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The Ministry of Education and Culture (MEC) has traditionally been considered as the most central actor and the powerhouse in the education policy field in Finland. While the position of the MEC in the Finnish education policy system seems stable, there have been several organisational changes within the MEC over the past three decades. One of these is the disintegration of the committee system and its replacement by the working groups system, a trend that is part of a more general change from governing to governance since the 1990s. In this chapter we analyse data containing the MEC’s working groups and their members with social network analysis in order to understand the ways in which the working group system affects the MEC and its operation. Our analysis suggests that the MEC is organised rather strongly by departments: early childhood and general education, vocational education and training, higher education and research, culture and arts, and youth and sports. Analysing the network through the individual working group members we observed that, in addition to public officials, individuals representing interest organisations such as labour and trade unions were important links between the working groups.

PurposeThis study aims to investigate the dispositions of early career teacher educators as young academics toward sustainability and accountability for sustainability issues. Through their interpretations, concerns, awareness and ownership of sustainability, the study portrays how a global phenomenon is articulated specifically within the local context of teachers colleges in Turkey.Design/methodology/approachThe study was designed as a survey, and the data were collected through a cross-sectional online questionnaire. The sample (n = 72) was limited, through purposeful sampling, to early career teacher educators teaching and being trained in well-established Turkish teachers colleges to become prospective faculty members of newly founded teachers colleges across the country. The data were analyzed primarily through quantitative methods. For the analyses, STATA software was used to perform descriptive and inferential statistics.FindingsThe general results indicated that the participants were highly concerned about sustainability problems. However, their concerns were not reflected to the same degree on their perceived awareness and ownership of education for sustainable development (ESD). Hunger and poverty, loss of biodiversity, climate change and epidemic diseases were all perceived to be urgent more in the global context. On the other hand, unemployment, refugees and terrorism were perceived to be locally urgent problems. Different agencies within the community were addressed to be accountable for different types of sustainability problems. The accountability for economic, environmental and societal problems were mainly placed on governments. Additionally, individuals/families and educators were held more accountable for environmental issues, while corporations and super powers were held more accountable for economic issues. As for societal issues, educators, individuals/families and non-governmental organizations were addressed to be more responsible.Originality/valueThe significance of the study is mainly twofold. If sustainable development is conceptualized with a futuristic viewpoint that attaches a great importance to next generations' needs, focusing on the dispositions of early career teacher educators as young academics is a reasonable way of addressing the current gaps and eliminating the future inefficacies. Building on the assumption that ESD would remain imperfect without the commitment of teacher educators who have the potential to bring changes in educational systems and shape knowledge and skills of future teachers, in turn future generations; this study becomes even more valuable as it includes specifically the academicians in the field of teacher education.

Background/context One of the most prominent educational social movements in the United States during the past two decades has been the opt-out movement, in which parents and caregivers refuse to have their school-aged children sit for federally mandated tests. Although early responses by government officials framed the movement in terms of race, class, and gender, in truth we know little about the actual motivations that drive opt-out activists. We also know little about the extent to which the movement was affected by recent seismic changes in the political and policy spheres (e.g., the election of Donald J. Trump and the collapse of the Common Core State Standards). Purpose/objective In this study, we build on social movements theories to examine who was opting out and why, as well as whether these participants or their motivations changed over time. By doing so, we seek to build upon the existing literature by synthesizing the two primary theoretical perspectives on social movements and activism—uniting the focus on the social psychological determinants of individual activism with the focus on the role of external factors. Research design Our analysis is based on data from two waves of the National Survey on Opting Out. The first survey was conducted from January 20 to March 31, 2016 (n = 1,611); the second was conducted from March 7 to May 18, 2018 (n =1,298). The National Survey asked respondents to indicate the main reasons or motivations for their participation in the movement. With these data we use descriptive statistics and multivariate analysis to examine the extent to which participant motivations changed between 2016 and 2018. As part of this process we also examine the association between sociodemographic backgrounds and motivations. Findings/results The results of our analysis show both stability and change in the opt-out movement between 2016 and 2018. Although the data reveal certain sociodemographic changes in the composition of the movement, these changes in demographics do not fully account for shifts in activist motivations over time. We also find that much of the variation in motivation across key social categories (e.g., political ideology, teachers/nonteachers, and parents/nonparents) holds over time. Conclusions/discussion In contrast to common perceptions of the opt-out movement, which often portray parental concerns over their child's achievement as the predominant motivation for participation, our study reveals that activists in the movement indicate they are motivated by political and ethical ideas. Participants in the opt-out movement are more concerned with collective problems, such as the well-being of teachers, broad curriculum, and privatization of public education, than with individual challenges. Given the massive changes that took place in the political and policy spheres during our period of study, the degree to which activist motivation stayed constant is notable—suggesting that many of these motivations are insulated from politics.

Although interest in ESE policy studies is on the rise, we argue there is a gap in scholarship about the nature and extent of interactions between policymakers and researchers in the ESE field. Thi...

Author(s): Alcalay, Roy N; Wolf, Pavlina; Chiang, Ming Sum Ruby; Helesicova, Karolina; Zhang, Xiaokui Kate; Merchant, Kalpana; Hutten, Samantha J; Scherzer, Clemens; Caspell-Garcia, Chelsea; Blauwendraat, Cornelis; Foroud, Tatiana; Nudelman, Kelly; Gan-Or, Ziv; Simuni, Tanya; Chahine, Lana M; Levy, Oren; Zheng, Dandi; Li, Gen; Sardi, Sergio Pablo; Parkinson’s Progression Markers Initiative | Abstract: ObjectiveReduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsWe measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, nn=n392; controls, nn=n175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing.ResultsFifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, nn=n20; controls, nn=n5), activity was significantly lower in PD carriers than control carriers (9.53nµmol/L/h vs. 11.68nµmol/L/h, Pn=n0.035). Glucocerebrosidase activity was moderately (rn=n0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time.InterpretationGCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

Background/ContextGovernment support for higher education has decreased over the past few decades. In turn, institutions are seeking alternative sources of funding and increasing reliance on alumni giving. Although trust is important to social institutions and nonprofits, we know little about the role of trust in alumni engagement.Purpose/Objective/Research Question/Focus of StudyWe empirically assess the association between trust and philanthropic giving. We aim to determine the effectiveness of using trust as a predictor for giving attitudes and behavior. More specifically, we seek to answer the following research questions: 1. To what extent does trust in alma mater vary across socio-demographic characteristics? 2. To what extent does trust in alma mater correlate with alumni engagement (self-reported behavior and attitudes) with philanthropic giving? 3. Does the strength of the association between trust in alma mater and alumni engagement hold after controlling for socio-demographic characteristics?Population/Participants/SubjectsData for this study came from the National Alumni Giving Experiment (NAGE) conducted in 2014 (n=1,553). The NAGE survey instrument was designed as a web-based, self-administered questionnaire, with attitudinal items developed based on previous research and common practices in public opinion research. Respondents were recruited and paid via Amazon's Mechanical Turk (MTurk). The NAGE sample is comparable with the General Social Survey's (2012/2014) college educated sample.Research DesignWe used a sequential mixed-methods research design (QUAN > qual). In the first stage, which is the main portion our study, we employed multivariate analysis to examine (a) socio-demographic variations in trust in alma mater, and (b) the correlations between trust and philanthropic giving. In the second stage, we coded and analyzed open-ended responses. We analyzed the quantitative and qualitative data separately, but we connect the findings to produce a comprehensive analysis of the role of trust in philanthropic giving to higher education.Findings/ResultsWe found that alumni trust is a strong predictor of self-reported giving and attitudes, even after accounting for socio-demographic characteristics. Analysis of open-ended responses suggests that alumni develop (dis)trust based on public discourse on higher education and their personal perceptions and observations of their alma maters’ institutional policies and spending.Conclusions/RecommendationsTrust is granted by individuals to others and to institutions. However, institutions cannot take trust for granted. Institutions of higher education must continually earn the trust of their constituents through creating transparent practices and educating students and alumni about funding, assuring them that they have measures in place to track and implement donor wishes.

This chapter discusses the theoretical and methodological foundations of the research project. Drawing on research in social network analysis and sociology of knowledge, this chapter explains how bibliometric network analysis can be applied to examine the architecture of policy knowledge in the five Nordic countries. Key concepts such as networks, nodes, edges, centrality, and density are defined, and the rationale and procedures for collecting, analyzing, and presenting data are described in detail. This chapter also acknowledges the limitations in its methodological approach and proposes the direction for future studies.

Significance Misfolding and accumulation of the protein α-synuclein (αS) inside nerve cells characterize Parkinson’s disease (PD) and related brain diseases, for which no disease-modifying therapies exist. Robust cell models are needed that recapitulate abnormal αS folding/accumulation in real time, especially for compound screening. We took advantage of the engineered αS “3K” (E35K+E46K+E61K) mutation, which amplifies the familial PD-causing E46K and readily forms round inclusions. We rescued the inclusions with known αS modulators and then screened a ∼2,000-compound library. We identified the potential therapeutic target stearoyl-CoA desaturase; its inhibition cleared αS inclusions, in accord with the effects of conditioning in saturated fatty acids. We propose a model for how fatty acids serve as key modulators of cellular αS homeostasis., Microscopy of Lewy bodies in Parkinson’s disease (PD) suggests they are not solely filamentous deposits of α-synuclein (αS) but also contain vesicles and other membranous material. We previously reported the existence of native αS tetramers/multimers and described engineered mutations of the αS KTKEGV repeat motifs that abrogate the multimers. The resultant excess monomers accumulate in lipid membrane-rich inclusions associated with neurotoxicity exceeding that of natural familial PD mutants, such as E46K. Here, we use the αS “3K” (E35K+E46K+E61K) engineered mutation to probe the mechanisms of reported small-molecule modifiers of αS biochemistry and then identify compounds via a medium-throughput automated screen. αS 3K, which forms round, vesicle-rich inclusions in cultured neurons and causes a PD-like, l-DOPA–responsive motor phenotype in transgenic mice, was fused to YFP, and fluorescent inclusions were quantified. Live-cell microscopy revealed the highly dynamic nature of the αS inclusions: for example, their rapid clearance by certain known modulators of αS toxicity, including tacrolimus (FK506), isradipine, nilotinib, nortriptyline, and trifluoperazine. Our automated 3K cellular screen identified inhibitors of stearoyl-CoA desaturase (SCD) that robustly prevent the αS inclusions, reduce αS 3K neurotoxicity, and prevent abnormal phosphorylation and insolubility of αS E46K. SCD inhibition restores the E46K αS multimer:monomer ratio in human neurons, and it actually increases this ratio for overexpressed wild-type αS. In accord, conditioning 3K cells in saturated fatty acids rescued, whereas unsaturated fatty acids worsened, the αS phenotypes. Our cellular screen allows probing the mechanisms of synucleinopathy and refining drug candidates, including SCD inhibitors and other lipid modulators.

Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed. Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome. Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Background Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered. Methods GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used. Results Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9–3.8, p Conclusion Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.

In this editorial, the authors situate the opt-out movement in the broader context of resistance to the global educational reform movement and its specific playing out in the USA in relation to the opt-out movement. The editors review the 11 articles and commentary and discuss the contributions of the collection as a whole to the literature. They note the contribution of the special issue to the literature on the application of social movement theory to educational politics and the literature on resistance to the global education reform movement.

Organizational networks shape education policy by influencing power holders and elites, but do they have similar effects on grassroots activists? We use data from the National Survey on Opting Out (2016 and 2018; n = 2,909) to examine the role of organizational networks in mobilizing activists in the opt-out movement (a movement in which parents and caregivers refuse to have their children sit for standardized tests). Despite characterizations of the opt-out movement as a bunch of “soccer moms” disappointed with their children’s test scores, our findings show that opt-out is in fact a structured movement reliant on social movement organizations (SMOs) with agendas that go beyond standardized tests. Further, we demonstrate a small but significant correlation between contact with SMOs and individual policy preferences. These patterns suggest that organizational networks may inform education policy by creating a social space for activists to learn about different policy ideas in education. We discuss implications for research and practice.

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).MethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.ResultsNo biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28–0.82, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.ConclusionsOur results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

Portugal is one of the most egalitarian countries in Europe in terms of lesbian, gay, bisexual, transgender, and intersex (LGBTI) individuals’ legal rights. However, regarding education Portugal still lacks specific policies, plans and interventions to protect LGBTI students. To assess the perceptions of self-identified LGBTI youth regarding their school context, a total of 663 participants (aged from 15 to 20 years old) filled in an on-line questionnaire about their school climate. One hundred and forty-six of them answered an open-ended question about their personal experiences. A thematic analysis of these answers was conducted, and four main categories were identified: (i) victimization, (ii) coming out experiences, (iii) support networks, and (iv) demands. Most participants reported experiences of discrimination, and several sources of prejudice were identified. Furthermore, participants also recognized a lack of LGBTI information in school curriculum and made several demands. Besides inclusive laws, we suggest that the safety and the well-being of LGBTI youths in Portuguese schools depend upon others measures, such as teacher and school staff training, curricula inclusive of LGBTI diversity, and local strategies, such as Gay-Straight Alliances.

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann–Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31–0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

This policy study examines how policymakers and policy experts in Norway made us of research and studies – produced in Norway, in the Nordic countries and outside the Nordic region – to explain the 2020 incremental school reform. In total, 2 White Papers, 12 Green Papers and 3438 texts, cited in the White and Green Papers, were used as data for the text-based social network analysis. The three major findings were the following: First, the policymakers and experts make excessive use of references (on average, 246 references per White or Green Paper). The publications they cite are highly specialized and issue centred with little overlap between the various papers. Second, the policy references for the 2020 reform were mainly domestic. Approximately 70% of the referenced texts were published in Norway. Finally, the social network analysis enabled the authors to identify five texts that were influential and that bridged curriculum with quality monitoring reform topics. The authors suggest that more attention should be paid to an analysis of incremental reforms such as the 2020 reform in Norway. They identify a few of the blind spots that the more commonly used focus on fundamental reforms tends to produce.

One of the overarching goals of international large-scale assessments (ILSA) is to inform public discourse about the quality of education different countries. To fulfill this function, the Organisation for Economic Co-operation and Development (OECD), for example, raises awareness of the Program for International Student Assessment (PISA) results through different forms of traditional and social media (e.g., press releases and other activities under the slogan PISA Day). Scholars have responded to the rapid growth of ILSA by examining public discourse through newspapers articles, policy documents, and other outlets. However, we know very little about whether and to what extent the general public is actually affected by PISA results. This article expands the range of stakeholders that engage with PISA by exploring public opinion. Specifically, the study uses data regarding public trust in education from the 2011 wave of the International Social Survey Program (ISSP). Drawing on survey data from 30 countries and Hierarchical Linear Models (HLM), the study shows that PISA ranking have a significant effect on public perceptions. After taking into account gross domestic product (GDP), we find that in high performing countries the general public expresses higher levels of confidence in the education system. We discuss these patterns in the context of growing politization of education policy making and the use of ILSA as evidence.

The aim of this special issue, “Learning Assessments for Sustainability?”, is to examine the interaction between the environmental and sustainability education (ESE) movement and the international large-scale assessments (ILSAs) movement. Both global educational movements emerged in the 1960s and their simultaneous work have affected each other since then. While the articles in this special issue highlight the potential benefits of ILSAs as a source of data for secondary analysis, they also demonstrate the limitations of ILSAs and their negative consequences to ESE. As such, we call for more research on the interaction between ESE and ILSAs and for a serious consideration of how test-based accountability practices might work against meaningful engagement with ESE. This introductory article includes three sections. The first section provides context about the movements. The second section presents an overview of the articles and alternative ways for reading them. The third section discusses lessons learned from the collection of articles. We conclude with a call for further research and reflection.

Mutations in the E3 ubiquitin ligase parkin are the most common known cause of autosomal recessive parkinsonism. Multiple types of stress decrease parkin protein levels, an effect that may be relevant to sporadic Parkinson's disease (PD), but the mechanism(s) involved in this loss remain largely unclear. We sought to elucidate these mechanisms using a PD-relevant stressor, L-DOPA, the precursor to dopamine, which forms reactive oxygen species (ROS) as well as toxic quinones via auto-oxidation. We find that L-DOPA causes parkin loss through both an oxidative stress-independent and an oxidative stress-dependent pathway. Characterization of the latter reveals that it requires both the kinase PINK1 and parkin's interaction with phosphorylated ubiquitin (phospho-Ub) and is mediated by proteasomal degradation. Surprisingly, mitochondrial parkin activity and autoubiquitination as well as mitophagy are not required for such loss. During stress induced by the oxidative stressor hydrogen peroxide or the metabolic uncoupler CCCP, parkin degradation also requires its association with phospho-Ub, indicating that this mechanism is broadly generalizable. As oxidative stress, metabolic dysfunction and phospho-Ub levels are all elevated in PD patients, we suggest that these changes may lead to the loss of parkin expression in PD.

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of late-onset PD (LOPD) patients.MethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 PD patients and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.ResultsNo bi-allelic carriers of rare VPS13C variants were found among patients and two carriers of compound heterozygous variants were found in two controls. There was no statistically significant burden of rare (MAFVPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V (OR=0.48, 95%CI=0.28-0.82, p=0.0052). This haplotype was not in linkage disequilibrium (LD) with the known genome-wide association study (GWAS) top hit.ConclusionsOur results do not support a role for rare heterozygous or bi-allelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

International audience; Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD.Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed.Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome.Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Importance There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). Objectives To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Design, Setting, and Participants This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Interventions Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. Main Outcomes and Measures The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson’s Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. Results At baseline, mean (SD) participants’ age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P Conclusions and Relevance While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. Trial Registration ClinicalTrials.gov Identifier:NCT03205488

Ellen Greenblatt's (2010) Serving LGBTIQ Library and Archives Users: Essays on Outreach, Service, Collections, and Access extends previous work on ways to make libraries and archives more inclusive and friendly places. This edited collection provides deeper understanding of how libraries and archives engage lesbian, gay, bisexual, transgender, intersex, and queer/questioning (LGBTIQ) resources and related research services and new directions for this engagement in the 21st century.

The H1 haplotype of the microtubule-associated protein tau gene (MAPT) is associated with an increased risk of Parkinson disease (PD) compared with the H2 haplotype, but its effect on Lewy body (LB) formation is unclear. In this study, we compared the MAPT haplotype frequency between pathologically confirmed PD patients (n = 71) and controls (n = 52). We analyzed Braak LB stage, Braak neurofibrillary tangle (NFT) stage, and CERAD amyloid score by haplotype. We further tested the association between MAPT haplotype and semi-quantitative counts of LBs, NFTs, and neuritic plaques (NPs) in multiple neocortical regions. Consistent with previous reports, PD cases had an increased likelihood of carrying an H1/H1 genotype compared to controls (OR = 5.72, 95 % CI 1.80–18.21, p = 0.003). Braak LB, Braak NFT and CERAD scores did not differ by haplotype. However, H1/H1 carriers had higher LB counts in parietal cortex (p = 0.02) and in overall neocortical LBs (p = 0.03) compared to non-H1/H1 cases. Our analyses suggest that PD patients homozygous for the H1 haplotype have a higher burden of neocortical LB pathology.

We explore how social safety nets shape the utilization of services in a free health care clinic. Sociological research demonstrates that social interactions greatly influence decision making and help-seeking behaviors. However, little is known about the role of community-based organizations (CBOs) in this process and whether the effect of social safety nets varies across different types of services. Using original survey data from 1,044 patients at a free health care clinic, we find clear evidence that one’s social safety net, comprising CBOs and health-related discussion network ties, significantly affects the utilization of specialty care. Patients who are embedded in a social safety net are more likely than others to use these types of services. Importantly, this pattern does not hold for a patient’s use of primary care services. Our findings emphasize the importance of further examining the role of social safety nets, once access to health care is guaranteed.

There has been increasing international attention to the experiences of lesbian, gay, bisexual, and transgender (LGBT) students in schools, and a growing concern regarding anti-LGBT violence and bias directed at youth as a serious human rights issue and barrier to global development goals. This special issue highlights research that has been done with and/or by nongovernmental organizations and provides a global perspective on the experiences of LGBT students. These articles provide insight into school climate for LGBT students in different country contexts but also on the efficacy of interventions on behalf of these youth (e.g., anti-bullying policies, educator professional development, awareness campaigns). Furthermore, this special issue demonstrates the multiple roles that research has played within advocacy communities working to create safer and more affirming school experiences for LGBT youth.

This article examines the school experience of lesbian, gay, bisexual, and transgender (LGBT) students in the United States and Israel. Through comparison of the sociocultural and educational contexts, the authors assess whether school experience of LGBT students differs or operates similarly across countries. The authors use data from the National School Climate Survey conducted in 2007 in the United States and the Israeli School Climate Survey conducted in 2008 in Israel. In comparison with their Israeli counterparts, LGBT students in the United States were more likely to experience assault and harassment in schools but were more likely to have access to LGBT supportive resources in their schools. Results from multivariate analysis show that negative school climate affect absenteeism and school belonging similarly for both countries. Journal of LGBT Youth

BACKGROUND AND PURPOSE: Absent or diminished α-galactosidase A (GLA) and acid alpha-glucosidase (GAA) enzyme activity are core features of Fabry and Pompe disease, respectively. Patients with Fabry or Pompe disease may have dilated intracranial arteries, but whether lower GLA or GAA enzyme activity relates to brain arterial dilatation in other populations is unknown. METHODS: Participants included Parkinson’s disease patients and non-blood-related controls, whose GLA and GAA enzymatic activities were measured in dried blood spots. Independent readers measured the axial arterial diameter of the ascending portion of the cavernous internal carotid arteries and the most proximal segment of the basilar artery in T2 black voids. Linear regression models were built to investigate the relationship between brain arterial diameters and lysosomal enzymatic activities. RESULTS: The cohort included 107 participants (mean age 66.5±10.3, 67% men). In an adjusted linear regression model, lower GLA activity was associated with larger brain arterial diameters (B=0.50 ± 0.23, P=0.03). The strength of association was the greatest for the basilar artery diameter (B=0.80 ± 0.33, P=0.02). Similarly, lower GAA activity was associated with increased basilar arterial diameter (B=0.73 ± 0.35, P=0.04). CONCLUSION: Lower GLA and GAA enzymatic activities were associated with larger brain arterial diameters, particularly the basilar artery diameter. Lower lysosomal enzymatic function in patients without Fabry or Pompe disease may play a role in brain arterial dilatation.

Reduced function of parkin appears to be a central pathogenic event in Parkinson disease (PD). Increasing parkin levels enhances survival in models of PD-related neuronal death and is a promising therapeutic objective. Previously, we demonstrated that the transcription factor ATF4 promotes survival in response to PD-mimetic stressors by maintaining parkin levels. ATF4 translation is up-regulated by phosphorylation of the translation initiation factor eIF2α. The small molecule guanabenz enhances eIF2α phosphorylation by blocking the function of GADD34, a regulatory protein that promotes eIF2α dephosphorylation. We tested the hypothesis that guanabenz, by inhibiting GADD34 and consequently increasing eIF2α phosphorylation and elevating ATF4, would improve survival in models of PD by up-regulating parkin. We found that GADD34 is strongly induced by 6-OHDA, and that GADD34 localization is dramatically altered in dopaminergic substantia nigra neurons in PD cases. We further demonstrated that guanabenz attenuates 6-hydroxydopamine (6-OHDA) induced cell death of differentiated PC12 cells and primary ventral midbrain dopaminergic neurons in culture, and of dopaminergic neurons in the substantia nigra of mice. In culture models, guanabenz also increases eIF2α phosphorylation and ATF4 and parkin levels in response to 6-OHDA. Furthermore, if either ATF4 or parkin is silenced, then the protective effect of guanabenz is lost. We also found similar results in a distinct model of neuronal death: primary cultures of cortical neurons treated with the topoisomerase I inhibitor camptothecin, in which guanabenz limited camptothecin-induced neuronal death in an ATF4- and parkin-dependent manner. In summary, our data suggest that guanabenz and other GADD34 inhibitors could be used as therapeutic agents to boost parkin levels and thereby slow neurodegeneration in PD and other neurodegenerative conditions.

Akt kinases are key signaling components in proliferation-competent and post-mitotic cells. Here, we sought to create a conditionally-inducible form of active Akt for both in vitro and in vivo applications. We fused a ligand-responsive Destabilizing Domain (DD) derived from E. coli dihydrofolate reductase to a constitutively active mutant form of Akt1, Akt(E40K). Prior work indicated that such fusion proteins may be stabilized and induced by a ligand, the antibiotic Trimethoprim (TMP). We observed dose-dependent, reversible induction of both total and phosphorylated/active DD-Akt(E40K) by TMP across several cellular backgrounds in culture, including neurons. Phosphorylation of FoxO4, an Akt substrate, was significantly elevated after DD-Akt(E40K) induction, indicating the induced protein was functionally active. The induced Akt(E40K) protected cells from apoptosis evoked by serum deprivation and was neuroprotective in two cellular models of Parkinson's disease (6-OHDA and MPP+ exposure). There was no significant protection without induction. We also evaluated Akt(E40K) induction by TMP in mouse substantia nigra and striatum after neuronal delivery via an AAV1 adeno-associated viral vector. While there was significant induction in striatum, there was no apparent induction in substantia nigra. To explore the possible basis for this difference, we examined DD-Akt(E40K) induction in cultured ventral midbrain neurons. Both dopaminergic and non-dopaminergic neurons in the cultures showed DD-Akt(E40K) induction after TMP treatment. However, basal DD-Akt(E40K) expression was 3-fold higher for dopaminergic neurons, resulting in a significantly lower induction by TMP in this population. Such findings suggest that dopaminergic neurons may be relatively inefficient in protein degradation, a property that could relate to their lack of apparent DD-Akt(E40K) induction in vivo and to their selective vulnerability in Parkinson's disease. In summary, we generated an inducible, biologically active form of Akt. The degree of inducibility appears to reflect cellular context that will inform the most appropriate applications for this and related reagents.

Parkinson9s disease (PD) is characterized by the progressive loss of select neuronal populations, but the prodeath genes mediating the neurodegenerative processes remain to be fully elucidated. Trib3 (tribbles pseudokinase 3) is a stress-induced gene with proapoptotic activity that was previously described as highly activated at the transcriptional level in a 6-hydroxydopamine (6-OHDA) cellular model of PD. Here, we report that Trib3 immunostaining is elevated in dopaminergic neurons of the substantia nigra pars compacta (SNpc) of human PD patients. Trib3 protein is also upregulated in cellular models of PD, including neuronal PC12 cells and rat dopaminergic ventral midbrain neurons treated with 6-OHDA, 1-methyl-4-phenylpyridinium (MPP + ), or α-synuclein fibrils (αSYN). In the toxin models, Trib3 induction is substantially mediated by the transcription factors CHOP and ATF4. Trib3 overexpression is sufficient to promote neuronal death; conversely, Trib3 knockdown protects neuronal PC12 cells as well as ventral midbrain dopaminergic neurons from 6-OHDA, MPP + , or αSYN. Mechanism studies revealed that Trib3 physically interacts with Parkin, a prosurvival protein whose loss of function is associated with PD. Elevated Trib3 reduces Parkin expression in cultured cells; and in the SNpc of PD patients, Parkin levels are reduced in a subset of dopaminergic neurons expressing high levels of Trib3. Loss of Parkin at least partially mediates the prodeath actions of Trib3 in that Parkin knockdown in cellular PD models abolishes the protective effect of Trib3 downregulation. Together, these findings identify Trib3 and its regulatory pathways as potential targets to suppress the progression of neuron death and degeneration in PD. SIGNIFICANCE STATEMENT Parkinson9s disease (PD) is the most common neurodegenerative movement disorder. Current treatments ameliorate symptoms, but not the underlying neuronal death. Understanding the core neurodegenerative processes in PD is a prerequisite for identifying new therapeutic targets and, ultimately, curing this disease. Here, we describe a novel pathway involving the proapoptotic protein Trib3 in neuronal death associated with PD. These findings are supported by data from multiple cellular models of PD and by immunostaining of postmortem PD brains. Upstream, Trib3 is induced by the transcription factors ATF4 and CHOP; and downstream, Trib3 interferes with the PD-associated prosurvival protein Parkin to mediate death. These findings establish this new pathway as a potential and promising therapeutic target for treatment of PD.

Calls for university and college professors to engage with public issues—for example, by collaborating with community organizations, participating in popular media outreach, and in other ways—are on the rise. However, engaged scholarship blurs conventional boundaries between producers of academic knowledge and the public. To what extent does participation in engaged scholarship affect professors’ credibility as sources of knowledge? We investigate this question using data from an experimental survey of university students ( n = 633). We find that although engaged scholars are perceived to be more liberal, students believe they are more knowledgeable and should be more influential in public policy decisions compared with nonengaged scholars. Open-ended responses indicate that scholarly engagement with the public is seen as an indicator of faculty members’ experiential expertise and personal commitment to public issues. Consequently, scholarly engagement with social problems often strengthens professors’ credibility among students as information sources. We conclude by discussing the implications of these findings for the engaged scholarship movement and for the sociology of knowledge.

Social scientists often have been called upon to weigh in on social issues, and same-sex marriage is no exception. We draw on quantitative and qualitative data from a national survey to evaluate four of the most prominent arguments raised by opponents of same-sex marriage in court cases. Our data undermine these claims, leading to four lessons about same-sex marriage that we can surmise from public opinion: (1) opposition to same-sex marriage is about animus, (2) marital status brings clear benefits to same-sex couples, (3) state variation in marital laws places same-sex couples in a vulnerable position, and (4) legal alternatives to same-sex marriage do not obviate the need for same-sex marriage. We briefly outline these four lessons and discuss the continuing importance of social science research—in particular, public opinion research—for understanding issues that will emerge as the perceptions of and legal rights afforded to same-sex couples change in the United States.

α-Synuclein (αS) forms round cytoplasmic inclusions in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Evidence suggests a physiological function of αS in vesicle trafficking and release. In contrast to earlier tenets, recent work indicates that αS normally exists in cells in a dynamic equilibrium between monomers and tetramers/multimers. We engineered αS mutants incapable of multimerization, leading to excess monomers at vesicle membranes. By EM, such mutants induced prominent vesicle clustering, leading to round cytoplasmic inclusions. Immunogold labeling revealed abundant αS intimately associated with vesicles of varied size. Fluorescence microscopy with marker proteins showed that the αS-associated vesicles were of diverse endocytic and secretory origin. An αS ‘3K’ mutant (E35K + E46K + E61K) that amplifies the PD/DLB-causing E46K mutation induced αS-rich vesicle clusters resembling the vesicle-rich areas of Lewy bodies, supporting pathogenic relevance. Mechanistically, E46K can increase αS vesicle binding via membrane-induced amphipathic helix formation, and ‘3K’ further enhances this effect. Another engineered αS variant added hydrophobicity to the hydrophobic half of αS helices, thereby stabilizing αS-membrane interactions. Importantly, substituting charged for uncharged residues within the hydrophobic half of the stabilized helix not only reversed the strong membrane interaction of the multimer-abolishing αS variant but also restored multimerization and prevented the aberrant vesicle interactions. Thus, reversible αS amphipathic helix formation and dynamic multimerization regulate a normal function of αS at vesicles, and abrogating multimers has pathogenic consequences.

Over the past two decades, the Organisation for Economic Co-operation and Development (OECD) has become an influential actor in the education sector. This has been accomplished, partly, by the administration of the Programme for International Student Assessment (PISA) since 2000. Overall, PISA is intended to inform the public, parents, teachers, and those who run education systems of the status of education in their country. Research shows that policymakers draw on PISA results when they launch and design education reforms. To date, however, we know very little about whether PISA is successfully informing the general public, which is the main sponsor and benefactor of PISA. Using public opinion surveys from the United States and Israel, this chapter examines knowledge and perception of PISA. Recent reports suggest that both countries are in the middle ranks of all countries participating in PISA, with the United States being in the middle ranks of OECD countries and Israel being in the lower ranks of this group. Findings from public opinion surveys reveal three interesting patterns. First, in both countries, the public tend to underestimate how well 15-year olds perform on international standardized tests. Second, college graduates are more likely than those with less education to underestimate the performance of teens on international standardized tests. Third, although the public seems to be misinformed about PISA results, we find considerable public support for PISA and international standardized tests more generally. Implications of the findings for policy and future research in the field of international and comparative education are discussed.