Single-cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer's risk gene mutation.

The R47H missense mutation of the TREM2 gene is a known risk factor for development of Alzheimer's Disease. In this study, we analyze the impact of the Trem2R47H mutation on specific cell types in multiple cortical and subcortical brain regions in the context of wild-type and 5xFAD mouse background. We profile 19 mouse brain sections consisting of wild-type, Trem2R47H, 5xFAD and Trem2R47H; 5xFAD genotypes using MERFISH spatial transcriptomics, a technique that enables subcellular profiling of spatial gene expression. Spatial transcriptomics and neuropathology data are analyzed using our custom pipeline to identify plaque and Trem2R47H-induced transcriptomic dysregulation. We initially analyze cell type-specific transcriptomic alterations induced by plaque proximity. Next, we analyze spatial distributions of disease associated microglia and astrocytes, and how they vary between 5xFAD and Trem2R47H; 5xFAD mouse models. Finally, we analyze the impact of the Trem2R47H mutation on neuronal transcriptomes. The Trem2R47H mutation induces consistent upregulation of Bdnf and Ntrk2 across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and Trem2R47H; 5xFAD mice. Overall, our MERFISH spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and Trem2R47H mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.

Localized Electrochemical Impedance Measurements on Nafion Membranes: Observation and Analysis of Spatially Diverse Proton Transport Using Atomic Force Microscopy.

The distribution of ion conductive channels on the Nafion membrane surface, which determines the formation of the three-phase boundary, plays a very important role in improving the performance of proton-exchange membrane fuel cells. Therefore, understanding the microstructures at the catalyst layer/membrane interfaces of proton-exchange membranes is essential. Although current-sensing atomic force microscopy (AFM) can present some surface conductance data, localized impedance measurement providing more accurate proton-transport information is desirable. To obtain this information, in our study, localized electrochemical impedance spectroscopy was measured automatically with a home-built AFM-electrochemical impedance spectroscopy setup in which AFM was coupled with an impedance tester by a customized procedure. By this method, the localized proton-transport resistance at different humidities was observed in spatially diverse locations, and the value decreased as the membrane became hydrated. Furthermore, the microstructure of the Nafion membrane was numerically reconstructed at different hydration levels to examine the relationship between the membrane microstructural morphology and proton-transport resistance. The results showed that the spatial diversity of proton-transport resistance arose from the variable concentration of hydrophilic groups at the contact location of the AFM tip and the membrane, and from the heterogeneity of dry sulfonic acid groups in the membrane that creates local variation in water content.

Socioeconomic position and self-harm among adolescents: a population-based cohort study in Stockholm, Sweden.

BACKGROUND: Understanding the association between parental socioeconomic position and self-harm in adolescence is crucial due to its substantial magnitude and associated inequality. Most previous studies have been either of cross-sectional nature or based solely on self-reports or hospital treated self-harm. The aim of this study is to determine the association between parental socioeconomic position and self-harm among adolescents with a specific focus on gender and severity of self-harm. METHODS: A total of 165,932 adolescents born 1988-1994 who lived in Stockholm at the age of 13 were followed in registers until they turned 18. Self-harm was defined as first time self-harm and severity of self-harm was defined as hospitalized or not. Socioeconomic position was defined by parental education and household income. Cox proportional hazards regression were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Analyses showed an association between parental socioeconomic position and self-harm. Among adolescents with parents with primary and secondary education compared to tertiary parental education the HR were 1.10 (95% CI 0.97-1.24) and 1.16 (95% CI 1.08-1.25) respectively. Compared to the highest income category, adolescents from the lower income categories were 1.08 (95% CI 0.97-1.22) to 1.19 (95% CI 1.07-1.33) times more likely to self-harm. In gender-stratified analyses, an association was found only among girls. Further, restriction to severe cases eliminated the association. CONCLUSIONS: This study suggested that low parental socioeconomic position is associated with self-harm in adolescence, predominantly among girls. The desertion of an association among severe cases may be explained by differences in suicidal intent and underlying psychiatric diagnosis. Efforts to prevent self-harm should consider children with low parental socioeconomic position as a potential target group.

The Greater Involvement of People Living with AIDS principle: theory versus practice in Ontario's HIV/AIDS community-based research sector.

Drawing on the Greater Involvement of People with HIV/AIDS (GIPA) principle, the HIV/AIDS movement began to "democratize" research in Canada in the mid-1990s. To date, there is little evidence about the success of the community-based research (CBR) movement in relation to the implementation of GIPA. We draw on findings from a larger study examining barriers and facilitating factors in relation to HIV-related CBR in Ontario, Canada. An online survey was completed by 39 senior managers in Ontario AIDS service organizations (ASOs). Twenty-five in-depth, semi-structured interviews were then conducted to further explore the survey findings. Survey respondents reported that, compared to researchers and frontline service providers, people living with HIV/AIDS (PLWHA) tended to be the least involved in all stages (input, process and outcome) of CBR projects. AIDS service organizations with a mandate that included serving rural and urban communities reported even lower levels of PLWHA involvement in CBR. Qualitative data reveal complex barriers that make meaningful PLWHA engagement in CBR difficult, including: HIV-related stigma; health-related challenges; "credentialism"; lack of capacity to engage in research; other issues taking priority; and mistrust of researchers. Facilitating factors included valuing lived experience; training and mentoring opportunities; financial compensation; trust building; and accommodating PLWHA's needs. While there is strong support for the GIPA principles in theory, practice lags far behind.