Design of Novel Protein-based MRI Contrast Agernets with High Relaxivity and Stability for Biomedical Imaging

Magnetic resonance imaging (MRI) is the leading imaging technique for disease diagnostics. MRI contrast agents facilitate MRI technique to obtain tissue-specific image with improved sensitivity and signal-to-noise ratio. However, the applications of current MRI contrast agents are hampered by their uncontrolled blood circulation time, low relaxivity, and low specificity. To address such need, I have developed a series of analitical methods to determine and evaluate the strong metal binding affinity and metal selectivity of developed protein-based contrast agents (ProCAs). In addition, we have successed designed contrast agents ProCA3 series based on key determinats for metal binding sites and relaxivity. We have dementrated that one of the ProCA3 variants, ProCA32, has a high Gd3+ affinity less than 10-21 M and high metal selectivity with relxivity of more than 30 mM-1s-1 per Gd and 60 mM-1s-1 per particle. Moreover, we have demonstrated that ProCA3 variants have proper blood circulation time, high relaxivity, high metal selectivity and low toxicity, which facilitate MR imaging of multiple organs, such as liver, kidney, and blood vessels, as well as tumors. ProCA32 is also able to image liver metastases a tumor size less than 0.25 mm, which is more than fourty times more sensitive than that of clinical diagnostics of liver metastases using MRI and our developed methodology. We have further created ProCA3 variants with targeting peptide moieties such as ProCA3.bomb or ProCA3.affi to against cancer biomarkers such as GRPR and HER2 with capability to imaging tumor biomarker expressions in vivo at molecular level. We have shown that ProCA3 has an excellent safety profile and pharmacokinetics for MRI in animals. With our additional effect in protein expression, modification, and scale up production of these developed protein contrast agents, ProCA3 is expected to be a promising MRI contrast for the diagnostics for disease, such as metastatic tumor and blood vessel abnormalities, and tumor biomarkers

DCCF: Deep Comprehensible Color Filter Learning Framework for High-Resolution Image Harmonization

Image color harmonization algorithm aims to automatically match the color distribution of foreground and background images captured in different conditions. Previous deep learning based models neglect two issues that are critical for practical applications, namely high resolution (HR) image processing and model comprehensibility. In this paper, we propose a novel Deep Comprehensible Color Filter (DCCF) learning framework for high-resolution image harmonization. Specifically, DCCF first downsamples the original input image to its low-resolution (LR) counter-part, then learns four human comprehensible neural filters (i.e. hue, saturation, value and attentive rendering filters) in an end-to-end manner, finally applies these filters to the original input image to get the harmonized result. Benefiting from the comprehensible neural filters, we could provide a simple yet efficient handler for users to cooperate with deep model to get the desired results with very little effort when necessary. Extensive experiments demonstrate the effectiveness of DCCF learning framework and it outperforms state-of-the-art post-processing method on iHarmony4 dataset on images' full-resolutions by achieving 7.63% and 1.69% relative improvements on MSE and PSNR respectively.Comment: ECCV 2022 (Oral

Myoplasmic resting Ca2+ regulation by ryanodine receptors is under the control of a novel Ca2+-binding region of the receptor

Passive SR (sarcoplasmic reticulum) Ca2+ leak through the RyR (ryanodine receptor) plays a critical role in the mechanisms that regulate [Ca2+ ]rest (intracellular resting myoplasmic free Ca2+ concentration) in muscle. This process appears to be isoform-specific as expression of either RyR1 or RyR3 confers on myotubes different [Ca2+ ]rest. Using chimaeric RyR3–RyR1 receptors expressed in dyspedic myotubes, we show that isoformdependent regulation of [Ca2+ ]rest is primarily defined by a small region of the receptor encompassing amino acids 3770– 4007 of RyR1 (amino acids 3620–3859 of RyR3) named as the CLR (Ca2+ leak regulatory) region. [Ca2+ ]rest regulation by the CLR region was associated with alteration of RyRs’ Ca2+ - activation profile and changes in SR Ca2+ -leak rates. Biochemical analysis using Tb3+ -binding assays and intrinsic tryptophan fluorescence spectroscopy of purified CLR domains revealed that this determinant of RyRs holds a novel Ca2+ -binding domainwith conformational properties that are distinctive to each isoform. Our data suggest that the CLR region provides channels with unique functional properties that modulate the rate of passive SR Ca2+ leak and confer on RyR1 and RyR3 distinctive [Ca2+ ]rest regulatory properties. The identification of a new Ca2+ -binding domain ofRyRswith a key modulatory role in [Ca2+ ]rest regulation provides new insights into Ca2+ -mediated regulation of RyRs

Myoplasmic resting Ca2+ regulation by ryanodine receptors is under the control of a novel Ca2+-binding region of the receptor

Passive SR (sarcoplasmic reticulum) Ca2+ leak through the RyR (ryanodine receptor) plays a critical role in the mechanisms that regulate [Ca2+]rest (intracellular resting myoplasmic free Ca2+ concentration) in muscle. This process appears to be isoform-specific as expression of either RyR1 or RyR3 confers on myotubes different [Ca2+]rest. Using chimaeric RyR3–RyR1 receptors expressed in dyspedic myotubes, we show that isoform-dependent regulation of [Ca2+]rest is primarily defined by a small region of the receptor encompassing amino acids 3770–4007 of RyR1 (amino acids 3620–3859 of RyR3) named as the CLR (Ca2+ leak regulatory) region. [Ca2+]rest regulation by the CLR region was associated with alteration of RyRs’ Ca2+-activation profile and changes in SR Ca2+-leak rates. Biochemical analysis using Tb3+-binding assays and intrinsic tryptophan fluorescence spectroscopy of purified CLR domains revealed that this determinant of RyRs holds a novel Ca2+-binding domain with conformational properties that are distinctive to each isoform. Our data suggest that the CLR region provides channels with unique functional properties that modulate the rate of passive SR Ca2+ leak and confer on RyR1 and RyR3 distinctive [Ca2+]rest regulatory properties. The identification of a new Ca2+-binding domain of RyRs with a key modulatory role in [Ca2+]rest regulation provides new insights into Ca2+-mediated regulation of RyRs

Structure and laminar flame speed of an ammonia/methane/air premixed flame under varying pressure and equivalence ratio

This paper presents a joint experimental and numerical study on premixed laminar ammonia/methane/air flames, aiming to characterize the flame structures and NO formation and determine the laminar flame speed under different pressure, equivalence ratio, and ammonia fraction in the fuel. The experiments were carried out in a lab-scale pressurized vessel with a Bunsen burner installed with a concentric co-flow of air. Measurements of NH and NO distributions in the flames were made using planar laser-induced fluorescence. A novel method was presented for determination of the laminar flame speed from Bunsen-burner flame measurements, which takes into account the non-uniform flow in the unburned mixture and local flame stretch. NH profiles were chosen as flame front markers. Direct numerical simulation of the flames and one-dimensional chemical kinetic modeling were performed to enhance the understanding of flame structures and evaluate three chemical kinetic mechanisms recently reported in the literature. The stoichiometric and fuel-rich flames exhibit a dual-flame structure, with an inner premixed flame and an outer diffusion flame. The two flames interact, which affects the NO emissions. The impact of the diffusion flame on the laminar flame speed of the inner premixed flame is however minor. At elevated pressures or higher ammonia/methane ratios, the emission of NO is suppressed as a result of the reduced radical mass fraction and promoted NO reduction reactions. It is found that the laminar flame speed measured in the present experiments can be captured by the investigated mechanisms, but quantitative predictions of the NO distribution require further model development

On element mass conservation in Eulerian stochastic fields modeling of turbulent combustion

Eulerian stochastic fields (ESF) based transported PDF method has evolved as one of the general purpose methods for the numerical simulation of complex chemically reactive turbulent flows in which the effect of turbulence on the chemical reaction rates can be computed directly without the need of modeling. It is found that ESF method may suffer from violation of the element mass conservation law due to the stochastic Wiener process and the highly non-linear dependence of the chemical reaction rates on the stochastic fields. This paper presents a modified ESF method to remove the error in the element mass conservation. The method is evaluated in numerical simulation of two turbulent flames, (i) Reynolds averaged Navier-Stokes (RANS) simulation of a turbulent non-premixed methane/air counterflow flame under stationary burning and transient flame extinction conditions, (ii) large eddy simulation of swirling turbulent methane/air non-premixed flames under local extinction and re-ignition conditions. The original ESF method violates the element mass conservation in both flames, and the element mass error would not disappear even if a large number of stochastic fields were used. The new method yields a satisfactory prediction of the element mass conservation even with a small number of stochastic fields. The new and original methods predict similar stationary flame structures but the results under flame extinction and re-ignition conditions are rather different

Large eddy simulation of n-heptane/syngas pilot ignition spray combustion : Ignition process, liftoff evolution and pollutant emissions

The utilization of syngas in the internal combustion engine is one way to reach low carbon emission engine. The n-heptane/syngas pilot ignition spray combustion is simulated here by high fidelity model with different syngas compositions. It is found that the ambient syngas suppresses the ignition by diluting the ambient oxidizer (non-chemical effect) and by affecting the chemical reactions (chemical effect). The consumption of OH radicals through H2+OH = H + H2O and CO + OH = CO2+H in low temperature combustion (LTC) stage is shown to be the main reason for the suppression of ignition. Cool flame propagation into the rich mixture in the mixing layer of n-heptane jet is observed during the transition process from LTC to high temperature combustion (HTC). CO is found to assist the transition to HTC through CO + HO2 = CO2+OH. On the contrary, H2 slows down the cool flame propagation and narrows down the cool flame flammability range, which retards the onset of HTC. The effects of syngas compositions on the flame structure and emission formation are discussed in detail. Due to the upstream auto-ignition, a cool/diffusion/hot flame structure is identified at the liftoff position in dual-fuel case, which drastically changes the flame structure. And more soot formation in early stage is found in dual-fuel cases due to the naturally richer mixture

Co-occurrence of pluvial and fluvial floods exacerbates inundation and economic losses: evidence from a scenario-based analysis in Longyan, China

AbstractHydrodynamics and socio-economic impacts of compound floods as the result of co-occurring pluvial and fluvial floods, have not been well studied, which challenges conventional urban flood risk management that treats different types of floods separately. This study generates a high-resolution land surface digital surface model based on images from unmanned aerial vehicles, and incorporates it into a combined flooding model that integrates the 1D river hydrodynamic model, 1D urban drainage hydrodynamic model and 2D overland flow model, in order to simulate the inundation characteristics of extreme floods when local pluvial floods coincide with upstream fluvial floods, and in a further step to quantify the direct economic losses on urban physical systems. As demonstrated by an empirical study of Longyan, China, the combination of pluvial and fluvial floods leads to substantial exacerbation in inundation extent and depth. Consequently, the joining of pluvial and fluvial floods greatly amplifies economic losses to urban physical systems, indicating that ignoring co-occurrence of different types of floods will potentially lead to underestimation of flood risk and insufficient adaptation. Our study emphasizes the need to account for the co-occurrence of multiple types of floods in flood risk assessment and management, to avoid the shortcomings of fragmented responses