Nitric oxide function in atherosclerosis

Atherosclerosis is a chronic inflammatory process in the intima of conduit arteries, which disturbs the endothelium-dependent regulation of the vascular tone by the labile liposoluble radical nitric oxide (NO) formed by the constitutive endothelial nitric oxide synthase (eNOS). This defect predisposes to coronary vasospasm and cardiac ischaemia, with anginal pain as the typical clinical manifestation. It is now appreciated that endothelial dysfunction is an early event in atherogenesis and that it may also involve the microcirculation, in which atherosclerotic lesions do not develop. On the other hand, the inflammatory environment in atherosclerotic plaques may result in the expression of the inducible NO synthase (iNOS) isozyme. Whether the dysfunction in endothelial NO production is causal to, or the result of, atherosclerotic lesion formation is still highly debated. Most evidence supports the hypothesis that constitutive endothelial NO release protects against atherogenesis e.g. by preventing smooth muscle cell proliferation and leukocyte adhesion. Nitric oxide generated by the inducible isozyme may be beneficial by replacing the failing endothelial production but excessive release may damage the vascular wall cells, especially in combination with reactive oxygen intermediates

Modulation of nitric oxide synthase activity in macrophages

L-Arginine is converted to the highly reactive and unstable nitric oxide (NO) and L-citrulline by an enzyme named nitric oxide synthase (NOS). NO decomposes into other nitrogen oxides such as nitrite (NO2-) and nitrate (NO2-), and in the presence of superoxide anion to the potent oxidizing agent peroxynitrite (ONOO−). Activated rodent macrophages are capable of expressing an inducible form of this enzyme (iNOS) in response to appropriate stimuli, i.e., lipopolysaccharide (LPS) and interferon-γ (IFNγ). Other cytokines can modulate the induction of NO biosynthesis in macrophages. NO is a major effector molecule of the anti-microbial and cytotoxic activity of rodent macrophages against certain micro-organisms and tumour cells, respectively. The NO synthesizing pathway has been demonstrated in human monocytes and other cells, but its role in host defence seems to be accessory. A delicate functional balance between microbial stimuli, host-derived cytokines and hormones in the microenvironment regulates iNOS expression. This review will focus mainly on the known and proposed mechanisms of the regulation of iNOS induction, and on agents that can modulate NO release once the active enzyme has been expressed in the macrophage

A strongly changing accretion morphology during the outburst decay of the neutron star X-ray binary 4U 1608−52

It is commonly assumed that the properties and geometry of the accretion flow in transient low-mass X-ray binaries (LMXBs) significantly change when the X-ray luminosity decays below ∼10⁻² of the Eddington limit (L_(Edd)). However, there are few observational cases where the evolution of the accretion flow is tracked in a single X-ray binary over a wide dynamic range. In this work, we use NuSTAR and NICER observations obtained during the 2018 accretion outburst of the neutron star LMXB 4U 1608−52, to study changes in the reflection spectrum. We find that the broad Fe–Kα line and Compton hump, clearly seen during the peak of the outburst when the X-ray luminosity is ∼10³⁷ erg s⁻¹ (∼0.05 L_(Edd)), disappear during the decay of the outburst when the source luminosity drops to ∼4.5 × 10³⁵ erg s⁻¹ (∼0.002 L_(Edd)). We show that this non-detection of the reflection features cannot be explained by the lower signal-to-noise ratio at lower flux, but is instead caused by physical changes in the accretion flow. Simulating synthetic NuSTAR observations on a grid of inner disc radius, disc ionization, and reflection fraction, we find that the disappearance of the reflection features can be explained by either increased disc ionization (log ξ ≳ 4.1) or a much decreased reflection fraction. A changing disc truncation alone, however, cannot account for the lack of reprocessed Fe–Kα emission. The required increase in ionization parameter could occur if the inner accretion flow evaporates from a thin disc into a geometrically thicker flow, such as the commonly assumed formation of a radiatively inefficient accretion flow at lower mass accretion rates

Oxidized Lipoproteins Suppress Nitric Oxide Synthase in Macrophages: Study of Glucocorticoid Receptor Involvement

Activated cholesterol-laden macrophages in atherosclerotic lesions are believed to influence the progression of this disease. The induction of nitric oxide synthase (iNOS) activity was investigated in control and cholesterol-laden J774 macrophages, obtained by pre-incubation with oxidized or acetylated low density lipoproteins (oxLDL, acLDL). Loading with oxLDL caused a small induction of NOS activity in unstimulated cells, as indicated by nitrite and citrulline accumulation in the supernatant. However, it suppressed the iNOS activity resulting from stimulation of the cells with lipopolysaccharide with or without interferon-γ. AcLDL had no inhibitory effect, indicating that cholesterol accumulation as such was not responsible. Since the induction of NOS in macrophages is inhibited by glucocorticoids, the possibility that a glucocorticoid-like factor, formed during oxidation of LDL, may cause the inhibition, was investigated. However, addition of the glucocorticoid receptor antagonist mifepristone did not prevent the oxLDL-dependent NOS inhibition, indicating that the glucocorticoid receptor is not involved in the suppressive effect of oxLDL

A NICER Discovery of a Low-Frequency Quasi-Periodic Oscillation in the Soft-Intermediate State of MAXI J1535-571

We present the discovery of a low-frequency $\approx 5.7$ Hz quasi-periodic oscillation (QPO) feature in observations of the black hole X-ray binary MAXI J1535-571 in its soft-intermediate state, obtained in September-October 2017 by the Neutron Star Interior Composition Explorer (NICER). The feature is relatively broad (compared to other low-frequency QPOs; quality factor $Q\approx 2$) and weak (1.9% rms in 3-10 keV), and is accompanied by a weak harmonic and low-amplitude broadband noise. These characteristics identify it as a weak Type A/B QPO, similar to ones previously identified in the soft-intermediate state of the transient black hole X-ray binary XTE J1550-564. The lag-energy spectrum of the QPO shows increasing soft lags towards lower energies, approaching 50 ms at 1 keV (with respect to a 3-10 keV continuum). This large phase shift has similar amplitude but opposite sign to that seen in Rossi X-ray Timing Explorer data for a Type B QPO from the transient black hole X-ray binary GX 339-4. Previous phase-resolved spectroscopy analysis of the Type B QPO in GX 339-4 pointed towards a precessing jet-like corona illuminating the accretion disk as the origin of the QPO signal. We suggest that this QPO in MAXI J1535-571 may have the same origin, with the different lag sign depending on the scale height of the emitting region and the observer inclination angle.Comment: Accepted for publication in ApJ Letter

The JAX Synteny Browser for mouse-human comparative genomics.

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the browser is limited to the reference genomes for the laboratory mouse and human, the software platform is intentionally genome agnostic. The JAX Synteny Browser software can be deployed for any two genomes where genome coordinates for syntenic blocks are defined and for which biological attributes of the features in one or both genomes are available in widely used standard bioinformatics file formats. The JAX Synteny Browser is available at: http://syntenybrowser.jax.org/. The code base is available from GitHub: https://github.com/TheJacksonLaboratory/syntenybrowser and is distributed under the Creative Commons Attribution license (CC BY)

In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts

Background: While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B-lineage ALL (B-ALL). Activating mutations or overexpression of Fms-related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK-659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK-659 against pediatric ALL patient-derived xenografts (PDXs). Methods: SYK and FLT3 mRNA expression was quantified by RNA-seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45+ cells (%huCD45+) in the peripheral blood. TAK-659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45+ ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event-free survival and stringent objective response measures. Results: FLT3 and SYK mRNA expression was significantly higher in B-lineage compared with T-lineage PDXs. TAK-659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45+ was significantly reduced in five out of eight PDXs in TAK-659-treated mice compared with vehicle controls. Conclusions: TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes

A strongly changing accretion morphology during the outburst decay of the neutron star X-ray binary 4U 1608−52

It is commonly assumed that the properties and geometry of the accretion flow in transient low-mass X-ray binaries (LMXBs) significantly change when the X-ray luminosity decays below ∼10⁻² of the Eddington limit (L_(Edd)). However, there are few observational cases where the evolution of the accretion flow is tracked in a single X-ray binary over a wide dynamic range. In this work, we use NuSTAR and NICER observations obtained during the 2018 accretion outburst of the neutron star LMXB 4U 1608−52, to study changes in the reflection spectrum. We find that the broad Fe–Kα line and Compton hump, clearly seen during the peak of the outburst when the X-ray luminosity is ∼10³⁷ erg s⁻¹ (∼0.05 L_(Edd)), disappear during the decay of the outburst when the source luminosity drops to ∼4.5 × 10³⁵ erg s⁻¹ (∼0.002 L_(Edd)). We show that this non-detection of the reflection features cannot be explained by the lower signal-to-noise ratio at lower flux, but is instead caused by physical changes in the accretion flow. Simulating synthetic NuSTAR observations on a grid of inner disc radius, disc ionization, and reflection fraction, we find that the disappearance of the reflection features can be explained by either increased disc ionization (log ξ ≳ 4.1) or a much decreased reflection fraction. A changing disc truncation alone, however, cannot account for the lack of reprocessed Fe–Kα emission. The required increase in ionization parameter could occur if the inner accretion flow evaporates from a thin disc into a geometrically thicker flow, such as the commonly assumed formation of a radiatively inefficient accretion flow at lower mass accretion rates

A strongly changing accretion morphology during the outburst decay of the neutron star X-ray binary 4U 1608-52

It is commonly assumed that the properties and geometry of the accretion flow in transient low-mass X-ray binaries (LMXBs) significantly change when the X-ray luminosity decays below $\sim 10^{-2}$ of the Eddington limit ($L_{\rm Edd}$). However, there are few observational cases where the evolution of the accretion flow is tracked in a single X-ray binary over a wide dynamic range. In this work, we use NuSTAR and NICER observations obtained during the 2018 accretion outburst of the neutron star LMXB 4U 1608-52, to study changes in the reflection spectrum. We find that the broad Fe-K$\alpha$ line and Compton hump, clearly seen during the peak of the outburst when the X-ray luminosity is $\sim 10^{37}$ erg/s ($\sim 0.05$ $L_{\rm Edd}$), disappear during the decay of the outburst when the source luminosity drops to $\sim 4.5 \times 10^{35}$ erg/s ($\sim 0.002$ $L_{\rm Edd}$). We show that this non-detection of the reflection features cannot be explained by the lower signal-to-noise at lower flux, but is instead caused by physical changes in the accretion flow. Simulating synthetic NuSTAR observations on a grid of inner disk radius, disk ionisation, and reflection fraction, we find that the disappearance of the reflection features can be explained by either increased disk ionisation ($\log \xi \geq 4.1$) or a much decreased reflection fraction. A changing disk truncation alone, however, cannot account for the lack of reprocessed Fe-K$\alpha$ emission. The required increase in ionisation parameter could occur if the inner accretion flow evaporates from a thin disk into a geometrically thicker flow, such as the commonly assumed formation of an radiatively inefficient accretion flow at lower mass accretion rates.Comment: Accepted for publication in MNRA