Synapse loss is well regarded as the underlying cause for the progressive decline of memory function over the course of Alzheimer's disease (AD) development. Recent observations suggest that the accumulation of the Wnt antagonist Dickkopf-1 (Dkk1) in the AD brain plays a critical role in triggering synaptic degeneration. Mechanistically, Dkk1 cooperates with Kremen1 (Krm1), its transmembrane receptor, to block the Wnt/β-catenin signaling pathway. Here, we show that silencing Krm1 with miR-431 prevents amyloid-β-mediated synapse loss in cortico-hippocampal cultures isolated from triple transgenic 3xTg-AD mice. Exposure to AβDDL (an amyloid-β derived diffusive ligand) or Dkk1 reduced the number of pre- and post-synaptic puncta in primary neuronal cultures, while treatment with miR-431 prevented synapse loss. In addition, treatment with miR-431 also prevented neurite degeneration. Our findings demonstrate that miR-431 protects synapses and neurites from Aβ-toxicity in an AD cell culture model and may be a promising therapeutic target.
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Background Drug overdose mortality is rising precipitously among Black people who use drugs. In NYC, the overdose mortality rate is now highest in Black (38.2 per 100,000) followed by the Latinx (33.6 per 100,000) and white (32.7 per 100,000) residents. Improved understanding of access to harm reduction including naloxone across racial/ethnic groups is warranted. Methods Using data from an ongoing study of people who use illicit opioids in NYC (N = 575), we quantified racial/ethnic differences in the naloxone care cascade. Results We observed gaps across the cascade overall in the cohort, including in naloxone training (66%), current possession (53%) daily access during using and non-using days (21%), 100% access during opioid use (20%), and complete protection (having naloxone and someone who could administer it present during 100% of opioid use events; 12%). Naloxone coverage was greater in white (training: 79%, possession: 62%, daily access: 33%, access during use: 27%, and complete protection: 13%, respectively) and Latinx (training: 67%, possession: 54%, daily access: 22%, access during use: 24%, and complete protection: 16%, respectively) versus Black (training: 59%, possession: 48%, daily access:13%, access during use: 12%, and complete protection: 8%, respectively) participants. Black participants, versus white participants, had disproportionately low odds of naloxone training (OR 0.40, 95% CI 0.22–0.72). Among participants aged 51 years or older, Black race (versus white, the referent) was strongly associated with lower levels of being trained in naloxone use (OR 0.20, 95% CI 0.07–0.63) and having 100% naloxone access during use (OR 0.34, 95% CI 0.13–0.91). Compared to white women, Black women had 0.27 times the odds of being trained in naloxone use (95% CI 0.10–0.72). Conclusions There is insufficient protection by naloxone during opioid use, with disproportionately low access among Black people who use drugs, and a heightened disparity among older Black people and Black women.
In this article we describe the process of an interdisciplinary case study that examined the social contexts of occupational and general health disparities among health care workers in two sets of New England hospitals and nursing homes. A political economy of the work environment framework guided the study, which incorporated dimensions related to market dynamics, technology, and political and economic power. The purpose of this article is to relate the challenges encountered in occupational health care settings and how these could have impacted the study results. An innovative data collection matrix that guided small-group analysis provided a firm foundation from which to make design modifications to address these challenges. Implications for policy and research include the use of a political and economic framework from which to frame future studies, and the need to maintain rigor while allowing flexibility in design to adapt to challenges in the field.
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