Formation and Function of the Rbl2p-beta-Tubulin Complex

The yeast protein Rbl2p suppresses the deleterious effects of excess beta-tubulin as efficiently as does alpha-tubulin. Both in vivo and in vitro, Rbl2p forms a complex with beta-tubulin that does not contain alpha-tubulin, thus defining a second pool of beta-tubulin in the cell. Formation of the complex depends upon the conformation of beta-tubulin. Newly synthesized beta-tubulin can bind to Rbl2p before it binds to alpha-tubulin. Rbl2p can also bind beta-tubulin from the alpha/beta-tubulin heterodimer, apparently by competing with alpha-tubulin. The Rbl2p-beta-tubulin complex has a half-life of ~2.5 h and is less stable than the alpha/beta-tubulin heterodimer. The results of our experiments explain both how excess Rbl2p can rescue cells overexpressing beta-tubulin and how it can be deleterious in a wild-type background. They also suggest that the Rbl2p-beta-tubulin complex is part of a cellular mechanism for regulating the levels and dimerization of tubulin chains

Lze najít pojítko mezi vysvětlením a porozuměním?

The problem of linking 'explanation' & 'understanding' remains unresolved -- as Weber left it. This paper challenges the view that their reconciliation is impossible, as some theorists have maintained. Their case is that the entities involved -- subjective meanings & objective relationships -- are too ontologically different to be combined. From the stratified ontology of Social Realism, which acknowledges that different properties & powers pertain to different components & levels of social reality, this is no barrier in principle to their combination. However, in practice Realists have not given an adequate account of how 'subjectivity' & 'objectivity' are linked, which also weakens Realism's solution to the 'problem of structure & agency.' This paper offers a refinement: the human power of reflexivity is viewed as mediating between our subjective concerns & our objective social contexts. Reflexive deliberations account for what agents actually do -- and they do not all do the same thing -- under very similar social circumstances. The introduction of reflexivity enables the (socially) objective & the (personally) subjective to be combined into a single account of socially structured & structuring action

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Impact of the COVID-19 pandemic on cancer assessment in primary care: a qualitative study of GP views

Funding This research was co-funded by the National Institute for Health Research (NIHR) Policy Research Programme, conducted through the Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis, PR-PRU-1217–21601. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The study was also supported by the CanTest Collaborative funded by Cancer Research UK C8640/A23385, of which Fiona Walter is director, Richard Neal is associate director, Suzanne Scott is co-investigator, and Natalia Calanzani and Stephanie Honey are researchers. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.Peer reviewedPublisher PD

The challenges and facilitators to successful translation and adaptation of written self-report psychological measures into sign languages: A systematic review.

Deaf people are known to have significantly poorer reading comprehension skills when compared to their hearing counterparts. This poses significant threats to text-based psychological assessments. The plethora of text-based self-report measures available provides ample opportunity to translate/adapt existing tools from text to sign language. This paper systematically reviewed the challenges and facilitators faced in previous translations/adaptations with the view to inform recommendations for future practice. This paper reports the results of a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-informed systematic review of 30 studies that had translated or discussed the translation of a written self-report measure into sign language following screening against inclusion/exclusion criteria. A systematic search (powered by EbscoHost Research Database and using search terms and Boolean operators), was performed in The Allied and Complementary Medicine Database (AMED), Cinahl, Medline, APA PsycInfo, and APA PsycArticles. The Quality Assessment with Diverse Studies tool was used for quality appraisal of the included papers. Challenges/facilitators to effective translation/adaptation were grouped under linguistic, procedural, and cultural. Examples of specific linguistic, procedural, cultural challenges, and facilitators are discussed in the context of previous research and study limitations. Translating/adapting text-based self-report measures to sign language is a linguistically and procedurally demanding endeavor that requires a deep bicultural/bilingual understanding of both deaf and hearing communities. The present results and recommendations can help researchers develop suitably accessible translated/adapted self-report psychological measures and this can have significant implications on healthcare service planning and delivery

Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension

<p>Aims: Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH.</p> <p>Methods and results: Dfen (5 mg kg−1 day−1 PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1−/− mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17β-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17β-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice.</p> <p>Conclusion: CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.</p&gt