103 research outputs found
What is the relationship between the situated learning of Unarmed Civilian Protection workers and gendered power dynamics?
This study used a mixed methods, grounded theory approach to investigate the situated learning of Unarmed Civilian Protection (UCP) workers and its relationship to hegemonic gender regimes. It reviews the everyday situated learning of UCP workers in the context of and structures gender and race. UCP is understood as a unique ‘Community of Practice’ subordinate to and nested within the overarching humanitarian infrastructure. The definition and contestation of UCP by different workers and related, fluid dynamics of complicity with and resistance to structural power are explored. The unique contributions to knowledge that this thesis makes are in three key areas: 1/ Firstly this study represents the first, hopefully of many forays into studying UCP via a new critical framing which situates the UCP practice in explicit relation to feminism, gender, identity and other subjectivities, 2/ Within this framing, and especially in the use of feminist care ethics, we can observe how care not only supports and makes possible knowledge creation and sharing, but is itself a form of social reproduction that sustains and ‘makes’ UCP. The differential distribution of the burden of care and knowledge creation in UCP teams demands further attention. This recognition of the centrality of Care to UCP sheds new light on how UCP is practiced and experienced differently by not only men and women but by people of numerous intersecting subjectivities. 3/ Finally this thesis indicates that greater attention to the intersectionality of identities within the UCP community is essential to future scholarship and action around this practice; especially the importance of the eldership of older, more experienced men and women from the Global South, and the embodied knowledge that these elders recognize, carry and share with peers. The findings of this study indicate ways in which UCP practice affects personal behavior, promotes critical reflection on questions of power and identify and that facilitates a diverse range of agency in their gender performance. However UCP is subject to the same structural challenges as other humanitarian work, including the privileging of certain types of white, Eurocentric masculinities and femininities. Unique components of the practice invert the masculinist security paradigm and foreground a radical ethics of care and collective knowing. However UCP practice currently exhibits only limited resistance to the disciplinary power of the technocratic ‘security-development nexus’. This thesis indicates the importance of further research and practice which attends to the intersectionality of identities within the UCP community; especially the importance of the eldership of experienced practitioners. Recommendations include greater attention to and diversity of learning approaches including mentorship and more concerted transnational exchange between practitioners in different countries and continents. These interventions, combined with organizational focusses on retention will consolidate and further the possibilities of agencies from UCP workers that actively embody resistance to dominative hegemonic regimes that normalize colonial, militarized ideals of gender
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Human Stem Cells for Modeling Amyotrophic Lateral Sclerosis Disease Mechanisms and Modifiers
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Although ALS has been extensively studied in post-mortem patient samples and animal models, there are currently no very effective treatments and there is no cure. One reason for the lack of treatment options in ALS may stem from the inaccessibility of living human motor neurons for use in disease research and subsequent therapeutic target validation. Recent developments in the field of stem cell biology can potentially provide access to living human motor neurons from individual ALS patients. It is now possible to derive induced pluripotent stem cells (iPS cells) from the somatic tissues of ALS patients and then to differentiate these iPS cells into motor neurons with the precise genetic makeup of the donor patient (iPS-MNs). Before iPS-MNs can be put to productive use, however, the iPS system as a whole must be validated as a reliable source of motor neurons with characteristics that closely resemble their endogenous or hES-derived counterparts. This thesis will first address a series of issues relating to the validation of iPS cells as a reliable source of motor neurons a then move on to expression profiling studies aimed at identifying a transcriptional signature of ALS in iPS-MNs. I will first describe a collaborative study aimed at determining whether or not iPS cells are as useful as ES cells for the production of motor neurons. By comparing motor neuron differentiation efficiency across a panel of 6 ES lines and 16 iPS lines, we demonstrated that iPS cells are equally capable of producing electrophysiologically active motor neurons as ES cells. Moreover, both ALS and control iPS lines produce motor neurons with equal efficiency, suggesting that iPS cells will be useful in the production of ALS iPS-MNs for disease research. In addition, our results identify some of the variables that contribute to differentiation efficiency, including donor identity and individual iPS/ES line identity. The following section will serve to provide a deeper molecular and electrophysiological understanding of human stem cell-derived motor neurons. I first generated expression profiles from purified hES-MNs to identify potential motor neuron-specific surface markers as well as maturational changes occurring in motor neurons in vitro. Using calcium imaging techniques, I then demonstrated that iPS-MNs behave functionally similarly to ES-MNs and described culture-wide rhythmic depolarizations that are likely influencing multiple properties of iPS-MNs. After characterizing the iPS-MN culture system, I made a first attempt at defining the transcriptional phenotypes of ALS in iPS-MNs. This work relied on the use of a motor neuron-specific lentiviral reporter that I developed to isolate and transcriptionally profile iPS-MNs from two control iPS lines and four ALS iPS lines. I show evidence of significant transcriptional differences between motor neurons isolated from ALS lines and those from control patients. These differences may in the future help to define ALS-specific phenotypes. Lastly, I conducted a meta-analysis comparing transcriptional changes in ALS iPS-MNs to those in existing models of ALS and identified some common stress-related features of ALS in iPS-MNs. In order to form new hypotheses about what sorts of individual patient-specific phenotypes may be present in iPS-MNs, I will then utilize published expression profiles from post-mortem ALS patient motor neurons to identify a previously-overlooked class of genes that exhibit expression levels highly correlated with individual age at ALS onset. This group of 43 onset-correlated genes contains many members with known or hypothesized relationships to neurodegenerative disease. I discuss how onset-correlated genes may function as disease-modifiers or biomarkers and design experiments to investigate these possibilities. Taken together, the work in this thesis will lay the foundations for developing a human iPS-based model of ALS and point toward numerous avenues of future investigation
Online health communities
Abstract Online health communities provide a means for patients and their families to learn about an illness, seek and offer support, and connect with others in similar circumstances. They are supported by a variety of technologies (e.g., email lists, forums, chat rooms) and are hosted by patients, advocacy groups, medical organizations, and corporations. They raise difficult design challenges because of the wide variability of members' medical expertise, the severity of problems due to misinformation, and the need for emotional support. The importance of on-line health communities is evidenced by their popularity, as well as the significant impact they have on the lives of their members. This Special Interest Group (SIG) will explore current trends in online health communities, as well as discuss the socio-technical design challenges and opportunities that they afford
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Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain
Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a “prion-like” spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate—i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau—, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease
3C. 3-Ketosteroid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Steroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [65, 193]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone)
3C. 3-Ketosteroid receptors in GtoPdb v.2021.3
Steroid hormone receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [74, 215, 3]) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (estrone and 17β-estradiol) and 3-ketosteroids (dihydrotestosterone [DHT], aldosterone, cortisol, corticosterone, progesterone and testosterone). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol
Common mouse models of tauopathy reflect early but not late human disease
BACKGROUND: Mouse models that overexpress human mutant Tau (P301S and P301L) are commonly used in preclinical studies of Alzheimer’s Disease (AD) and while several drugs showed therapeutic effects in these mice, they were ineffective in humans. This leads to the question to which extent the murine models reflect human Tau pathology on the molecular level. METHODS: We isolated insoluble, aggregated Tau species from two common AD mouse models during different stages of disease and characterized the modification landscape of the aggregated Tau using targeted and untargeted mass spectrometry-based proteomics. The results were compared to human AD and to human patients that suffered from early onset dementia and that carry the P301L Tau mutation. RESULTS: Both mouse models accumulate insoluble Tau species during disease. The Tau aggregation is driven by progressive phosphorylation within the proline rich domain and the C-terminus of the protein. This is reflective of early disease stages of human AD and of the pathology of dementia patients carrying the P301L Tau mutation. However, Tau ubiquitination and acetylation, which are important to late-stage human AD are not represented in the mouse models. CONCLUSION: AD mouse models that overexpress human Tau using risk mutations are a suitable tool for testing drug candidates that aim to intervene in the early formation of insoluble Tau species promoted by increased phosphorylation of Tau. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-023-00601-y
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