23 research outputs found
Making A Difference: Year Two Report of the Pennsylvania High School Coaching Initiative
This report examines the implementation of the second year of three for the Pennsylvania High School Coaching Initiative (PAHSCI). Funded by the Annenberg Foundation, this initiative focuses on literacy and math coaches providing support to teachers from across the major subject areas to create literacy-rich classrooms in which students actively engage in learning tasks that deepen their content knowledge and strengthen their abilities to think critically and communicate well. This report presents findings from the first two years of research. It includes survey research as well as in-depth qualitative research in participating schools and districts and provides recommendations for PAHSCI stakeholders as they refine the program and for other education reformers as they consider the benefits of instructional coaching as a strategy for improving high schools and student achievement
Links to Learning and Sustainability: Year Three Report of the Pennsylvania High School Coaching Initiative
At the request of the Accountability Review Council, Research for Action identified effective organizational practices used by better performing schools serving substantial numbers of low income middle and high school students in the School District of Philadelphia. These practices are organized into three spheres: Conditions for Teaching, Student-Centered School Community, and Instructional Program. For each sphere, the report offers broad strategies and specific practices to enact the strategies. Nuanced school case studies show how the practices can work synergistically and coherently in schools to help students succeed
Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial
Background: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. Methods: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5–9·5% (58–80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Findings: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89–6·70, p<0·0001; and trial product estimand: 5·54, 3·54–8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: −2·6 kg [SE 0·3] vs −0·7 kg [SE 0·2], estimated treatment difference [ETD] −1·9 kg, 95% CI −2·6 to −1·2; p<0·0001; and trial product estimand: −2·9 kg [SE 0·3] vs −0·8 kg [SE 0·3], ETD −2·2 kg, −2·9 to −1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Interpretation: Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Funding: Novo Nordisk A/S
Retrotranslocation of a viral A/B toxin from the yeast endoplasmic reticulum is independent of ubiquitination and ERAD
K28 is a viral A/B toxin that traverses eukaryotic cells by endocytosis and retrograde transport through the secretory pathway. Here we show that toxin retrotranslocation from the endoplasmic reticulum (ER) requires Kar2p/BiP, Pdi1p, Scj1p, Jem1p, and proper maintenance of Ca(2+) homeostasis. Neither cytosolic chaperones nor Cdc48p/Ufd1p/Npl4p complex components or proteasome activity are required for ER exit, indicating that K28 retrotranslocation is mechanistically different from classical ER-associated protein degradation (ERAD). We demonstrate that K28 exits the ER in a heterodimeric but unfolded conformation and dissociates into its subunits as it emerges into the cytosol where β is ubiquitinated and degraded. ER export and in vivo toxicity were not affected in a lysine-free K28 variant nor under conditions when ubiquitination and proteasome activity was blocked. In contrast, toxin uptake from the plasma membrane required Ubc4p (E2) and Rsp5p (E3) and intoxicated ubc4 and rsp5 mutants accumulate K28 at the cell surface incapable of toxin internalization. We propose a model in which ubiquitination is involved in the endocytic pathway of the toxin, while ER-to-cytosol retrotranslocation is independent of ubiquitination, ERAD and proteasome activity
Meta-analysis of evaluation results of psychiatric-psychosomatic rehabilitation in Austria
Dissecting toxin immunity in virus-infected killer yeast uncovers an intrinsic strategy of self-protection
Toxin-secreting “killer” yeasts were initially identified >40 years ago in Saccharomyces cerevisiae strains infected with a double-stranded RNA “killer” virus. Despite extensive research conducted on yeast killer toxins, the mechanism of protecting immunity by which toxin-producing cells evade the lethal activities of these proteins has remained elusive. Here, we identify the mechanism leading to protecting immunity in a killer yeast secreting a viral α/β protein toxin (K28) that enters susceptible cells by receptor-mediated endocytosis and, after retrograde transport into the cytosol, blocks DNA synthesis, resulting in both cell-cycle arrest and caspase-mediated apoptosis. We demonstrate that toxin immunity is effected within the cytosol of a toxin-secreting yeast and occurs via the formation of complexes between reinternalized toxin and unprocessed precursor moieties that are subsequently ubiquitinated and proteasomally degraded, eliminating the active form of the toxin. Interference with cellular ubiquitin homeostasis, either through overexpression of mutated ubiquitin (Ub-RR(48/63)) or by blocking deubiquitination, prevents ubiquitination of toxin and results in an impaired immunity and the expression of a suicidal phenotype. The results presented here reveal the uniquely elegant and efficient strategy that killer cells have developed to circumvent the lethal effects of the toxin they produce