Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy

Neurofibrillary tangles (NFTs) are associated with neuronal loss and correlate with cognitive impairment in Alzheimer disease, but how NFTs relate to neuronal death is not clear. We studied cell death in Tg4510 mice that reversibly express P301L mutant human tau and accumulate NFTs using in vivo multiphoton imaging of neurofibrillary pathology, propidium iodide (PI) incorporation into cells, caspase activation and DNA labeling. We first observed that in live mice a minority of neurons was labeled with the caspase probe or with PI fluorescence. These markers of cell stress were localized in the same cells and appeared to be specifically within NFT-bearing neurons. Contrary to expectations, the PI-stained neurons did not die over a day of observation; the presence of Hoechst-positive nuclei in them on the subsequent day indicated that the NFT-associated membrane disruption suggested by PI staining and caspase activation do not lead to acute death of neurons in this tauopathy model. This unique combination of in vivo multiphoton imaging with markers of cell death and pathologic alteration is a powerful tool for investigating neuronal damage associated with neurofibrillary pathology

Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model

Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and while they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Employing fluorescent in situ hybridization to detect Arc mRNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared to untreated transgenics, restoring enrichment-induced Arc mRNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, while tangles do not preclude neurons from responding in a functional circuit

Model for Prioritizing Best Management Practice Implementation: Sediment Load Reduction

Understanding the best way to allocate limited resources is a constant challenge for water quality improvement efforts. The synoptic approach is a tool for geographic prioritization of these efforts. It uses a benefit-cost framework to calculate indices for functional criteria in subunits (watersheds, counties) of a region and then rank the subunits. The synoptic approach was specifically designed to incorporate best professional judgment in cases where information and resources are limited. To date, the synoptic approach has been applied primarily to local or regional wetland restoration prioritization projects. The goal of this work was to develop a synoptic model for prioritizing watersheds within which suites of agricultural best management practices (BMPs) can be implemented to reduce sediment load at the watershed outlets. The model ranks candidate watersheds within an ecoregion or river basin so that BMP implementation within the highest ranked watersheds will result in the most sediment load reduction per conservation dollar invested. The model can be applied anywhere and at many scales provided that the selected suite of BMPs is appropriate for the evaluation area’s biophysical and climatic conditions. The model was specifically developed as a tool for prioritizing BMP implementation efforts in ecoregions containing watersheds associated with the USDA-NRCS conservation effects assessment project (CEAP). This paper presents the testing of the model in the little river experimental watershed (LREW) which is located near Tifton, Georgia, USA and is the CEAP watershed representing the southeastern coastal plain. The application of the model to the LREW demonstrated that the model represents the physical drivers of erosion and sediment loading well. The application also showed that the model is quite responsive to social and economic drivers and is, therefore, best applied at a scale large enough to ensure differences in social and economic drivers across the candidate watersheds. The prioritization model will be used for planning purposes. Its results are visualized as maps which enable resource managers to identify watersheds within which BMP implementation would result in the most water quality improvement per conservation dollar invested

Images of survival, stories of destruction: Nuclear war on British screens from 1945 to the early 1960s

This article discusses a range of depictions and discussions of nuclear war, which appeared on British screens in the first half of the Cold War, in order to understand the changing way nuclear weapons were viewed within British culture. Using such screened images to understand how nuclear war was constructed and represented within British culture, the article argues that the hydrogen bomb, not the atomic bomb, was the true harbinger of the nuclear revolution that transformed cultural understandings of warfare and destruction. Although the atomic bomb created a great deal of anxiety within British popular culture, representations of atomic attack elided atomic destruction with that experienced in 1939-45, emphasising the 'survivability' of atomic war. In the thermonuclear era, the Second World War could not undertake the same symbolic work. The image of the city-destroying bomb was an imaginative as well as technological step-change. Screened representations stressed that a thermonuclear war would literally end the world. As such, they preceded, and indeed provided the cultural climate for, the rise of the Campaign for Nuclear Disarmament (CND). The Campaign exploited and further popularised this idea of the apocalyptic nuclear war as a key aspect of its political and moral standpoint. The article concludes, however, that the cultural hegemony of this vision of nuclear war equally helped underpin notions of nuclear deterrence. The basic assumptions about the nature of nuclear war constructed and circulated on British screens therefore formed part of CND's 'cultural' victory but the article also explains why this did not translate into the political realm. © Edinburgh University Press

Monitoring international migration flows in Europe. Towards a statistical data base combining data from different sources

The paper reviews techniques developed in demography, geography and statistics that are useful for bridging the gap between available data on international migration flows and the information required for policy making and research. The basic idea of the paper is as follows: to establish a coherent and consistent data base that contains sufficiently detailed, up-to-date and accurate information, data from several sources should be combined. That raises issues of definition and measurement, and of how to combine data from different origins properly. The issues may be tackled more easily if the statistics that are being compiled are viewed as different outcomes or manifestations of underlying stochastic processes governing migration. The link between the processes and their outcomes is described by models, the parameters of which must be estimated from the available data. That may be done within the context of socio-demographic accounting. The paper discusses the experience of the U.S. Bureau of the Census in combining migration data from several sources. It also summarizes the many efforts in Europe to establish a coherent and consistent data base on international migration. The paper was written at IIASA. It is part of the Migration Estimation Study, which is a collaborative IIASA-University of Groningen project, funded by the Netherlands Organization for Scientific Research (NWO). The project aims at developing techniques to obtain improved estimates of international migration flows by country of origin and country of destination

The Democratic Biopolitics of PrEP

PrEP (Pre-Exposure Prophylaxis) is a relatively new drug-based HIV prevention technique and an important means to lower the HIV risk of gay men who are especially vulnerable to HIV. From the perspective of biopolitics, PrEP inscribes itself in a larger trend of medicalization and the rise of pharmapower. This article reconstructs and evaluates contemporary literature on biopolitical theory as it applies to PrEP, by bringing it in a dialogue with a mapping of the political debate on PrEP. As PrEP changes sexual norms and subjectification, for example condom use and its meaning for gay subjectivity, it is highly contested. The article shows that the debate on PrEP can be best described with the concepts ‘sexual-somatic ethics’ and ‘democratic biopolitics’, which I develop based on the biopolitical approach of Nikolas Rose and Paul Rabinow. In contrast, interpretations of PrEP which are following governmentality studies or Italian Theory amount to either farfetched or trivial positions on PrEP, when seen in light of the political debate. Furthermore, the article is a contribution to the scholarship on gay subjectivity, highlighting how homophobia and homonormativity haunts gay sex even in liberal environments, and how PrEP can serve as an entry point for the destigmatization of gay sexuality and transformation of gay subjectivity. ‘Biopolitical democratization’ entails making explicit how medical technology and health care relates to sexual subjectification and ethics, to strengthen the voice of (potential) PrEP users in health politics, and to renegotiate the profit and power of Big Pharma

Food choices and practices during pregnancy of immigrant women with high-risk pregnancies in Canada: a pilot study

Background: Immigrant women may be regarded as a vulnerable population with respect to access and navigation of maternity care services. They may encounter difficulties when accessing culturally safe and appropriate maternity care, which may be further exacerbated by language difficulties and discriminatory practices or attitudes. The project aimed to understand ethnocultural food and health practices and how these intersect in a particular social context of cultural adaptation and adjustment in order to improve the care-giving capacities of health practitioners working in multicultural perinatal clinics. Methods: This four-phase study employed a case study design allowing for multiple means of data collection and different units of analysis. Phase one consists of a scoping review of the literature. Phases two and three incorporate pictorial representations of food choices with semi-structured photo-elicited interviews. This study was undertaken at a Prenatal and Obstetric Clinic, in an urban Canadian city. In phase four, the research team will inform the development of culturally appropriate visual tools for health promotion. Results: Five themes were identified: (a) Perceptions of Health, (b) Social Support (c) Antenatal Foods (d) Postnatal Foods and (e) Role of Health Education. These themes provide practitioners with an understanding of the cultural differences that affect women’s dietary choices during pregnancy. The project identified building collaborations between practitioners and families of pregnant immigrant women to be of utmost importance in supporting healthy pregnancies, along with facilitating social support for pregnant and breastfeeding mothers. Conclusion: In a multicultural society that contemporary Canada is, it is challenging for health practitioners to understand various ethnocultural dietary norms and practices. Practitioners need to be aware of customary practices of the ethnocultural groups that they work with, while simultaneously recognizing the variation within—not everyone follows customary practices, individuals may pick and choose which customary guidelines they follow. What women choose to eat is also influenced by their own experiences, access to particular foods, socioeconomic status, family context, and so on. The pilot study demonstrated the efficacy of the employed research strategies and we subsequently acquired funding for a national study

The selection of comparators for randomized controlled trials of health-related behavioral interventions : recommendations of an NIH expert panel

Funding and logistical support for the expert panel was provided by the National Institutes of Health Office of Behavioral and Social Sciences Research.Peer reviewedPostprin

Propagation of Tau Pathology in a Model of Early Alzheimer's Disease

SummaryNeurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration

Prisoners of the Capitalist Machine: Captivity and the Corporate Engineer

This chapter will focus on how engineering practice is conditioned by an economic system which promotes production for profit and economic growth as an end in itself. As such it will focus on the notion of the captivity of engineering which emanates from features of the economic system. By drawing on Critical Realism and a Marxist literature, and by focusing on the issues of safety and sustainability (in particular the issue of climate change), it will examine the extent to which disasters and workplace accidents result from the economic imperative for profitable production and how efforts by engineers to address climate change are undermined by an on-going commitment to growth. It will conclude by arguing that the structural constraints on engineering practice require new approaches to teaching engineers about ethics and social responsibility. It will argue that Critical Realism offers a framework for the teaching of engineering ethics which would pay proper attention to the structural context of engineers work without eliminating the possibility of engineers working for radical change