Search

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope–immunofluorescence pipeline and high-dimensional MERFISH. We also leverage our dataset as a classification resource, finding that induced pluripotent stem cell model systems capture substantial in vivo heterogeneity. Finally, we identify and validate compounds that recapitulate certain subtypes in vitro, including camptothecin, which downregulates the signature of disease-enriched subtypes and upregulates a signature previously associated with Alzheimer’s disease.

This paper presents a personal view (a view coloured by my cultural environment and upbringing) of young people's education. I look in particular at assessment practices and detail my understanding of the nature of learning, focusing on creativity and the tensions associated with schooling and creative behaviour. Drawing upon and developing my earlier work in the light of further research and experience, I give an overview of assessment practices and approaches to teaching and learning and argue for a learner‐centred approach with a focus on practical work and an environment that promotes creative problem‐solving across the whole curriculum. A pedagogical strategy is presented that is based on four areas of activity: reacting, researching, responding, and reflecting.

The classification of adenohypophysial neoplasms as “pituitary neuroendocrine tumors” (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

Atypical intraductal cribriform proliferations of the prostate (AIP) are loose cribriform proliferations of luminal cells that exhibit greater architectural complexity and/or nuclear atypia than high-grade prostatic intraepithelial neoplasia (HGPIN), but lack the diagnostic criteria for intraductal carcinoma (IDC). The significance of AIP has not been formally established. We compared the clinical, morphologic, and immunohistochemical characteristics of AIP with classic IDC in 310 radical prostatectomy specimens that were received over an 18-month period. Of the 310 cases, 46 cases had AIP only (n=10), IDC only (n=6), or AIP coexisting with IDC (n=30). The ERG status of all 46 AIP/IDC cases was identical to the nearby acinar carcinoma, contrasted to just 3 cases of HGPIN (7%, P<0.01). The degree of uniform phosphatase and tensin homolog (PTEN) loss in 34 selected cases was identical in AIP and IDC (66.7%). No foci of HGPIN showed uniform PTEN loss; there was only 38% concordance of PTEN expression pattern between HGPIN and the nearby acinar carcinoma, unlike AIP and IDC (77% and 81%, respectively, P<0.01). AIP-associated and/or IDC-associated carcinoma (n=46) showed a higher stage and grade compared with acinar-only carcinoma (n=264, P<0.01). AIP-associated carcinoma had similar clinicopathologic features as IDC-associated carcinoma, including preoperative prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis (n=36, P>0.05). In conclusion, AIP shares similar ERG/PTEN immunoprofiles and exhibits similar clinical behavior as IDC, warranting immediate repeat biopsy when AIP is identified on biopsy, as is recommended in the most recent WHO Classification of Tumours of the Urinary System and Male Genital Organs, 2016.

Malignancies involving the central nervous system present unique challenges for diagnosis and monitoring due to the difficulties and risks of direct biopsies and the low specificity and/or sensitivity of other techniques for assessment. In recent years, liquid biopsy of the cerebrospinal fluid (CSF) has emerged as a convenient alternative that combines minimal invasiveness with the ability to detect disease-defining or therapeutically actionable genetic alterations from circulating tumor DNA (ctDNA). Since CSF can be obtained by lumbar puncture, or an established ventricular access device at multiple time points, ctDNA analysis enables initial molecular characterization and longitudinal monitoring throughout a patient's disease course, promoting optimization of treatment regimens.

AbstractUsing the different voices of the mentor and mentee, we engage with the notion of creating and conferring aesthetic significance as it occurs in the everyday lives of everyday peoples. We investigate how the arts empower marginalized ‘voice’ by enabling multimodal expressions and access to information that other methods may not elicit. This article takes the form of a ‘duography’, reporting an empirical study that focused upon an Adi Jan Jaati or Particularly Vulnerable Tribal Group (PVTG) of Jharkhand, in north-eastern India. In particular, we focus upon this indigenous community’s epistemic and aesthetic practices. The article thus offers discussions on how aesthetic experiences and activities are essential means of being, of engagement and communication, and of (re)building trust with the community. We conclude by demonstrating the relevance of everyday aesthetics for the development of sustainable educational systems and future citizenship. Standing back, we acknowledge the reciprocal learning that occurs between the researcher and the ‘researched’, the doctoral student and supervisor.

Alzheimer disease (AD) represents one of the greatest medical challenges of this century; the condition is becoming increasingly prevalent worldwide and no effective treatments have been developed for this terminal disease. Because the disease manifests at a late stage after a long period of clinically silent neurodegeneration, knowledge of the modifiable risk factors and the implementation of biomarkers is crucial in the primary prevention of the disease and presymptomatic detection of AD, respectively. This article discusses the growing epidemic of AD and antecedent risk factors in the disease process. Disease biomarkers are discussed, and the implications that this may have for the treatment of this currently incurable disease.

AbstractThis article aims to address a number of interrelated issues concerning criteria for arts-based research. We start by responding to current discussions and debates over criteria, with a tacit goal of redefining the nature and goal of emerging visions of doing qualitative-oriented research. After reviewing some emerging frameworks for judging qualitative-oriented research and arts-based studies, we explore the prospect of integrating poetic elements into visual inquiry. This feeds into our suggestion of poetic-visual inquiry as a form of arts-based research, which we elaborate through three existing studies. In relation to this, we raise tension and care as two keys for thinking through researchers’ consciousness when carrying out arts-based research.

AbstractThe reference to ‘whippet-fancying’ in the title refers to the notion of connoisseurship; teachers, who best know their students’ abilities, play the part of the connoisseur. Procrustean references, when applied to education, refer to the tendency to trim the curriculum according to the prevailing assessment practices. There appears to have been a tendency in many developed countries to de-professionalize the profession of teaching, nowhere more so than in the area of assessment, with external examining boards making decisions about students’ capabilities. Such tendencies are felt particularly harshly in the arts. This article argues for assessment practices in visual art that are student-centred and that take the form of a dialogue between teacher and student, taking into account the developing nature of a student’s portfolio. I argue further that meaningful learning in art should not be pre-specified, and that the objectives model of teaching and learning is inappropriate, given our innate need to create and confer aesthetic significance.

Increasingly, engagement in the arts is believed to have the ability to address the challenges faced during adolescence and effect change beyond the scope of developing technical skills or aesthetic understanding. The purpose of this article is to review the literature on the benefits of arts engagement and self-efficacy: specifically its relation to the experiences of adolescent females. We will begin by providing a rationale for the focus on adolescent females by reviewing the role of self-efficacy in the developmental needs of adolescent women. Following this will be a review of the literature on youth engagement in the arts focusing on the potential positive outcomes on the affective domain. We argue that self-efficacy is fundamental for the positive development of young women and that within the context of arts education research further investigation into the relationship between arts engagement and self-efficacy is needed.

Carcinosarcoma of the anus is rare and has yet to be reportedly associated with the keratinocyte-specific Human Papilloma Virus (HPV). We describe a case of anal carcinosarcoma with HPV infection in both the epithelial and mesenchymal components of the tumor by immunohistochemistry, chromogenic in-situ hybridization (CISH) and further supported by electron microscopy (EM). Microscopic examination of the tumor showed nests of poorly-differentiated invasive squamous cell carcinoma with basaloid features intermixed with a hypercellular, atypical spindle cell proliferation. Immunohistochemistry demonstrated that the epithelial component was positive for AE1/AE3, p63, CK5/6 and p16, whilst the mesenchymal component was positive for smooth muscle actin, vimentin, and focally positive for desmin and p16, consistent with carcinosarcoma. The tumor was negative for GATA-3, CK7 and CK20. CISH demonstrated that the tumor was positive for high risk HPV (subtype 16/18) in both tumor components. EM further supported the presence of intracellular virus particles (~50nm) that is compatible with HPV infection. Infection of both epithelial and mesenchymal tumor components by HPV has not been previously observed in the gastrointestinal tract. This finding may represent initial epithelial HPV infection with subsequent divergent tumoral differentiation and suggests the presence of viral replication in both biphasic tumor components.

This paper draws on an analysis of case studies from the line of research that examines contractual and working relationships in the aerospace industry (Cullen, Keast and Simpson, 2002; Cullen, Hickman, 2001; Cullen, 2005). These studies found a divergence between the parties’ intended working relationship and the agenda prescribed by formal contracts. The paper proposes that the ramifications of the contractual arrangements engender strains between the dynamic nature of collaborative transactions and the laissez-faire presumption of conflictual relations that underpins western commercial contract law, which in turn influences contractual relations and formal agreements.

Art education in Singapore has evolved over a number of years to cater for the educational needs and aspirations of modern Singaporeans. This evolution is paralleled by the development of a new art syllabus for secondary schools and new In-Service and Pre-Service art education courses at the Institute of Education (IE). This paper seeks to locate current trends in Singaporean art education within a broad cultural context. The training of specialist art teachers for the secondary sector will be discussed against this background.

Several letters to the editor are presented in response to previous articles such as reactor sizes, reactor design, a reduction in carbon emissions worldwide by 2050, and storage of spent nuclear fuel.