Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium ...marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A4 hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B4. We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
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► Conserved eicosanoids are regulated by LTA4H activity and impact inflammatory state ► Genotype-directed modulation of TNF improves outcomes in a zebrafish tuberculosis model ► Drug therapies tailored to lta4h genotype improve infection outcome in zebrafish ► In humans, LTA4H genotype associates with responsiveness to therapy for TB meningitis
A polymorphism in a locus that controls the balance between pro- and anti-inflammatory mediators is predictive of response to anti-inflammatory therapy in tuberculous meningitis.
The importance of real-time polymerase chain reaction (PCR) has increased steadily in clinical applications over the last decade. Many applications utilize SYBR Green I dye to follow the accumulation ...of amplicons in real time. SYBR Green I has, however, a number of limitations that include the inhibition of PCR, preferential binding to GC-rich sequences and effects on melting curve analysis. Although a few alternative dyes without some of these limitations have been recently proposed, no large-scale investigation into the properties of intercalating dyes has been performed. In this study, we investigate 15 different intercalating DNA dyes for their inhibitory effects on PCR, effects on DNA melting temperature and possible preferential binding to GC-rich sequences. Our results demonstrated that in contrast to the results of SYBR Green I, two intercalating dyes SYTO-13 and SYTO-82 do not inhibit PCR, show no preferential binding to GC rich sequences and do not influence melting temperature, Tm, even at high concentrations. In addition, SYTO-82 demonstrated a 50-fold lower detection limit in a dilution series assay. In conclusion, the properties of SYTO-82 and SYTO-13 will simplify the development of multiplex assays and increase the sensitivity of real-time PCR.
•A new crack growth model is proposed to provide a unified modeling framework.•The modeling approach incorporates both short and long propagation behavior.•Data sets of 2024-T3, 7075-T561 and ...Ti-6Al-4V alloys are used for model validation.•The model accurately predicts crack growth rates and fatigue lives of three alloys.•The model accurately simulates the variability of short crack growth behavior.
The propagation life of short cracks has a great influence on the accurate fatigue life prediction. A new crack growth model is proposed to provide a unified modeling framework for integrating short and long crack propagation in the formulation of the crack driving force to account for multiple crack growth controlling parameters. Crack propagation rates and fatigue lives predicted by the model are compared with crack growth and fatigue life data sets of 2024-T3, 7075-T561 aluminum and Ti-6Al-4V titanium alloys. Predicted results are found to be in good agreement with crack growth data and fatigue life data for these materials.
Detecting the cosmological sky-averaged (global) 21 cm signal as a function of observed frequency will provide a powerful tool to study the ionization and thermal history of the intergalactic medium ...(IGM) in the early universe (∼400 million years after the big bang). The greatest challenge in conventional total-power global 21 cm experiments is the removal of the foreground synchrotron emission (∼103-104 K) to uncover the weak cosmological signal (tens to hundreds of millikelvin), especially because the intrinsic smoothness of the foreground spectrum is corrupted by instrumental effects. Although the EDGES (Experiment to Detect the Global EoR Signature) team has recently reported an absorption profile at 78 MHz in the sky-averaged spectrum, it is necessary to confirm this detection with an independent approach. The projection effect from observing anisotropic foreground source emission with a wide-view antenna pointing at the North Celestial Pole can induce a net polarization, referred to as the projection-induced polarization effect (PIPE). Due to Earth's rotation, observations centered at the circumpolar region will impose a dynamic sky modulation on the net polarization's waveforms that is unique to the foreground component. In this study, we review the implementation practicality and underlying instrumental effects of this new polarimetry-based technique with detailed numerical simulations and a test-bed instrument, the Cosmic Twilight Polarimeter. In addition, we explore a singular value decomposition-based analysis approach for separating the foreground and instrumental effects from the background global 21 cm signal using the sky-modulated PIPE.
A novel peridynamic fatigue model is introduced that incorporates the R-ratio effects on fatigue crack growth using a two-parameter remaining-life formulation. The remaining-life formulation is ...expressed as a function of two independent peridynamic damage controlling parameters, namely cyclic bond strain and maximum cyclic bond strain. The predicted crack growth results obtained using the proposed model are in good agreement with experimental data for four different R-ratios. The proposed model provides a capability that more accurate crack growth results are determined by accounting for R-ratio effects under various loading conditions.
•The peridynamic fatigue model is solved by numerical and analytical approaches.•Experimental data of 2024-T3 aluminum is used for the model validation.•The numerical approach has shortcomings in ...accurate crack growth predictions.•The analytical approach offers good prediction accuracy for various load cases.
Fatigue crack growth assessment of 2024-T3 aluminum alloy is carried out on the basis of a recently developed peridynamic fatigue model. The governing remaining-life equation of the peridynamic fatigue model has been solved by two different approaches i.e. numerical and analytical approaches to perform fatigue-crack growth simulations for 2024-T3 aluminum specimen with a pre-existing crack. Remaining-life parameters of the numerical and analytical solution approaches are determined by calibrating with the experimental crack growth data. Fatigue crack growth predictions, and associated material deformation of the specimen under various loading conditions are simulated by the two approaches. Predicted results show that the numerical approach has shortcomings in accurate predictions of crack growth rates for the application of different loading conditions, while the analytical approach can be applied for a wide range of loading conditions with good prediction accuracy and stable simulations of the material deformation with a growing crack. Furthermore, it is found that the computational time of the analytical approach is considerably shorter in comparison with the numerical approach.
The cosmological global (sky-averaged) 21 cm signal is a powerful tool to probe the evolution of the intergalactic medium in high-redshift universe ( ). One of the biggest observational challenges is ...to remove the foreground spectrum which is at least four orders of magnitude brighter than the cosmological 21 cm emission. Conventional global 21 cm experiments rely on the spectral smoothness of the foreground synchrotron emission to separate it from the unique 21 cm spectral structures in a single total-power spectrum. However, frequency-dependent instrumental and observational effects are known to corrupt such smoothness and complicate the foreground subtraction. We introduce a polarimetric approach to measure the projection-induced polarization of the anisotropic foreground onto a stationary dual-polarized antenna. Due to Earth rotation, when pointing the antenna at a celestial pole, the revolving foreground will modulate this polarization with a unique frequency-dependent sinusoidal signature as a function of time. In our simulations, by harmonic decomposing this dynamic polarization, our technique produces two separate spectra in parallel from the same observation: (i) a total sky power consisting both the foreground and the 21 cm background and (ii) a model-independent measurement of the foreground spectrum at a harmonic consistent to twice the sky rotation rate. In the absence of any instrumental effects, by scaling and subtracting the latter from the former, we recover the injected global 21 cm model within the assumed uncertainty. We further discuss several limiting factors and potential remedies for future implementation.
In this study, a new crack growth prediction modeling approach based on an ordinary state-based peridynamic formulation is developed to improve predictive modeling of
R-
ratio effects on fatigue ...crack growth behavior. The proposed modeling method integrates the recently developed analytical remaining-life solution of the peridynamic fatigue model and a generalized two-parameter crack driving force model to predict crack growth rates at various
R-
ratios. The two-parameter driving force model is formulated to combine two independent crack growth driving force parameters of
K
max
and
Δ
K
to incorporate
R-
ratio effects on crack growth behavior. Predicted crack growth rates are validated with crack growth data at various
R
-ratio effects for 2024-T3 and 7075-T6 aluminum alloys. Results show that very good agreements between experimental data and model predictions at four different
R-
ratios for both aluminum alloys. The proposed modeling approach shows efficient and accurate computations of crack growth rates by accounting different
R-
ratio loading conditions.
Abstract
We present a Bayesian analysis of data from the FIELDS instrument on board the Parker Solar Probe (PSP) spacecraft with the aim of constraining low-frequency (≲6 MHz) sky in preparation for ...several upcoming lunar-based experiments. We utilize data recorded during PSP’s
coning roll
maneuvers, in which the axis of the spacecraft is pointed 45° off of the Sun. The spacecraft then rotates about a line between the Sun and the spacecraft with a period of 24 minutes. We reduce the data into two formats: roll-averaged, in which the spectra are averaged over the roll, and phase-binned, in which the spectra are binned according to the phase of the roll. We construct a forward model of the FIELDS observations that includes numerical simulations of the antenna beam, an analytic emissivity function of the galaxy, and estimates of the absorption due to free electrons. Fitting 5 parameters, we find that the roll-averaged data can be fit well by this model, and we obtain posterior parameter constraints that are in general agreement with previous estimates. The model is not, however, able to fit the phase-binned data well, likely due to limitations such as the lack of nonsmooth emission structure at both small and large scales, enforced symmetry between the northern and southern galactic hemispheres, and large uncertainties in the free electron density. This suggests that significant improvement in the low-frequency sky model is needed in order to fully and accurately represent the sky at frequencies below 6 MHz.
Rivers typically present heterogeneous bed material, but the effects of sediment nonuniformity on river bar characteristics are still unclear. This work investigates the impact of sediment size ...heterogeneity on alternate bars with a morphodynamic numerical model. The model is first used to reproduce a laboratory experiment showing alternate bar formation with nonuniform bed material. Subsequently, the influence of sediment size heterogeneity on alternate bars is investigated distinguishing hybrid from free bars, definition based on the presence/absence of morphodynamic forcing, considering the results of nine scenarios. In four of them, a transverse obstacle is used to generate forcing. The computations are carried out with the Telemac‐Mascaret system solving the two‐dimensional shallow‐water equations with a finite element approach, accounting for horizontal and vertical sediment sorting processes. The results show that sediment heterogeneity affects free migrating and hybrid bars in a different way. The difference lies in the presence/absence of a migration front, so that distinct relations between bed topography, bed shear stress, and sediment sorting are obtained. Sediment sorting and associated planform redistribution of bed roughness only slightly modify free migrating bar morphodynamics, whereas hybrid bars are greatly impacted, with decreased amplitude and increased wavelength. Increased sediment size heterogeneity increases the degree of sediment sorting, while the sorting pattern remains the same for both free and hybrid bars. Moreover, it produces averagely higher, longer, and faster free bars, while in the case of hybrid bars their wavelength is increased but no general trend can be determined for their amplitude.
Key Points
Free bars and hybrid bars show distinct topography, bed shear stress, sediment transport, and sediment sorting patterns
Increased sediment heterogeneity induces longer free/hybrid bars, higher free bars but no general trend for the hybrid bar amplitude
Sediment sorting does not impact the averaged free bar characteristics, while hybrid bars become longer and damped
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