Showing papers by "Trinity College, Dublin published in 2022"

The role of itaconate in host defense and inflammation

Abstract: Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate's emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.

Emerging role of exosomes as biomarkers in cancer treatment and diagnosis

Abstract: Cancer is a leading cause of death worldwide and cancer incidence and mortality are rapidly growing. These massive amounts of cancer patients require rapid diagnosis and efficient treatment strategies. However, the currently utilized methods are invasive and cost-effective. Recently, the effective roles of exosomes as promising diagnostic, prognostic, and predictive biomarkers have been revealed. Exosomes are membrane-bound extracellular vesicles containing RNAs, DNAs, and proteins, and are present in a wide array of body fluids. Exosomal cargos have shown the potential to detect various types of cancers at early stages with high sensitivity and specificity. They can also delivery therapeutic agents efficiently. In this article, an overview of recent advances in the research of exosomal biomarkers and their applications in cancer diagnosis and treatment has been provided. Furthermore, the advantages and challenges of exosomes as liquid biopsy targets are discussed and the clinical implications of using exosomal miRNAs have been revealed.

Toward exact predictions of spin-phonon relaxation times: An ab initio implementation of open quantum systems theory

Abstract: Spin-phonon coupling is the main drive of spin relaxation and decoherence in solid-state semiconductors at finite temperature. Controlling this interaction is a central problem for many disciplines, ranging from magnetic resonance to quantum technologies. Spin relaxation theories have been developed for almost a century but often employ a phenomenological description of phonons and their coupling to spin, resulting in a non-predictive tool and hindering our detailed understanding of spin dynamics. Here we combine fourth-order time-local quantum master equations with advanced electronic structure methods and perform predictions of spin-phonon relaxation time for a series of solid-state coordination compounds based on both transition metals and lanthanide Kramers ions. The agreement between experiments and simulations demonstrates that an accurate, universal and fully ab initio implementation of spin relaxation theory is possible, thus paving the way to a systematic study of spin-phonon relaxation in solid-state materials.

Measuring the Commercial Determinants of Health and Disease: A Proposed Framework.

Abstract: The commercial determinants of health (CDoH) describe the adverse health effects associated with for-profit actors and their actions. Despite efforts to advance the definition, conceptualization, and empirical analyses of CDoH, the term's practical application to mitigate these effects requires the capacity to measure the influences of specific components of CDoH and the cumulative impacts of CDoH on the health and well-being of specific populations. Building on the Global Burden of Disease Study, we begin by conceptualizing CDoH as risk factor exposures that span agency and structural influences. We identify 6 components of these influences and propose an initial set of indicators and datasets to rank exposures as high, medium, or low. These are combined into a commercial determinants of health index (CDoHi) and illustrated by 3 countries. Although now a proof of concept, comparative analysis of CDoH exposures by population, over time and space, and their associated health outcomes will become possible with further development of indicators and datasets. Expansion of the CDoHi and application to varied populations groups will enable finer targeting of interventions to reduce health harms. The measurement of improvements to health and wellness from such interventions will, in turn, inform overall efforts to address the CDoH.

Application of Nonlinear Time Series and Machine Learning Algorithms for Forecasting Groundwater Flooding in a Lowland Karst Area

Abstract: In karst limestone areas interactions between ground and surface waters can be frequent, particularly in low lying areas, linked to the unique hydrogeological dynamics of that bedrock aquifer. In extreme hydrological conditions, however, this can lead to wide-spread, long-duration flooding, resulting in significant cost and disruption. This study develops and compares a nonlinear time-series analysis based nonlinear autoregressive model with exogenous variables (NARX), machine learning based near support vector regression as well as a linear time-series ARX model in terms of their performance to predict groundwater flooding in a lowland karst area of Ireland. The models have been developed upon the results of several years of field data collected in the area, as well as the outputs of a highly calibrated semi-distributed hydraulic/hydrological model of the karst network. The prediction of total flooding volume indicates that the performances of all the models are similarly accurate up to 10 days into the future. A NARX model taking inputs of the past 5 days' flood volume; rainfall data and tidal amplitude data across the past 4 days, showed the best flood forecasting performance up to 30 days into the future. Existing real-time telemetric monitoring of water level data at two points in the catchment can be fed into the model to provide an early warning flood warning tool. The model also predicts freshwater discharge from the inter-tidal spring into the Atlantic Ocean which hitherto had not been possible to monitor.

Graviton particle statistics and coherent states from classical scattering amplitudes

Abstract: In the two-body scattering problem in general relativity, we study the final graviton particle distribution using a perturbative approach. We compute the mean, the variance and the factorial moments of the distribution from the expectation value of the graviton number operator in the KMOC formalism. For minimally coupled scalar particles, the leading deviation from the Poissonian distribution is given by the unitarity cut involving the six-point tree amplitude with the emission of two gravitons. We compute this amplitude in two independent ways. First, we use an extension of the Cheung-Remmen parametrization that includes minimally coupled scalars. We then repeat the calculation using on-shell BCFW-like techniques, finding complete agreement. In the classical limit, this amplitude gives a purely quantum contribution, proving that we can describe the final semiclassical radiation state as a coherent state at least up to order $\mathcal{O}(G^4)$ for classical radiative observables. Finally, we give general arguments about why we expect this to hold also at higher orders in perturbation theory.

Understanding of adopting flat-top laser in laser powder bed fusion processed Inconel 718 alloy: simulation of single-track scanning and experiment

Abstract: Laser beam intensity profile used in laser powder bed fusion (LPBF) process is generally Gaussian, which may not be the best to deliver site-specific microstructures. In this study, a flat-top laser with large-size laser spot and uniform intensity distribution is adopted in the LPBF process with Inconel 718 powder. Comparison investigations are conducted to the standard Gaussian laser. Firstly, the parameters for the flat-top laser are optimized by multi-physics simulation of single tracks. Then, the thermodynamic behaviors and morphologies of the molten pool are observed combined with experiments. A cubic sample is also fabricated utilizing double-laser system to reveal the different characteristics of the resultant microstructures. The results show that the flat-top laser can work at a relatively wider range of laser power without depression, which often occurs in the case of Gaussian laser. The molten pool induced by the flat-top laser has large width-depth ratio with a flat bottom boundary, and more moderate flow in the half bottom. These features combined with the temperature and flow fields of the flat-top laser provide advantageous conditions for directional epitaxial growth of columnar grains during multi-layer fabrication. The epitaxial growth is retained and can extends to 4 mm from the single-crystal baseplate. This demonstrates great potential of LPBF with the adopted flat-top laser to be applied in fabricating or repairing components with directional crystal structures or single-crystal structures.

Numerical experiments to help understand cause and effect in massive star evolution

Abstract: The evolution of massive stars is affected by a variety of physical processes including convection, rotation, mass loss and binary interaction. Because these processes modify the internal chemical abundance profiles in multiple ways simultaneously, it can be challenging to determine which properties of the stellar interior are primarily driving the overall evolution. Building on previous work, we develop a new modelling approach called SNAPSHOT that allows us to isolate the key features of the internal abundance profile that drive the evolution of massive stars. Using our approach, we compute numerical stellar structure models in thermal equilibrium covering key phases of stellar evolution. For the main sequence, we demonstrate that models with the same mass and very similar surface properties can have different internal distributions of hydrogen and convective core masses. We discuss why massive stars expand after the main sequence and the fundamental reasons for why they become red, blue or yellow supergiants. For the post-main sequence, we demonstrate that small changes in the abundance profile can cause very large effects on the surface properties. We also discuss the effects that produce blue supergiants and the cause of blue loops. Our models show that massive stars with lower metallicity tend to be more compact due to the combined effect of lower CNO abundances in the burning regions and lower opacity in the envelope.

The political economy of reforms in Central Bank design: evidence from a new dataset

Abstract: Abstract What explains the worldwide changes in central bank design over the past five decades? Using a new dataset on central bank institutional design, this paper investigates the timing, pace and magnitude of reforms in a sample of 154 countries over the period 1972–2017. I construct a new dynamic index of central bank independence (CBI) and show that past levels of independence, as well as regional convergence, represent important drivers of changes in central bank design. An external pressure, such as obtaining an IMF loan, or political events, such as democratic reforms and the election of nationalistic governments, also impact the reform process. Reforms also follow periods of high inflation rates suggesting an endogenous evolution of CBI. The results also reveal important heterogeneities in the reform process depending on the level of development, the size and direction of reforms, as well as the different dimensions along which central bank legislation can be amended.

Bioprinting of biomimetic self-organised cartilage with a supporting joint fixation device.

Abstract: Despite sustained efforts, engineering truly biomimetic articular cartilage (AC) via traditional top-down approaches remains challenging. Emerging biofabrication strategies, from 3D bioprinting to scaffold-free approaches that leverage principles of cellular self-organisation, are generating significant interest in the field of cartilage tissue engineering as a means of developing biomimetic tissue analoguesin vitro.Although such strategies have advanced the quality of engineered cartilage, recapitulation of many key structural features of native AC, in particular a collagen network mimicking the tissue's 'Benninghoff arcade', remains elusive. Additionally, a complete solution to fixating engineered cartilagesin situwithin damaged synovial joints has yet to be identified. This study sought to address both of these key challenges by engineering biomimetic AC within a device designed to anchor the tissue within a synovial joint defect. We first designed and fabricated a fixation device capable of anchoring engineered cartilage into the subchondral bone. Next, we developed a strategy for inkjet printing porcine mesenchymal stem/stromal cells (MSCs) into this supporting fixation device, which was also designed to provide instructive cues to direct the self-organisation of MSC condensations towards a stratified engineered AC. We found that a higher starting cell-density supported the development of a more zonally defined collagen network within the engineered tissue. Dynamic culture was implemented to further enhance the quality of this engineered tissue, resulting in an approximate 3 fold increase in glycosaminoglycan and collagen accumulation. Ultimately this strategy supported the development of AC that exhibited near-native levels of glycosaminoglycan accumulation (>5% WW), as well as a biomimetic collagen network organisation with a perpendicular to a parallel fibre arrangement (relative to the tissue surface) from the deep to superficial zones via arcading fibres within the middle zone of the engineered tissue. Collectively, this work demonstrates the successful convergence of novel biofabrication methods, bioprinting strategies and culture regimes to engineer a hybrid implant suited to resurfacing AC defects.

Celestial holography on Kerr-Schild backgrounds

Abstract: A bstract We explore the celestial holography proposal for non-trivial asymptotically flat backgrounds including the Coulomb field of a static and spinning point charge, their gravitational counterparts described by the Schwarzschild and Kerr metrics, as well as the Aichelburg-Sexl shockwave and spinning shockwave geometries and their electromagnetic cousins. We compute celestial two-point amplitudes on these Kerr-Schild type backgrounds which have the desirable feature, due to the presence of an external source, that they are non-vanishing for general operator positions and are not constrained by the kinematic delta functions of flat space celestial CFT correlators. Of particular interest is the case of shockwave backgrounds where the two-point scattering amplitude of massless scalars can be interpreted as a standard CFT three-point correlator between two massless asymptotic states and a conformal primary shockwave operator. We furthermore show that the boundary on-shell action for general backgrounds becomes the generating functional for tree-level correlation functions in celestial CFT. Finally, we derive (conformal) Faddeev-Kulish dressings for particle-like backgrounds which remove all infrared divergent terms in the two-point functions to all orders in perturbation theory.

Electrical conductivity of polymer-graphene composites

Abstract: In this chapter, the focus has been put on the electrical conductivity of polymer/graphene composites prepared by different techniques. Initially, we discussed the electrical conductivity of different types of graphenes like pristine graphene, graphene oxide (GO), reduced GO, chemically vapor deposited graphene, and liquid exfoliated graphene. Thermally exfoliated pristine graphene showed the highest electrical conductivity; whereas, highly functionalized GO exhibited the lowest conductivity. The electrical percolation threshold and the ultimate conductivity values of these graphene-based polymer composites are reported and discussed elaborately. Several dependent phenomena of electrical conductivity like types of polymer and graphene, loading of graphene, processing techniques, alignment of graphene etc. are presented here in details. Finally, possible applications of these conductive polymer/graphene composites like sensors, electromagnetic interference shielding are mentioned within the text.

No evidence for tephra in Greenland from the historic eruption of Vesuvius in 79 CE: implications for geochronology and paleoclimatology

Abstract: Abstract. Volcanic fallout in polar ice sheets provides important opportunities to date and correlate ice-core records as well as to investigate the environmental impacts of eruptions. Only the geochemical characterization of volcanic ash (tephra) embedded in the ice strata can confirm the source of the eruption, however, and is a requisite if historical eruption ages are to be used as valid chronological checks on annual ice layer counting. Here we report the investigation of ash particles in a Greenland ice core that are associated with a volcanic sulfuric acid layer previously attributed to the 79 CE eruption of Vesuvius. Major and trace element composition of the particles indicates that the tephra does not derive from Vesuvius but most likely originates from an unidentified eruption in the Aleutian arc. Using ash dispersal modeling, we find that only an eruption large enough to include stratospheric injection is likely to account for the sizable (24–85 µm) ash particles observed in the Greenland ice at this time. Despite its likely explosivity, this event does not appear to have triggered significant climate perturbations, unlike some other large extratropical eruptions. In light of a recent re-evaluation of the Greenland ice-core chronologies, our findings further challenge the previous assignation of this volcanic event to 79 CE. We highlight the need for the revised Common Era ice-core chronology to be formally accepted by the wider ice-core and climate modeling communities in order to ensure robust age linkages to precisely dated historical and paleoclimate proxy records.

Reappraisal of Fall-Cone Flow Curve for Soil Plasticity Determinations

Abstract: Several attempts have been made to devise alternate plastic limit (PL) determination methods, targeting higher degrees of repeatability and reproducibility. Among these, empirical-type correlations linking the plasticity index (PI) to the flow index (FI)—the slope magnitude of the flow curve—seem to be gaining increased attention, particularly for the fall-cone (FC) approach, and hence demand further examination. To better understand the true potentials and limitations of this emerging practice for soil plasticity determination, this study presents a critical statistical appraisal of FI-based correlations—using a large and diverse database of 230 FC tests (for the 80 g–30° cone)—in estimating the PI (and hence the PL). It is demonstrated that the so-called “strong” correlation between the PI and FI reported in some literature, favoring the use of FI as a PI estimator, is an overlooked “statistical pitfall” originating from an over-reliance on the coefficient of determination (R2) statistic. Employing appropriate error-related statistics, it is shown that the PI predictions made by FI-based correlations are associated with high average errors of 22–33 %. Hence, such correlations, at best, can only provide a rough approximation of the actual PI (and hence PL). An attempt is also made to assess the validity of FI-based correlations in the context of soil classification using the Casagrande-style plasticity chart. The agreement level between the conventional classification approach and that performed using PI deduced from FI-based correlations was 75–80 %. This analysis, however, did not account for errors in the rolling-thread plastic limit data, maintaining a strong possibility that FI-based correlations may be suitable for routine soil classification purposes.

Immunothrombosis and the molecular control of tissue factor by pyroptosis: prospects for new anticoagulants

Abstract: The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional 'waterfall' model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1β and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.

CROSS Versus FLOT Regimens in Esophageal and Esophagogastric Junction Adenocarcinoma

Abstract: The FLOT protocol and the CROSS trimodality regimen represent current standards in the management of locally advanced esophageal adenocarcinoma. In the absence of published Randomised Controlled Trial data, this propensity-matched comparison evaluated tolerance, toxicity, impact on sarcopenia and pulmonary physiology, operative complications, and oncologic metrics.Two hundred and twenty-two patients, 111 in each arm, were included from 2 high-volume centers. Computed tomography-measured sarcopenia, and pulmonary function (forced expiratory volume in first second/forced vital capacity/diffusion capacity for carbon monoxide) were compared pretherapy and posttherapy. Operative complications were defined as per the Esophageal Complications Consensus Group (ECCG) criteria, and severity per Clavien-Dindo. Tumor regression grade and R status were measured, and survival estimated per Kaplan-Meier.A total of 83% were male, cT3/cN+ was 92%/68% for FLOT, and 86%/60% for CROSS. The full prescribed regimen was tolerated in 40% of FLOT patients versus 92% for CROSS. Sarcopenia increased from 16% to 33% for FLOT, and 14% to 30% in CROSS ( P <0.01 between arms). Median decrease in diffusion capacity for carbon monoxide was -8.25% (-34 to 25) for FLOT, compared with -13.8%(-38 to 29), for CROSS ( P =0.01 between arms). Major pathologic response was 27% versus 44% for FLOT and CROSS, respectively ( P =0.03). In-hospital mortality, respectively, was 1% versus 2% ( P =0.9), and Clavien Dindo >III 22% versus 27% ( P =0.59), however, respiratory failure was increased by CROSS, at 13% versus 3% ( P <0.001). Three-year survival was similar at 63% (FLOT) and 60% (CROSS) ( P =0.42).Both CROSS and FLOT resulted in equivalent survival. Operative outcomes were similar, however, the CROSS regimen increased postoperative respiratory failure and atrial fibrillation. Less than half of patients received the prescribed FLOT regimen, although toxicity rates were acceptable. These data support clinical equipoise, caution, however, may be advised with CROSS in patients with greatest respiratory risk.

Coronal Mass Ejections and Type II Radio Emission Variability during a Magnetic Cycle on the Solar-type Star ϵ Eridani

Abstract: Abstract We simulate possible stellar coronal mass ejection (CME) scenarios over the magnetic cycle of ϵ Eridani (18 Eridani; HD 22049). We use three separate epochs from 2008, 2011, and 2013, and estimate the radio emission frequencies associated with these events. These stellar eruptions have proven to be elusive, although a promising approach to detect and characterize these phenomena are low-frequency radio observations of potential type II bursts as CME-induced shocks propagate through the stellar corona. Stellar type II radio bursts are expected to emit below 450 MHz, similarly to their solar counterparts. We show that the length of time these events remain above the ionospheric cutoff is not necessarily dependent on the stellar magnetic cycle, but more on the eruption location relative to the stellar magnetic field. We find that these type II bursts would remain within the frequency range of LOFAR for a maximum of 20–30 minutes post-eruption for the polar CMEs (50 minutes for second harmonics). We find evidence of slower equatorial CMEs, which result in slightly longer observable windows for the 2008 and 2013 simulations. Stellar magnetic geometry and strength have a significant effect on the detectability of these events. We place the CMEs in the context of the stellar mass-loss rate (27–48× solar mass-loss rate), showing that they can amount to 3%–50% of the stellar wind mass-loss rate for ϵ Eridani. Continuous monitoring of likely stellar CME candidates with low-frequency radio telescopes will be required to detect these transient events.

Lyapunov equation in open quantum systems and non-Hermitian physics

Abstract: The continuous-time differential Lyapunov equation is widely used in linear optimal control theory, a branch of mathematics and engineering. In quantum physics, it is known to appear in Markovian descriptions of linear (quadratic Hamiltonian, linear equations of motion) open quantum systems, typically from quantum master equations. Despite this, the Lyapunov equation is seldom considered a fundamental formalism for linear open quantum systems. In this work we aim to change that. We establish the Lyapunov equation as a fundamental and efficient formalism for linear open quantum systems that can go beyond the limitations of various standard quantum master equation descriptions, while remaining of much less complexity than general exact formalisms. This also provides valuable insights for non-Hermitian quantum physics. In particular, we derive the Lyapunov equation for the most general number conserving linear system in a lattice of arbitrary dimension and geometry, connected to an arbitrary number of baths at different temperatures and chemical potentials. Three slightly different forms of the Lyapunov equation are derived via an equation of motion approach, by making increasing levels of controlled approximations, without reference to any quantum master equation. Then we discuss their relation with quantum master equations, positivity, accuracy and additivity issues, the possibility of describing dark states, general perturbative solutions in terms of single-particle eigenvectors and eigenvalues of the system, and quantum regression formulas. Our derivation gives a clear understanding of the origin of the non-Hermitian Hamiltonian describing the dynamics and separates it from the effects of quantum and thermal fluctuations. Many of these results would have been hard to obtain via standard quantum master equation approaches.