Showing papers by "Trinity College, Dublin published in 2018"
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Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4 +414 more•Institutions (209)
TL;DR: The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities, and a checklist is provided with summaries of key points.
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
5,988 citations
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Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4 +183 more•Institutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
3,301 citations
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TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
1,898 citations
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Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan1, Brendan Bulik-Sullivan2 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
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TL;DR: It is shown that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 by lipopolysaccharide in mouse and human macrophages and that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconates production.
Abstract: WebTreatment of lipopolysaccharide-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-inflammatory transcription factor Nrf2 by alkylating key cysteine residues on the KEAP1 protein.
948 citations
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20 May 2018TL;DR: OmniLedger ensures security and correctness by using a bias-resistant public-randomness protocol for choosing large, statistically representative shards that process transactions, and by introducing an efficient cross-shard commit protocol that atomically handles transactions affecting multiple shards.
Abstract: Designing a secure permissionless distributed ledger (blockchain) that performs on par with centralized payment processors, such as Visa, is a challenging task. Most existing distributed ledgers are unable to scale-out, i.e., to grow their total processing capacity with the number of validators; and those that do, compromise security or decentralization. We present OmniLedger, a novel scale-out distributed ledger that preserves longterm security under permissionless operation. It ensures security and correctness by using a bias-resistant public-randomness protocol for choosing large, statistically representative shards that process transactions, and by introducing an efficient cross-shard commit protocol that atomically handles transactions affecting multiple shards. OmniLedger also optimizes performance via parallel intra-shard transaction processing, ledger pruning via collectively-signed state blocks, and low-latency "trust-but-verify" validation for low-value transactions. An evaluation of our experimental prototype shows that OmniLedger’s throughput scales linearly in the number of active validators, supporting Visa-level workloads and beyond, while confirming typical transactions in under two seconds.
856 citations
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TL;DR: In this article, the authors analyse the relationship between three popular cryptocurrencies and a variety of other financial assets and find evidence of the relative isolation of these assets from the financial and economic assets.
813 citations
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VU University Amsterdam1, Erasmus University Rotterdam2, Karolinska Institutet3, Charité4, Virginia Commonwealth University5, South London and Maudsley NHS Foundation Trust6, QIMR Berghofer Medical Research Institute7, King's College London8, University of Southern Denmark9, University of California, Riverside10, University of Southern California11, University of Minnesota12, University of Queensland13, University College London14, Johns Hopkins University15, University of California, Los Angeles16, University of Crete17, Harvard University18, Veterans Health Administration19, Icahn School of Medicine at Mount Sinai20, Yale University21, Haukeland University Hospital22, Trinity College, Dublin23, University of Edinburgh24, North Shore-LIJ Health System25, Hofstra University26, National Institutes of Health27, University of Bergen28, Oslo University Hospital29, National University of Ireland, Galway30, University of Helsinki31, University of Oslo32, Martin Luther University of Halle-Wittenberg33, Duke University34, Mental Health Research Institute35, National and Kapodistrian University of Athens36, University of Colorado Boulder37, Imperial College London38, University of Manchester39, Wellcome Trust40, Manchester Academic Health Science Centre41, Stanford University42, University of Oregon43, University of Toronto44, University of Michigan45, Erasmus University Medical Center46, Broad Institute47, University of North Carolina at Chapel Hill48
TL;DR: A large-scale genetic association study of intelligence identifies 190 new loci and implicates 939 new genes related to neurogenesis, neuron differentiation and synaptic structure, a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Abstract: Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
800 citations
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TL;DR: Through MixSIAR, an inclusive, rich, and flexible Bayesian tracer mixing model framework implemented as an open-source R package, the disparate array of mixing model tools are consolidated into a single platform, diversified the set of available parameterizations, and provided developers a platform upon which to continue improving mixing model analyses in the future.
Abstract: The ongoing evolution of tracer mixing models has resulted in a confusing array of software tools that differ in terms of data inputs, model assumptions, and associated analytic products. Here we introduce MixSIAR, an inclusive, rich, and flexible Bayesian tracer (e.g., stable isotope) mixing model framework implemented as an open-source R package. Using MixSIAR as a foundation, we provide guidance for the implementation of mixing model analyses. We begin by outlining the practical differences between mixture data error structure formulations and relate these error structures to common mixing model study designs in ecology. Because Bayesian mixing models afford the option to specify informative priors on source proportion contributions, we outline methods for establishing prior distributions and discuss the influence of prior specification on model outputs. We also discuss the options available for source data inputs (raw data versus summary statistics) and provide guidance for combining sources. We then describe a key advantage of MixSIAR over previous mixing model software-the ability to include fixed and random effects as covariates explaining variability in mixture proportions and calculate relative support for multiple models via information criteria. We present a case study of Alligator mississippiensis diet partitioning to demonstrate the power of this approach. Finally, we conclude with a discussion of limitations to mixing model applications. Through MixSIAR, we have consolidated the disparate array of mixing model tools into a single platform, diversified the set of available parameterizations, and provided developers a platform upon which to continue improving mixing model analyses in the future.
580 citations
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TL;DR: For the first time, specific loci that distinguish between BD and SCZ are discovered and polygenic components underlying multiple symptom dimensions are identified that point to the utility of genetics to inform symptomology and potential treatment.
569 citations
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TL;DR: The use of nanoparticles still presents a challenge to therapy and much more research is needed in order to overcome this, so the current research on nanoparticles and other nanomaterials are summarized.
Abstract: Infectious diseases remain one of the leading causes of morbidity and mortality worldwide. The WHO and CDC have expressed serious concern regarding the continued increase in the development of multidrug resistance among bacteria. Therefore, the antibiotic resistance crisis is one of the most pressing issues in global public health. Associated with the rise in antibiotic resistance is the lack of new antimicrobials. This has triggered initiatives worldwide to develop novel and more effective antimicrobial compounds as well as to develop novel delivery and targeting strategies. Bacteria have developed many ways by which they become resistant to antimicrobials. Among those are enzyme inactivation, decreased cell permeability, target protection, target overproduction, altered target site/enzyme, increased efflux due to over-expression of efflux pumps, among others. Other more complex phenotypes, such as biofilm formation and quorum sensing do not appear as a result of the exposure of bacteria to antibiotics although, it is known that biofilm formation can be induced by antibiotics. These phenotypes are related to tolerance to antibiotics in bacteria. Different strategies, such as the use of nanostructured materials, are being developed to overcome these and other types of resistance. Nanostructured materials can be used to convey antimicrobials, to assist in the delivery of novel drugs or ultimately, possess antimicrobial activity by themselves. Additionally, nanoparticles (e.g., metallic, organic, carbon nanotubes, etc.) may circumvent drug resistance mechanisms in bacteria and, associated with their antimicrobial potential, inhibit biofilm formation or other important processes. Other strategies, including the combined use of plant-based antimicrobials and nanoparticles to overcome toxicity issues, are also being investigated. Coupling nanoparticles and natural-based antimicrobials (or other repurposed compounds) to inhibit the activity of bacterial efflux pumps; formation of biofilms; interference of quorum sensing; and possibly plasmid curing, are just some of the strategies to combat multidrug resistant bacteria. However, the use of nanoparticles still presents a challenge to therapy and much more research is needed in order to overcome this. In this review, we will summarize the current research on nanoparticles and other nanomaterials and how these are or can be applied in the future to fight multidrug resistant bacteria.
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TL;DR: It is shown that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α- synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates.
Abstract: Parkinson's disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein-rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD.
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TL;DR: The present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide, and is believed to be the first ever large-scale coordinated study of WM microstructural differences in schizophrenia.
Abstract: The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
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TL;DR: The purpose of this study was to finalize the development of the International Trauma Questionnaire (ITQ), a self‐report diagnostic measure of post‐traumatic stress disorder (PTSD) and complex PTSD (CPTSD), as defined in the 11th version of theInternational Classification of Diseases (ICD‐11).
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Abstract
Objective
The purpose of this study was to finalize the development of the International Trauma Questionnaire (ITQ), a self‐report diagnostic measure of post‐traumatic stress disorder (PTSD) and complex PTSD (CPTSD), as defined in the 11th version of the International Classification of Diseases (ICD‐11).
Method
The optimal symptom indicators of PTSD and CPTSD were identified by applying item response theory (IRT) analysis to data from a trauma‐exposed community sample (n = 1051) and a trauma‐exposed clinical sample (n = 247) from the United Kingdom. The validity of the optimized 12‐item ITQ was assessed with confirmatory factor analyses. Diagnostic rates were estimated and compared to previous validation studies.
Results
The latent structure of the 12‐item, optimized ITQ was consistent with prior findings, and diagnostic rates of PTSD and CPTSD were in line with previous estimates.
Conclusion
The ITQ is a brief, simply worded measure of the core features of PTSD and CPTSD. It is consistent with the organizing principles of the ICD‐11 to maximize clinical utility and international applicability through a focus on a limited but central set of symptoms. The measure is freely available and can be found in the body of this paper.
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TL;DR: In this article, a scalable, low-cost stamping strategy was used to produce flexible all-MXene MSCs with controlled architectures, which can be easily scaled up by designing pad or cylindrical stamps, followed by a cold rolling process.
Abstract: The fast growth of portable smart electronics and internet of things have greatly stimulated the demand for miniaturized energy storage devices. Micro-supercapacitors (MSCs), which can provide high power density and a long lifetime, are ideal stand-alone power sources for smart microelectronics. However, relatively few MSCs exhibit both high areal and volumetric capacitance. Here rapid production of flexible MSCs is demonstrated through a scalable, low-cost stamping strategy. Combining 3D-printed stamps with arbitrary shapes and 2D titanium carbide or carbonitride inks (Ti3C2Tx and Ti3CNTx, respectively, known as MXenes), flexible all-MXene MSCs with controlled architectures are produced. The interdigitated Ti3C2Tx MSC exhibits high areal capacitance: 61 mF cm−2 at 25 μA cm−2 and 50 mF cm−2 as the current density increases by 32 fold. The Ti3C2Tx MSCs also showcase capacitive charge storage properties, good cycling lifetime, high energy and power densities, etc. The production of such high-performance Ti3C2Tx MSCs can be easily scaled up by designing pad or cylindrical stamps, followed by a cold rolling process. Collectively, the rapid, efficient production of flexible allMXene MSCs with state-of-the-art performance opens new exciting opportunities for future applications in wearable and portable electronics.
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Harvard University1, Max Planck Society2, University of Tübingen3, Hungarian Academy of Sciences4, Howard Hughes Medical Institute5, University College Dublin6, University of Vienna7, University of Coimbra8, University of Ferrara9, University of Adelaide10, Trinity College, Dublin11, University of Cambridge12, Broad Institute13, Emory University14, University of Florence15, Bulgarian Academy of Sciences16, Danube Private University17, Romanian Academy18, Centre national de la recherche scientifique19, Eötvös Loránd University20, Sofia University21, University of Oxford22, University of Wyoming23, University of Zagreb24, Pennsylvania State University25, National Academy of Sciences of Ukraine26, Université de Montréal27, University of Bucharest28, Ludwig Maximilian University of Munich29, University of Edinburgh30, University of Wisconsin-Madison31, University of Palermo32, Croatian Academy of Sciences and Arts33, Naturhistorisches Museum34, Russian Academy of Sciences35, University of Toronto36, University of Latvia37, Durham University38, University of Hull39, Grand Valley State University40, Columbia University41
TL;DR: It is shown that southeastern Europe continued to be a nexus between east and west after the arrival of farmers, with intermittent genetic contact with steppe populations occurring up to 2,000 years earlier than the migrations from the steppe that ultimately replaced much of the population of northern Europe.
Abstract: Farming was first introduced to Europe in the mid-seventh millennium bc, and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe. Here, to und ...
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TL;DR: Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia and Charcot-Marie-Tooth type 2.
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TL;DR: In this paper, the authors combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci associated with general cognitive function.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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TL;DR: This tutorial review takes a look back on and provides an overview of the birth and growth of the field of molecular logics, and "boldly go where no silicon-based logic gate has gone before" and seek out a new deeper understanding of life inside tissues and cells.
Abstract: The field of molecular logic gates originated 25 years ago, when A. P. de Silva published a seminal article in Nature. Stimulated by this ground breaking research, scientists were inspired to join the race to simulate the workings of the fundamental components of integrated circuits using molecules. The rules of this game of mimicry were flexible, and have evolved and morphed over the years. This tutorial review takes a look back on and provides an overview of the birth and growth of the field of molecular logics. Spinning-off from chemosensor research, molecular logic gates quickly proved themselves to be more than intellectual exercises and are now poised for many potential practical applications. The ultimate goal of this vein of research became clearer only recently – to “boldly go where no silicon-based logic gate has gone before” and seek out a new deeper understanding of life inside tissues and cells.
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TL;DR: It is found that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS.
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TL;DR: In this paper, the authors identify the state of the art in process optimisation which is being used to confront these challenges in the as-built state with a view to removing the reliance on post processing.
Abstract: Selective Laser Melting (SLM) is an additive manufacturing (AM) technique which has been heavily investigated for the processing of Ti-6Al-4V (Ti64) which is used in the biomedical, aerospace and other industries. To date the SLM processing of this material has been inhibited by the requirement of post processes due to three primary challenges of martensitic microstructures, undesired porosity and residual stresses which are present in the as-built state. This work identifies the state of the art in process optimisation which is being used to confront these challenges in the as-built state with a view to removing the reliance on post processing. Regarding process optimisation, maximising part density is the primary goal due to the negative influence of pores on fracture and fatigue properties. To accomplish this, a high energy input is required which results in high cooling rates during processing. It is these cooling rates which are instrumental in the microstructural evolution and residual stress production. Accordingly novel methods have been proposed which aim to maintain the necessary high level of energy input but control the cooling rates to tailor the microstructure and reduce residual stresses. Research gaps have been identified pertaining to all three of these challenges when considering mechanical properties of as-built components. Thus in its current state post processes remain critical, however promising techniques in early stage development provide encouragement going forward.
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TL;DR: It is demonstrated that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete ‘paralysis’ of their cellular metabolism and trafficking and suggested that metabolic reprogramming of NK cells may improve cancer outcomes in obesity.
Abstract: Up to 49% of certain types of cancer are attributed to obesity, and potential mechanisms include overproduction of hormones, adipokines, and insulin. Cytotoxic immune cells, including natural killer (NK) cells and CD8+ T cells, are important in tumor surveillance, but little is known about the impact of obesity on immunosurveillance. Here, we show that obesity induces robust peroxisome proliferator-activated receptor (PPAR)-driven lipid accumulation in NK cells, causing complete 'paralysis' of their cellular metabolism and trafficking. Fatty acid administration, and PPARα and PPARδ (PPARα/δ) agonists, mimicked obesity and inhibited mechanistic target of rapamycin (mTOR)-mediated glycolysis. This prevented trafficking of the cytotoxic machinery to the NK cell-tumor synapse. Inhibiting PPARα/δ or blocking the transport of lipids into mitochondria reversed NK cell metabolic paralysis and restored cytotoxicity. In vivo, NK cells had blunted antitumor responses and failed to reduce tumor growth in obesity. Our results demonstrate that the lipotoxic obese environment impairs immunosurveillance and suggest that metabolic reprogramming of NK cells may improve cancer outcomes in obesity.
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TL;DR: A new implementation of the Laporta algorithm to reduce scalar multi-loop integrals appearing in quantum field theoretic calculations to a set of master integrals is presented by using an additional algorithm based on modular arithmetic to remove linearly depen- dent equations from the system of equations arising from integration-by-parts and Lorentz identities.
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TL;DR: Findings identify citrate as an important metabolite for macrophage and DC effector function and itaconate has a direct antibacterial effect and also has been shown to act as an anti-inflammatory agent, inhibiting succinate dehydrogenase.
Abstract: Metabolism in immune cells is no longer thought of as merely a process for adenosine triphosphate (ATP) production, biosynthesis, and catabolism. The reprogramming of metabolic pathways upon activation is also for the production of metabolites that can act as immune signaling molecules. Activated dendritic cells (DCs) and macrophages have an altered Krebs cycle, one consequence of which is the accumulation of both citrate and succinate. Citrate is exported from the mitochondria via the mitochondrial citrate- carrier. Cytosolic metabolism of citrate to acetyl-coenzyme A (acetyl-CoA) is important for both fatty-acid synthesis and protein acetylation, both of which have been linked to macrophage and DC activation. Citrate-derived itaconate has a direct antibacterial effect and also has been shown to act as an anti-inflammatory agent, inhibiting succinate dehydrogenase. These findings identify citrate as an important metabolite for macrophage and DC effector function.
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TL;DR: The cold spray additive manufacturing (CSAM) has been shown to retain the original properties of the feedstock, to produce oxide-free deposits, and to not adversely influence underlying substrate materials during manufacture.
Abstract: Cold spray is a solid-state coating deposition technology which has recently been applied as an additive manufacturing process to fabricate individual components and to repair damaged components. In comparison with fusion-based high-temperature additive manufacturing processes, cold spray additive manufacturing (CSAM) has been shown to retain the original properties of the feedstock, to produce oxide-free deposits, and to not adversely influence underlying substrate materials during manufacture. Therefore, CSAM is attracting considerable attention from both scientific and industrial communities. Although CSAM is an emerging additive manufacturing technology, a body of work has been carried out by various research groups and the technology has been applied across a range of manufacturing areas. The purpose of this paper is to systematically summarize and review the CSAM-related work to date.
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TL;DR: In this paper, the authors investigate the performance and photostability of metal halide perovskites across a compositional space of formamidinium (FA) and cesium (Cs) at the A-site at various halide compositions.
Abstract: Metal halide perovskites are attractive candidates for the wide band gap absorber in tandem solar cells. While their band gap can be tuned by partial halide substitution, mixed halide perovskites often have lower open-circuit voltage than would be expected and experience photoinduced trap formation caused by halide segregation. We investigate solar cell performance and photostability across a compositional space of formamidinium (FA) and cesium (Cs) at the A-site at various halide compositions and show that using more Cs at the A-site rather than more Br at the X-site to raise band gap is more ideal as it improves both VOC and photostability. We develop band gap maps and design criteria for the selection of perovskite compositions within the CsxFA1–xPb(BryI1–y)3, space. With this, we identify perovskites with tandem-relevant band gaps of 1.68 and 1.75 eV that demonstrate high device efficiencies of 17.4 and 16.3%, respectively, and significantly improved photostability compared to that of the higher Br-co...
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University Medical Center Utrecht1, Trinity College, Dublin2, University of Turin3, King's College London4, University of Sheffield5, University of Oxford6, Instituto de Medicina Molecular7, Hannover Medical School8, University of Ulm9, Kantonsspital St. Gallen10, Katholieke Universiteit Leuven11, Beaumont Hospital12
TL;DR: An externally validated model is developed to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS and could be applied to individualised patient management, counselling, and future trial design.
Abstract: Summary Background Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. Methods We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy, or death) and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations (ie, populations not used to develop the model) using internal–external cross-validation, and quantified the discrimination using the concordance ( c ) statistic (area under the receiver operator characteristic curve) and calibration using a calibration slope. Findings Data were collected between Jan 1, 1992, and Sept 22, 2016 (the largest data-set included data from 1936 patients). The median follow-up time was 97·5 months (IQR 52·9–168·5). Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset (univariable hazard ratio [HR] 1·71, 95% CI 1·63–1·79), age at onset (1·03, 1·03–1·03), definite versus probable or possible ALS (1·47, 1·39–1·55), diagnostic delay (0·52, 0·51–0·53), forced vital capacity (HR 0·99, 0·99–0·99), progression rate (6·33, 5·92–6·76), frontotemporal dementia (1·34, 1·20–1·50), and presence of a C9orf72 repeat expansion (1·45, 1·31–1·61), all p c statistic for external predictive accuracy of the model was 0·78 (95% CI 0·77–0·80; 95% prediction interval [PI] 0·74–0·82) and the calibration slope was 1·01 (95% CI 0·95–1·07; 95% PI 0·83–1·18). The model was used to define five groups with distinct median predicted (SE) and observed (SE) times in months from symptom onset to the composite survival outcome: very short 17·7 (0·20), 16·5 (0·23); short 25·3 (0·06), 25·2 (0·35); intermediate 32·2 (0·09), 32·8 (0·46); long 43·7 (0·21), 44·6 (0·74); and very long 91·0 (1·84), 85·6 (1·96). Interpretation We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only. Funding Netherlands ALS Foundation.
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University of Geneva1, University College Dublin2, Swiss Federal Institute of Aquatic Science and Technology3, Instituto Superior de Agronomia4, Institut national de la recherche agronomique5, University of Coimbra6, University of Milano-Bicocca7, Naturalis8, Queen Mary University of London9, University of Cantabria10, Trinity College, Dublin11, University of Salento12, International Sleep Products Association13, American Museum of Natural History14, Free University of Berlin15, University of Duisburg-Essen16, Swedish University of Agricultural Sciences17
TL;DR: The main advantages and pitfalls of metabarcoding approaches to assess parameters such as richness, abundance, taxonomic composition and species ecological values, to be used for calculation of biotic indices are discussed.
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TL;DR: These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers.
Abstract: Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response.Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2 Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154-61. ©2018 AACR.
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TL;DR: These findings demonstrate that, when successfully comprehending natural speech, the human brain responds to the contextual semantic content of each word in a relatively time-locked fashion.