p21 is decreased in polycystic kidney disease and leads to increased epithelial cell cycle progression: roscovitine augments p21 levels.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21.Methodsp21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay.ResultsWe show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis.ConclusionThe novelty of our study is the demonstration in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy

Nutrition Education, Fad Diets, and Social Media in the University of Saskatchewan Community

https://doi.org/10.17605/OSF.IO/BE9S

Early childhood educators’ understanding of early communication: Application to their work with young children

This paper has been published in final form at http://dx.doi.org/10.1177/0265659016630034 Copyright © 2017 SAGE Publications.Reprinted by permission of SAGE PublicationsYoung children need rich learning experiences to maximize their potential. Early childhood educators (ECEs) working in childcare have knowledge of individual children as well as skills and professional knowledge that afford opportunities to provide language-rich environments for learning. To successfully work in partnership with ECEs, speech-language pathologists need to understand what they know about early communication development and how they apply it in their work. This study explored ECEs’ understanding of early communication development in childcare contexts, and how they related this to the education and care they provided. In this exploratory study we conducted three focus groups with 19 ECEs who were employed in eight different childcare centres in low socio-economic areas in metropolitan Adelaide, South Australia. Data were analysed thematically revealing three core themes: ‘Knowing and doing in context’; ‘ECEs’ role’; and ‘ECEs’ challenges’. Participants articulated understanding of early communication development and the importance of strong relationships between ECEs, children and their families. These ECEs’ skills and knowledge of children in their care was the basis from which they provided language-rich learning environments with individually tailored educational programmes to support all children, including those experiencing communication difficulties. They highlighted challenges in delivering this care, including the need for more explicit support from speech-language pathologists. There is potential to further develop interdisciplinary partnerships between ECEs in childcare and other professionals, such as speech-language pathologists, to maximize early developmental opportunities for children attending childcare

Childcare educators’ understandings of early communication and attachment

This article has been published in final form at http://www.earlychildhoodaustralia.org.au/our-publications/australasian-journal-early-childhood/index-abstracts/ajec-vol-40-no-4-december-2016/childcare-educators-understandings-early-communication-attachment/Giving voice to the discipline-specific knowledge and pedagogical practices of childcare educators, this paper attempts to explore new ways of defining educators’ work with young children, given the post-structural turn in Australian and international early childhood policy. Three focus groups (n = 8 children’s education and care services; n = 19 educators) were held in metropolitan Adelaide (South Australia) to explore their professional understandings of early communication and attachment development. Childcare educators described the relational and communicative elements of their work that supported or constrained their capacity to understand individual children’s socio-emotional needs at enrolment, during transitions and in day-to-day routines. Whether attachment relationships were forged or being built, these educators explained how emotional reciprocity and an understanding of the child through secure attachment relationships enabled them to notice young children’s communication abilities and needs, and vice versa. While the findings illuminate the expertise childcare educators bring to their work, we argue that there is a need to further explore how this expertise shapes their programs, practices and professional development needs

Single-cell analysis of early antiviral gene expression reveals a determinant of stochastic IFNB1 expression

RIG-I-like receptors (RLRs) are cytoplasmic sensors of viral RNA that trigger the signaling cascade that leads to type I interferon (IFN) production. Transcriptional induction of RLRs by IFN is believed to play the role of positive feedback to further amplify viral sensing. We found that RLRs and several other IFN-stimulated genes (ISGs) are induced early in viral infection independent of IFN. Expression of these early ISGs requires IRF3/IRF7 and is highly correlated amongst them. Simultaneous detection of mRNA of IFNB1, viral replicase, and ISGs revealed distinct populations of IFNB1 expressing and non-expressing cells which are highly correlated with the levels of early ISGs but are uncorrelated with IFN-dependent ISGs and viral gene expression. Individual expression of RLRs made IFNB1 expression more robust and earlier, suggesting a causal relation between levels of RLR and induction of IFN.112Ysciescopu

On a Sugar High: Role of O-GlcNAcylation in Cancer

Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication in cancer have gained increasing attention as potential targets due to the critical role of glycosylation in regulating tumor-specific pathways that contribute to cancer cell survival, proliferation, and progression. A special type of glycosylation that has been gaining momentum in cancer research is the modification of nuclear, cytoplasmic, and mitochondrial proteins, termed O-GlcNAcylation. This protein modification is catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses the final product of the Hexosamine Biosynthetic Pathway (HBP) to connect altered nutrient availability to changes in cellular signaling that contribute to multiple aspects of tumor progression. Both O-GlcNAc and its enzyme OGT are highly elevated in cancer and fulfill the crucial role in regulating many hallmarks of cancer. In this review, we present and discuss the latest findings elucidating the involvement of OGT and O-GlcNAc in cancer

Effects of Drug Physicochemical Properties on In-Situ Forming Implant Polymer Degradation and Drug Release Kinetics

In-situ forming implants (ISFIs) represent a simple, tunable, and biodegradable polymer-based platform for long-acting drug delivery. However, drugs with different physicochemical properties and physical states in the polymer-solvent system exhibit different drug release kinetics. Although a few limited studies have been performed attempting to elucidate these effects, a large, systematic study has not been performed until now. The purpose of this study was to characterize the in vitro drug release of 12 different small molecule drugs with differing logP and pKa values from ISFIs. Drug release was compared with polymer degradation as measured by lactic acid (LA) release and change in poly(DL-lactide-co-glycolide) (PLGA) molecular weight (MW) measured by size exclusion chromatography with multi-angle laser light scattering (SEC-MALS). Drug physical state and morphology were also measured using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Together, these results demonstrated that hydrophilic drugs have higher burst release at 24 h (22.8–68.4%) and complete drug release within 60 days, while hydrophobic drugs have lower burst release at 24 h (1.8–18.9%) and can sustain drug release over 60–285 days. Overall, drug logP and drug physical state in the polymer–solvent system are the most important factors when predicting the drug release rate in an ISFI for small-molecule drugs. Hydrophilic drugs exhibit high initial burst and less sustained release due to their miscibility with the aqueous phase, while hydrophobic drugs have lower initial burst and more sustained release due to their affinity for the hydrophobic PLGA. Additionally, while hydrophilic drugs seem to accelerate the degradation of PLGA, hydrophobic drugs on the other hand seem to slow down the PLGA degradation process compared with placebo ISFIs. Furthermore, drugs that were in a crystalline state within the ISFI drugs exhibited more sustained release compared with amorphous drugs

Clinical practice guideline for best practice management of pediatric patients by chiropractors: Results of a Delphi consensus process

Objective: To build upon existing recommendations on best practices for chiropractic management of children by conducting a formal consensus process and best evidence synthesis. Design: Best practice guide based on recommendations from current best available evidence and formal consensus of a panel of experienced practitioners, consumers, and experts for chiropractic management of pediatric patients. Methods: Synthesis of results of a literature search to inform the development of recommendations from a multidisciplinary steering committee, including experts in pediatrics, followed by a formal Delphi panel consensus process. Results: The consensus process was conducted June to August 2022. All 60 panelists completed the process and reached at least 80% consensus on all recommendations after three Delphi rounds. Recommendations for best practices for chiropractic care for children addressed these aspects of the clinical encounter: patient communication, including informed consent; appropriate clinical history, including health habits; appropriate physical examination procedures; red flags/contraindications to chiropractic care and/or spinal manipulation; aspects of chiropractic management of pediatric patients, including infants; modifications of spinal manipulation and other manual procedures for pediatric patients; appropriate referral and comanagement; and appropriate health promotion and disease prevention practices. Conclusion: This set of recommendations represents a general framework for an evidence-informed and reasonable approach to the management of pediatric patients by chiropractors

Experimental infection of calves by two genetically-distinct strains of rift valley fever virus

Citation: Wilson, W. C., Davis, A. S., Gaudreault, N. N., Faburay, B., Trujillo, J. D., Shivanna, V., . . . Richt, J. A. (2016). Experimental infection of calves by two genetically-distinct strains of rift valley fever virus. Viruses, 8(5). doi:10.3390/v8050145Additional Authors: McVey, D. S.Recent outbreaks of Rift Valley fever in ruminant livestock, characterized by mass abortion and high mortality rates in neonates, have raised international interest in improving vaccine control strategies. Previously, we developed a reliable challenge model for sheep that improves the evaluation of existing and novel vaccines in sheep. This sheep model demonstrated differences in the pathogenesis of Rift Valley fever virus (RVFV) infection between two genetically-distinct wild-type strains of the virus, Saudi Arabia 2001 (SA01) and Kenya 2006 (Ken06). Here, we evaluated the pathogenicity of these two RVFV strains in mixed breed beef calves. There was a transient increase in rectal temperatures with both virus strains, but this clinical sign was less consistent than previously reported with sheep. Three of the five Ken06-infected animals had an early-onset viremia, one day post-infection (dpi), with viremia lasting at least three days. The same number of SA01-infected animals developed viremia at 2 dpi, but it only persisted through 3 dpi in one animal. The average virus titer for the SA01-infected calves was 1.6 logs less than for the Ken06-infected calves. Calves, inoculated with either strain, seroconverted by 5 dpi and showed time-dependent increases in their virus-neutralizing antibody titers. Consistent with the results obtained in the previous sheep study, elevated liver enzyme levels, more severe liver pathology and higher virus titers occurred with the Ken06 strain as compared to the SA01 strain. These results demonstrate the establishment of a virulent challenge model for vaccine evaluation in calves. © 2016 by the authors; licensee MDPI, Basel, Switzerland