Abstract
We present the long-term analysis of GS 1826-238, a neutron star X-ray binary known as the
Clocked Burster
, using data from NuSTAR StrayCats. StrayCats, a catalog of NuSTAR stray light ...data, contains data from bright, off-axis X-ray sources that have not been focused by the NuSTAR optics. We obtained stray light observations of the source from 2014–2021, reduced and analyzed the data using nustar-gen-utils Python tools, demonstrating the transition of the source from the
island
atoll state to a
banana
branch. We also present the light-curve analysis of Type I X-ray bursts from the Clocked Burster and show that the bursts from the banana/soft state are systematically shorter in duration than those from the island/hard state and have a higher burst fluence. From our analysis, we note an increase in the mass accretion rate of the source, and a decrease in burst frequency with the transition.
Abstract
We present the first joint NuSTAR and NICER observations of the ultracompact X-ray binary 4U 0614+091. This source shows quasiperiodic flux variations on the timescale of ∼days. We use ...reflection modeling techniques to study various components of the accretion system as the flux varies. We find that the flux of the reflected emission and the thermal components representing the disk and the compact object trend closely with the overall flux. However, the flux of the power-law component representing the illuminating X-ray corona scales in the opposite direction, increasing as the total flux decreases. During the lowest flux observation, we see evidence of accretion disk truncation from roughly 6 gravitational radii to 11.5 gravitational radii. This is potentially analogous to the truncation seen in black hole low-mass X-ray binaries, which tends to occur during the low/hard state at sufficiently low Eddington ratios.
Noroviruses are the leading cause of acute gastroenteritis in the United States and outbreaks frequently occur in daycare settings. Results of norovirus vaccine trials have been promising, however ...there are open questions as to whether vaccination of daycare children would be cost-effective. We investigated the incremental cost-effectiveness of a hypothetical norovirus vaccination for children in daycare settings compared to no vaccination.
We conducted a model-based cost-effectiveness analysis using a disease transmission model of children attending daycare. Vaccination with a 90% coverage rate in addition to the observed standard of care (exclusion of symptomatic children from daycare) was compared to the observed standard of care. The main outcomes measures were infections and deaths averted, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER). Cost-effectiveness was analyzed from a societal perspective, including medical costs to children as well as productivity losses of parents, over a two-year time horizon. Data sources included outbreak surveillance data and published literature.
A 50% efficacious norovirus vaccine averts 571.83 norovirus cases and 0.003 norovirus-related deaths per 10,000 children compared to the observed standard of care. A $200 norovirus vaccine that is 50% efficacious has a net cost increase of $178.10 per child and 0.025 more QALYs, resulting in an ICER of $7,028/QALY. Based on the probabilistic sensitivity analysis, we estimated that a $200 vaccination with 50% efficacy was 94.0% likely to be cost-effective at a willingness-to-pay of $100,000/QALY threshold and 95.3% likely at a $150,000/QALY threshold.
Due to the large disease burden associated with norovirus, it is likely that vaccinating children in daycares could be cost-effective, even with modest vaccine efficacy and a high per-child cost of vaccination. Norovirus vaccination of children in daycare has a cost-effectiveness ratio similar to other commonly recommended childhood vaccines.
Background and Objective: Porphyromonas gingivalis, an anaerobic bacterium associated with adult periodontal disease, employs a number of pathogenic mechanisms, including protease/adhesin complexes ...(gingipains), fimbriae and hemagglutinins, to maintain attachment within colonized hosts. Here we examined the binding of gingipains and whole, live P. gingivalis cells to immobilized extracellular matrix proteins in the presence of soluble forms of the same proteins, to investigate whether this may constitute a colonization mechanism in the oral environment.
Material and Methods: Binding of purified gingipain molecules and whole bacterial cells to immobilized matrix proteins was examined in the presence and absence of soluble competitors using enzyme‐linked immunosorbent assays.
Results: Purified gingipains or whole, live bacteria preferentially bound immobilized forms of matrix proteins, even in the presence of soluble forms of the same proteins. Fimbriae appeared to be redundant for adhesion to immobilized proteins in the presence of the gingipains, indicating that the protease/adhesins and hemagglutinins may be more important for adhesion under these conditions.
Conclusion: The data presented here provide evidence for a model of adhesion for P. gingivalis within the fluid environment of the oral cavity, where preferential binding of matrix‐located proteins over soluble forms facilitates colonization of the host.
Oligonucleotides have been synthesized on hydrogen-terminated Si(111) and porous silicon using surface hydrosilation of difunctional molecules (1,(omega)-dimethoxytritylundecenol) to produce a ...monolayer bearing suitable reactive groups to allow automated solid-phase DNA synthesis. The absence of an intervening oxide enables electrochemical characterisation of the surface-bound oligonucleotides. Complementary sequences to the DNA synthesized on Si(111) undergo hybridisation at the surface and a straightforward electrochemical quantitation of the amount of synthesized DNA and its hybridisation efficiency (47%) is possible using Ru(NH3)6(3+) as a redox label. In the case of DNA synthesized in porous silicon, electron transfer (ET) between DNA and the underlying bulk semiconductor can be studied by cyclic voltammetry, however the anisotropic diffusion inside the porous layer and the large resistance of the porous silicon results in voltammograms for which thin-layer behaviour is not observed and the peak currents increase with the square root of scan rate. We interpret these voltammograms in terms of charge transport limitations in the layer of metal centres bound to the DNA inside the pores. Further evidence for this interpretation has been obtained using scanning electrochemical microscopy (SECM) to study the charge transport between redox species in films of DNA synthesized on Si(111) surfaces that are in contact with an aqueous phase. As the bulk concentration of Ru(NH3)6(3+) is reduced below about 250 microM the SECM feedback indicates that the rate of charge transport between surface-bound Ru(NH3)6(3+) exceeds that due to diffusion in the liquid phase. Electrochemical quantitation of the DNA is not possible in this situation, however we have been able to obtain independent determinations using radioassay based on 32P or UV/VIS spectrophotometry of dimethoxytrityl cation cleaved from the porous layer. In the case of the former, use of labelled complementary sequences shows an inverse relationship between the current density used to prepare the porous silicon and the amount of hybridisation. This can be interpreted in terms of the specific surface area of the porous silicon layers since the hybridisation efficiencies (ca. 40%) obtained by comparing DMT+ cleaved from sequences synthesized on the surface and then from complementary sequences after hybridisation were relatively insensitive to the current density used to prepare the layers. Our recent work has also been concerned with individual Si nanocrystals generated by breaking up porous silicon during thermal hydrosilation reactions. FTIR spectroscopy shows these particles are also coated with an organic Si-C-bonded monolayer and they form stable, non-turbid and strongly luminescent (lambdamax = 600-650 nm) dispersions in apolar solvents (L. H. Lie, M. S. Duerdin, E. M. Tuite, A. Houlton and B. R. Horrocks, J. Electroanal. Chem., 2002, 538/539, 183). The effect of carrying out synthetic reactions on the porous silicon prior to breaking up the layer is to produce instead larger, micron-scale assemblies with a nanometre scale internal structure. Micron-sized particles of porous silicon produced by breaking up the layer can be probed by confocal Raman spectroscopy using the electric field of a focused laser to trap such particles. Although these particles are also luminescent, the use of relatively long wavelength laser excitation (lambda = 785 nm) allows acquisition of Raman spectra from individual particles in the optical trap. The bulk optical phonon mode at ca. 520 cm(-1) characteristic of crystalline silicon is red-shifted and broadened providing evidence for an internal nanometre scale substructure in these micron-sized particles and we also see evidence for this mode in the colloidal suspensions of the Si nanoparticles. We propose a model for the formation of these two types of particles and briefly discuss the prospects to extend our solid-phase synthesis on porous silicon to allow the facile synthesis of luminescent Si nanocrystals bearing DNA or other biomolecules.
Abstract
Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME Foundation Leducq
BACKGROUND
In cardiac myocytes, desmosomal proteins and ion ...channels form macromolecular complexes important for maintaining cell adhesion and electrical integrity. High serum levels of androgenic anabolic steroids (AAS) promote cardiac muscle growth, but any detrimental impact on atrial gene transcription and/or electrophysiological function is unknown.
PURPOSE
To investigate the effects of chronic AAS exposure on atria in a mouse model with desmosomal impairment.
METHODS
Young (8-10 week) male wild-type (WT) and heterozygous plakoglobin-deficient (plako+/-) mice were challenged with the AAS dihydrotestosterone (DHT) or placebo for 6 weeks by osmotic mini pumps. RNA sequencing (n = 3-6 atria/group) revealed effects of genotype and DHT on left atrial (LA) transcription. Membrane-localised cardiac sodium channels (Nav1.5) were visualised using direct STochastic Optical Reconstruction Microscopy (dSTORM, n = 5-11 LA/group, 122 cells in total) and clustering of individual molecules was quantified using persistence-based clustering. Patch clamping of LA cardiac myocytes was used to record whole cell sodium currents (n = 4-5 LA/group, 77 cells in total). LA action potentials and conduction velocity were evaluated using microelectrode and optical mapping techniques (n = 5-9 LA/group).
RESULTS
DHT increased expression of pro-hypertrophic transcripts, e.g. Igf1, Mtpn, fibrosis-associated transcripts, e.g. Col1a1, Col3a1, Lox and pro-inflammatory transcripts, e.g. Ccl6, C7, in both WT and plako+/- LA. Despite Scn5a transcript levels being maintained, dSTORM identified a 29% reduction (p = 0.042) in the number of Nav1.5 localisations at the membrane of plako+/- DHT LA cardiomyocytes, and 25% fewer localisations (p = 0.005) were found within Nav1.5 clusters, compared to WT DHT. Electrophysiological methods revealed a significant reduction in peak sodium current density, decreased action potential amplitude and conduction slowing in plako+/- LA after exposure to DHT.
CONCLUSION
This data suggests that a reduction in plakoglobin expression predisposes atrial cardiomyocytes to detrimental electrophysiological effects of high testosterone levels. This is characterised by a perturbed spatial organisation of Nav1.5, decreased sodium current density and conduction slowing. Abstract Figure. Abstract Picture
Antichymotrypsin (SERPINA3) is a widely expressed member of the serpin superfamily, required for the regulation of leukocyte proteases released during an inflammatory response and with a permissive ...role in the development of amyloid encephalopathy. Despite its biological significance, there is at present no available structure of this serpin in its native, inhibitory state. We present here the first fully refined structure of a murine antichymotrypsin orthologue to 2.1 A, which we propose as a template for other antichymotrypsin-like serpins. A most unexpected feature of the structure of murine serpina3n is that it reveals the reactive center loop (RCL) to be partially inserted into the A beta-sheet, a structural motif associated with ligand-dependent activation in other serpins. The RCL is, in addition, stabilized by salt bridges, and its plane is oriented at 90 degrees to the RCL of antitrypsin. A biochemical and biophysical analysis of this serpin demonstrates that it is a fast and efficient inhibitor of human leukocyte elastase (ka: 4 +/- 0.9 x 10(6) m(-1) s(-)1) and cathepsin G (ka: 7.9 +/- 0.9 x 10(5) m(-1) s(-)1) giving a spectrum of activity intermediate between that of human antichymotrypsin and human antitrypsin. An evolutionary analysis reveals that residues subject to positive selection and that have contributed to the diversity of sequences in this sub-branch (A3) of the serpin superfamily are essentially restricted to the P4-P6' region of the RCL, the distal hinge, and the loop between strands 4B and 5B.
We present the long term analysis of GS 1826-238, a neutron star X-ray binary known as the "Clocked Burster", using data from NuSTAR StrayCats. StrayCats, a catalogue of NuSTAR stray light data, ...contains data from bright, off-axis X-ray sources that have not been focused by the NuSTAR optics. We obtained stray light observations of the source from 2014-2021, reduced and analyzed the data using nustar-gen-utils Python tools, demonstrating the transition of source from the "island" atoll state to a "banana" branch. We also present the lightcurve analysis of Type I X-Ray bursts from the Clocked Burster and show that the bursts from the banana/soft state are systematically shorter in durations than those from the island/hard state and have a higher burst fluence. From our analysis, we note an increase in mass accretion rate of the source, and a decrease in burst frequency with the transition.
Antithrombin: in control of coagulation Quinsey, Noelene S; Greedy, Ainslie L; Bottomley, Stephen P ...
The international journal of biochemistry & cell biology,
03/2004, Volume:
36, Issue:
3
Journal Article
Peer reviewed
Antithrombin is a serine proteinase inhibitor (serpin) which controls the process of coagulation. It has a well defined structure, consisting of three β-sheets, nine α-helices and a reactive centre ...loop (RCL). The RCL contains the reactive centre which harbours a bait sequence for target proteases; cleavage results in inhibition by a unique mechanism. The inhibitory activity of antithrombin is controlled by its interaction with the co-factor, heparin, which accelerates its interaction with target proteases. This ensures that heparin and its newer derivatives, such as heparin pentasaccharide, are the mainstay therapeutics for control of thrombosis or inappropriate clotting. The clinical importance of antithrombin is manifested by its clear association with thrombosis when deficiency states occur.
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