A familial missense variant in the Alzheimer's disease gene SORL1 impairs its maturation and endosomal sorting.

The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset > 75 years. All offspring were affected with AD with ages at onset ranging from 53 years to 74 years. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.

Race, gender, and scholarly impact: Disparities for women and faculty of color in clinical psychology.

OBJECTIVE: We sought to determine if gender and race are associated with scientific impact, scholarly productivity, career advancement, and prestige. METHODS: Publicly available data on publications, h-index, advancement, and prestige were assessed across core faculty in all American Psychological Association-accredited clinical psychology programs at R1 institutions in the United States (87 programs, 918 scientists). RESULTS: There were significant effects of both gender and race on productivity and impact, which were most apparent among the most senior faculty. Men and white faculty in associate and full professor ranks had higher scholarly productivity and impact. Among associate professors, men were more likely to get tenure earlier, even when controlling for scientific impact (h-index). Neither gender nor race was associated with prestige among full professors. CONCLUSION: These findings, along with under-representation of non-White faculty across levels (11.2%) and women at the full professor level (42.8%), suggest disparities in academic clinical psychology that must be addressed.

'We are all in this together': Investigating alignments in intersectoral partnerships dedicated to K-12 food literacy education.

BACKGROUND: Activities to foster food literacy in young people are increasingly common in schools, driven both by the public health sector and by curriculum mandates from education officials in government. In Canada, both Kindergarten-Grade 12 (K-12) classroom teachers and educators from community organisations deliver food literacy education programmes in schools, often framed as partnerships working in the interests of young people. OBJECTIVE: The study examines the alignment between what both classroom teachers and community educators state are the desired outcomes for students of their food literacy education work and the topics/activities they engage in with students. DESIGN SETTING AND METHOD: We surveyed and interviewed teachers and community educators in British Columbia, Canada, and utilised participant observation and secondary data from food literacy education network activities. RESULTS: Shared food literacy education goals and topics/activities were evident in the responses of classroom teachers and community educators. Teachers framed their food literacy education programmes around the curriculum-as-plan - in this case, the provincial curriculum known as the BC Curriculum - and then enacted a lived curriculum that students experienced in the classroom. Community educators offered programmes that were initially designed to meet their organisation's focus, but which varied in terms of how much of the BC Curriculum was addressed. CONCLUSION: Our results show broad alignment between teachers and community educators in food literacy education goals and practices; however, there is potential to increase this alignment and build stronger partnerships that support teachers in enacting the BC curriculum and meeting the needs of their students.

Proteomics-Metabolomics Combined Approach Identifies Peroxidasin as a Protector against Metabolic and Oxidative Stress in Prostate Cancer.

Peroxidasin (PXDN), a human homolog of Drosophila PXDN, belongs to the family of heme peroxidases and has been found to promote oxidative stress in cardiovascular tissue, however, its role in prostate cancer has not been previously elucidated. We hypothesized that PXDN promotes prostate cancer progression via regulation of metabolic and oxidative stress pathways. We analyzed PXDN expression in prostate tissue by immunohistochemistry and found increased PXDN expression with prostate cancer progression as compared to normal tissue or cells. PXDN knockdown followed by proteomic analysis revealed an increase in oxidative stress, mitochondrial dysfunction and gluconeogenesis pathways. Additionally, Liquid Chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomics confirmed that PXDN knockdown induced global reprogramming associated with increased oxidative stress and decreased nucleotide biosynthesis. We further demonstrated that PXDN knockdown led to an increase in reactive oxygen species (ROS) associated with decreased cell viability and increased apoptosis. Finally, PXDN knockdown decreased colony formation on soft agar. Overall, the data suggest that PXDN promotes progression of prostate cancer by regulating the metabolome, more specifically, by inhibiting oxidative stress leading to decreased apoptosis. Therefore, PXDN may be a biomarker associated with prostate cancer and a potential therapeutic target.

Contraceptive Use Among Women Experiencing Intimate Partner Violence and Reproductive Coercion: The Moderating Role of PTSD and Depression.

Women experiencing reproductive coercion (RC) report more unintended pregnancies and mental health symptoms that can influence contraceptive use patterns. We examined associations between RC and contraceptive use among intimate partner violence (IPV) exposed women aged 18-35 (N = 283). We tested depression, post-traumatic stress disorder (PTSD), and co-morbid depression and PTSD as effect modifiers. Though no association was found between RC and contraception, PTSD significantly modified this relationship. Among Black women (n = 112), those reporting RC and either PTSD or comorbid PTSD and depression were less likely to use partner-independent contraception compared to those reporting RC without mental health symptoms. PTSD could be a barrier to contraceptive choice among this population.

What Is a School Farm? Results of a Scoping Review.

As school farms become more prominent programs to teach food education, research is needed to support school farms' implementation and sustainability. This scoping review included 94 articles on school farms from three bibliometric databases covering broad international literature. Vocational agricultural training, animal husbandry, and crop production were common characteristics of school farms across 103 years of publications. Themes of sustainability, healthy eating, and food systems were more prominent in recent literature. Peer-reviewed studies (1985-2019) provided some empirical research showing school farms' impact on students. This review discusses school farms' structures and objectives as promising food education and production programming.

A familial missense variant in the Alzheimer's Disease gene SORL1 impairs its maturation and endosomal sorting.

The SORL1 gene has recently emerged as a strong Alzheimer's Disease (AD) risk gene. Over 500 different variants have been identified in the gene and the contribution of individual variants to AD development and progression is still largely unknown. Here, we describe a family consisting of 2 parents and 5 offspring. Both parents were affected with dementia and one had confirmed AD pathology with an age of onset >75 years. All offspring were affected with AD with ages at onset ranging from 53yrs-74yrs. DNA was available from the parent with confirmed AD and 5 offspring. We identified a coding variant, p.(Arg953Cys), in SORL1 in 5 of 6 individuals affected by AD. Notably, variant carriers had severe AD pathology, and the SORL1 variant segregated with TDP-43 pathology (LATE-NC). We further characterized this variant and show that this Arginine substitution occurs at a critical position in the YWTD-domain of the SORL1 translation product, SORL1. Functional studies further show that the p.R953C variant leads to retention of the SORL1 protein in the endoplasmic reticulum which leads to decreased maturation and shedding of the receptor and prevents its normal endosomal trafficking. Together, our analysis suggests that p.R953C is a pathogenic variant of SORL1 and sheds light on mechanisms of how missense SORL1 variants may lead to AD.

Mechanistic insights gained from cell and molecular analysis of the neuroprotective potential of bioactive natural compounds in an immortalized hippocampal cell line.

Evaluating novel compounds for neuroprotective effects in animal models of traumatic brain injury (TBI) is a protracted, labor-intensive and costly effort. However, the present lack of effective treatment options for TBI, despite decades of research, shows the critical need for alternative methods for screening new drug candidates with neuroprotective properties. Because natural products have been a leading source of new therapeutic agents for human diseases, we used an in vitro model of stretch injury to rapidly assess pro-survival effects of three bioactive compounds, two isolated from natural products (clovanemagnolol [CM], vinaxanthone [VX]) and the third, a dietary compound (pterostilbene [PT]) found in blueberries. The stretch injury experiments were not used to validate drug efficacy in a comprehensive manner but used primarily, as proof-of-principle, to demonstrate that the neuroprotective potential of each bioactive agent can be quickly assessed in an immortalized hippocampal cell line in lieu of comprehensive testing in animal models of TBI. To gain mechanistic insights into potential molecular mechanisms of neuroprotective effects, we performed a pathway-specific PCR array analysis of the effects of CM on the rat hippocampus and microRNA sequencing analysis of the effects of VX and PT on cultured hippocampal progenitor neurons. We show that the neuroprotective properties of these natural compounds are associated with altered expression of several genes or microRNAs that have functional roles in neurodegeneration or cell survival. Our approach could help in quickly assessing multiple natural products for neuroprotective properties and expedite the process of new drug discovery for TBI therapeutics.

SNAIL Transctiption factor in prostate cancer cells promotes neurite outgrowth.

Neurite outgrowth involves reciprocal signaling interactions between tumor cells and nerves where invading tumor cells have acquired the ability to respond to pro-invasive signals within the nerve environment. Neurite outgrowth could serve as a mechanism leading to invasion of cancer cells into the nerve sheath and subsequent metastasis. Snail transcription factor can promote migration and invasion of prostate cancer cells. We hypothesized that prostate cancer cell interaction with nerve cells will be mediated by Snail expression within prostate cancer cells. For this study we utilized various prostate cancer cell lines: C4-2 non-silencing (NS, control); C4-2 Snail shRNA, (stable Snail knockdown); LNCaP Neo (empty vector control) and LNCaP Snail (stably over-expressing Snail). Cancer cell adhesion and migration towards nerve cells (snF96.2 or NS20Y) was examined by co-culture assays. Conditioned media (CM) collected from C4-2 cells was cultured with nerve cells (PC-12 or NS20Y) for 48 h followed by qualitative or quantitative neurite outgrowth assay. Our results showed that cancer cells expressing high levels of Snail (LNCaP Snail/C4-2 NS) displayed significantly higher migration adherence to nerve cells, compared to cells with lower levels of Snail (LNCaP Neo/C4-2 Snail shRNA). Additionally, LNCaP Snail or C4-2 NS (Snail-high) CM led to a higher neurite outgrowth compared to the LNCaP Neo or C4-2 Snail shRNA (Snail-low). In conclusion, Snail promotes migration and adhesion to nerve cells, as well as neurite outgrowth via secretion of soluble factors. Therefore, targeting cancer cell interaction with nerves may contribute to halting prostate cancer progression/metastasis.