Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid

Caspase-8 is involved in death receptor-mediated apoptosis in type II cells, the proapoptotic programme of which is triggered by truncated Bid. Indeed, caspase-8 and Bid are the known intermediates of this signalling pathway. Cardiolipin has been shown to provide an anchor and an essential activating platform for caspase-8 at the mitochondrial membrane surface. Destabilisation of this platform alters receptor-mediated apoptosis in diseases such as Barth Syndrome, which is characterised by the presence of immature cardiolipin which does not allow caspase-8 binding. We used a simplified in vitro system that mimics contact sites and/or cardiolipin-enriched microdomains at the outer mitochondrial surface in which the platform consisting of caspase-8, Bid and cardiolipin was reconstituted in giant unilamellar vesicles. We analysed these vesicles by flow cytometry and confirm previous results that demonstrate the requirement for intact mature cardiolipin for caspase-8 activation and Bid binding and cleavage. We also used confocal microscopy to visualise the rupture of the vesicles and their revesiculation at smaller sizes due to alteration of the curvature following caspase-8 and Bid binding. Biophysical approaches, including Laurdan fluorescence and rupture/tension measurements, were used to determine the ability of these three components (cardiolipin, caspase-8 and Bid) to fulfil the minimal requirements for the formation and function of the platform at the mitochondrial membrane. Our results shed light on the active functional role of cardiolipin, bridging the gap between death receptors and mitochondria

Unassisted solar lignin valorisation using a compartmented photo-electro-biochemical cell

Lignin is a major component of lignocellulosic biomass. Although it is highly recalcitrant to break down, it is a very abundant natural source of valuable aromatic carbons. Thus, the effective valorisation of lignin is crucial for realising a sustainable biorefinery chain. Here, we report a compartmented photo-electro-biochemical system for unassisted, selective, and stable lignin valorisation, in which a TiO2 photocatalyst, an atomically dispersed Co-based electrocatalyst, and a biocatalyst (lignin peroxidase isozyme H8, horseradish peroxidase) are integrated, such that each system is separated using Nafion and cellulose membranes. This cell design enables lignin valorisation upon irradiation with sunlight without the need for any additional bias or sacrificial agent and allows the protection of the biocatalyst from enzymedamaging elements, such as reactive radicals, gas bubbles, and light. The photo-electrobiochemical system is able to catalyse lignin depolymerisation with a 98.7% selectivity and polymerisation with a 73.3% yield using coniferyl alcohol, a lignin monomer

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study

2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naı¨ve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P¼0.004). There was no interaction between AR and docetaxel status (P¼0.83 for OS, P¼0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; PA (p.L702H) and 520 3

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.

Background There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC.Methods We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial).Results In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts.Conclusion Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required.Clinical trial number NCT02288936 (PREMIERE trial)

Gaia Data Release 3: Mapping the asymmetric disc of the Milky Way

With the most recent Gaia data release the number of sources with complete 6D phase space information (position and velocity) has increased to well over 33 million stars, while stellar astrophysical parameters are provided for more than 470 million sources, in addition to the identification of over 11 million variable stars. Using the astrophysical parameters and variability classifications provided in Gaia DR3, we select various stellar populations to explore and identify non-axisymmetric features in the disc of the Milky Way in both configuration and velocity space. Using more about 580 thousand sources identified as hot OB stars, together with 988 known open clusters younger than 100 million years, we map the spiral structure associated with star formation 4-5 kpc from the Sun. We select over 2800 Classical Cepheids younger than 200 million years, which show spiral features extending as far as 10 kpc from the Sun in the outer disc. We also identify more than 8.7 million sources on the red giant branch (RGB), of which 5.7 million have line-of-sight velocities, allowing the velocity field of the Milky Way to be mapped as far as 8 kpc from the Sun, including the inner disc. The spiral structure revealed by the young populations is consistent with recent results using Gaia EDR3 astrometry and source lists based on near infrared photometry, showing the Local (Orion) arm to be at least 8 kpc long, and an outer arm consistent with what is seen in HI surveys, which seems to be a continuation of the Perseus arm into the third quadrant. Meanwhile, the subset of RGB stars with velocities clearly reveals the large scale kinematic signature of the bar in the inner disc, as well as evidence of streaming motions in the outer disc that might be associated with spiral arms or bar resonances. (abridged

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Training future generations to deliver evidence-based conservation and ecosystem management

Data availability statement: No data was used in this study.Peer review: The peer review history for this article is available at: https://publons.com/publon/10.1002/2688-8319.12032.Supporting Information: eso312032-sup-0001-SuppMat.docx (21.1 KB) available at: https://besjournals.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2F2688-8319.12032&file=eso312032-sup-0001-SuppMat.docx. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.Copyright © 2021 The Authors. 1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis. 2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice. 3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses. 4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas. Making informed conservation and ecosystem management choices is based upon a sound understanding of the relevant evidence. There is an increasing wealth of conservation science available, and access to this is becoming easier. But, are conservation practitioners being trained to utilize this information? In conservation, decision-making is often based upon past experience or expert knowledge, as opposed to the full body of scientific literature (e.g., Pullin, Knight, Stone, & Charman, 2004; Rafidimanantsoa, Poudyal, Ramamonjisoa, & Jones, 2018). The failure to include scientific evidence in decision-making has the potential to reduce the effectiveness of management, or even lead to detrimental actions being undertaken (Walsh, Dicks, & Sutherland, 2015). Evidence-based conservation (EBC) seeks to avoid this by providing tools to facilitate and inform decision-making. To do this, scientific evidence is collated and critically appraised for its quality and relevance, and integrated with other knowledge, experience, values and costs (Sutherland, Pullin, Dolman, & Knight, 2004). Wider adoption of EBC requires conservation professionals to be trained in its principles and taught how to use it to inform conservation decision-making.MAVA Foundation; Arcadia Fund