Development of methods for predicting large crack growth in elastic-plastic work-hardening materials in fully plastic conditions

The objects of the first, exploratory, stage of the project were listed as: (1) to make a detailed and critical review of the Boundary Element method as already published and with regard to elastic-plastic fracture mechanics, to assess its potential for handling present concepts in two-dimensional and three-dimensional cases. To this was subsequently added the Finite Volume method and certain aspects of the Finite Element method for comparative purposes; (2) to assess the further steps needed to apply the methods so far developed to the general field, covering a practical range of geometries, work hardening materials, and composites: to consider their application under higher temperature conditions; (3) to re-assess the present stage of development of the energy dissipation rate, crack tip opening angle and J-integral models in relation to the possibilities of producing a unified technology with the previous two items; and (4) to report on the feasibility and promise of this combined approach and, if appropriate, make recommendations for the second stage aimed at developing a generalized crack growth technology for its application to real-life problems

Miro proteins coordinate microtubule- and actin-dependent mitochondrial transport and distribution

In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho-GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double-knockout mouse embryos and single- and double-knockout embryonic fibroblasts, we demonstrate the essential and non-redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double-knockout cells. In contrast, we show that TRAK2-mediated retrograde mitochondrial transport is Miro1-dependent. Interestingly, we find that Miro is critical for recruiting and stabilising the mitochondrial myosin Myo19 on the mitochondria for coupling mitochondria to the actin cytoskeleton. Moreover, Miro depletion during PINK1/Parkin-dependent mitophagy can also drive a loss of mitochondrial Myo19 upon mitochondrial damage. Finally, aberrant positioning of mitochondria in Miro1/2 double-knockout cells leads to disruption of correct mitochondrial segregation during mitosis. Thus, Miro proteins can fine-tune actin- and tubulin-dependent mitochondrial motility and positioning, to regulate key cellular functions such as cell proliferation

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

Ethanolamine phosphoglycerol attachment to eEF1A is not essential for normal growth of Trypanosoma brucei

Eukaryotic elongation factor 1A (eEF1A) is the only protein modified by ethanolamine phosphoglycerol (EPG). In mammals and plants, EPG is attached to conserved glutamate residues located in eEF1A domains II and III, whereas in the unicellular eukaryote, Trypanosoma brucei, a single EPG moiety is attached to domain III. A biosynthetic precursor of EPG and structural requirements for EPG attachment to T. brucei eEF1A have been reported, but the role of this unique protein modification in cellular growth and eEF1A function has remained elusive. Here we report, for the first time in a eukaryotic cell, a model system to study potential roles of EPG. By down-regulation of EF1A expression and subsequent complementation of eEF1A function using conditionally expressed exogenous eEF1A (mutant) proteins, we show that eEF1A lacking EPG complements trypanosomes deficient in endogenous eEF1A, demonstrating that EPG attachment is not essential for normal growth of T. brucei in culture

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta‐analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive–compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta‐analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First‐degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field