MOOCs: When Opening Doors to Education, Institutions Must Ensure That People with Disabilities Have Equal Access

Massive Open Online Courses (“MOOCs”) are free online courses offered by institutions of higher education to individuals across the world, without any admissions criteria. Through web-based courses hosted by MOOC platforms, such as Coursera or edX, student-participants learn by accessing media, including documents, pictures and uploaded lectures on the course website. While MOOCs may make access to education easier for individuals with certain disabilities, their format may render the courses inaccessible to individuals who have vision or hearing impairment. Many individuals with vision impairment use “assistive technology,” such as screen readers and voice recognition software, to use computers and access the Internet. Individuals with hearing impairment, meanwhile, often rely upon captioning when watching videos. Therefore, MOOCs may be inaccessible for individuals with vision or hearing impairment if the websites are not designed to work with assistive technology or if the lectures are not captioned or transcribed. If the MOOC courses are inaccessible to students with certain disabilities, the institutions and/or the platform providers may be found to have violated the Rehabilitation Act of 1973 or the Americans with Disabilities Act (ADA) of 1990

A developmental analysis of juxtavascular microglia dynamics and interactions with the vasculature [preprint]

Microglia, the resident macrophages of the central nervous system (CNS), are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared to older ages and the timing of these associations are dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the prenatal human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages contact vascular areas void of astrocyte endfeet and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted upon the arrival of astrocyte endfeet when juxtavascular microglia then establish a long-term, stable contact with the vasculature

A Developmental Analysis of Juxtavascular Microglia Dynamics and Interactions with the Vasculature

Microglia, a resident CNS macrophage, are dynamic cells, constantly extending and retracting their processes as they contact and functionally regulate neurons and other glial cells. There is far less known about microglia-vascular interactions, particularly under healthy steady-state conditions. Here, we use the male and female mouse cerebral cortex to show that a higher percentage of microglia associate with the vasculature during the first week of postnatal development compared with older ages and that the timing of these associations is dependent on the fractalkine receptor (CX3CR1). Similar developmental microglia-vascular associations were detected in the human brain. Using live imaging in mice, we found that juxtavascular microglia migrated when microglia are actively colonizing the cortex and became stationary by adulthood to occupy the same vascular space for nearly 2 months. Further, juxtavascular microglia at all ages associate with vascular areas void of astrocyte endfeet, and the developmental shift in microglial migratory behavior along vessels corresponded to when astrocyte endfeet more fully ensheath vessels. Together, our data provide a comprehensive assessment of microglia-vascular interactions. They support a mechanism by which microglia use the vasculature to migrate within the developing brain parenchyma. This migration becomes restricted on the arrival of astrocyte endfeet such that juxtavascular microglia become highly stationary and stable in the mature cortex. SIGNIFICANCE STATEMENT We report the first extensive analysis of juxtavascular microglia in the healthy, developing, and adult brain. Live imaging revealed that juxtavascular microglia within the cortex are highly motile and migrate along vessels as they are colonizing cortical regions. Using confocal, expansion, super-resolution, and electron microscopy, we determined that microglia associate with the vasculature at all ages in areas lacking full astrocyte endfoot coverage and motility of juxtavascular microglia ceases as astrocyte endfeet more fully ensheath the vasculature. Our data lay the fundamental groundwork to investigate microglia-astrocyte cross talk and juxtavascular microglial function in the healthy and diseased brain. They further provide a potential mechanism by which vascular interactions facilitate microglial colonization of the brain to later regulate neural circuit development

Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNF signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls

BACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society

International medical graduates in family medicine in the United States of America: an exploration of professional characteristics and attitudes

BACKGROUND: The number of international medical graduates (IMGs) entering family medicine in the United States of America has steadily increased since 1997. Previous research has examined practice locations of these IMGs and their role in providing care to underserved populations. To our knowledge, research does not exist comparing professional profiles, credentials and attitudes among IMG and United States medical graduate (USMG) family physicians in the United States. The objective of this study is to determine, at the time when a large influx of IMGs into family medicine began, whether differences existed between USMG and IMG family physicians in regard to personal and professional characteristics and attitudes that may have implications for the health care system resulting from the increasing numbers of IMGs in family medicine in the United States. METHODS: This is a secondary data analysis of the 1996–1997 Community Tracking Study (CTS) Physician Survey comparing 2360 United States medical graduates and 366 international medical graduates who were nonfederal allopathic or osteopathic family physicians providing direct patient care for at least 20 hours per week. RESULTS: Compared to USMGs, IMGs were older (p < 0.001) and practised in smaller (p = 0.0072) and younger practices (p < 0.001). Significantly more IMGs practised in metropolitan areas versus rural areas (p = 0.0454). More IMG practices were open to all new Medicaid (p = 0.018) and Medicare (p = 0.0451) patients, and a greater percentage of their revenue was derived from these patients (p = 0.0020 and p = 0.0310). Fewer IMGs were board-certified (p < 0.001). More IMGs were dissatisfied with their overall careers (p = 0.0190). IMGs and USMGs did not differ in terms of self-rated ability to deliver high-quality care to their patients (p = 0.4626). For several of the clinical vignettes, IMGs were more likely to order tests, refer patients to specialists or require office visits than USMGs. CONCLUSION: There are significant differences between IMG and USMG family physicians' professional profiles and attitudes. These differences from 1997 merit further exploration and possible follow-up, given the increased proportion of family physicians who are IMGs in the United States

Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR

Pretreatment Engineering Platform Phase 1 Final Test Report

Pacific Northwest National Laboratory (PNNL) was tasked by Bechtel National Inc. (BNI) on the River Protection Project, Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to conduct testing to demonstrate the performance of the WTP Pretreatment Facility (PTF) leaching and ultrafiltration processes at an engineering-scale. In addition to the demonstration, the testing was to address specific technical issues identified in Issue Response Plan for Implementation of External Flowsheet Review Team (EFRT) Recommendations - M12, Undemonstrated Leaching Processes.( ) Testing was conducted in a 1/4.5-scale mock-up of the PTF ultrafiltration system, the Pretreatment Engineering Platform (PEP). Parallel laboratory testing was conducted in various PNNL laboratories to allow direct comparison of process performance at an engineering-scale and a laboratory-scale. This report presents and discusses the results of those tests

Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the prometastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy

MOOCs: When Opening Doors to Education, Institutions Must Ensure That People with Disabilities Have Equal Access

Massive Open Online Courses (“MOOCs”) are free online courses offered by institutions of higher education to individuals across the world, without any admissions criteria. Through web-based courses hosted by MOOC platforms, such as Coursera or edX, student-participants learn by accessing media, including documents, pictures and uploaded lectures on the course website. While MOOCs may make access to education easier for individuals with certain disabilities, their format may render the courses inaccessible to individuals who have vision or hearing impairment. Many individuals with vision impairment use “assistive technology,” such as screen readers and voice recognition software, to use computers and access the Internet. Individuals with hearing impairment, meanwhile, often rely upon captioning when watching videos. Therefore, MOOCs may be inaccessible for individuals with vision or hearing impairment if the websites are not designed to work with assistive technology or if the lectures are not captioned or transcribed. If the MOOC courses are inaccessible to students with certain disabilities, the institutions and/or the platform providers may be found to have violated the Rehabilitation Act of 1973 or the Americans with Disabilities Act (ADA) of 1990