Analytical sun synchronous low-thrust manoeuvres

Article describes analytical sun synchronous low-thrust manoeuvres

Coupling heterogeneous continuum-particle fields to simulate non-isothermal microscale gas flows

This paper extends the hybrid computational method proposed by Docherty et al. (2014) for simulating non-isothermal rarefied gas flows at the microscale. Coupling a continuum fluid description to a direct simulation Monte Carlo (DSMC) solver, the original methodology considered the transfer of heat only, with validation performed on 1D micro Fourier flow. Here, the coupling strategy is extended to consider the transport of mass, momentum, and heat, and validation in 1D is performed on the high-speed micro Couette flow problem. Sufficient micro resolution in the hybrid method enables good agreement with an equivalent pure DSMC simulation, but the method offers no computational speed-up for this 1D problem. However, considerable speed-up is achieved for a 2D problem: gas flowing through a microscale crack is modelled as a microchannel with a high-aspect-ratio cross-section. With a temperature difference imposed between the walls of the cross-section, the hybrid method predicts the velocity and temperature variation over the cross-section very accurately; an accurate mass flow rate prediction is also obtained

Amelioration of Streptozotocin-Induced Diabetes in Mice with Cells Derived from Human Marrow Stromal Cells

Pluri-potent bone marrow stromal cells (MSCs) provide an attractive opportunity to generate unlimited glucose-responsive insulin-producing cells for the treatment of diabetes. We explored the potential for human MSCs (hMSCs) to be differentiated into glucose-responsive cells through a non-viral genetic reprogramming approach.Two HMSC lines were transfected with three genes: PDX-1, NeuroD1 and Ngn3 without subsequent selection, followed by differentiation induction in vitro and transplantation into diabetic mice. Human MSCs expressed mRNAs of the archetypal stem cell markers: Sox2, Oct4, Nanog and CD34, and the endocrine cell markers: PDX-1, NeuroD1, Ngn3, and Nkx6.1. Following gene transfection and differentiation induction, hMSCs expressed insulin in vitro, but were not glucose regulated. After transplantation, hMSCs differentiated further and approximately 12.5% of the grafted cells expressed insulin. The graft bearing kidneys contained mRNA of insulin and other key genes required for the functions of beta cells. Mice transplanted with manipulated hMSCs showed reduced blood glucose levels (from 18.9+/-0.75 to 7.63+/-1.63 mM). 13 of the 16 mice became normoglycaemic (6.9+/-0.64 mM), despite the failure to detect the expression of SUR1, a K(+)-ATP channel component required for regulation of insulin secretion.Our data confirm that hMSCs can be induced to express insulin sufficient to reduce blood glucose in a diabetic mouse model. Our triple gene approach has created cells that seem less glucose responsive in vitro but which become more efficient after transplantation. The maturation process requires further study, particularly the in vivo factors influencing the differentiation, in order to scale up for clinical purposes

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Les progrès dans la réalisation de la classification quantitative de la psychopathologie

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level'' dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity'' by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach. (C) 2020 Published by Elsevier Masson SAS

A prenylated dsRNA sensor protects against severe COVID-19

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Rarefied gas flows in microscale geometries, a hybrid simulation method

Accurate predictions of the flow behaviour in microscale geometries are needed, for example, to design and optimise micro devices, and to ensure their safety/reliability. Rarefied gas flows in such geometries tend, however, to be far from local thermodynamic equilibrium, meaning that the flow behaviour cannot be described by conventional fluid mechanics. Alternative approaches for modelling 'non-equilibrium' gas flows have been proposed in recent years; because analytical solution methods are subject to significant limitations, the direct simulation Monte Carlo (DSMC) method is, at present, the most practical numerical simulation tool for dilute gases. Unfortunately, the computational expense of tracking and computing collisions between thousands (or perhaps millions) of DSMC particles means that simulating the scales of realistic flow problems can require months (or even years) of computing time. This has resulted in the development of continuum-DSMC 'hybrid' methods, which aim to combine the efficiency of a conventional continuum-fluid description with the detail and accuracy of the DSMC method. This thesis focuses on the development of a continuum-DSMC method that offers a more general approach than existing methods. Using a heterogeneous framework with a field-wise coupling strategy, this new method is not subject to the limitations of the well-known domain decomposition framework, or the restrictions of the heterogeneous point-wise coupling approach. The continuum-fluid description is applied across the entire flow field, while the DSMC method is performed in dispersed micro elements that can be any size and at any location; these elements then provide the continuum description with updated constitutive and boundary information. Unlike most methods in the literature, the coupling strategy presented here is able to cope with heat transfer, and so non-isothermal flows can be simulated. Testing and validation of this new continuum-DSMC method is performed by simulating a number of benchmark cases and comparing the results with full DSMC solutions of the same cases. Two 1D flow problems are considered: a micro Fourier flow problem tests the energy coupling procedure of the method, and a high-speed micro Couette flow problem demonstrates the full coupling algorithm. In general, the method's accuracy is found to depend on the arrangement of the micro elements - with sufficient micro resolution, good agreement with the equivalent full DSMC simulations can be obtained. Although the hybrid method offers no computational speed-up over the full DSMC simulations for several of these 1D test cases and only modest speed-ups for the others, both of these 1D ow problems are simulated only to validate the coupling strategy of the method. Considerable speed-ups are offered by the method when simulating a larger and more realistic flow problem: a microchannel with a high-aspect-ratio cross-section acts as a representative geometry for modelling a gas flow through a narrow microscale crack. While the limitations of existing hybrid methods preclude their use for this type of high-aspect-ratio geometry, the new hybrid method is able to model this problem under isothermal and non-isothermal conditions. The implementation of the method is simplified to 2D by assuming that the flow variation in the streamwise direction is negligible, i.e. the method is applied to the microchannel cross-section only. Accurate predictions of the mass flow rate and the streamwise velocity field are obtained for a number of test cases; accurate predictions of the temperature field are also obtained when there is a temperature difference between the bounding walls.Accurate predictions of the flow behaviour in microscale geometries are needed, for example, to design and optimise micro devices, and to ensure their safety/reliability. Rarefied gas flows in such geometries tend, however, to be far from local thermodynamic equilibrium, meaning that the flow behaviour cannot be described by conventional fluid mechanics. Alternative approaches for modelling 'non-equilibrium' gas flows have been proposed in recent years; because analytical solution methods are subject to significant limitations, the direct simulation Monte Carlo (DSMC) method is, at present, the most practical numerical simulation tool for dilute gases. Unfortunately, the computational expense of tracking and computing collisions between thousands (or perhaps millions) of DSMC particles means that simulating the scales of realistic flow problems can require months (or even years) of computing time. This has resulted in the development of continuum-DSMC 'hybrid' methods, which aim to combine the efficiency of a conventional continuum-fluid description with the detail and accuracy of the DSMC method. This thesis focuses on the development of a continuum-DSMC method that offers a more general approach than existing methods. Using a heterogeneous framework with a field-wise coupling strategy, this new method is not subject to the limitations of the well-known domain decomposition framework, or the restrictions of the heterogeneous point-wise coupling approach. The continuum-fluid description is applied across the entire flow field, while the DSMC method is performed in dispersed micro elements that can be any size and at any location; these elements then provide the continuum description with updated constitutive and boundary information. Unlike most methods in the literature, the coupling strategy presented here is able to cope with heat transfer, and so non-isothermal flows can be simulated. Testing and validation of this new continuum-DSMC method is performed by simulating a number of benchmark cases and comparing the results with full DSMC solutions of the same cases. Two 1D flow problems are considered: a micro Fourier flow problem tests the energy coupling procedure of the method, and a high-speed micro Couette flow problem demonstrates the full coupling algorithm. In general, the method's accuracy is found to depend on the arrangement of the micro elements - with sufficient micro resolution, good agreement with the equivalent full DSMC simulations can be obtained. Although the hybrid method offers no computational speed-up over the full DSMC simulations for several of these 1D test cases and only modest speed-ups for the others, both of these 1D ow problems are simulated only to validate the coupling strategy of the method. Considerable speed-ups are offered by the method when simulating a larger and more realistic flow problem: a microchannel with a high-aspect-ratio cross-section acts as a representative geometry for modelling a gas flow through a narrow microscale crack. While the limitations of existing hybrid methods preclude their use for this type of high-aspect-ratio geometry, the new hybrid method is able to model this problem under isothermal and non-isothermal conditions. The implementation of the method is simplified to 2D by assuming that the flow variation in the streamwise direction is negligible, i.e. the method is applied to the microchannel cross-section only. Accurate predictions of the mass flow rate and the streamwise velocity field are obtained for a number of test cases; accurate predictions of the temperature field are also obtained when there is a temperature difference between the bounding walls