Mechanical and fracture performance of carbon fibre reinforced composites with nanoparticle modified matrices

The microstructure and fracture performance of carbon-fibre reinforced polymer (CFRP) composites with an epoxy resin cured with an anhydride hardener containing silica nanoparticles and/or polysiloxane core-shell rubber (CSR) particles was investigated in the current work. Double cantilever beam tests were performed in order to evaluate the fracture energy of the CFRP composites, while the single edge notched bend (SENB) specimen was employed to evaluate the fracture energy of the bulk polymers. Tests were conducted at room temperature and at -80°C. The transferability of the toughness from the bulk polymers to the fibre-composite systems is discussed, with an emphasis on elucidating the toughening mechanism

Adhesion Improvement of Thermoplastics-Based Composites by Atmospheric Plasma and UV Treatments

The present work is concerned with adhesive bonding of thermoplastic composites used in general aerospace applications, including polyphenylene sulfide (PPS), polyetherimide (PEI) and polyetheretherketone (PEEK) carbon fibre composites. Three different surface treatments have been applied to the PEEK, PPS and PEI-based composites in order to enhance the adhesion: atmospheric plasma, ultraviolet radiation (UV) and isopropanol wiping as a control. Water contact angles and free surface energies were measured following the standard experimental procedure based on the employment of three different liquid droplets. Infrared spectroscopy and X-ray photoelectron spectroscopy (XPS) were subsequently performed to characterize the surface chemistry of the samples after treatment. The single lap joints were manufactured and bonded by an Aerospace grade epoxy-based film adhesive originally developed for use on metals but with the ability to bond treated thermoplastics to good strength (supplied by Henkel Ireland). Quasi-static (QS) tests were conducted. The lap shear strength was evaluated, and the failure mechanisms of the different joints were examined for the range of surface treatments considered. It was found that the performances of the PEEK and PPS joints were considerably improved by the plasma and UV treatments resulting in cohesive and delamination failures, while PEI was unaffected by the plasma and UV treatments and performed very well throughout

Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy

Impairment of the autophagy-lysosome pathway (ALP) is implicated with the changes in α-synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resultingin ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH-SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock down (KD) cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB KD.. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC-1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain ALP and mitochondrial biogenesis. Therefore strategies to increase TFEB may improve both the clearance of α-synuclein and mitochondrial dysfunction in PD. This article is protected by copyright. All rights reserved

DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites

The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development

Miro clusters regulate ER-mitochondria contact sites and link cristae organization to the mitochondrial transport machinery

Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and Endoplasmic Reticulum-Mitochondria Contacts Sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality

Managing COVID-19 within and across health systems:why we need performance intelligence to coordinate a global response

Background The COVID-19 pandemic is a complex global public health crisis presenting clinical, organisational and system-wide challenges. Different research perspectives on health are needed in order to manage and monitor this crisis. Performance intelligence is an approach that emphasises the need for different research perspectives in supporting health systems’ decision-makers to determine policies based on well-informed choices. In this paper, we present the viewpoint of the Innovative Training Network for Healthcare Performance Intelligence Professionals (HealthPros) on how performance intelligence can be used during and after the COVID-19 pandemic. Discussion A lack of standardised information, paired with limited discussion and alignment between countries contribute to uncertainty in decision-making in all countries. Consequently, a plethora of different non-data-driven and uncoordinated approaches to address the outbreak are noted worldwide. Comparative health system research is needed to help countries shape their response models in social care, public health, primary care, hospital care and long-term care through the different phases of the pandemic. There is a need in each phase to compare context-specific bundles of measures where the impact on health outcomes can be modelled using targeted data and advanced statistical methods. Performance intelligence can be pursued to compare data, construct indicators and identify optimal strategies. Embracing a system perspective will allow countries to take coordinated strategic decisions while mitigating the risk of system collapse.A framework for the development and implementation of performance intelligence has been outlined by the HealthPros Network and is of pertinence. Health systems need better and more timely data to govern through a pandemic-induced transition period where tensions between care needs, demand and capacity are exceptionally high worldwide. Health systems are challenged to ensure essential levels of healthcare towards all patients, including those who need routine assistance. Conclusion Performance intelligence plays an essential role as part of a broader public health strategy in guiding the decisions of health system actors on the implementation of contextualised measures to tackle COVID-19 or any future epidemic as well as their effect on the health system at large. This should be based on commonly agreed-upon standardised data and fit-for-purpose indicators, making optimal use of existing health information infrastructures. The HealthPros Network can make a meaningful contribution

Axonal autophagosome maturation defect through failure of ATG9A sorting underpins pathology in AP-4 deficiency syndrome

Adaptor protein (AP) complexes mediate key sorting decisions in the cell through selective incorporation of transmembrane proteins into vesicles. Little is known of the roles of AP-4, despite its loss of function leading to a severe early onset neurological disorder, AP-4 deficiency syndrome. Here we demonstrate an AP-4 epsilon subunit knockout mouse model that recapitulates characteristic neuroanatomical phenotypes of AP-4 deficiency patients. We show that ATG9A, critical for autophagosome biogenesis, is an AP-4 cargo, which is retained within the trans-Golgi network (TGN) in vivo and in culture when AP-4 function is lost. TGN retention results in depletion of axonal ATG9A, leading to defective autophagosome generation and aberrant expansions of the distal axon. The reduction in the capacity to generate axonal autophagosomes leads to defective axonal extension and de novo generation of distal axonal swellings containing accumulated ER, underlying the impaired axonal integrity in AP-4 deficiency syndrome

Prospective Validation of the Emergency Heart Failure Mortality Risk Grade for Acute Heart Failure: The ACUTE Study

Background: Improved risk stratification of acute heart failure in the emergency department may inform physicians\u27 decisions regarding patient admission or early discharge disposition. We aimed to validate the previously-derived Emergency Heart failure Mortality Risk Grade for 7-day (EHMRG7) and 30-day (EHMRG30-ST) mortality. Methods: We conducted a multicenter, prospective validation study of patients with acute heart failure at 9 hospitals. We surveyed physicians for their estimates of 7-day mortality risk, obtained for each patient before knowledge of the model predictions, and compared these with EHMRG7 for discrimination and net reclassification improvement. We also prospectively examined discrimination of the EHMRG30-ST model, which incorporates all components of EHMRG7 as well as the presence of ST-depression on the 12-lead ECG. Results: We recruited 1983 patients seeking emergency department care for acute heart failure. Mortality rates at 7 days in the 5 risk groups (very low, low, intermediate, high, and very high risk) were 0%, 0%, 0.6%, 1.9%, and 3.9%, respectively. At 30 days, the corresponding mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%. Compared with physician-estimated risk of 7-day mortality (PER7; c-statistic, 0.71; 95% CI, 0.64-0.78) there was improved discrimination with EHMRG7 (c-statistic, 0.81; 95% CI, 0.75-0.87; P=0.022 versus PER7) and with EHMRG7 combined with physicians\u27 estimates (c-statistic, 0.82; 95% CI, 0.76-0.88; P=0.003 versus PER7). Model discrimination increased nonsignificantly by 0.014 (95% CI, -0.009-0.037) when physicians\u27 estimates combined with EHMRG7 were compared with EHMRG7 alone (P=0.242). The c-statistic for EHMRG30-ST alone was 0.77 (95% CI, 0.73-0.81) and 30-day model discrimination increased nonsignificantly by addition of physician-estimated risk to 0.78 (95% CI, 0.73-0.82; P=0.187). Net reclassification improvement with EHMRG7 was 0.763 (95% CI, 0.465-1.062) when assessed continuously and 0.820 (0.560-1.080) using risk categories compared with PER7. Conclusions: A clinical model allowing simultaneous prediction of mortality at both 7 and 30 days identified acute heart failure patients with a low risk of events. Compared with physicians\u27 estimates, our multivariable model was better able to predict 7-day mortality and may guide clinical decisions. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02634762