ABSTRACT
In this paper, we compare the characteristics of pulsars with a high spin‐down energy‐loss rate () against those with a low . We show that the differences in the total intensity pulse ...morphology between the two classes are in general rather subtle. A much more significant difference is the fractional polarization which is very high for high pulsars and low for low pulsars. The at the transition is very similar to the death line predicted for curvature radiation. This suggests a possible link between high energy and radio emission in pulsars and could imply that γ‐ray efficiency is correlated with the degree of linear polarization in the radio band. The degree of circular polarization is in general higher in the second component of doubles, which is possibly caused by the effect of corotation on the curvature of the field lines in the inertial observer frame.
The most direct link between the high‐energy emission and the radio emission could be the subgroup of pulsars which we call the energetic wide beam pulsars. These young pulsars have very wide profiles with steep edges and are likely to be emitted from a single magnetic pole. The similarities with the high‐energy profiles suggest that both types of emission are produced at the same extended height range in the magnetosphere. Alternatively, the beams of the energetic wide beam pulsars could be magnified by propagation effects in the magnetosphere. This would naturally lead to decoupling of the wave modes, which could explain the high degree of linear polarization. As part of this study, we have discovered three previously unknown interpulse pulsars (and we detected one for the first time at 20 cm). We also obtained rotation measures for 18 pulsars whose values had not previously been measured.
The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune ...system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin 'flashes' occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Cryptococcus neoformans and C. gattii cause infection in the immunocompromised and immunocompetent respectively.•Compromised T cell immunity is the main predisposing factor for cryptococcal ...infection and cryptococcal meningitis.•Immunity to Cryptococcus relies on innate immune cells coordinating adaptive responses to stimulate fungal killing.•Differences in C. gattii immunity are not well studied but may result from differences in activation of inflammation.
The vast majority of infection with cryptococcal species occurs with Cryptococcus neoformans in the severely immunocompromised. A significant exception to this is the infections of those with apparently normal immune systems by Cryptococcus gattii. Susceptibility to cryptococcosis can be broadly categorised as a defect in adaptive immune responses, especially in T cell immunity. However, innate immune cells such as macrophages play a key role and are likely the primary effector cell in the killing and ultimate clearance of cryptococcal infection. In this review we discuss the current state of our understanding of how the immune system responds to cryptococcal infection in health and disease, with reference to the work communicated at the 9th International Conference on Cryptococcus and Cryptococcosis (ICCC9). We have focussed on cell mediated responses, particularly early in infection, but with the aim of presenting a broad overview of our understanding of immunity to cryptococcal infection, highlighting some recent advances and offering some perspectives on future directions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We examine the effect of Galactic diffractive interstellar scintillation as a means of explaining the reported deficit of fast radio burst (FRB) detections at low Galactic latitude. We model the ...unknown underlying FRB flux density distribution as a power law with a rate scaling as
$S_\nu ^{-5/2+\delta }$
and account for the fact that the FRBs are detected at unknown positions within the telescope beam. We find that the event rate of FRBs located off the Galactic plane may be enhanced by a factor of ∼30–300 per cent relative to objects near the Galactic plane without necessarily affecting the slope of the distribution. For FRBs whose flux densities are subject to relatively weak diffractive scintillation, as is typical for events detected at high Galactic latitudes, we demonstrate that an effect associated with Eddington bias is responsible for the enhancement. The magnitude of the enhancement increases with the steepness of the underlying flux density distribution, so that existing limits on the disparity in event rates between high and low Galactic latitudes suggest that the FRB population has a steep differential flux density distribution, scaling as
$S_\nu ^{-3.5}$
or steeper. Existing estimates of the event rate in the flux density range probed by the High Time Resolution Universe survey overestimate the true rate by a factor of ∼3.
Meningitis caused by infectious pathogens is associated with vessel damage and infarct formation, however the physiological cause is often unknown. Cryptococcus neoformans is a human fungal pathogen ...and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of patients, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model that permitted noninvasive in vivo imaging. We find that cryptococcal cells become trapped within the vasculature (dependent on their size) and proliferate there resulting in vasodilation. Localised cryptococcal growth, originating from a small number of cryptococcal cells in the vasculature was associated with sites of dissemination and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension reporter we identified dissemination from intact blood vessels and where vessel rupture occurred. Finally, we manipulated blood vessel tension via cell junctions and found increased tension resulted in increased dissemination. Our data suggest that global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction during cryptococcal meningitis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
6.
Diagnostics of timing noise in middle-aged pulsars Namkham, Nakornping; Jaroenjittichai, Phrudth; Johnston, Simon
Monthly Notices of the Royal Astronomical Society,
08/2019, Volume:
487, Issue:
4
Journal Article
Peer reviewed
Open access
ABSTRACT
Radio pulsars are often used as clocks in a wide variety of experiments. Imperfections in the clock, known as timing noise, have the potential to reduce the significance of, or even thwart ...e.g. the attempt to find a stochastic gravitational wave (GW) background. We measure the timing noise in a group of 129 mostly middle-aged pulsars (i.e. characteristic ages near 1 Myr) observed with the Parkes radio telescope on a monthly basis since 2014. We examine four different metrics for timing noise, but it remains unclear which, if any, provides the best determination. In spite of this, it is evident that these pulsars have significantly less timing noise than their younger counterparts, but significantly more than the (much older) millisecond pulsars (MSPs). As with previous authors, we find a strong correlation between timing noise and the pulsar spin-down rate, $\dot{\nu}$. However, for a given $\dot{\nu}$ there is a spread of about a factor of 30 in the strength of the timing noise likely indicating that nuclear conditions in the interior of the stars differ between objects. We briefly comment on the implications for GW detection through pulsar timing arrays as the level of timing noise in MSPs may be less than predicted.
Cryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid ...immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The cytokine interleukin-6 (IL6) and its downstream effector STAT3 constitute a key oncogenic pathway, which has been thought to be functionally connected to estrogen receptor α (ER) in breast ...cancer. We demonstrate that IL6/STAT3 signaling drives metastasis in ER+ breast cancer independent of ER. STAT3 hijacks a subset of ER enhancers to drive a distinct transcriptional program. Although these enhancers are shared by both STAT3 and ER, IL6/STAT3 activity is refractory to standard ER-targeted therapies. Instead, inhibition of STAT3 activity using the JAK inhibitor ruxolitinib decreases breast cancer invasion in vivo. Therefore, IL6/STAT3 and ER oncogenic pathways are functionally decoupled, highlighting the potential of IL6/STAT3-targeted therapies in ER+ breast cancer.
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•IL6/STAT3 signaling drives metastasis in ER+ breast cancer mouse models•IL6/STAT3 establishes shared ER-FOXA1-STAT3 enhancers independent of FOXA1•STAT3 co-opts shared enhancers to drive a distinct gene program independent of ER•JAK inhibitor ruxolitinib represses IL6/STAT3 activity and in vivo invasion
Siersbæk et al. show that IL6/STAT3 signaling is functionally decoupled from ER in breast cancer. IL6-activated STAT3 promotes metastasis by co-opting a subset of shared ER-FOXA1-STAT3 enhancers to drive a distinct transcriptional program independent of ER and FOXA1. This suggests a clinical potential for targeting IL6/STAT3 in ER+ breast cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Cryptococcus is a potentially fatal fungal pathogen and a leading cause of death in immunocompromised patients. As an opportunistic and facultative intracellular pathogen of humans, ...Cryptococcus exhibits a complex set of interactions with the host immune system in general, and macrophages in particular. Cryptococcus is resistant to phagocytosis but is also able to survive and proliferate within the mature phagolysosome. It can cause the lysis of host cells, can be transferred between macrophages or exit non‐lytically via vomocytosis. Efficient phagocytosis is reliant on opsonization and Cryptococcus has a number of anti‐phagocytic strategies including formation of titan cells and a thick polysaccharide capsule. Following uptake, phagosome maturation appears to occur normally, but the internalized pathogen is able to survive and replicate. Here we review the interactions and host manipulation processes that occur within cryptococcal‐infected macrophages and highlight areas for future research.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Upon Cryptococcus neoformans infection of the host lung, the fungus enters a nutrient poor environment and must adapt to a variety of host-specific stress conditions (temperature, nutrient ...limitation, pH, CO2). Fungal spores enter this milieu with limited nutritional reserves, germinate, and begin proliferating by budding as yeast. Although relatively little is known about the initial stages of infection, recent work has characterized changes that occur upon germination. This program and subsequent yeast-phase proliferation progress in a dynamic environment as host nutrient immunity responds to the infection via toxic accumulation or sequestration of essential micronutrients and innate immune cells are recruited to the site of infection. Adaptation to the host environment and evasion of the immune response through pathogenicity factor expression allows proliferation and dissemination to multiple sites throughout the body, including, most significantly for human disease, the central nervous system. Here we will discuss recent insights into mechanisms underlying C. neoformans interactions with the host during infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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