Co-chaperones are limiting in a depleted chaperone network

To probe the limiting nodes in the chaperoning network which maintains cellular proteostasis, we expressed a dominant negative mutant of heat shock factor 1 (dnHSF1), the regulator of the cytoplasmic proteotoxic stress response. Microarray analysis of non-stressed dnHSF1 cells showed a two- or more fold decrease in the transcript level of 10 genes, amongst which are the (co-)chaperone genes HSP90AA1, HSPA6, DNAJB1 and HSPB1. Glucocorticoid signaling, which requires the Hsp70 and the Hsp90 folding machines, was severely impaired by dnHSF1, but fully rescued by expression of DNAJA1 or DNAJB1, and partially by ST13. Expression of DNAJB6, DNAJB8, HSPA1A, HSPB1, HSPB8, or STIP1 had no effect while HSP90AA1 even inhibited. PTGES3 (p23) inhibited only in control cells. Our results suggest that the DNAJ co-chaperones in particular become limiting in a depleted chaperoning network. Our results also suggest a difference between the transcriptomes of cells lacking HSF1 and cells expressing dnHSF1

Modulation of the expression of components of the stress response by dietary arachidonic acid in European sea bass (Dicentrarchus labrax) larvae

This study reports for the first time in European sea bass, Dicentrarchus labrax (L.), larvae, the effect of different levels of dietary arachidonic acid (ARA; 20:4n-6) on the expression of genes related to the fish stress response. Copies of mRNA from genes related to steroidogenesis (StAR (steroidogenic acute regulatory protein), c-Fos, and CYP11β (11β- hydroxylase gene)), glucocorticoid receptor complex (GR (glucorticoid receptor) and HSP (heat shock proteins) 70 and 90) and antioxidative stress (catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX)) were quantified. Eighteen day-old larvae were fed for 14 days with three experimental diets with increasing levels of ARA (0.3, 0.6 and 1.2% d.w.) and similar levels of docosahexaenoic (DHA; 22:6n-3) and eicosapentaenoic (EPA; 20:5n-3) acids (5 and 3%, respectively). The quantification of stress-related genes transcripts was conducted by One-Step TaqMan real time RT-PCR with the standard curve method (absolute quantification). Increase dietary levels of ARA induced a significantly (p<0.05) down-regulation of genes related to cortisol synthesis, such as StAR and CYP11β and up-regulated genes related to glucocorticoid receptor complex, such as HSP70 and GR. No effects were observed on antioxidant enzymes gene expression. These results revealed the regulatory role of dietary ARA on the expression of stress-related genes in European sea bass larvae

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies

Mechanisms of Hsp90 regulation

Heat shock protein 90 (Hsp90) is a molecular chaperone that is involved in the activation of disparate client proteins. This implicates Hsp90 in diverse biological processes that require a variety of co-ordinated regulatory mechanisms to control its activity. Perhaps the most important regulator is heat shock factor 1 (HSF1), which is primarily responsible for upregulating Hsp90 by binding heat shock elements (HSEs) within Hsp90 promoters. HSF1 is itself subject to a variety of regulatory processes and can directly respond to stress. HSF1 also interacts with a variety of transcriptional factors that help integrate biological signals, which in turn regulate Hsp90 appropriately. Because of the diverse clientele of Hsp90 a whole variety of co-chaperones also regulate its activity and some are directly responsible for delivery of client protein. Consequently, co-chaperones themselves, like Hsp90, are also subject to regulatory mechanisms such as post translational modification. This review, looks at the many different levels by which Hsp90 activity is ultimately regulated

Social media in undergraduate medical education: A systematic review.

INTRODUCTION: There are over 3.81 billion worldwide active social media (SoMe) users. SoMe are ubiquitous in medical education, with roles across undergraduate programmes, including professionalism, blended learning, well being and mentoring. Previous systematic reviews took place before recent explosions in SoMe popularity and revealed a paucity of high-quality empirical studies assessing its effectiveness in medical education. This review aimed to synthesise evidence regarding SoMe interventions in undergraduate medical education, to identify features associated with positive and negative outcomes. METHODS: Authors searched 31 key terms through seven databases, in addition to references, citation and hand searching, between 16 June and 16 July 2020. Studies describing SoMe interventions and research on exposure to existing SoMe were included. Title, abstract and full paper screening were undertaken independently by two reviewers. Included papers were assessed for methodological quality using the Medical Education Research Study Quality Instrument (MERSQI) and/or the Standards for Reporting Qualitative Research (SRQR) instrument. Extracted data were synthesised using narrative synthesis. RESULTS: 112 studies from 26 countries met inclusion criteria. Methodological quality of included studies had not significantly improved since 2013. Engagement and satisfaction with SoMe platforms in medical education are described. Students felt SoMe flattened hierarchies and improved communication with educators. SoMe use was associated with improvement in objective knowledge assessment scores and self-reported clinical and professional performance, however evidence for long term knowledge retention was limited. SoMe use was occasionally linked to adverse impacts upon mental and physical health. Professionalism was heavily investigated and considered important, though generally negative correlations between SoMe use and medical professionalism may exist. CONCLUSIONS: Social media is enjoyable for students who may improve short term knowledge retention and can aid communication between learners and educators. However, higher-quality study is required to identify longer-term impact upon knowledge and skills, provide clarification on professionalism standards and protect against harms