Multi-Scale Simulation of Complex Systems: A Perspective of Integrating Knowledge and Data

Complex system simulation has been playing an irreplaceable role in understanding, predicting, and controlling diverse complex systems. In the past few decades, the multi-scale simulation technique has drawn increasing attention for its remarkable ability to overcome the challenges of complex system simulation with unknown mechanisms and expensive computational costs. In this survey, we will systematically review the literature on multi-scale simulation of complex systems from the perspective of knowledge and data. Firstly, we will present background knowledge about simulating complex system simulation and the scales in complex systems. Then, we divide the main objectives of multi-scale modeling and simulation into five categories by considering scenarios with clear scale and scenarios with unclear scale, respectively. After summarizing the general methods for multi-scale simulation based on the clues of knowledge and data, we introduce the adopted methods to achieve different objectives. Finally, we introduce the applications of multi-scale simulation in typical matter systems and social systems

Molten flux growth of single crystals of quasi-1D hexagonal chalcogenide BaTiS3

BaTiS3, a quasi-1D complex chalcogenide, has gathered considerable scientific and technological interest due to its giant optical anisotropy and electronic phase transitions. However, the synthesis of high-quality BaTiS3 crystals, particularly those featuring crystal sizes of millimeters or larger, remains a challenge. Here, we investigate the growth of BaTiS3 crystals utilizing a molten salt flux of either potassium iodide, or a mixture of barium chloride and barium iodide. The crystals obtained through this method exhibit a substantial increase in volume compared to those synthesized via the chemical vapor transport method, while preserving their intrinsic optical and electronic properties. Our flux growth method provides a promising route towards the production of high-quality, large-scale single crystals of BaTiS3, which will greatly facilitate advanced characterizations of BaTiS3 and its practical applications that require large crystal dimensions. Additionally, our approach offers an alternative synthetic route for other emerging complex chalcogenides

Sex-specific neural circuits of emotion regulation in the centromedial amygdala

Sex-related differences in emotion regulation (ER) in the frequency power distribution within the human amygdala, a brain region involved in emotion processing, have been reported. However, how sex differences in ER are manifested in the brain networks which are seeded on the amygdala subregions is unclear. The goal of this study was to investigate this issue from a brain network perspective. Utilizing resting-state functional connectivity (RSFC) analysis, we found that the sex-specific functional connectivity patterns associated with ER trait level were only seeded in the centromedial amygdala (CM). Women with a higher trait-level ER had a stronger negative RSFC between the right CM and the medial superior frontal gyrus (mSFG), and stronger positive RSFC between the right CM and the anterior insula (AI) and the superior temporal gyrus (STG). But men with a higher trait-level ER was associated with weaker negative RSFC of the right CM-mSFG and positive RSFCs of the right CM-left AI, right CM-right AI/STG, and right CM-left STG. These results provide evidence for the sex-related effects in ER based on CM and indicate that men and women may differ in the neural circuits associated with emotion representation and integration

Fractionated regimen-suitable immunoradiotherapy sensitizer based on ultrasmall Fe4Se2W18 nanoclusters enable tumor-specific radiosensitization augment and antitumor immunity boost

Immunoradiotherapy involving the combination of spatial control of radiotherapy and systemic survival of immunotherapy together has emerged as a promising strategy for both local and systemic tumor rejection. However, immunoradiotherapeutic efficacy is highly impeded by the radiation-induced immunosuppression and the insufficiency of antitumor immunity. Herein, ultrasmall Sandwich-type polyoxotungstate nanoclusters (Fe4Se2W18 NCs) with abundant high Z elements, efficient catalytic property, and unique electron structure are designed as the immunoradio-sensitizers. Apart from enhancing X-ray deposition for dose reduction, Fe4Se2W18 NCs exhibit tumor microenvironment-responsive catalytic activity, mainly through GSH depletion and Fenton reaction. Upon X-ray irradiation, Fe4Se2W18 NCs generate hydroxyl radical cascade to elevate tumor-specific oxidative stress, which can not only selectively ablate the local tumor but also effectively activate antitumor immune response. More importantly, ultrasmall Fe4Se2W18 NCs can be rapidly eliminated from the body, which can satisfy the needs of the fractionated regimen of radiotherapy clinically to reduce radiation-induced immunosuppression. Immune checkpoint inhibitor (anti-PD-Ll antibody) is further introduced into this system to boost a robust antitumor immunity, resulting in the inhibition of both primary and distant tumors. By presenting the Sandwich-type polyoxotungstate nanoclusters for immunoradiotherapy augmentation, this study is anticipated to establish a novel paradigm for immunoradio-sensitizer design based on polyoxometalate nanoclusters. (C) 2020 Elsevier Ltd. All rights reserved

Endogenous G(S)-coupled receptors in smooth muscle exhibit differential susceptibility to GRK2/3-mediated desensitization

Although G protein-coupled receptor (GPCR) kinases (GRKs) have been shown to mediate desensitization of numerous GPCRs in studies using cellular expression systems, their function under physiological conditions is less well understood. In the current study, we employed various strategies to assess the effect of inhibiting endogenous GRK2/3 on signaling and function of endogenously expressed G(s)-coupled receptors in human airway smooth muscle (ASM) cells. GRK2/3 inhibition by expression of a Gβγ sequestrant, a GRK2/3 dominant-negative mutant, or siRNA-mediated knockdown increased intracellular cAMP accumulation mediated via β-agonist stimulation of the beta-2-adrenergic receptor (β(2)AR). Conversely, neither 5′-(N-ethylcarboxamido)-adenosine (NECA; activating the A2b adenosine receptor) nor prostaglandin E2 (PGE(2); activating EP2 or EP4 receptors)-stimulated cAMP was significantly increased by GRK2/3 inhibition. Selective knockdown using siRNA suggested the majority of PGE(2)-stimulated cAMP in ASM was mediated by the EP2 receptor. Although a minor role for EP3 receptors in influencing PGE(2)-mediated cAMP was determined, the GRK2/3-resistant nature of EP2 receptor signaling in ASM was confirmed using the EP2-selective agonist butaprost. Somewhat surprisingly, GRK2/3 inhibition did not augment the inhibitory effect of the β-agonist on mitogen-stimulated increases in ASM growth. These findings demonstrate that with respect to G(s)-coupled receptors in ASM, GRK2/3 selectively attenuates β(2)AR signaling, yet relief of GRK2/3-dependent β(2)AR desensitization does not influence at least one important physiological function of the receptor

Exploiting functional domains of GRK2/3 to alter the competitive balance of pro- and anticontractile signaling in airway smooth muscle

To clarify the potential utility of targeting GRK2/3-mediated desensitization as a means of manipulating airway smooth muscle (ASM) contractile state, we assessed the specificity of GRK2/3 regulation of procontractile and relaxant G-protein-coupled receptors in ASM. Functional domains of GRK2/3 were stably expressed, or siRNA-mediated GRK2/3 knockdown was performed, in human ASM cultures, and agonist-induced signaling was assessed. Regulation of contraction of murine tracheal rings expressing GRK2 C terminus was also assessed. GRK2/3 knockdown or expression of the GRK2 C terminus caused a significant (∼30–90%) increase in maximal β-agonist and histamine [phosphoinositide (PI) hydrolysis] signaling, without affecting the calculated EC(50). GRK2 C-terminal expression did not affect signaling by methacholine, thrombin, or LTD4. Expression of the GRK2 N terminus or kinase-dead holo-GRK2 diminished (∼30–70%) both PI hydrolysis and Ca(2+) mobilization by every G(q)-coupled receptor examined. Under conditions of GRK2 C-terminal expression, β-agonist inhibition of methacholine-stimulated PI hydrolysis was greater. Finally, transgenic expression of the GRK2 C terminus in murine ASM enabled ∼30–50% greater β-agonist-mediated relaxation of methacholine-induced contraction. Collectively these data demonstrate the relative selectivity of GRKs for the β(2)AR in ASM and the ability to exploit GRK2/3 functional domains to render ASM hyporesponsive to contractile agents while increasing responsiveness to bronchodilating β-agonist.—Deshpande, D. A., Yan, H., Kong, K.-C., Tiegs, B. C., Morgan, S. J., Pera, T., Panettieri, R. A., Eckhart, A. D., Penn, R. B. Exploiting functional domains of GRK2/3 to alter the competitive balance of pro- and anticontractile signaling in airway smooth muscle

MOESM2 of Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease

Additional file 2: Figure S1. The line graph of the glucose tolerance test (0–3 h). Data were mean ± SD, LSI: lifestyle intervention, BBR plus LSI: berberine treatment plus lifestyle intervention. *P < 0.05 when comparing before and after berberine plus lifestyle intervention treatment, #P < 0.05 when comparing before and after lifestyle intervention alone treatment

Enhancing radiation-resistance and peroxidase-like activity of single-atom copper nanozyme via local coordination manipulation

Abstract The inactivation of natural enzymes by radiation poses a great challenge to their applications for radiotherapy. Single-atom nanozymes (SAzymes) with high structural stability under such extreme conditions become a promising candidate for replacing natural enzymes to shrink tumors. Here, we report a CuN3-centered SAzyme (CuN3-SAzyme) that exhibits higher peroxidase-like catalytic activity than a CuN4-centered counterpart, by locally regulating the coordination environment of single copper sites. Density functional theory calculations reveal that the CuN3 active moiety confers optimal H2O2 adsorption and dissociation properties, thus contributing to high enzymatic activity of CuN3-SAzyme. The introduction of X-ray can improve the kinetics of the decomposition of H2O2 by CuN3-SAzyme. Moreover, CuN3-SAzyme is very stable after a total radiation dose of 500 Gy, without significant changes in its geometrical structure or coordination environment, and simultaneously still retains comparable peroxidase-like activity relative to natural enzymes. Finally, this developed CuN3-SAzyme with remarkable radioresistance can be used as an external field-improved therapeutics for enhancing radio-enzymatic therapy in vitro and in vivo. Overall, this study provides a paradigm for developing SAzymes with improved enzymatic activity through local coordination manipulation and high radioresistance over natural enzymes, for example, as sensitizers for cancer therapy