Target mRNA inhibition by oligonucleotide drugs in man

Oligonucleotide delivery in vivo is commonly seen as the principal hurdle to the successful development of oligonucleotide drugs. In an analysis of 26 oligonucleotide drugs recently evaluated in late-stage clinical trials we found that to date at least half have demonstrated suppression of the target mRNA and/or protein levels in the relevant cell types in man, including those present in liver, muscle, bone marrow, lung, blood and solid tumors. Overall, this strongly implies that the drugs are being delivered to the appropriate disease tissues. Strikingly we also found that the majority of the drug targets of the oligonucleotides lie outside of the drugable genome and represent new mechanisms of action not previously investigated in a clinical setting. Despite the high risk of failure of novel mechanisms of action in the clinic, a subset of the targets has been validated by the drugs. While not wishing to downplay the technical challenges of oligonucleotide delivery in vivo, here we demonstrate that target selection and validation are of equal importance for the success of this fiel

Much to do about identity: Successful women in science reflect on their school years

This study presents the recollections of 12 successful women in science duringtheir school years before postsecondary education. The participants shareddetailed descriptions of their science experiences through three semi-structured interviews. An identity works conceptual framework consisting offigured worlds, positioning, and agency constructs to portray the complexdynamics of their experiences was used to analyze the data. The following fourthemes emerged from the data analysis: participants had an early interest inmathematics and science; they were“stubbornly”persistent in science-figuredworlds; they engaged in science-figured worlds beyond school; and they posi-tioned themselves as science leaders. These findings add to the evolution of sci-ence identity development theoretical models because they are from anondeficit perspective. Participants engaged in identity work that advancedtheir science identities despite the gender biases in science-figured worlds.From a practical stance, girls and women could employ the agentic and posi-tive positioning identity work that the findings show to develop their scienceidentity in educational contexts. Science educators and researchers are encour-aged to structure figured worlds where girls feel empowered to enact identitywork to build strong science identities

Re-Designing Infrastructure as a Strategy for Crafting Coherence Across Three Networks Focused on the Implementation of the Next Generation Science Standards

This design-based research project reports on three multilevel networks that were focused on implementing the Next Generation Science Standards (NGSS). Given the recent attention to understanding infrastructure to craft coherence in NGSS implementation, this research investigated how these networks iteratively re-designed infrastructure as they engaged in implementing the NGSS. This focus is particularly important in the current context of NGSS implementation since needed infrastructure did not accompany the dissemination of the standards. The three networks were the following: mentor teachers, district specialists, and interim assessment specialists. Qualitative cases based on recordings of network working sessions, interviews with members, and artifacts of their work were generated for each network and then compared and contrasted. Findings show the work on infrastructure re-design across the networks not only involved identifying useful NGSS-designed resources and frameworks, but also translating these into meaningful supports or scaffolds that could ultimately lead to productive forms of engagement for either supporting teacher professional learning or student learning. Also, collegial workspaces were beneficial for institutionalizing networks\u27 foci by creating spaces for all actors to share their experiences, challenges, and needs. This meant focusing on curriculum and instructional routines for mentor teachers, focusing on NGSS instructional principles for district leaders, and focusing on the development of an interim assessment practice brief for interim assessment leaders—foci identified as central to and immediately applicable in the day-to-day work of the respective network members

Scholarly Activity in Residency: A Needs Assessment of Challenges and Proposed Solutions

Introduction Resident physician participation in scholarly activity is associated with significant benefits ranging from trainees’ personal development to improved quality of patient care. Residency programs have taken varied approaches to improve resident engagement in scholarship, though interventions have demonstrated mixed results regarding objective measures of scholarly productivity. Concerns regarding waining interest in scholarship amongst internal medicine residents prompted a department-wide needs assessment to evaluate opportunities for scholarship and challenges preventing resident participation. Methods A web-based survey was developed and distributed to Department of Internal Medicine faculty and residents at the PGY2 level or higher and recent graduates within the last year prior to the study. We investigated perceived opportunities for resident scholarship, perceived challenges with resident scholarly activity, preferences regarding scholarly projects, and faculty experiences with mentorship. Descrptive statistics were used to describe survey responses. Results Faculty and trainees shared similar perceptions of inadequate opportunities for resident participation in scholarly activity and endorsed a preference to join ongoing projects early in their course as opposed to starting new projects or joining projects near their completion. Both groups identified lack of resident time as a barrier to resident participation in scholarly activity but faculty were more likely to report lack of resident aptitude for research and lack of faculty time and aptitude for mentorship as challenges. Conclusions Residents and faculty are not aware of all the resources in place to support scholarship opportunities for trainees. Resident and faculty time is a significant barrier to resident scholarship and further efforts are needed to support faculty and trainee collaboration while mitigating challenges which limit the use of currently available resources. Regular curricular assessment is necessary to ensure that trainees and faculty are aware of available resources and that those resources are meeting the departments specific needs

Time-Series Ensemble Photometry and the Search for Variable Stars in the Open Cluster M11

This work presents the first large-scale photometric variability survey of the intermediate age (~200 Myr) open cluster M11. Thirteen nights of data over two observing seasons were analyzed (using crowded field and ensemble photometry techniques) to obtain high relative precision photometry. In this study we focus on the detection of candidate member variable stars for follow-up studies. A total of 39 variable stars were detected and can be categorized as follows: 1 irregular (probably pulsating) variable, 6 delta Scuti variables, 14 detached eclipsing binary systems, 17 W UMa variables, and 1 unidentified/candidate variable. While previous proper motion studies allow for cluster membership determination for the brightest stars, we find that membership determination is significantly hampered below V=15,R=15.5 by the large population of field stars overlapping the cluster MS. Of the brightest detected variables that have a high likelihood of cluster membership, we find five systems where further work could help constrain theoretical stellar models, including one potential W UMa member of this young cluster.Comment: 38 pages, 13 figures, accepted for December 2005 AJ, high-resolution version available upon reques

Understanding the Role of Science-Specific Literacy Strategies in Supporting Science Teaching and Student Learning: A Case Study of Preservice Elementary Teachers in a Science Methods Course That Integrated a Disciplinary Literacy Framework

The shift to student engagement in scientific and engineering practices to learn science provides opportunities for science learning and language learning to occur in tandem. These opportunities also pose new challenges for elementary pre-service teachers (PSTs) since literacy methods courses have been presented separately from science methods courses. We integrated a disciplinary literacy framework in a science methods course to help elementary PSTs understand the synergistic connections between literacy and science teaching. The purpose of this study was to examine elementary PSTs’ understanding of the use of science-specific literacy strategies to support science teaching and learning through three points of observation. Findings from three data sources indicated that PSTs showed a developing understanding of the role of disciplinary literacy in supporting student engagement in science practices and learning disciplinary core ideas. Implications for future uses of a disciplinary literacy framework for teaching and learning science and elementary PSTs’ science preparation are presented

Building a Community of Practice: A Case Study of Introductory College Chemistry Students

Engagement in active learning and learning communities is important for persistence of STEM students early in their academic programs. Colleges and universities have an ongoing call to facilitate active learning techniques, yet large group, lecture-based instruction is still the prominent method of instruction. This qualitative case study examines interviews and classroom observations of undergraduate chemistry students enrolled at a primarily undergraduate institution. Critical educational elements were identified for chemistry students participating in a redesigned, introductory course which included a collaborative peer-lead learning experience. The participants engaged in required, weekly sessions structured around community building and active learning. The data were framed through a community of practice (CoP) framework, and emergent themes were centered on the following components: mutual engagement, joint enterprise, and shared repertoire. Findings show participant engagement created opportunities for collaboration beyond the required, weekly sessions, which included forming study groups and seeking assistance from chemistry tutors. Participants also shared study techniques based on a mutual understanding that effective learning required routine practice. Implications for STEM departments and researchers about implementing research-based curriculum are discussed

Determining tan⁡β\tan\beta at the NLC with SUSY Higgs Bosons

We examine the prospects for determining $\tan\beta$ from heavy Higgs scalar production in the minimal supersymmetric standard model at a future $e^+e^-$ collider. Our analysis is independent of assumptions of parameter unification, and we consider general radiative corrections in the Higgs sector. Bounds are presented for $\sqrt{s} = 500$ GeV and 1 TeV, several Higgs masses, and a variety of integrated luminosities. For all cases considered, it is possible to distinguish low, moderate, and high $\tan\beta$. In addition, we find stringent constraints for $3\lesssim\tan\beta\lesssim 10$, and, for some scenarios, also interesting bounds on high $\tan\beta$ through $tbH^{\pm}$ production. Such measurements may provide strong tests of the Yukawa unifications in grand unified theories and make possible highly precise determinations of soft SUSY breaking mass parameters.Comment: Talk presented by T. Moroi at the SUSY'97 Conference, May 27-31, Philadelphia, PA, US

Hierarchy and Anarchy in Quark Mass Matrices, or Can Hierarchy Tolerate Anarchy?

The consequences of adding random perturbations (anarchy) to a baseline hierarchical model of quark masses and mixings are explored. Even small perturbations of the order of 5% of the smallest non-zero element can already give deviations significantly affecting parameters of the Cabibbo-Kobayashi-Maskawa (CKM) matrix, so any process generating the anarchy should in general be limited to this order of magnitude. The regularities of quark masses and mixings thus appear to be far from a generic feature of randomness in the mass matrices, and more likely indicate an underlying order.Comment: 11 pages, LaTeX, 3 figures, to be submitted to Phys. Lett. B. Abstract and Introduction changed to better reflect conclusion