Professional Development School Support of the Elementary GLOBE Curriculum A Facilitated Adaptation of Inquiry Science

This qualitative study focused on identifying barriers and remedies to those barriers found when teaching elementary school science. The Elementary GLOBE Program (2006) was the curriculum selected when doing the 18 month study. The researcher asked what made Elementary GLOBE (EG) easy and/or difficult to use. The researcher also wished to ascertain what impact did the adoption of EG have on the delivery of science instruction in the K-4 grade classrooms participating in this study. Two professional developments schools (PDS), located in a Mid Atlantic state were the sites for the study. Both schools are in an urban setting and affiliated with a nearby land grant university.;The main purpose of this study was to investigate how elementary teachers integrate inquiry-based science in their classrooms. This was accomplished by providing an inservice workshop on an elementary science curriculum (EG) to six teachers. Then teachers were observed instructing with the newly learned curriculum. During the course of the study, teachers kept journals about their experiences teaching science. Later, they gave interviews about their classroom and school environments while teaching science.;To ascertain trustworthiness, a member check in the form of a questionnaire was given to the participating teachers to determine the reliability of the findings at the conclusion of the study. Seven out of seven teachers agreed that EG changed the way their students experienced science. Five out of seven participants felt EG increased their confidence to teach science. Time management was identified as the major barrier to teaching science with six out seven teachers agreeing with this finding. Although accommodation was identified as a barrier, four out of seven agreed to this finding even though there was a high prevalence of diversity in the studied schools and EG was not presented in the any language other than English. Five of the seven participants preferred teaching science with EG over the approved textbook used by the schools. There is a dearth of primary level earth system science materials, so the findings from this study provide evidence for an engaging curriculum promoting science and literacy

HIV-1 Vpr Triggers Mitochondrial Destruction by Impairing Mfn2-Mediated ER-Mitochondria Interaction

Human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) has been shown to induce host cell death by increasing the permeability of mitochondrial outer membrane (MOM). The mechanism underlying the damage to the mitochondria by Vpr, however, is not clearly illustrated. In this study, Vpr that is introduced, via transient transfection or lentivirus infection, into the human embryonic kidney cell line HEK293, human CD4+ T lymphoblast cell line SupT1, or human primary CD4+ T cells serves as the model system to study the molecular mechanism of Vpr-mediated HIV-1 pathogenesis. The results show that Vpr injures MOM and causes a loss in membrane potential (MMP) by posttranscriptionally reducing the expression of mitofusin 2 (Mfn2) via VprBP-DDB1-CUL4A ubiquitin ligase complex, gradually weakening MOM, and increasing mitochondrial deformation. Vpr also markedly decreases cytoplasmic levels of dynamin-related protein 1 (DRP1) and increases bulging in mitochondria-associated membranes (MAM), the specific regions of endoplasmic reticulum (ER) which form physical contacts with the mitochondria. Overexpression of Mfn2 and DRP1 significantly decreased the loss of MMP and apoptotic cell death caused by Vpr. Furthermore, by employing time-lapse confocal fluorescence microscopy, we identify the transport of Vpr protein from the ER, via MAM to the mitochondria. Taken together, our results suggest that Vpr-mediated cellular damage may occur on an alternative protein transport pathway from the ER, via MAM to the mitochondria, which are modulated by Mfn2 and DRP1

Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels

Introduction: MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this. Methods: We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer’s Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated. Results: H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03). Conclusions: These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression

HIV and Aging

HIV risk behaviors, susceptibility to HIV acquisition, progression of disease after infection, and response to antiretroviral therapy all vary by age. In those living with HIV, current effective treatment has increased the median life expectancy to >70 years of age. Biologic, medical, individual, social, and societal issues change as one ages with HIV infection, but there has been only a small amount of research in this field. Therefore, the Office of AIDS Research of the National Institutes of Health commissioned a working group to develop an outline of the current state of knowledge and areas of critical need for research in HIV and Aging; the working groups' findings and recommendations are summarized in this report. Key overarching themes identified by the group included the following: multimorbidity, polypharmacy, and the need to emphasize maintenance of function; the complexity of assessing HIV versus treatment effects versus aging versus concurrent disease; the inter-related mechanisms of immune senescence, inflammation, and hypercoagulability; the utility of multivariable indices for predicting outcomes; a need to emphasize human studies to account for complexity; and a required focus on issues of community support, caregivers, and systems infrastructure. Critical resources are needed to enact this research agenda and include expanded review panel expertise in aging, functional measures, and multimorbidity, and facilitated use and continued funding to allow long-term follow-up of cohorts aging with HIV

Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants

<div><p>Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n = 197, temporal cortex n = 202) and with other brain pathologies (non–AD, cerebellar n = 177, temporal cortex n = 197). We conducted an expression genome-wide association study (eGWAS) using 213,528 <em>cis</em>SNPs within ±100 kb of the tested transcripts. We identified 2,980 cerebellar <em>cis</em>SNP/transcript level associations (2,596 unique <em>cis</em>SNPs) significant in both ADs and non–ADs (q<0.05, p = 7.70×10⁻⁵–1.67×10⁻⁸²). Of these, 2,089 were also significant in the temporal cortex (p = 1.85×10⁻⁵–1.70×10⁻¹⁴¹). The top cerebellar <em>cis</em>SNPs had 2.4-fold enrichment for human disease-associated variants (p<10⁻⁶). We identified novel <em>cis</em>SNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy <em>SLCO1A2</em>/rs11568563, Parkinson's disease (PD) <em>MMRN1</em>/rs6532197, Paget's disease <em>OPTN</em>/rs1561570; and we confirmed others, including PD <em>MAPT</em>/rs242557, systemic lupus erythematosus and ulcerative colitis <em>IRF5</em>/rs4728142, and type 1 diabetes mellitus <em>RPS26</em>/rs1701704. In our eGWAS, there was 2.9–3.3 fold enrichment (p<10⁻⁶) of significant <em>cis</em>SNPs with suggestive AD–risk association (p<10⁻³) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain <em>cis</em>SNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non–CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.</p> </div

Novel late-onset Alzheimer disease loci variants associate with brain gene expression

OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations. RESULTS: CLU rs11136000 (p = 7.81 × 10(−4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(−4)–1.86 × 10(−4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(−5)–9.09 × 10(−9)), some of which also associate with AD risk (p = 2.64 × 10(−2)–6.25 × 10(−5)). CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci