Order in the Chaos: Spin-up and Spin-down during the 2002 Outburst of SAX J1808.4-3658

We present a timing analysis of the 2002 outburst of the accreting millisecond pulsar SAX J1808.4-3658. A study of the phase delays of the entire pulse profile shows a behavior that is surprising and difficult to interpret: superposed to a general trend, a big jump by about 0.2 in phase is visible, starting at day 14 after the beginning of the outburst. An analysis of the pulse profile indicates the presence of a significant first harmonic. Studying the fundamental and the first harmonic separately, we find that the phase delays of the first harmonic are more regular, with no sign of the jump observed in the fundamental. The fitting of the phase delays of the first harmonic with a model which takes into account the observed exponential decay of the X-ray flux (and therefore of the mass accretion rate onto the neutron star) gives important information on the torque acting on the neutron star during the outburst. We find that the source shows spin-up in the first part of the outburst, while a spin-down dominates at the end. From these results we derive an estimate of the neutron star magnetic field strength.Comment: 6 pages, including 3 figures. ApJ Letters, in pres

A Systematic Review and Meta-Analysis of Alpha Synuclein Auto-Antibodies in Parkinson's Disease

Immune dysfunction has been associated with Parkinson's disease (PD) and its progression. Antibodies play an important role in both innate and adaptive responses, acting as powerful effector molecules that can propagate inflammation by activating innate immune cells. Alpha synuclein binding antibodies have been described in PD patients with conflicting associations. In this article, we consider the potential mechanistic basis of alpha synuclein auto-antibody development and function in PD. We present a systematic review and meta-analysis of antibody studies in PD cohorts showing that there is weak evidence for an increase in alpha synuclein auto-antibodies in PD patients particularly in early disease. The confidence with which this conclusion can be drawn is limited by the heterogeneity of the clinical cohorts used, inclusion of unmatched controls, inadequate power and assay related variability. We have therefore made some recommendations for the design of future studies

Tunneling transverse to a magnetic field, and how it occurs in correlated 2D electron systems

We investigate tunneling decay in a magnetic field. Because of broken time-reversal symmetry, the standard WKB technique does not apply. The decay rate and the outcoming wave packet are found from the analysis of the set of the particle Hamiltonian trajectories and its singularities in complex space. The results are applied to tunneling from a strongly correlated 2D electron system in a magnetic field parallel to the layer. We show in a simple model that electron correlations exponentially strongly affect the tunneling rate.Comment: 4 pages, 3 figure

Monocyte Function in Parkinson's Disease and the Impact of Autologous Serum on Phagocytosis.

Background: Increasing evidence implicates involvement of the innate immune system in the initiation and progression of Parkinson's disease (PD). Monocytes and monocyte-derived cells perform a number of functions, such as phagocytosis, chemotaxis, and cytokine secretion, which may be particularly relevant to PD pathology. The behavior of these cells in early-moderate disease, in conditions more similar to the in-vivo environment has not been fully evaluated. Research Question: Does monocyte function, including phagocytosis, chemotaxis and cytokine secretion, differ in early-moderate PD compared to age and gender-matched controls? Methods: Participants included PD patients (n = 41) with early-moderate stage disease (Hoehn and Yahr ≤2) and age and gender matched controls (n = 41). Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and monocytes were further separated using CD14 magnetic beads. Functional assays, including bead phagocytosis (in standard medium and autologous serum), Boyden chamber trans-well chemotaxis, and cytokine secretion on lipopolysaccharide stimulation were performed. Monocyte surface markers relating to chemotaxis were measured using immunohistochemistry and flow cytometry. Between-group analysis was performed using paired t-tests. Results: An autologous serum environment significantly increased bead phagocytosis compared to standard medium as expected, in both patients and controls. When in autologous serum, PD monocytes demonstrated enhanced phagocytosis compared to control monocytes (p = 0.029). The level of serum-based phagocytosis was influenced by complement inactivation and the origin of the serum. There were no significant differences between PD and controls in terms of standard medium based monocyte migration or cytokine secretion in this cohort. Conclusions: Autologous serum has a significant influence on monocyte phagocytosis and reveals increased phagocytic capacity in early-moderate PD compared to controls. These conditions may better reflect the function of monocytes in-vivo in PD patients than standard medium based phagocytosis assays. Further studies will be required to replicate these results in larger cohorts, including earlier and later stages of disease, and to understand which serum factors are responsible for this observation and the potential mechanistic relevance to PD pathogenesis.Funding for this work was provided by Addenbrooke’s Charitable Trust, the Rosetrees Trust and the NIHR Cambridge Biomedical Research Centre. RSW was supported by a Fellowship from Addenbrooke’s Charitable Trust. DKV is supported by a Junior Research Fellowship from Homerton College, Cambridge. KMS is supported by a Fellowship from the Wellcome Trust. CHWG is supported by a Clinician Scientist Fellowship from the Medical Research Council. RAB is an NIHR Senior Investigator and is supported by the Wellcome Trust-MRC Cambridge Stem Cell Institute

Active adaptive conservation of threatened species in the face of uncertainty

Adaptive management has a long history in the natural resource management literature, but despite this, few practitioners have developed adaptive strategies to conserve threatened species. Active adaptive management provides a framework for valuing learning by measuring the degree to which it improves long-run management outcomes. The challenge of an active adaptive approach is to find the correct balance between gaining knowledge to improve management in the future and achieving the best short-term outcome based on current knowledge. We develop and analyze a framework for active adaptive management of a threatened species. Our case study concerns a novel facial tumor disease affecting the Australian threatened species Sarcophilus harrisii: the Tasmanian devil. We use stochastic dynamic programming with Bayesian updating to identify the management strategy that maximizes the Tasmanian devil population growth rate, taking into account improvements to management through learning to better understand disease latency and the relative effectiveness of three competing management options. Exactly which management action we choose each year is driven by the credibility of competing hypotheses about disease latency and by the population growth rate predicted by each hypothesis under the competing management actions. We discover that the optimal combination of management actions depends on the number of sites available and the time remaining to implement management. Our approach to active adaptive management provides a framework to identify the optimal amount of effort to invest in learning to achieve long-run conservation objectives

Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease.

The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease

Tunneling decay in a magnetic field

We provide a semiclassical theory of tunneling decay in a magnetic field and a three-dimensional potential of a general form. Because of broken time-reversal symmetry, the standard WKB technique has to be modified. The decay rate is found from the analysis of the set of the particle Hamiltonian trajectories in complex phase space and time. In a magnetic field, the tunneling particle comes out from the barrier with a finite velocity and behind the boundary of the classically allowed region. The exit location is obtained by matching the decaying and outgoing WKB waves at a caustic in complex configuration space. Different branches of the WKB wave function match on the switching surface in real space, where the slope of the wave function sharply changes. The theory is not limited to tunneling from potential wells which are parabolic near the minimum. For parabolic wells, we provide a bounce-type formulation in a magnetic field. The theory is applied to specific models which are relevant to tunneling from correlated two-dimensional electron systems in a magnetic field parallel to the electron layer.Comment: 16 pages, 11 figure

The Eps8/IRSp53/VASP Network Differentially Controls Actin Capping and Bundling in Filopodia Formation

There is a body of literature that describes the geometry and the physics of filopodia using either stochastic models or partial differential equations and elasticity and coarse-grained theory. Comparatively, there is a paucity of models focusing on the regulation of the network of proteins that control the formation of different actin structures. Using a combination of in-vivo and in-vitro experiments together with a system of ordinary differential equations, we focused on a small number of well-characterized, interacting molecules involved in actin-dependent filopodia formation: the actin remodeler Eps8, whose capping and bundling activities are a function of its ligands, Abi-1 and IRSp53, respectively; VASP and Capping Protein (CP), which exert antagonistic functions in controlling filament elongation. The model emphasizes the essential role of complexes that contain the membrane deforming protein IRSp53, in the process of filopodia initiation. This model accurately accounted for all observations, including a seemingly paradoxical result whereby genetic removal of Eps8 reduced filopodia in HeLa, but increased them in hippocampal neurons, and generated quantitative predictions, which were experimentally verified. The model further permitted us to explain how filopodia are generated in different cellular contexts, depending on the dynamic interaction established by Eps8, IRSp53 and VASP with actin filaments, thus revealing an unexpected plasticity of the signaling network that governs the multifunctional activities of its components in the formation of filopodia

Monocyte Function in Parkinson's Disease and the Impact of Autologous Serum on Phagocytosis

Background: Increasing evidence implicates involvement of the innate immune system in the initiation and progression of Parkinson's disease (PD). Monocytes and monocyte-derived cells perform a number of functions, such as phagocytosis, chemotaxis, and cytokine secretion, which may be particularly relevant to PD pathology. The behavior of these cells in early-moderate disease, in conditions more similar to the in-vivo environment has not been fully evaluated.Research Question: Does monocyte function, including phagocytosis, chemotaxis and cytokine secretion, differ in early-moderate PD compared to age and gender-matched controls?Methods: Participants included PD patients (n = 41) with early-moderate stage disease (Hoehn and Yahr ≤2) and age and gender matched controls (n = 41). Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and monocytes were further separated using CD14 magnetic beads. Functional assays, including bead phagocytosis (in standard medium and autologous serum), Boyden chamber trans-well chemotaxis, and cytokine secretion on lipopolysaccharide stimulation were performed. Monocyte surface markers relating to chemotaxis were measured using immunohistochemistry and flow cytometry. Between-group analysis was performed using paired t-tests.Results: An autologous serum environment significantly increased bead phagocytosis compared to standard medium as expected, in both patients and controls. When in autologous serum, PD monocytes demonstrated enhanced phagocytosis compared to control monocytes (p = 0.029). The level of serum-based phagocytosis was influenced by complement inactivation and the origin of the serum. There were no significant differences between PD and controls in terms of standard medium based monocyte migration or cytokine secretion in this cohort.Conclusions: Autologous serum has a significant influence on monocyte phagocytosis and reveals increased phagocytic capacity in early-moderate PD compared to controls. These conditions may better reflect the function of monocytes in-vivo in PD patients than standard medium based phagocytosis assays. Further studies will be required to replicate these results in larger cohorts, including earlier and later stages of disease, and to understand which serum factors are responsible for this observation and the potential mechanistic relevance to PD pathogenesis