1,878 research outputs found

    Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5--implications for dementia with Lewy bodies.

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    BackgroundIn dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus.ResultsWe generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells.ConclusionsTogether, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB

    Weaving Together Indigenous and Western Knowledge in Science Education: Reflections and Recommendations

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    The Culturally Responsive Indigenous Science (CRIS) project was a collaborative effort between three Tribal communities in the Pacific Northwest and faculty and students from Washington State University, many of who are Tribal citizens. The project was designed to integrate Indigenous Traditional Ecological Knowledge (ITEK) and Western Knowledge into science curricula and professional learning opportunities. At the end of the 5-year grant project, members of the CRIS team (including Tribal and university partners) gathered to reflect on the work accomplished and the lessons learned about the process of integrating ITEK within science education. In this conceptual paper, the authors discuss four key takeaways from their reflections: 1) Creating relational space for cultural values and practices, 2) Indigenous science education requires many educators with diverse expertise, 3) Respecting Tribal and individual autonomy and timelines, and 4) Remembering who the work is meant to serve. In summary, the authors highlighted important recommendations to be considered when weaving together ITEK and Western science to better serve and engage Native American youth

    Stuck in the Past? Rumination-Related Memory Integration

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    Memories connected to ruminative concerns repetitively capture attention, even in situations designed to alter them. However, recent research on memory updating suggests that memory for benign substitutes (e.g., reinterpretations) might be facilitated by integration with the ruminative memories. As a first approach, two experiments (Ns = 72) mimicked rumination-related memories with rumination-themed stimuli and an imagery task. College undergraduates screened for ruminative status first studied and imaged ruminative cue-target word pairs, and then in a second phase they studied the same cues re-paired with benign targets (along with new and repeated pairs). On the test of cued recall of benign targets, they judged whether each recalled word had been repeated or changed across the two phases (or was new in the second phase). When target changes were not remembered, recall of benign targets revealed proactive interference that was insensitive to ruminative status. However, when participants remembered change and the ruminative targets, their recall of benign targets was facilitated, particularly if they identified as ruminators (Experiment 1). When the test simply asked for recall of either or both targets (Experiment 2), ruminators recalled both targets more frequently than did others. These outcomes suggest that ruminative memories might provide bridges to remembering associated benign memories, such as reinterpretations, under conditions consistent with everyday ruminative retrieval

    Age-dependent effect of APOE and polygenic component on Alzheimer's disease

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    Alzheimer’s disease (AD) is a devastating neurodegenerative condition with significant genetic heritability. Several genes have been implicated in the onset of AD with the apolipoprotein E (APOE) gene being the strongest single genetic risk loci. Evidence suggests that the effect of APOE alters with age during disease progression. Here, we aim to investigate the impact of APOE and other variants outside the APOE region on AD risk in younger and older participants. Using data from both the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the UK Biobank (UKBB) we computed the polygenic risk score (PRS) of each individual informed by the latest genetic study from the International Genomics of Alzheimer’s Project (IGAP). Our analysis showed that the effect of APOE on the disease risk is greater in younger participants and reduces as participant age increases. Our findings indicate the increased impact of PRS as participant age increases. Therefore, AD in older individuals can potentially be triggered by the cumulative effect of genes which are outside the APOE region

    Characterizing the sublethal effects of SmartStax PRO dietary exposure on life history traits of the western corn rootworm, \u3ci\u3e Diabrotica virgifera virgifera\u3c/i\u3e LeConte

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    The western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte, is an economically important pest of field corn (Zea mays L.) across the United States (U.S.) Corn Belt. Repeated use of transgenic hybrids expressing Bacillus thuringiensis (Bt) proteins has selected for field-evolved resistance to all current rootworm-active Bt proteins. The newest product available for WCR management is SmartStax® PRO, a rootworm-active pyramid containing Cry3Bb1, Cry34/35Ab1 [now reclassified as Gpp34Ab1/Tpp35Ab1] and a new mode of action, DvSnf7 dsRNA. Understanding the fitness of adult WCR after dietary exposure to SmartStax® PRO will identify potential impacts on WCR population dynamics and inform efforts to optimize resistance management strategies. Therefore, the objective of the present study was to characterize the effect of SmartStax® PRO dietary exposure on WCR life history traits. Adult WCR were collected during 2018 and 2019 from emergence tents placed over replicated field plots of SmartStax® PRO or non-rootworm Bt corn at a site with a history of rootworm-Bt trait use and suspected resistance to Cry3Bb1 and Cry34/35Ab1. Adult survival was reduced by 97.1–99.7% in SmartStax® PRO plots relative to the non-rootworm Bt corn plots during the study. Individual male/female pairs were fed different diets of ear tissue to simulate lifetime or adult exposure. Life history parameters measured included adult longevity, adult head capsule width, lifetime female egg production, and egg viability. Results indicate that lifetime or adult exposure to SmartStax® PRO significantly reduced adult longevity and lifetime egg production. Larval exposure to SmartStax® PRO significantly reduced WCR adult size. Results from this study collectively suggest that SmartStax® PRO may negatively impact WCR life history traits, which may lead to reduced population growth when deployed in an area with WCR resistance to Bt traits

    Towards refining WCRF/AICR cancer prevention recommendations for red and processed meat intake: Insights from Alberta\u27s Tomorrow Project cohort

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    Current cancer prevention recommendations advise limiting red meat intake to \u3c500g/week and avoiding consumption of processed meat, but do not differentiate the source of processed meat. We examined the associations of processed meat derived from red vs. non-red meats with cancer risk in a prospective cohort of 26,218 adults who reported dietary intake using the Canadian Diet History Questionnaire. Incidence of cancer was obtained through data linkage with Alberta Cancer Registry with median (IQR) follow-up of 13.3 (5.1) years. Multivariable Cox proportional hazards regression models were adjusted for covariates and stratified by age and gender. The median (IQR) consumption (g/week) of red meat, processed meat from red meat and processed meat from non-red meat were 267.9 (269.9), 53.6 (83.3), and 11.9 (31.8), respectively. High intakes (4th Quartile) of processed meat from red meat was associated with increased risk of gastro-intestinal cancer Adjusted Hazard Ratio (AHR) (95% CI): 1.68 (1.09-2.57) and colorectal cancers AHR (95% CI): 1.90 (1.12-3.22), respectively in women. No statistically significant associations were observed for intakes of red meat or processed meat from non-red meat. Results suggests that the carcinogenic effect associated with processed meat intake may be limited to processed meat derived from red meats. The findings provide preliminary evidence toward refining cancer prevention recommendations for red and processed meat intake

    The Affordances and Challenges of Enacting Culturally Relevant STEM Pedagogy

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    In this chapter, the current literature base involving the use of culturally relevant pedagogy (CRP) in elementary STEM classroom settings is reviewed. The review reveals three main categories of how CRP is used in classrooms. These categories are: student engagement and outcomes (SEO), instructional practices and dispositions (IPD), and curricular materials (CM). In the chapter, each of these categories is explained and practical examples are described. Finally, reflections on why some components of CRP, as revealed from the literature review, are enacted more or less frequently are discussed
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