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Akt is frequently activated in human cancers. However, it is unknown whether systemic inhibition of a single Akt isoform could regress cancer progression in cancers that are not driven by Akt activation. We systemically deleted Akt1 after tumor onset in p53−/− mice, which develop tumors independently of Akt activation. Systemic Akt1 deletion regresses thymic lymphoma in p53−/− mice emulating p53 restoration. Furthermore, pharmacological inhibition of Akt selectively kills thymic lymphoma cells and not primary thymocytes. Mechanistically, Akt1 inhibition in p53−/− thymic lymphoma inhibits Skp2 expression and induces FasL, which is the primary cause of cell death. Skp2 exerts resistance to cell death by antagonizing the induction of FasL and reducing FAS expression, which is linked to cyclin D1 expression. The results established a paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation and a mechanism of cell survival by Skp2.

Host cells produce variety of antiviral factors that create an antiviral state and target various stages of influenza A virus (IAV) life cycle to inhibit infection. However, IAV has evolved various strategies to antagonize those antiviral factors. Recently, we reported that a member of class I host histone deacetylases (HDACs), HDAC1 possesses an anti-IAV function. Herein, we provide evidence that HDAC2, another class I member and closely related to HDAC1 in structure and function, also possesses anti-IAV properties. In turn, IAV, like HDAC1, dysregulates HDAC2, mainly at the polypeptide level through proteasomal degradation to potentially minimize its antiviral effect. We found that IAV downregulated the HDAC2 polypeptide level in A549 cells in an H1N1 strain-independent manner by up to 47%, which was recovered to almost 100% level in the presence of proteasome-inhibitor MG132. A further knockdown in HDAC2 expression by up to 90% via RNA interference augmented the growth kinetics of IAV in A549 cells by more than four-fold after 24 h of infection. Furthermore, the knockdown of HDAC2 expression decreased the IAV-induced phosphorylation of the transcription factor, Signal Transducer and Activator of Transcription I (STAT1) and the expression of interferon-stimulated gene, viperin in infected cells by 41 and 53%, respectively. The role of HDAC2 in viperin expression was analogous to that of HDAC1, but it was not in the phosphorylation of STAT1. This indicated that, like HDAC1, HDAC2 is a component of IAV-induced host innate antiviral response and performs both redundant and non-redundant functions vis-a-vis HDAC1; however, IAV dysregulates them both in a redundant manner.

The main objective of this study was to investigate the underlying factors contributing to unsafe behavior among machinery operators through questionnaires distributed among a sample of 48 operators. Data analysis conducted via SPSS software and Spearman analysis revealed several key contributors to unsafe behavior. These factors encompassed demographical aspects (such as age and educational background), job-related stress, dissatisfaction at work, social support, and the impact of addictive behaviors. Spearman correlation analysis further elucidated the interconnectedness among these variables offering insights valuable in mitigating unsafe behaviors. [ABSTRACT FROM AUTHOR]

In the present study, the effect of expansion corner on suddenly expanded flow process has been studied. Experimental investigations have been carried out on a convergent-divergent (C-D) nozzle and isolator duct, where the expansion of the channel is formed through the presence of a 1, 2 and 3 expansion corners (EC) respectively. Flow from nozzle exit of the nozzle of Mach, M = 2.0 was suddenly expanded into the axi-symmetric duct having a cross sectional area of 4.84 times the nozzle exit area. The wall static pressure along the length of the duct and the Pitot pressure at the exit plane of the duct were measured for all the configurations. Computational fluid dynamics (CFD) technique was employed for visualizing the shock-train in the expanded duct. The isolator with one expansion corner was found to be more efficient in achieving a high static pressure rise. The experimental and numerical wall static pressure distribution values were compared for isolators with EC = 2 and found to be in good agreement with each other with a maximum absolute percentage deviation of 11%. [ABSTRACT FROM AUTHOR]

The CuFe2O4 nanoparticle has been successfully synthesized from bio-mediated (Aloe-Vera) combustion process. The structural characterization of synthesized nanoparticle was achieved by spectral-characterizations viz; XRD, SEM, FT-IR and optical examinations. The XRD studies displays a spinel cubic phase development of nanoparticle and its average-particle size (19.3 nm). Low band gap energy of synthesized nanoparticle has been recorded to be 2.84 eV using UV-Visible absorption spectroscopy, which impacts to higher photodegradation efficiency. The potential photocatalytic activity of synthesized nanoparticle was examined using Malachite Green (MG) organic dye as a model, which is performed under specific quantities of stock solution (60 ppm) and obtained nanoparticle (50 mg). The photodegradation efficiency of synthesized material was evaluated for MG dye degradation achieved with 87.5% at 140 min under Sun-light. The excellent oxidation-reduction peak potentials were observed for synthesized spinel ferrite nanoparticle modified with carbon paste investigated by electrochemical analysis using 0.1 M KCl in the different scan rates 0.01-0.05 V/s. The charge-discharge studies of CuFe2O4-graphite electrode at current density (0.4 A/g) was discussed which is well correspondence to pseudo-capacitive behaviour. The synthesized NPs through bio-resources extract has become a potential new insight into multiple practical applications. [ABSTRACT FROM AUTHOR]

Most chronic liver diseases progress to liver fibrosis, which, when left untreated, can lead to cirrhosis and hepatocellular carcinoma. MicroRNA (miRNA)-targeted therapeutics have become attractive approaches to treat diseases. In this study, we investigated the therapeutic effect of miR-155 inhibition in the bile duct ligation (BDL) mouse model of liver fibrosis and evaluated the role of miR-155 in chronic liver fibrosis using miR-155-deficient (miR-155 knockout [KO]) mice. We found increased hepatic miR-155 expression in patients with cirrhosis and in the BDL- and CCl4-induced mouse models of liver fibrosis. Liver fibrosis was significantly reduced in miR-155 KO mice after CCl4 administration or BDL. To assess the therapeutic potential of miR-155 inhibition, we administered an rAAV8-anti-miR-155 tough decoy in vivo that significantly reduced liver damage and fibrosis in BDL. BDL-induced protein levels of transforming growth factor β (TGF-β), p-SMAD2/3, and p-STAT3 were attenuated in anti-miR-155-treated compared with control mice. Hepatic stellate cells from miR-155 KO mice showed attenuation in activation and mesenchymal marker expression. In vitro, miR-155 gain- and loss-of-function studies revealed that miR-155 regulates activation of stellate cells partly via STAT3 signaling. Our study suggests that miR-155 is the key regulator of liver fibrosis and might be a potential therapeutic target to attenuate fibrosis progression.

Background and aims: Granulocyte colony-stimulating factor (G-CSF) has been proposed as a therapeutic option for patients with ACLF, however clinical outcomes are controversial. We aimed at dissecting the role of G-CSF in an alcohol-induced murine model of ACLF.Methods: ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis model. A subgroup of mice received two G-CSF (200 μg/kg) or vehicle injections prior to acute decompensation with alcohol. Liver, blood and brain tissues were assessed.Results: Alcohol binge administered to BDL-fibrotic mice resulted in features of ACLF indicated by a significant increase in liver damage and systemic inflammation compared to BDL alone. G-CSF treatment in ACLF mice induced an increase in liver regeneration and neutrophil infiltration in the liver compared to vehicle-treated ACLF mice. Moreover, liver-infiltrating neutrophils in G-CSF-treated mice exhibited an activated phenotype indicated by increased expression of CXC motif chemokine receptor 2, leukotriene B4 receptor 1, and calprotectin. In the liver, G-CSF triggered increased oxidative stress, type I interferon response, extracellular matrix remodeling and inflammasome activation. Circulating IL-1β was also increased after G-CSF treatment. In the cerebellum, G-CSF increased neutrophil infiltration and S100a8/9 expression, induced microglia proliferation and reactive astrocytes, which was accompanied by oxidative stress, and inflammasome activation compared to vehicle-treated ACLF mice.Conclusion: In our novel ACLF model triggered by alcohol binge that mimics ACLF pathophysiology, neutrophil infiltration and S100a8/9 expression in the liver and brain indicate increased tissue damage, accompanied by oxidative stress and inflammasome activation after G-CSF treatment.

Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1β via NLRP3 activation and that IL-1β acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment.

Introduction: Genetic and environmental factors play a significant role in the development of Cardiovascular Disease (CVD). With advancements in molecular techniques, it is now possible to study genes that may provide evidence of the role of genetic factors in Coronary Artery Disease (CAD). Genetic variants of the Apo A-1 gene might play an important role in regulating lipid profiles and their alteration, leading to the subsequent development of Myocardial Infarction (MI). Aim: The aim of this study was to evaluate the association between C+83T sequence variations in the first intron of the Apo A-1 gene and lipid variables in patients with MI. Materials and Methods: A case-control study was conducted at the Department of Biochemistry in association with the Department of Cardiology, Kilpauk Medical College Hospital, Chennai, Tamil Nadu, India, from October 2013 to March 2014. The study included 52 MI cases and 52 age-, gender-, and risk factor-matched controls. Fasting venous blood samples were collected from each patient, and routine investigations, lipid profile assessments, and polymorphic studies were carried out. Allele frequencies between cases and controls were compared using the Chi-square test. Analysis of Variance (ANOVA) was performed to determine the association between fasting serum lipid variables and allele distribution. Results: Both study groups were matched for age, gender, and risk factors such as alcohol consumption, smoking, Hypertension (HT), and Diabetes Mellitus (DM). The results were compared and found to be statistically insignificant. Genotype analysis between the groups disclosed that the TT homozygous genotype was more prevalent in cases, while the ‘CC’ genotype was more prevalent in controls, and the CT genotype was approximately equal in both cases and controls. The genotype difference between cases and controls was statistically significant (p-value=0.006). The ‘T’ allele frequency was higher among cases (0.36) compared to controls (0.13), while the frequency of the ‘C’ allele was higher among controls (0.86) compared to cases (0.63). In the CC genotype, there was a higher mean value of Apo A-1 and a lower ApoB/Apo A-1 ratio compared to the TT genotype. It was observed that carriers of the C allele and T allele showed no statistical difference in lipid variables except for High-density Lipoprotein (HDL). Conclusion: This study found a significantly increased T allele frequency in cases compared to controls, suggesting that the presence of the T allele in the C+83T (first intron) of the Apo A-1 gene may increase the risk of developing MI.