24-Hour efficacy of single primary selective laser trabeculoplasty versus latanoprost eye drops for Naïve primary open-angle glaucoma and ocular hypertension patients.

This prospective, observer-masked, randomized clinical trial was conducted between December 2018 and June 2021 at Eye Hospital, China Academy of Chinese Medical Sciences. A total of 45 glaucoma patients from Beijing, China, were enrolled in this clinical trial to compare the short-term efficacy of primary single-selective laser trabeculoplasty (SLT) to 0.005% latanoprost eye drops for the treatment of 24-h intraocular pressure (IOP) in patients with newly diagnosed primary open angle glaucoma (POAG) and ocular hypertension (OHT). Both SLT and latanoprost significantly decreased mean 24-h IOP and peak IOP, although the latanoprost group effect was more potent when compared to the SLT group (both Ps < 0.05). Compared with the SLT group, the latanoprost group had a significant and stable decrease in IOP after treatment. The latanoprost group had a more pronounced reduction in IOP at weeks 4 and 12 (P < 0.05) but had no difference at week 1 (P = 0.097). As a first-line treatment, both SLT and latanoprost eye drops are effective in newly diagnosed POAG and OHT patients. However, the latanoprost eye drops may be better in decreasing mean and peak 24-h IOP and thus controlling 24-h IOP fluctuation compared to SLT.

Development and validation of a microenvironment-related prognostic model for hepatocellular carcinoma patients based on histone deacetylase family.

BACKGROUND: Histone deacetylase (HDAC) family can remove acetyl groups from histone lysine residues, and their high expression is closely related to the poor prognosis of hepatocellular carcinoma (HCC) patients. Recently, it has been reported to play an immunosuppressive role in the microenvironment, but little is known about the mechanism. METHODS: Through machine learning, we trained and verified the prognostic model composed of HDACs. CIBERSORT was used to calculate the percentage of immune cells in the microenvironment. Based on co-expression network, potential targets of HDACs were screened. After that, qRT-PCR was employed to evaluate the expression of downstream genes of HDACs, while HPLC-CAD analysis was applied to detect the concentration of arachidonic acid (AA). Finally, Flow cytometry, WB and IHC experiments were used to detect CD86 expression in RAW246.7. RESULTS: We constructed a great prognostic model composed of HDAC1 and HDAC11 that was significantly associated with overall survival. These HDACs were related to the abundance of macrophages, which might be attributed to their regulation of fatty-acid-metabolism related genes. In vitro experiments, the mRNA expression of ACSM2A, ADH1B, CYP2C8, CYP4F2 and SLC27A5 in HCC-LM3 was significantly down-regulated, and specific inhibitors of HDAC1 and HDAC11 significantly promoted the expression of these genes. HDAC inhibitors can promote the metabolism of AA, which may relieve the effect of AA on the polarization of M1 macrophages. CONCLUSIONS: Our study revealed the blocking effect of HDAC1 and HDAC11 on the polarization of macrophages M1 in the microenvironment by inhibiting fatty acid metabolism.

Measuring protein biomarker concentrations using antibody tagged magnetic nanoparticles.

Under physiological conditions biomarker concentrations tend to rise and fall over time e.g. for inflammation. Ex vivo measurements provide a snapshot in time of biomarker concentrations, which is useful, but limited. Approaching real time monitoring of biomarker concentration(s) using a wearable, implantable or injectable in vivo sensor is therefore an appealing target. As an early step towards developing an in vivo biomarker sensor, antibody (AB) tagged magnetic nanoparticles (NPs) are used here to demonstrate the in vitro measurement of ~5 distinct biomarkers with high specificity and sensitivity. In previous work, aptamers were used to target a given biomarker in vitro and generate magnetic clusters that exhibit a characteristic rotational signature quite different from free NPs. Here the method is expanded to detect a much wider range of biomarkers using polyclonal ABs attached to the surface of the NPs. Commercial ABs exist for a wide range of targets allowing accurate and specific concentration measurements for most significant biomarkers. We show sufficient detection sensitivity, using an in-house spectrometer to measure the rotational signatures of the NPs, to assess physiological concentrations of hormones, cytokines and other signaling molecules. Detection limits for biomarkers drawn mainly from pain and inflammation targets were: 10 pM for mouse Granzyme B (mGZM-B), 40 pM for mouse interferon-gamma (mIFN-γ), 7 pM for mouse interleukin-6 (mIL-6), 40 pM for rat interleukin-6 (rIL-6), 40 pM for mouse vascular endothelial growth factor (mVEGF) and 250 pM for rat calcitonin gene related peptide (rCGRP). Much lower detection limits are certainly possible using improved spectrometers and nanoparticles.

Quantification of magnetic nanoparticles by compensating for multiple environment changes simultaneously.

The quantification of magnetic nanoparticles is important for many applications, especially for in vivo biosensing. The magnetization harmonics used in spectroscopy of magnetic nanoparticles can be used to estimate nanoparticle number or weight. However, other effects such as temperature or relaxation time change can also influence the nanoparticle magnetization. Therefore, it is necessary to compensate for these factors when estimating the amount of magnetic nanoparticles. This paper shows through simulation that a two-dimensional scaling method can be used to improve the accuracy of nanoparticle quantification, especially when multiple effects are present which can influence the nanoparticle magnetization. Finally, an experiment was performed on a Magnetic Spectroscopy of Brownian motion (MSB) apparatus to demonstrate this method, and nanoparticle weight was determined with a mean error of 1.3 ng (1.81%).

Concurrent quantification of magnetic nanoparticles temperature and relaxation time.

PURPOSE: The harmonic spectrum of the magnetization of magnetic nanoparticles (MNPs) in the presence of an applied magnetic field can be used to characterize the properties of the microenvironment of the MNPs. The change in temperature and relaxation time has been measured by varying the magnetic field amplitudes or frequency to obtain the harmonic spectrum. However, scaling estimates of temperature or relaxation time are poor if both change simultaneously. In this work, we show that scaling over both the amplitude and frequency of the applied magnetic field allows both the temperature and relaxation to be estimated simultaneously. METHODS: The scaling methods previously used to measure temperature and relaxation times individually have been expanded to two dimensions allowing both parameters to be estimated simultaneously. Samples with different temperature and relaxation times were measured using a magnetic nanoparticle spectrometer to verify this two-dimensional scaling method. Simulations were also carried out for a range of nanoparticle sizes, and the best particle sizes were estimated for this two-dimensional method. RESULTS: The two-dimensional scaling method achieved a mean error of 0.83% for relaxation time by considering the temperature variation as well as relaxation time changes. The temperature and viscosity of the MNPs were measured simultaneously with the mean error of 1.03°C and 0.011 mPas. For monodisperse particles with Brownian relaxation, simulation showed that core radius of 16 nm and hydrodynamic radius of 23 nm had best accuracy for the scaling method. CONCLUSIONS: The two-dimensional scaling method allows both temperature and relaxation time to be estimated simultaneously. The measurement accuracy can be improved by combining information in ratios and phases of the magnetic harmonics of the magnetization and by choosing the optimal particle sizes.

Evaluating blood clot progression using magnetic particle spectroscopy.

PURPOSE: To evaluate the thrombus maturity noninvasively providing the promise of much earlier and more accurate diagnosis of diseases ranging from stroke to myocardial infarction to deep vein thrombosis. METHODS: Magnetic spectroscopy of nanoparticle Brownian rotation (MSB), a form of magnetic particle spectroscopy sensitive to Brownian rotation of magnetic nanoparticles, was used for the detection and characterization of blood clots. The nanoparticles' relaxation time was quantified by scaling the MSB spectra in frequency to match the spectra from nanoparticles in a reference state. The nanoparticles' relaxation time, in the bound state, was used to characterize the nanoparticle binding to thrombin on the blood clot. The number of nanoparticles bound to the clot was also estimated. Both the relaxation time and the weight of bound nanoparticles were obtained for clots of several ages, reflecting different stages of development and organization. The impact of clot development was explored using functionalized nanoparticles present during clot formation. RESULTS: The relaxation time of the bound nanoparticles decreases for more mature, organized clots. The number of nanoparticles able to bind the clot diminishes quantitatively with clot age. On mature clots, the nanoparticles bind the thrombin on the surface while for developing clots the nanoparticles bind several thrombin molecules or become trapped in the clot matrix during formation. CONCLUSIONS: By estimating the magnetic nanoparticles' relaxation time the clot age and organization can be predicted. The purposed methods are quick and minimally invasive for in vivo applications.

[Preparation and application of polyclonal antibody against non-structural protein 1 (NS1) of duck Tembusu virus].

Objective To express prokaryotically the non-structural protein 1 (NS1) of duck Tembusu virus (DTMUV) and prepare NS1-specific polyclonal antibodies. Methods The NS1 gene of DTMUV strain AH-F10 was amplified by PCR, followed by subcloning and expression in the prokaryotic vector pET-32a. The recombinant NS1 protein was successfully expressed in Escherichia coli BL21 (DE3), and purified with hydroxymethyl urea and renatured by gradient centrifugation. The BALB/c mice were immunized with the purified recombinant NS1 protein to prepare polyclonal antibodies against the NS1 protein. Furthermore, the titer of the polyclonal antibodies was determined by agar diffusion test (AGP), and the specificity of the polyclonal antibodies was verified by Western blotting and indirect immunofluorescence assay (IFA). Results Polyclonal antibodies against NS1 protein in serum was successfully obtained with an AGP titer of 1:8. Western blotting and IFA demonstrated that the serum with polyclonal antibodies had a high-level specificity and reactivity to the NS1 protein of DTMUV. Conclusion Polyclonal antibodies against DTMUV NS1 protein were successfully prepared and validated in this study.

Harmonic phase angles used for nanoparticle sensing.

A series of techniques have been developed to use magnetic nanoparticles as biosensors to characterize their local microenvironment. Two approaches have been used to obtain quantitative information: model based approaches and scaling based approaches. We have favored scaling based approaches, because approximations made in models can lead to limitations in the accuracy. Currently all the scaling approaches use harmonic ratios to retrieve physical parameters like temperature, viscosity and relaxation time. In this work, we showed that the phase angle of the signal at a single harmonic frequency is an alternative to the ratio. The phase angle is nanoparticle density-independent, and can be used to improve sensitivity, enabling us to measure smaller biomedical effects. With the phase angle as an example, we showed that scaling methods are general and do not depend on specific approximations. We showed that the same scaling techniques can be used with both the phase angle and harmonic ratio because they both depend on the same combinations of physical parameters. Using the phase angle improves the precision and using the combination of phase angles and harmonic ratio provides the best precision.

Blood clot detection using magnetic nanoparticles.

Deep vein thrombosis, the development of blood clots in the peripheral veins, is a very serious, life threatening condition that is prevalent in the elderly. To deliver proper treatment that enhances the survival rate, it is very important to detect thrombi early and at the point of care. We explored the ability of magnetic particle spectroscopy (MSB) to detect thrombus via specific binding of aptamer functionalized magnetic nanoparticles with the blood clot. MSB uses the harmonics produced by nanoparticles in an alternating magnetic field to measure the rotational freedom and, therefore, the bound state of the nanoparticles. The nanoparticles' relaxation time for Brownian rotation increases when bound [A.M. Rauwerdink and J. B. Weaver, Appl. Phys. Lett. 96, 1 (2010)]. The relaxation time can therefore be used to characterize the nanoparticle binding to thrombin in the blood clot. For longer relaxation times, the approach to saturation is more gradual reducing the higher harmonics and the harmonic ratio. The harmonic ratios of nanoparticles conjugated with anti-thrombin aptamers (ATP) decrease significantly over time with blood clot present in the sample medium, compared with nanoparticles without ATP. Moreover, the blood clot removed from the sample medium produced a significant MSB signal, indicating the nanoparticles are immobilized on the clot. Our results show that MSB could be a very useful non-invasive, quick tool to detect blood clots at the point of care so proper treatment can be used to reduce the risks inherent in deep vein thrombosis.

Energy cascade and its locality in compressible magnetohydrodynamic turbulence.

We investigate energy transfer across scales in three-dimensional compressible magnetohydrodynamic (MHD) turbulence, a model often used to study space and astrophysical plasmas. Analysis shows that kinetic and magnetic energies cascade conservatively from large to small scales in cases with varying degrees of compression. With more compression, energy fluxes due to pressure dilation and subscale mass flux are greater, but conversion between kinetic and magnetic energy by magnetic line stretching is less efficient. Energy transfer between the same fields is dominated by local contributions regardless of compressive effects. In contrast, the conversion between kinetic and internal energy by pressure dilation is dominated by the largest scale contributions. Energy conversion between the velocity and magnetic fields is weakly local.

Generalized Scaling and the Master Variable for Brownian Magnetic Nanoparticle Dynamics.

Understanding the dynamics of magnetic particles can help to advance several biomedical nanotechnologies. Previously, scaling relationships have been used in magnetic spectroscopy of nanoparticle Brownian motion (MSB) to measure biologically relevant properties (e.g., temperature, viscosity, bound state) surrounding nanoparticles in vivo. Those scaling relationships can be generalized with the introduction of a master variable found from non-dimensionalizing the dynamical Langevin equation. The variable encapsulates the dynamical variables of the surroundings and additionally includes the particles' size distribution and moment and the applied field's amplitude and frequency. From an applied perspective, the master variable allows tuning to an optimal MSB biosensing sensitivity range by manipulating both frequency and field amplitude. Calculation of magnetization harmonics in an oscillating applied field is also possible with an approximate closed-form solution in terms of the master variable and a single free parameter.

Toward Localized In Vivo Biomarker Concentration Measurements.

We know a great deal about the biochemistry of cells because they can be isolated and studied. The biochemistry of the much more complex in vivo environment is more difficult to study because the only ways to quantitate concentrations is to sacrifice the animal or biopsy the tissue. Either method disrupts the environment profoundly and neither method allows longitudinal studies on the same individual. Methods of measuring chemical concentrations in vivo are very valuable alternatives to sacrificing groups of animals. We are developing microscopic magnetic nanoparticle (mNP) probes to measure the concentration of a selected molecule in vivo. The mNPs are targeted to bind the selected molecule and the resulting reduction in rotational freedom can be quantified remotely using magnetic spectroscopy. The mNPs must be contained in micrometer sized porous shells to keep them from migrating and to protect them from clearance by the immune system. There are two key issues in the development of the probes. First, we demonstrate the ability to measure concentrations in the porous walled alginate probes both in phosphate buffered saline and in blood, which is an excellent surrogate for the complex and challenging in vivo environment. Second, sensitivity is critical because it allows microscopic probes to measure very small concentrations very far away. We report sensitivity measurements on recently introduced technology that has allowed us to improve the sensitivity by two orders of magnitude, a factor of 200 so far.

Symmetric and asymmetric meniscus collapse in wetting transition on submerged structured surfaces.

The wetting transition from the Cassie-Baxter to the Wenzel state is a phenomenon critically pertinent to the functionality of microstructured superhydrophobic surfaces. This work focuses on the last stage of the transition, when the liquid-gas interface touches the bottom of the microstructure, which is also known as the "collapse" phenomenon. The process was examined in situ on a submerged surface patterned with cylindrical micropores using confocal microscopy. Both symmetric and asymmetric collapses were observed. The latter significantly shortens the progression of the metastable state prior to the collapse when compared with the former and hence may affect the lifespan of superhydrophobicity. Further experiments identified that asymmetric collapse were induced by impurities due to prior use of the structure. The problem is thus of broad relevance, since endurance through cycles is a practical requirement for these functional surfaces. Finally, the use of hierarchical structures is proposed as a remedy. The embedded self-cleaning mechanism serves to effectively remove the impurities, so as to avoid the triggering mechanism for asymmetric collapses.

Metastable states and wetting transition of submerged superhydrophobic structures.

Superhydrophobicity on structured surfaces is frequently achieved via the maintenance of liquid-air interfaces adjacent to the trapped air pockets. These interfaces, however, are subject to instabilities due to the Cassie-Baxter-to-Wenzel transition and total wetting. The current work examines in situ liquid-air interfaces on a submerged surface patterned with cylindrical micropores using confocal microscopy. Both the pinned Cassie-Baxter and depinned metastable states are directly observed and measured. The metastable state dynamically evolves, leading to a transition to the Wenzel state. This process is extensively quantified under different ambient pressure conditions, and the data are in good agreement with a diffusion-based model prediction. A similarity law along with a characteristic time scale is derived which governs the lifetime of the air pockets and which can be used to predict the longevity of underwater superhydrophobicity.

Enhanced load-carrying capacity of hairy surfaces floating on water.

Water repellency of hairy surfaces depends on the geometric arrangement of these hairs and enables different applications in both nature and engineering. We investigate the mechanism and optimization of a hairy surface floating on water to obtain its maximum load-carrying capacity by the free energy and force analyses. It is demonstrated that there is an optimum cylinder spacing, as a result of the compromise between the vertical capillary force and the gravity, so that the hairy surface has both high load-carrying capacity and mechanical stability. Our analysis makes it clear that the setae on water striders' legs or some insects' wings are in such an optimized geometry. Moreover, it is shown that surface hydrophobicity can further increase the capacity of a hairy surface with thick cylinders, while the influence is negligible when the cylinders are thin.

Joint-constraint model for large-eddy simulation of helical turbulence.

A three-term mixed subgrid-scale (SGS) stress model is proposed for large-eddy simulation (LES) of helical turbulence. The new model includes a Smagorinsky-Lilly term, a velocity gradient term, and a symmetric vorticity gradient term. The model coefficients are determined by minimizing the mean square error between the realistic and modeled Leonard stresses under a joint constraint of kinetic energy and helicity fluxes. The model formulated as such is referred to as joint-constraint dynamic three-term model (JCD3TM). First, the new model is evaluated a priori using the direct numerical simulation (DNS) data of homogeneous isotropic turbulence with helical forcing. It is shown that the SGS dissipation fractions from all three terms in JCD3TM have the properties of length-scale invariance in inertial subrange. JCD3TM can predict the SGS stresses, energy flux, and helicity flux more accurately than the dynamic Smagorinsky model (DSM) and dynamic mixed helical model (DMHM) in both pointwise and statistical senses. Then, the performance of JCD3TM is tested a posteriori in LESs of both forced and freely decaying helical isotropic turbulence. It is found that JCD3TM possesses certain features of superiority over the other two models in predicting the energy spectrum, helicity spectrum, high-order statistics, etc. It is also noteworthy that JCD3TM is capable of simulating the evolutions of both energy and helicity spectra more precisely than other models in decaying helical turbulence. We claim that the present SGS model can capture the main helical features of turbulent motions and may serve as a useful tool for LES of helical turbulent flows.

Cascade of kinetic energy in three-dimensional compressible turbulence.

The conservative cascade of kinetic energy is established using both Fourier analysis and a new exact physical-space flux relation in a simulated compressible turbulence. The subgrid scale (SGS) kinetic energy flux of the compressive mode is found to be significantly larger than that of the solenoidal mode in the inertial range, which is the main physical origin for the occurrence of Kolmogorov's -5/3 scaling of the energy spectrum in compressible turbulence. The perfect antiparallel alignment between the large-scale strain and the SGS stress leads to highly efficient kinetic energy transfer in shock regions, which is a distinctive feature of shock structures in comparison with vortex structures. The rescaled probability distribution functions of SGS kinetic energy flux collapse in the inertial range, indicating a statistical self-similarity of kinetic energy cascades.

Acceleration of passive tracers in compressible turbulent flow.

In compressible turbulence at high Reynolds and Mach numbers, shocklets emerge as a new type of flow structure in addition to intense vortices as in incompressible turbulence. Using numerical simulation of compressible homogeneous isotropic turbulence, we conduct a Lagrangian study to explore the effects of shocklets on the dynamics of passive tracers. We show that shocklets cause very strong intermittency and short correlation time of tracer acceleration. The probability density function of acceleration magnitude exhibits a -2.5 power-law scaling in the high compression region. Through a heuristic model, we demonstrate that this scaling is directly related to the statistical behavior of strong negative velocity divergence, i.e., the local compression. Tracers experience intense acceleration near shocklets, and most of them are decelerated, usually with large curvatures in their trajectories.

Scaling and statistics in three-dimensional compressible turbulence.

The scaling and statistical properties of three-dimensional compressible turbulence are studied using high-resolution numerical simulations and a heuristic model. The two-point statistics of the solenoidal component of the velocity field are found to be not significantly different from those of incompressible turbulence, while the scaling exponents of the velocity structure function for the compressive component become saturated at high orders. Both the simulated flow and the heuristic model reveal the presence of a power-law tail in the probability density function of negative velocity divergence (high compression regime). The power-law exponent is different from that in Burgers turbulence, and this difference is shown to have a major contribution from the pressure effect, which is absent in the Burgers turbulence.

Three-dimensional synthetic turbulence constructed by spatially randomized fractal interpolation.

A spatially randomized fractal interpolation algorithm to construct three-dimensional synthetic turbulence from original coarse field is reported. As in the one-dimensional case by Ding et al. (Phys. Rev. E 82, 036311, 2010), during the fractal interpolation, positions mapping between large and small scale cubes are chosen randomly, and the stretching factors are drawn from a log-Poisson random multiplicative process. A linear combination function defined as the base part in fractal interpolation and a theoretical energy spectrum model for fully developed turbulence are introduced into the procedure. Statistical analysis shows that the synthetic field displays some properties very close to the direct numeric simulated field, such as probability distributions of velocity, velocity gradient, velocity increment, and the anomalous scaling behavior of the longitude velocity structure functions, which follows the SL94 model precisely. After a short time using direct numeric simulation with the synthetic field as initial data, the typical local dynamical structures described by the teardrop shape of the Q-R plane for empirical turbulence can be reproduced.