Abstract
Extracellular vesicles (EV) and the microRNAs that they contain are increasingly recognised as a rich source of informative biomarkers, reflecting pathological processes and fundamental ...biological pathways and responses. Their presence in biofluids makes them particularly attractive for biomarker identification. However, a frequent caveat in relation to clinical studies is low abundance of EV RNA content. In this study, we used NanoString nCounter technology to assess the microRNA profiles of
n
= 64 EV low concentration RNA samples (180–49125 pg), isolated from serum and cell culture media using precipitation reagent or sequential ultracentrifugation. Data was subjected to robust quality control parameters based on three levels of limit of detection stringency, and differential microRNA expression analysis was performed between biological subgroups. We report that RNA concentrations > 100 times lower than the current NanoString recommendations can be successfully profiled using nCounter microRNA assays, demonstrating acceptable output ranges for imaging parameters, binding density, positive/negative controls, ligation controls and normalisation quality control. Furthermore, despite low levels of input RNA, high‐level differential expression analysis between biological subgroups identified microRNAs of biological relevance. Our results demonstrate that NanoString nCounter technology offers a sensitive approach for the detection and profiling of low abundance EV‐derived microRNA, and may provide a solution for research studies that focus on limited sample material.
Summary Background Evidence suggests that inflammatory mediators contribute to development and progression of chronic heart failure. We therefore tested the hypothesis that immunomodulation might ...counteract this pathophysiological mechanism in patients. Methods We did a double-blind, placebo-controlled study of a device-based non-specific immunomodulation therapy (IMT) in patients with New York Heart Association (NYHA) functional class II–IV chronic heart failure, left ventricular (LV) systolic dysfunction, and hospitalisation for heart failure or intravenous drug therapy in an outpatient setting within the past 12 months. Patients were randomly assigned to receive IMT (n=1213) or placebo (n=1213) by intragluteal injection on days 1, 2, 14, and every 28 days thereafter. Primary endpoint was the composite of time to death from any cause or first hospitalisation for cardiovascular reasons. The study continued until 828 primary endpoint events had accrued and all study patients had been treated for at least 22 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00111969. Findings During a mean follow-up of 10·2 months, there were 399 primary events in the IMT group and 429 in the placebo group (hazard ratio 0·92; 95% CI 0·80–1·05; p=0·22). In two prespecified subgroups of patients—those with no history of previous myocardial infarction (n=919) and those with NYHA II heart failure (n=689)—IMT was associated with a 26% (0·74; 0·57–0·95; p=0·02) and a 39% (0·61; 95% CI 0·46–0·80; p=0·0003) reduction in the risk of primary endpoint events, respectively. Interpretation Non-specific immunomodulation may have a role as a potential treatment for a large segment of the heart failure population, which includes patients without a history of myocardial infarction (irrespective of their functional NYHA class) and patients within NYHA class II.
The first direct gravitational‐wave detection was made by the Advanced Laser Interferometer Gravitational Wave Observatory on September 14, 2015. The GW150914 signal was strong enough to be apparent, ...without using any waveform model, in the filtered detector strain data. Here, features of the signal visible in the data are analyzed using concepts from Newtonian physics and general relativity, accessible to anyone with a general physics background. The simple analysis presented here is consistent with the fully general‐relativistic analyses published elsewhere, in showing that the signal was produced by the inspiral and subsequent merger of two black holes. The black holes were each of approximately 35M⊙, still orbited each other as close as ∼350 km apart and subsequently merged to form a single black hole. Similar reasoning, directly from the data, is used to roughly estimate how far these black holes were from the Earth, and the energy that they radiated in gravitational waves.
Advanced LIGO made the first gravitational‐wave detection on September 14, 2015. The GW150914 signal was strong enough to be apparent in the cleaned detector strain data. Those features of the signal visible in these data are analyzed, using only such concepts from Newton and general relativity as are accessible to anyone with a general physics background. This simple analysis presented here is consistent with the full published analyses, in showing that the signal was produced by the inspiral and merger of two black holes, and in estimating the distance from the Earth and the energy radiated in gravitational waves.
Numerical simulations form an indispensable tool to understand the behavior of a hot plasma that is created inside a tokamak for providing nuclear fusion energy. Various aspects of tokamak plasmas ...have been successfully studied through the reduced magnetohydrodynamic (MHD) model. The need for more complete modeling through the full MHD equations is addressed here. Our computational method is presented along with measures against possible problems regarding pollution, stability, and regularity.
The problem of ensuring continuity of solutions in the center of a polar grid is addressed in the context of a finite element discretization of the full MHD equations. A rigorous and generally applicable solution is proposed here.
Useful analytical test cases are devised to verify the correct implementation of the momentum and induction equation, the hyperdiffusive terms, and the accuracy with which highly anisotropic diffusion can be simulated. A striking observation is that highly anisotropic diffusion can be treated with the same order of accuracy as isotropic diffusion, even on non-aligned grids, as long as these grids are generated with sufficient care. This property is shown to be associated with our use of a magnetic vector potential to describe the magnetic field.
Several well-known instabilities are simulated to demonstrate the capabilities of the new method. The linear growth rate of an internal kink mode and a tearing mode are benchmarked against the results of a linear MHD code. The evolution of a tearing mode and the resulting magnetic islands are simulated well into the nonlinear regime. The results are compared with predictions from the reduced MHD model.
Finally, a simulation of a ballooning mode illustrates the possibility to use our method as an ideal MHD method without the need to add any physical dissipation.
Previous work has indicated that complement is a mediator of ischemia/reperfusion (I/R) injury. To investigate the components of complement responsible for this effect, we examined a model of renal ...I/R injury in C3-, C4-, C5-, and C6-deficient mice. We occluded the renal arteries and veins (40-58 minutes) and, after reperfusion (0-72 hours), assessed renal structural and functional injury. C3-, C5-, and C6-deficient mice were protected from renal I/R injury, whereas C4-deficient mice were not protected. C6-deficient mice treated with antibody to block C5a generation showed no additional protection from I/R injury. Reconstitution with C6 alone restored the I/R injury in C6-deficient mice. Tubular epithelial cells were the main structures damaged by complement-mediated attack, and, in contrast, the renal vessels were spared. Neutrophil infiltration and myeloperoxidase activity were reduced in C-deficient mouse kidney, but by a similar extent in C3-deficient and C6-deficient mice. We conclude that the membrane attack complex of complement (in which C5 and C6 participate) may account for the effect of complement on mouse renal I/R injury. Neither C5a-mediated neutrophil infiltration nor the classic pathway, in which C4 participates, appears to contribute to I/R injury in this model. By contrast with other organs, such as the heart, the primary effect of complement in the ischemic area is on the parenchymal cell rather than the vascular endothelial cell. The membrane attack complex of complement is a potential target for prevention of I/R injury in this model.
Surface optimised S 2p photoelectron spectra show that both surface S
2− monomers and (S–S)
2− dimers are present at pyrite (1
0
0) fracture surfaces. In order to determine which sulfur species are ...involved in Cu adsorption, fresh pyrite surfaces were exposed to Cu
2+ in solution. The S 2p spectra suggest that both types of S surface species are involved in the mechanism of Cu adsorption (activation).
Ab initio density functional theory was used to model Cu adsorbed onto pyrite (1
0
0) to support the interpretation of the spectroscopy. Mulliken population analysis confirms the charge distribution suggested by the core line shifts as observed in the photoelectron spectra. The
ab initio calculations were consistent with a two-coordinate bond between Cu(I), a surface S monomer and a surface S dimer.
Euclid preparation Meneghetti, M.; Borgani, S.; Despali, G. ...
Astronomy and astrophysics (Berlin),
01/2024, Letnik:
681
Journal Article
Recenzirano
Odprti dostop
The photometric catalogue of galaxy clusters extracted from ESA
Euclid
data is expected to be very competitive for cosmological studies. Using dedicated hydrodynamical simulations, we present ...systematic analyses simulating the expected weak-lensing profiles from clusters in a variety of dynamic states and for a wide range of redshifts. In order to derive cluster masses, we use a model consistent with the implementation within the
Euclid
Consortium of the dedicated processing function and find that when we jointly model the mass and concentration parameter of the Navarro–Frenk–White halo profile, the weak-lensing masses tend to be biased low by 5–10% on average with respect to the true mass, up to
z
= 0.5. For a fixed value for the concentration
c
200
= 3, the mass bias is decreases to lower than 5%, up to
z
= 0.7, along with the relative uncertainty. Simulating the weak-lensing signal by projecting along the directions of the axes of the moment of inertia tensor ellipsoid, we find that orientation matters: when clusters are oriented along the major axis, the lensing signal is boosted, and the recovered weak-lensing mass is correspondingly overestimated. Typically, the weak-lensing mass bias of individual clusters is modulated by the weak-lensing signal-to-noise ratio, which is related to the redshift evolution of the number of galaxies used for weak-lensing measurements: the negative mass bias tends to be stronger toward higher redshifts. However, when we use a fixed value of the concentration parameter, the redshift evolution trend is reduced. These results provide a solid basis for the weak-lensing mass calibration required by the cosmological application of future cluster surveys from
Euclid
and
Rubin
.
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