Orbit period modulation for relative motion using continuous low thrust in the two-body and restricted three-body problems

This paper presents rich new families of relative orbits for spacecraft formation flight generated through the application of continuous thrust with only minimal intervention into the dynamics of the problem. Such simplicity facilitates implementation for small, low-cost spacecraft with only position state feedback, and yet permits interesting and novel relative orbits in both two- and three-body systems with potential future applications in space-based interferometry, hyperspectral sensing, and on-orbit inspection. Position feedback is used to modify the natural frequencies of the linearised relative dynamics through direct manipulation of the system eigenvalues, producing new families of stable relative orbits. Specifically, in the Hill–Clohessy–Wiltshire frame, simple adaptations of the linearised dynamics are used to produce a circular relative orbit, frequency-modulated out-of-plane motion, and a novel doubly periodic cylindrical relative trajectory for the purposes of on-orbit inspection. Within the circular restricted three-body problem, a similar minimal approach with position feedback is used to generate new families of stable, frequency-modulated relative orbits in the vicinity of a Lagrange point, culminating in the derivation of the gain requirements for synchronisation of the in-plane and out-of-plane frequencies to yield a singly periodic tilted elliptical relative orbit with potential use as a Lunar far-side communications relay. The Δv requirements for the cylindrical relative orbit and singly periodic Lagrange point orbit are analysed, and it is shown that these requirements are modest and feasible for existing low-thrust propulsion technology

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

Reversal of beta-Amyloid-Induced Microglial Toxicity In Vitro by Activation of Fpr2/3

Microglial inflammatory activity is thought to be a major contributor to the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD), and strategies to restrain their behaviour are under active investigation. Classically, anti-inflammatory approaches are aimed at suppressing proinflammatory mediator production, but exploitation of inflammatory resolution, the endogenous process whereby an inflammatory reaction is terminated, has not been fully investigated as a therapeutic approach in AD. In this study, we sought to provide proof-of-principle that the major proresolving actor, formyl peptide receptor 2, Fpr2, could be targeted to reverse microglial activation induced by the AD-associated proinflammatory stimulus, oligomeric β-amyloid (oAβ). The immortalised murine microglial cell line BV2 was employed as a model system to investigate the proresolving effects of the Fpr2 ligand QC1 upon oAβ-induced inflammatory, oxidative, and metabolic behaviour. Cytotoxic behaviour of BV2 cells was assessed through the use of cocultures with retinoic acid-differentiated human SH-SY5Y cells. Stimulation of BV2 cells with oAβ at 100 nM did not induce classical inflammatory marker production but did stimulate production of reactive oxygen species (ROS), an effect that could be reversed by subsequent treatment with the Fpr2 ligand QC1. Further investigation revealed that oAβ-induced ROS production was associated with NADPH oxidase activation and a shift in BV2 cell metabolic phenotype, activating the pentose phosphate pathway and NADPH production, changes that were again reversed by QC1 treatment. Microglial oAβ-stimulated ROS production was sufficient to induce apoptosis of bystander SH-SY5Y cells, an effect that could be prevented by QC1 treatment. In this study, we provide proof-of-concept data that indicate exploitation of the proresolving receptor Fpr2 can reverse damaging oAβ-induced microglial activation. Future strategies that are aimed at restraining neuroinflammation in conditions such as AD should examine proresolving actors as a mechanism to harness the brain’s endogenous healing pathways and limit neuroinflammatory damage

Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease

We have recently observed that the corticotrophin releasing hormone (CRF) related peptide urocortin (UCN) reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS) neuroinflammatory paradigm of Parkinson's disease (PD). To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA) and also tyrosine hydroxylase (TH) activity. Fourteen days following intranigral injections of LPS and UCN, rats showed only modest circling after DA receptor stimulation with apomorphine, in contrast to those given LPS and vehicle where circling was pronounced. In separate experiments, rats received UCN seven days following LPS, and here apomorphine challenge caused near identical circling intensity to those that received LPS and UCN concomitantly. In a similar and consistent manner with the preservation of motor function, UCN 'protected' the nigra from both DA depletion and loss of TH activity, indicating preservation of DA cells. The effects of UCN were antagonised by the non-selective CRF receptor antagonist α-helical CRF and were not replicated by the selective CRF2 ligand UCN III. This suggests that UCN is acting via CRF1 receptors, which have been shown to be anti-inflammatory in the periphery. Our data therefore indicate that UCN is capable of maintaining adequate nigrostriatal function in vivo, via CRF1 receptors following a neuro-inflammatory challenge. This has potential therapeutic implications in PD

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD.</p> <p>Methods</p> <p>Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated <it>in vivo </it>and <it>ex vivo </it>with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system.</p> <p>Results</p> <p>EX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats.</p> <p>Conclusion</p> <p>The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay.</p

The quantitative proteomic response of Synechocystis sp. PCC6803 to phosphate acclimation.

BACKGROUND: Inorganic phosphate (Pi) is a critical nutrient for all life and is periodically limiting in marine and freshwater provinces, yet little is understood how organisms acclimate to fluctuations in Pi within their environment. To investigate whole cell adaptation, we grew Synechocystis sp. PCC6803, a model freshwater cyanobacterium, in 3%, and 0.3% inorganic phosphate (Pi) media. The cells were allowed to acclimate over 60 days, and cells were harvested for quantitative high throughput mass spectrometry-based proteomics using the iTRAQ™ labelling technology. RESULTS: In total, 120 proteins were identified, and 52 proteins were considered differentially abundant compared to the control. Alkaline phosphatase (APase) activities correlated significantly (p < 0.05) with observed relative PhoA abundances. PstS1 and PstS2 were both observed, yet PstS1 was not differentially more abundant than the control. Phycobilisome protein abundances appeared to be coordinated, and are significantly less abundant in 0.3% Pi than 3% Pi cultures. Also, the central metabolic cell function appears to have shifted towards the production of (NADPH) reducing energy and nucleotide sugars. CONCLUSIONS: This acclimation response bears strong similarity to the previously reported response to nitrogen deprivation within Synechocystis sp. PCC 6803. However, it also demonstrates some characteristics of desiccation stress, such as the regulation of fatty acids and increased abundance of rehydrin in the 3% Pi culture

Substructures in lens galaxies: PG1115+080 and B1555+375, two fold configurations

We study the anomalous flux ratio which is observed in some four-image lens systems, where the source lies close to a fold caustic. In this case two of the images are close to the critical curve and their flux ratio should be equal to unity, instead in several cases the observed value differs significantly. The most plausible solution is to invoke the presence of substructures, as for instance predicted by the Cold Dark Matter scenario, located near the two images. In particular, we analyze the two fold lens systems PG1115+080 and B1555+375, for which there are not yet satisfactory models which explain the observed anomalous flux ratios. We add to a smooth lens model, which reproduces well the positions of the images but not the anomalous fluxes, one or two substructures described as singular isothermal spheres. For PG1115+080 we consider a smooth model with the influence of the group of galaxies described by a SIS and a substructure with mass $\sim 10^{5} M_{\odot}$ as well as a smooth model with an external shear and one substructure with mass $\sim 10^{8} M_{\odot}$ . For B1555+375 either a strong external shear or two substructures with mass $\sim 10^{7} M_{\odot}$ reproduce the data quite well.Comment: 26 pages, updated bibliography, Accepted for publication in Astrophysics & Space Scienc

Erratum: "A Gravitational-wave Measurement of the Hubble Constant Following the Second Observing Run of Advanced LIGO and Virgo" (2021, ApJ, 909, 218)

[no abstract available

Quin-C1: a selective Fpr2 agonist that shifts microglial phenotype following LPS and Aβ1-42 exposure

Oxidative stress and inflammation are both central contributors to Alzheimer’s disease (AD) pathology [1,2]. Microglia, the resident immune cells of the brain and spinal cord, are primary contributors the chronic oxidative and inflammatory brain environment seen in AD. Through their persistent and inappropriate activation, they consequentially contribute to neuronal damage [3]. Dampening this microglial state may provide neurons protection from this ever increasing chronic environment and is thus a potential therapeutic strategy for AD. Formyl peptide receptor 2 (Fpr2) is known to play a key role in peripheral inflammation resolution [4,5], and is expressed in microglia [6]. We have hypothesised that activation of this receptor with the agonist Quin-C1 can reduce both LPS and Aβ1-42 induced reactive oxygen species (ROS), and promote a pro-resolving microglial phenotype. Immortalised murine microglia (BV2 cells) were stimulated with LPS (50ng/ml) for 1h prior to treatment with 100nM Quin-C1. Cytokine (TNFα and IL-10) and nitric oxide (NO) production was detected at 24 and 48h. ROS were monitored with carboxy-H2DCFDA. LPS (50ng/ml) or Aβ1-42 (100nM) was administered for 10 minutes prior to Quin-C1 (100nM). ROS production was detected every 5 minutes for up to 2h. Primary murine microglia were treated with Aβ1-42 for 24h prior to Quin-C1. Expression of CD38 and CD206 were detected by flow cytometry 48h post-Aβ1-42 administration. Quin-C1 significantly suppressed LPS-induced production of TNFα and NO at both 24 and 48h. Further, Quin-C1 significantly enhanced the production of IL-10 48h post-exposure. Strikingly, Quin-C1 reduced LPS and Aβ1-42-induced ROS production back to baseline levels. This was then blocked when the Fpr2 antagonist, WRW4 (10μM), was added 5 minutes prior to Quin-C1. Finally, Quin-C1 successfully increased CD206 and reduced CD38 expression in primary murine microglia, following Aβ1-42 exposure. Together, these data highlight selective targeting of Fpr2 as a potential therapeutic target to dampen oxidative stress and neuroinflammation in AD. 1. Heneka et al. (2015). Lancet Neurol 14: 388-405. 2. Kamat et al. (2016). Mol Neurobiol 53: 648-661. 3. Cunningham C (2013). Glia 61: 71-90. 4. Vital et al. (2016). Circulation 133: 2169-79. 5. McArthur et al. (2015). J Immunol 195: 1139-51. 6. Zhu et al. (2015). J Alzheimers Dis 43: 1237-50