Whole‐brain microscopy reveals distinct temporal and spatial efficacy of anti‐Aβ therapies

Many efforts targeting amyloid-β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-Aβ treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to β-secretase inhibitors, polythiophenes, or anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance, with polythiophenes emerging as a potent anti-Aβ compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aβ therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aβ plaques. This may also contribute to the clinical trial failures of Aβ-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition. Keywords: Alzheimer's disease; amyloid-beta; brain; light-sheet microscopy; tissue clearin

The materiality of digital media: The hard disk drive, phonograph, magnetic tape and optical media in technical close-up

Popular discourses surrounding contemporary digital media often misrepresent it as immaterial and ephemeral, overlooking the material devices that store and generate our media objects. This article materially ‘descends’ into a selection of prior media forms that make up the genealogy of the hard disk drive (HDD) to challenge our reliance on conceptual misrepresentations. This material analysis is used to situate digital media in a genealogy of prior media forms, to enrich our understanding of how media’s affordances arise from the interplay of both formal and forensic materiality and to demonstrate the value of reintegrating materiality back into the study of media

Alert but less alarmed: a pooled analysis of terrorism threat perception in Australia

<p>Abstract</p> <p>Background</p> <p>Previous Australian research has highlighted disparities in community perceptions of the threat posed by terrorism. A study with a large sample size is needed to examine reported concerns and anticipated responses of community sub-groups and to determine their consistency with existing Australian and international findings.</p> <p>Methods</p> <p>Representative samples of New South Wales (NSW) adults completed terrorism perception questions as part of computer assisted telephone interviews (CATI) in 2007 (N = 2081) and 2010 (N = 2038). Responses were weighted against the NSW population. Data sets from the two surveys were pooled and multivariate multilevel analyses conducted to identify health and socio-demographic factors associated with higher perceived risk of terrorism and evacuation response intentions, and to examine changes over time.</p> <p>Results</p> <p>In comparison with 2007, Australians in 2010 were significantly more likely to believe that a terrorist attack would occur in Australia (Adjusted Odd Ratios (AOR) = 1.24, 95%CI:1.06-1.45) but felt less concerned that they would be directly affected by such an incident (AOR = 0.65, 95%CI:0.55-0.75). Higher perceived risk of terrorism and related changes in living were associated with middle age, female gender, lower education and higher reported psychological distress. Australians of migrant background reported significantly lower likelihood of terrorism (AOR = 0.52, 95%CI:0.39-0.70) but significantly higher concern that they would be personally affected by such an incident (AOR = 1.57, 95%CI:1.21-2.04) and having made changes in the way they live due to this threat (AOR = 2.47, 95%CI:1.88-3.25). Willingness to evacuate homes and public places in response to potential incidents increased significantly between 2007 and 2010 (AOR = 1.53, 95%CI:1.33-1.76).</p> <p>Conclusion</p> <p>While an increased proportion of Australians believe that the national threat of terrorism remains high, concern about being personally affected has moderated and may reflect habituation to this threat. Key sub-groups remain disproportionately concerned, notably those with lower education and migrant groups. The dissonance observed in findings relating to Australians of migrant background appears to reflect wider socio-cultural concerns associated with this issue. Disparities in community concerns regarding terrorism-related threat require active policy consideration and specific initiatives to reduce the vulnerabilities of known risk groups, particularly in the aftermath of future incidents.</p

The materiality of the intangible: Literary metaphor in multimodal texts

Based on a larger practice-based research project in digital writing, this article examines how the materiality of digital media contributes to a layered metaphor that delivers meaning, reflects on the cognitive processes (the writer’s and the reader’s) of navigation and generates a dynamic narrative structure through multimodality, unnatural narration and user interaction. Many writers and artists engage with their chosen medium through an instinctive understanding of the materials at hand, gained through experience; the explicit study of a medium’s materiality is not always required for artistic success, however, that may be judged. This article offers insights into the creative process of creating digital, multimodal fiction, based on a practice-based research project designed to explore the effects of digital media on author and text, and argues that digital media have a significant effect on the outcome of the artefact itself. Awareness of these effects, their variations according to hardware and software, and the affordances of these various materials offer the digital writer greater insight and capability to craft his/her texts for the desired metaphorical meaning

How Digital Are the Digital Humanities? An Analysis of Two Scholarly Blogging Platforms

In this paper we compare two academic networking platforms, HASTAC and Hypotheses, to show the distinct ways in which they serve specific communities in the Digital Humanities (DH) in different national and disciplinary contexts. After providing background information on both platforms, we apply co-word analysis and topic modeling to show thematic similarities and differences between the two sites, focusing particularly on how they frame DH as a new paradigm in humanities research. We encounter a much higher ratio of posts using humanities-related terms compared to their digital counterparts, suggesting a one-way dependency of digital humanities-related terms on the corresponding unprefixed labels. The results also show that the terms digital archive, digital literacy, and digital pedagogy are relatively independent from the respective unprefixed terms, and that digital publishing, digital libraries, and digital media show considerable cross-pollination between the specialization and the general noun. The topic modeling reproduces these findings and reveals further differences between the two platforms. Our findings also indicate local differences in how the emerging field of DH is conceptualized and show dynamic topical shifts inside these respective contexts

Psychotherapy in historical perspective

This article will briefly explore some of the ways in which the past has been used as a means to talk about psychotherapy as a practice and as a profession, its impact on individuals and society, and the ethical debates at stake. It will show how, despite the multiple and competing claims about psychotherapy’s history and its meanings, historians themselves have, to a large degree, not attended to the intellectual and cultural development of many therapeutic approaches. This absence has the potential consequence of implying that therapies have emerged as value-free techniques, outside of a social, economic and political context. The relative neglect of psychotherapy, by contrast with the attention historians have paid to other professions, particularly psychiatry, has also underplayed its societal impact. This article will foreground some of the instances where psychotherapy has become an object of emerging historical interest, including the new research that forms the substance of this special issue of History of the Human Sciences

Barriers to disseminating brief CBT for voices from a lived experience and clinician perspective

Access to psychological therapies continues to be poor for people experiencing psychosis. To address this problem, researchers are developing brief interventions that address the specific symptoms associated with psychosis, i.e., hearing voices. As part of the development work for a brief Cognitive Behaviour Therapy (CBT) intervention for voices we collected qualitative data from people who hear voices (study 1) and clinicians (study 2) on the potential barriers and facilitators to implementation and engagement. Thematic analysis of the responses from both groups revealed a number of anticipated barriers to implementation and engagement. Both groups believed the presenting problem (voices and psychosis symptoms) may impede engagement. Furthermore clinicians identified a lack of resources to be a barrier to implementation. The only facilitator to engagement was reported by people who hear voices who believed a compassionate, experienced and trustworthy therapist would promote engagement. The results are discussed in relation to how these barriers could be addressed in the context of a brief intervention using CBT techniques

The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

BACKGROUND: The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. METHODS: In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. RESULTS: Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. CONCLUSION: Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases