Investigating directed differentiation strategies in hiPSCs to model cell type-specific vulnerability in ALS

The concept of vulnerability is highly relevant to neurodegenerative diseases, whereby specific subsets of neurons display marked and devastating disease-related pathologies, but neighbouring cells may not. Amyotrophic lateral sclerosis (ALS) provides a perfect example, where spinal pathology manifests in lower motor neurons (MNs), with neighbouring cells remaining relatively unaffected, at least until late-stage disease. Interestingly, spinal MNs display selective vulnerability, with larger and more heavily myelinated alpha motor neurons degenerating the earliest. Additionally, the role of cell types surrounding MNs in contributing to ALS pathogenesis have become more evident over recent years. This includes non-cell-autonomous toxicity mediated by astrocytes and the denervation of Renshaw interneurons (INs) from MNs. Subsequent elucidation of mechanisms underlying cell type-specific vulnerability in ALS would drastically improve our understanding of ALS, the spectrum of cell types affected and provide alternative and tractable cellular targets for therapeutic intervention. The advent of human induced pluripotent stem cells (hiPSCs) has revolutionised disease modelling, providing a virtually inexhaustible source of patient-specific material. As a consequence, a variety of cell types has been generated using ontogeny-driven directed differentiation strategies. However, there is a pressing need for deeper phenotyping and further refinement of differentiation strategies, in order to generate more enriched and disease-relevant populations. With this in mind, I employed an established hiPSC-derived MN protocol and manipulated extrinsic signalling cues during two distinct developmental phases; patterning and terminal differentiation. In this manner, I was able to induce post-mitotic motor columnar diversity, resulting in the specification of lateral motor column phenotype; highly susceptible to degeneration in ALS. Separately, I was able to generate hiPSC-derived dorsal spinal INs arising from dI4-6, which subserve pain, temperature, itch and touch sensations (dI4&5) or indeed those regulating left-right coordination (dI6). Importantly, these INs retain the same axial identity, but are positioned more dorsally in the absence of sonic hedgehog signalling. Lastly, hiPSC-derived INs and MNs were investigated in a valosin-containing protein (VCP) mutant model of ALS. This revealed key differences relating to cell type vulnerability between MNs and INs, including RNA binding protein mislocalisation and alternative splicing events. Overall, the results of this PhD present novel ontogeny-driven directed differentiation strategies of hiPSC-derived cell types and a robust platform for modelling mechanisms of selective vulnerability in ALS. The experiments contained herein also demonstrate that iPSC models can capture neuronal subtype-selective vulnerability

Are income-related differences in active travel associated with physical environmental characteristics? A multi-level ecological approach

Background: Rates of active travel vary by socio-economic position, with higher rates generally observed among less affluent populations. Aspects of both social and built environments have been shown to affect active travel, but little research has explored the influence of physical environmental characteristics, and less has examined whether physical environment affects socio-economic inequality in active travel. This study explored income-related differences in active travel in relation to multiple physical environmental characteristics including air pollution, climate and levels of green space, in urban areas across England. We hypothesised that any gradient in the relationship between income and active travel would be least pronounced in the least physically environmentally-deprived areas where higher income populations may be more likely to choose active transport as a means of travel.<p></p> Methods: Adults aged 16+ living in urban areas (n = 20,146) were selected from the 2002 and 2003 waves of the UK National Travel Survey. The mode of all short non-recreational trips undertaken by the sample was identified (n = 205,673). Three-level binary logistic regression models were used to explore how associations between the trip being active (by bike/walking) and three income groups, varied by level of multiple physical environmental deprivation.<p></p> Results: Likelihood of making an active trip among the lowest income group appeared unaffected by physical environmental deprivation; 15.4% of their non-recreational trips were active in both the least and most environmentally-deprived areas. The income-related gradient in making active trips remained steep in the least environmentally-deprived areas because those in the highest income groups were markedly less likely to choose active travel when physical environment was ‘good’, compared to those on the lowest incomes (OR = 0.44, 95% CI = 0.22 to 0.89).<p></p> Conclusions: The socio-economic gradient in active travel seems independent of physical environmental characteristics. Whilst more affluent populations enjoy advantages on some health outcomes, they will still benefit from increasing their levels of physical activity through active travel. Benefits of active travel to the whole community would include reduced vehicle emissions, reduced carbon consumption, the preservation or enhancement of infrastructure and the presentation of a ‘normalised’ behaviour

Place, space, and health inequalities

No abstract available

The discipline’s escalating whisper: Social work and black men’s mental health.

http://deepblue.lib.umich.edu/bitstream/2027.42/117270/1/29. Watkins Hawkins Mitchell, 2014.pdfDescription of 29. Watkins Hawkins Mitchell, 2014.pdf : Main articl

Factors associated with cancer family history communication between African American men and their relatives

http://deepblue.lib.umich.edu/bitstream/2027.42/117265/1/Cancer family history communicaton 2013 JMS.pdfDescription of Cancer family history communicaton 2013 JMS.pdf : Main articl

Older, church-going African Americans’ attitudes and expectations about formal depression care

Journal articleThis phenomenological study involved focus groups with church-affiliated, African American women and men (N ¼ 50; ages 50 and older) in southeast Michigan to determine their attitudes and expectations around formal mental health care. Data analysis employed a constant comparative approach and yielded themes related to formal mental health care, along with delineating concerns about defining depression, health, and well-being. Health and wellbeing were defined as inclusive of physical and spiritual aspects of self. Churches have a central role in how formal mental health care is viewed by their attendees, with prayer being an important aspect of this care. Provider expectations included privacy and confidentiality; respect for autonomy and need for information, having providers who discuss treatment options; and issues related to environmental cleanliness, comfort, and accessibility. Implications include providing effective, culturally tailored formal depression care that acknowledges and integrates faith for this group.Michigan Center for Urban African American Aging ResearchNational Institutes of Health, 5P30 AG015281Program for Positive Aging at the University of Michigan Department of PsychiatryPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152349/1/Wharton Watkins Mitchell Kales 2018 Older Church going African Americans attitudes and expectations about formal depression care.pd