Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7 − 12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
3-(Imidazo1,2-
apyridin-3-yl)-, its aza-analogs, and 3-(pyrazolo1,5-
apyridin-3-yl)-4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl))maleimides are very potent inhibitors of GSK3 (⩽5
nM) ...with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII.
Many 3-aryl-4-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100
nM IC
50), although few show significant selectivity (>100
×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo1,2-
apyridin-3-yl), 3-(pyrazolo1,5-
apyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5
nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
Renaissance women were to have no other identity outside of their husbands. They were to be chaste, silent, and obedient. Elizabeth Cary in her play The Tragedy of Mariam: The Fair Queen of Jewry ...questions this gender ideology by portraying marginal female characters. The character of Graphina represents the ideal Renaissance woman. In contrast, the "femme-covert," the character Salome, is a woman neither chaste, silent, nor obedient but is unpunished by the patriarchy because she follows the dominant discourse of gender ideology. However, Mariam stands up for her convictions, much like Cary herself, and is executed because she breaks the codes of silence and obedience and therefore appears to her husband unchaste. Because Cary's drama can be construed as politically subversive, she uses the genre of closet drama to question a wife's role in early modern England.
Male gametes (spermatozoids) are the only motile cells produced during the life cycle of land plants. While absent from flowering and most cone-bearing plants, motile cells are found in less derived ...taxa, including bryophytes (mosses, liverworts and hornworts), pteridophytes (lycophytes and ferns) and some seed plants (
and cycads). During development, these cells undergo profound changes that involve the production of a locomotory apparatus, unique microtubule (MT) arrays, and a series of special cell walls that are produced in sequence and are synchronized with cellular differentiation. Immunogold labeling in the transmission electron microscope (TEM) provides information on the exact location and potential function of macromolecules involved with this developmental process. Specifically, it is possible to localize epitopes to proteins that are associated with the cellular inclusions involved in MT production and function. Spermatogenesis in these plants is also ideal for examining the differential expression of carbohydrates and glycoproteins that comprise the extracellular matrixes associated with the dramatic architectural changes in gamete shape and locomotory apparatus development. Here we provide methodologies using monoclonal antibodies (MAbs) and immunogold labeling in the TEM to localize macromolecules that are integral to spermatozoid development.
Motile male gametes (spermatozoids) of land plants are coiled and contain a modified and precisely organized complement of organelles that includes a locomotory apparatus with two to thousands of ...flagella. Each flagellum is generated from a basal body that originates
as a centriole in spermatogenous cell lineages. Much of what is known about the diversity of plant male gametes was derived from detailed transmission electron microscopic studies. Because the process of spermatogenesis results in complete transformation of the shape and organization of these cells, TEM studies have yielded a wealth of information on cellular differentiation. Because green algal progenitor groups contain centrioles and a variety of motile cells, land plant spermatozoids also provide a plethora of opportunities to examine the evolution and eventual loss of centrioles and locomotory apparatus during land colonization. Here we provide a brief overview of the studies and methodologies we have conducted over the past 20 years that have elucidated not only the structural diversity of these cells but also the development of microtubule organizing centers, the
origin of centrioles and the ontogeny of structurally complex motile cells.
Increased life expectancy has resulted in more older patients at trauma centers. Traditional assessments of injuries alone may not be sufficient; age, comorbidities, and medications should be ...considered.
446 older trauma patients were analyzed in two groups, 45–65 years and <65, using Injury Severity Score (ISS), the Charlson Comorbidity Index (CCI), and Comorbidity-Polypharmacy Score (CPS).
CCI and CPS were associated with HLOS in patients <65. In patients aged 45–65, only CPS was associated with HLOS. CPS was inversely associated with in-hospital mortality in patients <65, but not patients aged 45–65. CCI score was not associated with in-hospital mortality in either group.
Increased CCI and CPS were associated with increased HLOS. In patients over 65, increased CPS was associated with decreased mortality. This could be due to return toward physiologic normalcy in treated patients not seen in their peers with undiagnosed or untreated comorbidities.
In this article, we explore how the reading and writing of poetry can be a form of critical hope within secondary English teacher education courses, and across our experiences as English teachers. We ...begin by discussing a particular moment from our secondary English teacher education course, where one of our teacher interns prompted us to respond thoughtfully about the ways we have enacted critical hope by asking, "How do I teach with hope?" From this moment, we share five vignettes of how as former teachers and current teacher educators, we each read and taught with poetry and the ways these moments evoked possibilities for how we might trace the contours of critical hope through a deeper engagement of the relational and poetic within teaching.
•This is an overview of the state of tES/TMS applied in drug addictions.•Neuroscience will be translated into tES/TMS tools for clinical practice in addiction.•Heterogeneity of methods and outcome ...measures in the literature are addressed.•This article provides guidelines for best practices in tES/TMS addiction research.
There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data – emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.
Abstract
Child care-based interventions offer an opportunity to reach children at a young and impressionable age to support healthy eating and physical activity behaviors. Ideally, these ...interventions engage caregivers, including both childcare providers and parents, in united effort. This study evaluated the impact of the Healthy Me, Healthy We intervention on children’s diet quality and physical activity. A sample of 853 three- to four-year-old children from 92 childcare centers were enrolled in this cluster-randomized control trial. Healthy Me, Healthy We was an 8-month, social marketing intervention delivered through childcare that encouraged caregivers (childcare providers and parents) to use practices that supported children’s healthy eating and physical activity behaviors. Outcome measures, collected at baseline and post-intervention, assessed children’s diet quality, physical activity, and BMI as well as caregivers’ feeding and physical activity practices. Generalized Linear Mixed Models were used to assess change from baseline to post-intervention between intervention and control arms. No significant changes were noted in any of the outcome measures except for small improvements in children’s sodium intake and select parent practices. Despite the negative findings, this study offers many lessons about the importance and challenges of effective parent engagement which is critical for meaningful changes in children’s health behaviors.
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