A well-balanced lattice Boltzmann model for binary fluids based on the incompressible phase-field theory

Spurious velocities arising from the imperfect offset of the undesired term at the discrete level are frequently observed in numerical simulations of equilibrium multiphase flow systems using the lattice Boltzmann equation (LBE) method. To capture the physical equilibrium state of two-phase fluid systems and eliminate spurious velocities, a well-balanced LBE model based on the incompressible phase-field theory is developed. In this model, the equilibrium distribution function for the Cahn-Hilliard (CH) equation is designed by treating the convection term as a source to avoid the introduction of undesired terms, enabling achievement of possible discrete force balance. Furthermore, this approach allows for the attainment of a divergence-free velocity field, effectively mitigating the impact of artificial compression effects and enhancing numerical stability. Numerical tests, including a flat interface problem, a stationary droplet, and the coalescence of two droplets, demonstrate the well-balanced properties and improvements in the stability of the present model

Interleukin-6 is required for cell cycle arrest and activation of DNA repair enzymes after partial hepatectomy in mice

BACKGROUND: Interleukin-6 (IL-6) has been shown to be vital for liver regeneration, however the specific mechanisms and factors involved remain incompletely defined. The present study aimed to investigate whether IL-6 exerts its protective effects via arresting the cell cycle allowing base excision and repair of oxidized DNA after hepatectomy. RESULTS: Following seventy percent partial hepatectomy (PH) in wild type (WT) mice IL-6 serum levels increased reaching peak levels at 3 hours. This was associated with markers of cell cycle arrest as p21 expression was increased and cyclin D1 and proliferating cell nuclear antigen (PCNA) expression decreased. In the absence of IL-6, markers of cell cycle arrest were absent and the number of bromodeoxyuridine (BrdU) positive cells was significantly higher at 28, 32 and 36 hours after PH. The mRNAs for DNA repair enzymes, including Neil-1, 8-oxodGTPase, OGG1, Apex1, and UDG (DNA glycosylase) were increased 2 to 4 fold in WT mice at 6 and/or 12 hours after PH compared to IL-6 knockout (KO) mice. The protein levels of Neil1 and OGG1 were also significantly increased in WT mice compared to KO mice. Pathological changes were far greater and survival was less in IL-6 KO mice than in WT mice. Administration of IL-6 in KO mice restored p21 and DNA repair enzyme expression to wild-type levels and survival was improved. CONCLUSIONS: IL-6 caused cell cycle arrest and delayed proliferation during the first day after PH. This delay was associated with the activation of DNA repair enzymes resulting in accurate replication and restoration of hepatic mass

High-Resolution 3D Heart Models of Cardiomyocyte Subpopulations in Cleared Murine Heart

Biological tissues are naturally three-dimensional (3D) opaque structures, which poses a major challenge for the deep imaging of spatial distribution and localization of specific cell types in organs in biomedical research. Here we present a 3D heart imaging reconstruction approach by combining an improved heart tissue-clearing technique with high-resolution light-sheet fluorescence microscopy (LSFM). We have conducted a three-dimensional and multi-scale volumetric imaging of the ultra-thin planes of murine hearts for up to 2,000 images per heart in x-, y-, and z three directions. High-resolution 3D volume heart models were constructed in real-time by the Zeiss Zen program. By using such an approach, we investigated detailed three-dimensional spatial distributions of two specific cardiomyocyte populations including HCN4 expressing pacemaker cells and Pnmt(+) cell-derived cardiomyocytes by using reporter mouse lines Hcn4(DreER/tdTomato) and Pnmt(Cre/ChR2−tdTomato). HCN4 is distributed throughout right atrial nodal regions (i.e., sinoatrial and atrioventricular nodes) and the superior-inferior vena cava axis, while Pnmt(+) cell-derived cardiomyocytes show distinct ventral, left heart, and dorsal side distribution pattern. Our further electrophysiological analysis indicates that Pnmt + cell-derived cardiomyocytes rich left ventricular (LV) base is more susceptible to ventricular arrhythmia under adrenergic stress than left ventricular apex or right ventricle regions. Thus, our 3D heart imaging reconstruction approach provides a new solution for studying the geometrical, topological, and physiological characteristics of specific cell types in organs

Grape seed proanthocyanidin extract targets p66Shc to regulate mitochondrial biogenesis and dynamics in diabetic kidney disease

Mitochondrial biogenesis and dynamics are associated with renal mitochondrial dysfunction and the pathophysiological development of diabetic kidney disease (DKD). Decreased p66Shc expression prevents DKD progression by significantly regulating mitochondrial function. Grape seed proanthocyanidin extract (GSPE) is a potential therapeutic medicine for multiple kinds of diseases. The effect of GSPE on the mitochondrial function and p66Shc in DKD has not been elucidated. Hence, we decided to identify p66Shc as a therapeutic target candidate to probe whether GSPE has a renal protective effect in DKD and explored the underlying mechanisms. Methods. In vivo, rats were intraperitoneally injected with streptozotocin (STZ) and treated with GSPE. Biochemical changes, mitochondrial morphology, the ultrastructure of nephrons, and protein expression of mitochondrial biogenesis (SIRT1, PGC-1α, NRF1, TFAM) and dynamics (DRP1, MFN1) were determined. In vitro, HK-2 cells were transfected with p66Shc and treated with GSPE to evaluate changes in cell apoptosis, reactive oxygen species (ROS), mitochondrial quality, the protein expression. Results. In vivo, GSPE significantly improved the renal function of rats, with less proteinuria and a lower apoptosis rate in the injured renal tissue. Besides, GSPE treatment increased SIRT1, PGC-1α, NRF1, TFAM, and MFN1 expression, decreased p66Shc and DRP1 expression. In vitro, overexpression of p66Shc decreased the resistance of HK-2 cells to high glucose toxicity, as shown by increased apoptosis and ROS production, decreased mitochondrial quality and mitochondrial biogenesis, and disturbed mitochondrial dynamic homeostasis, ultimately leading to mitochondrial dysfunction. While GSPE treatment reduced p66Shc expression and reversed these changes. Conclusion. GSPE can maintain the balance between mitochondrial biogenesis and dynamics by negatively regulating p66Shc expression

IIS: Intelligent identification scheme of massive IoT devices

Device identification is of great importance in system management and network security. Especially, it is the priority in industrial internet of things (IIoT) scenario. Since there are massive devices producing various kinds of information in manufacturing process, the robustness, reliability, security and real-time control of the whole system is based on the identification of the massive IIoT devices. Previous IIoT device identification solutions are mostly based on a centralized architecture, which brings a lot of problems in scalability and security. In addition, most traditional identification systems can only identify inherent types of devices which is not suitable for the adaptive device management in IIoT. In order to solve these problems, this paper proposes a Intelligent Identification Scheme(IIS) of Massive IoT Devices, a completely distributed intelligent identification scheme of massive IIoT devices. The scheme changes the traditional centralized architecture and realizes more efficient clustering identification of massive IIoT devices. Moreover, IIS can identify more and more types of devices intelligently with the continuous learning ability since the identification model is constantly updated according to the ledger which is maintained by all gateways collaboratively. We also conduct experiments to evaluate the performance of IIS based on the data obtained from real IIoT devices, which proves that IIS is efficient in device identification and intelligent for the adaptive device management in IIoT

Secretory leukocyte protease inhibitor as a novel predictive biomarker in patients with diabetic kidney disease

BackgroundSecretory leukocyte protease inhibitor (SLPI) is a multifunctional protein involved in the chronic inflammatory process, implicated in the pathogenesis of diabetic kidney disease (DKD). However, its potential as a diagnostic and prognostic biomarker of DKD has yet to be evaluated. This study explored the clinical utility of SLPI in the diagnosis and prognosis of renal endpoint events in patients with DKD.MethodsA multi-center cross-sectional study comprised of 266 patients with DKD and a predictive cohort study comprised of 120 patients with stage IV DKD conducted between December 2016 and January 2022. The clinical parameters were collected for statistical analysis, a multivariate Cox proportional hazards model was used to evaluate the independent risk factors for renal endpoints.ResultsSerum SLPI levels gradually increased with DKD progression (p<0.01). A significant correlation was observed between serum SLPI levels and renal function in patients with DKD. The mean follow-up duration in this cohort study was 2.32 ± 1.30 years. Multivariate Cox regression analysis showed SLPI levels≥51.61ng/mL (HR=2.95, 95% CI[1.55, 5.60], p<0.01), 24h urinary protein levels≥3500 mg/24h (HR=3.02, 95% CI[1.66, 5.52], p<0.01), Alb levels<30g/l (HR=2.19, 95% CI[1.12, 4.28], p<0.05), HGB levels<13g/dl (HR=3.18, 95% CI[1.49, 6.80], p<0.01), and urea levels≥7.1 mmol/L (HR=8.27, 95% CI[1.96, 34.93], p<0.01) were the independent risk factors for renal endpoint events in DKD patients.ConclusionsSerum SLPI levels increased with DKD progression and were associated with clinical parameters of DKD. Moreover, elevated SLPI levels showed potential prognostic value for renal endpoint events in individuals with DKD. These findings validate the results of previous studies on SLPI in patients with DKD and provide new insights into the role of SLPI as a biomarker for the diagnosis and prognosis of DKD that require validation

Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway

Alcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD

The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice

BACKGROUND & AIMS: As a nicotinamide adenine dinucleotide-dependent deacetylase and a key epigenetic regulator, sirtuin 6 (SIRT6) has been implicated in the regulation of metabolism, DNA repair, and inflammation. However, the role of SIRT6 in alcohol-related liver disease (ALD) remains unclear. The aim of this study was to investigate the function and mechanism of SIRT6 in ALD pathogenesis. METHODS: We developed and characterized Sirt6 knockout (KO) and transgenic mouse models that were treated with either control or ethanol diet. Hepatic steatosis, inflammation, and oxidative stress were analyzed using biochemical and histological methods. Gene regulation was analyzed by luciferase reporter and chromatin immunoprecipitation assays. RESULTS: The Sirt6 KO mice developed severe liver injury characterized by a remarkable increase of oxidative stress and inflammation, whereas the Sirt6 transgenic mice were protected from ALD via normalization of hepatic lipids, inflammatory response, and oxidative stress. Our molecular analysis has identified a number of novel Sirt6-regulated genes that are involved in antioxidative stress, including metallothionein 1 and 2 (Mt1 and Mt2). Mt1/2 genes were downregulated in the livers of Sirt6 KO mice and patients with alcoholic hepatitis. Overexpression of Mt1 in the liver of Sirt6 KO mice improved ALD by reducing hepatic oxidative stress and inflammation. We also identified a critical link between SIRT6 and metal regulatory transcription factor 1 (Mtf1) via a physical interaction and functional coactivation. Mt1/2 promoter reporter assays showed a strong synergistic effect of SIRT6 on the transcriptional activity of Mtf1. CONCLUSIONS: Our data suggest that SIRT6 plays a critical protective role against ALD and it may serve as a potential therapeutic target for ALD. LAY SUMMARY: The liver, the primary organ for ethanol metabolism, can be damaged by the byproducts of ethanol metabolism, including reactive oxygen species. In this study, we have identified a key epigenetic regulator SIRT6 that plays a critical role in protecting the liver from oxidative stress-induced liver injury. Thus, our data suggest that SIRT6 may be a potential therapeutic target for alcohol-related liver disease

Transcriptomic analysis reveals the miRNAs responsible for liver regeneration associated with mortality in alcoholic hepatitis

We conducted a comprehensive serum transcriptomic analysis to explore the roles of miRNAs in alcoholic hepatitis (AH) pathogenesis and their prognostic significance. Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, the expression of miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell cycle progression pathways, including RRM2, CCND1, CCND2, MYC, and PMAIP1. We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1 in AH patients who underwent liver transplantation; miR-26b-5p and miR-30b-5p inhibited the 3’-UTR luciferase activity of RRM2 and CCND2, and miR-20a-5p reduced the 3’-UTR luciferase activity of CCND1 and CCND2. During a median follow-up of 346 days, 21% of AH patients died; these patients had higher BMI, MELD, serum miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p than those who survived. Cox regression analysis showed BMI, MELD score, miR-20a-5p, miR-146a-5p, and miR-26b-5p predicted the mortality. Conclusion: Patients with AH attempt to deal with hepatocyte injury by down-regulating specific miRNAs and upregulating genes responsible for DNA synthesis and cell cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short-term mortality in AH patients