example retrieval and an outline of our plans for extending Taiscealai into an integrated digital library for news.

Observed differences in corneal response to contact lens wear have been attributed to variations in individual corneal oxygen requirements. Anterior corneal oxygen flux was measured on 100 human eyes using a polarographic oxygen sensor to determine if differences could be measured among subjects. A distribution in corneal epithelial oxygen use was found to exist in the population.

Various membrane materials have been attached to oxygen sensors during measurement of corneal oxygen uptake. Differences in the oxygen solubility characteristics of these membranes directly affect resulting flux values. Human corneal epithelial oxygen uptake values were obtained using an oxygen sensor in conjunction with polyethylene, Teflon, and polypropylene membranes attached to its tip. Conversion coefficients were calculated to relate findings obtained with each membrane-sensor system. New solubility constants were derived for polyethylene, Teflon, and polypropylene based on previous findings obtained with a saline (hydrophilic lens) membrane reservoir.

An experiment that uses an interference paradigm is used to investigate coding processes in the visuo-spatial sketchpad. The results confirm that a spatial interference task involving movement is more disruptive than a visual interference task. In addition, it is shown that the sketchpad is particularly susceptible to interference during the encoding of information while interference has little effect on the maintenance of information.