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Carbonation of concrete is one of the key factors causing deterioration for reinforced concrete structures. Carbonation depth is typically used to estimate the concrete service life. Among the most important factors that can greatly affect carbonation resistance of concrete are relative humidity (RH) and water cement ratio. This paper investigates the effect of variation of RH on carbonation resistance of concrete made with different cementitious materials; CEMI42.5N, CEMIII/A42.5N, and CEMIII/A42.5N with 10% silica fume as an addition. Compressive strength and accelerated carbonation test were conducted on different concrete mixes. The relation between carbonation depth and RH had been analyzed, based on most common carbonation models; model code-FIB, Chinese codes model and Jiang et al. s-model. The results indicated that relation between RH and depth of carbonation is a polynomial function within certain range which agrees with the Chinese code. This finding is crucial for accurately predicting the carbonation behavior of concrete structure using different models. Keywords: Carbonation resistance, Relative humidity, Carbonation model

A solid polymer electrolyte system based on poly(vinyl alcohol) (PVA) and poly(3,4-Etylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) complexed with magnesium bromide (MgBr2) salt was prepared using solution cast technique. The ionic conductivity is observed to increase with increasing MgBr2 concentration. The maximum conductivity was found to be 9.89 × 10−6 S/cm for optimum polymer composite film (30 wt.% MgBr2) at room temperature. The increase in the conductivity is attributed to the increase in the number of ions as the salt concentration is increased. This has been proven by dielectric studies. The increase in conductivity is also attributable to the increase in the fraction of amorphous region in the electrolyte films as confirmed by their structural, thermal, electrical and optical properties.

Kafrelsheikh, situated in the middle of the Nile Delta, significantly contributes to Egypt's aquaculture and agriculture sectors. However, the local use of organochlorine pesticides (OCPs) in agriculture is often a source of OCP residues in associated drainage waters, which may threaten aquatic ecosystems. These pesticides persist in local water bodies, jeopardizing aquatic ecosystems and potentially impacting human health. This comprehensive study assessed the seasonal variations of 17 OCPs in both water sources and Nile tilapia across eight fish farming locations in Kafrelsheikh. Using gas chromatography coupled with mass spectrometry (GC-MS), we detected OCP concentrations in water that varied seasonally where winter recorded the highest levels at 22.5 ng/mL and, summer showed the lowest levels at 6.2 ng/mL. Despite water samples occasionally showing risk quotients (RQs) greater than 1, indicating a potential threat to aquatic life, the OCP levels in Nile tilapia were sufficiently low, with target hazard quotients (THQ) below 1, suggesting no significant risk for human consumption. The research highlights a pressing need for regular environmental monitoring and stricter regulatory control over pesticide use to protect aquatic life and ensure the safety of aquaculture products. These findings provide a critical basis for policy-making, aimed at balancing agricultural productivity with environmental sustainability in regions heavily dependent on both.

Brucellosis is recognized as a significant global zoonotic infection that disproportionately affects low-income settings. A community cross-sectional survey was carried out in a rural setting of northwest Iran between February and May 2023. Rural individuals were interviewed according to a questionnaire with questions about demographic characteristics, knowledge, attitudes, and practices relating to human brucellosis. We employed descriptive statistics to study knowledge, attitudes, and practice patterns. In addition, we applied a multivariable logistic regression model to assess potential predictors of knowledge, attitudes, and practice related to brucellosis using odds ratios and 95% confidence intervals. Among 700 participants, 91.1% were aware of brucellosis, and 85.7% identified cows, sheep, and goats as primary transmission sources. 75.6% and 78.7% recognized transmission risks via unpasteurized and raw milk products. 60.5% understood the benefits of boiling milk and using gloves. Attitudinally, 64.3% perceived higher risk for livestock owners and supported practices like milk pasteurization (70.5%), protective gear (84.4%), handwashing (92.2%), and animal vaccination (71.0%). 90% expressed a need for more information. In practice, 44.8% exclusively consumed boiled and pasteurized milk, 37.8% consumed fresh cheese, and 92.2% solely consumed thoroughly cooked animal meat. Logistic regression revealed that higher education and no prior history of the disease correlated with good knowledge and attitudes, while older participants displayed inappropriate practices compared to their younger counterparts. This study highlights the reasonably high awareness of brucellosis, particularly regarding transmission sources and preventive measures. However, the gaps in knowledge, attitudes, and practices still exist, with education level emerging as a significant factor. To improve prevention practices, tailored interventions addressing age-related disparities are necessary.

Recent reinforced concrete Flat slabs (RC) failures under two-way shear have raised a question mark on the reliability of the current understanding of the two-way shear design. Moreover, the two-way shear strength of Flat slabs subjected to membrane tensile forces is a dilemma, where design codes provision varies significantly for this case. In this study, the full behavior of flat RC slabs subjected to combined two-way shear and axial tension is investigated. The behavior in terms of load versus deformation, ultimate strength, and deformation. Firstly, an extensive review of the existing literature on the experimental testing and design models for Flat slabs under combined two-way shear and axial tensile forces was conducted. Secondly, an experimental test setup designed to apply combined two-way shear and tensile forces simultaneously on flat slabs was presented. Four flat slabs (1500 × 1500 × 150 mm) were tested under two-way shear up to failure, while subjected to different levels of membrane tensile forces. Thirdly, experimentally measured strength from current and previous studies were compared with that calculated using selected design codes and mechanical models. For flat slabs under two-way shear combined with membrane tensile forces, the following was concluded: (1) a disagreement between selected design codes, while the European design code is the closer to the experimental results; (2) The stiffness and the strength were reduced by 57% and 29% respectively which is highly dependent on the level of tension.

Salinity stress reduces crop growth and agricultural productions around the world. The effects of salinity stress on seed germination, some morphological, physiological and biochemistry traits, and expression of four genes at seedling stage in salt contrasting barley genotypes were investigated in the current study. Seed germination percentage and morphological traits were analyzed based on a factorial randomized complete design which ANOVA results showed that interaction between salinity (150 and 250 mM NaCl) and genotype (Afzal and Sahand (salt tolerant), and Fajr and Reyhan (sensitive)) was significat (p

A comparative field study was performed to assess the heavy metals contamination in surficial sediments of highly and less polluted zones at the northern part of the Suez Gulf. In addition, to highlight the relationship among metal contamination and enzyme activity. Seven heavy metals Mn, Fe, Pb, Cd, Zn, Ni, and Cu were analyzed using atomic absorption spectrophotometer. The activity of enzymes (alkaline phosphatase and urease) was estimated in the sediment samples. The statistical results showed that there were high significant differences at p ≤ 0.01 among Cu, Pb, Cd, Ni, Mn and Zn between highly polluted and less polluted sediments. Urease activity had no significant relationship with the tested metals concentrations. Cd, Cu, Mn, Ni, Pb and Zn may inhibit alkaline phosphatase activity. Alkaline phosphatase activity showed high significant difference at p ≤ 0.01 between summer and winter seasons in highly polluted sediment. Moreover, there was significant seasonal difference in Pb concentration at p ≤ 0.01 in the same category. Correlations of the enzymes with each metal showed that alkaline phosphatase activity had significant negative correlation coefficients (r = −0.55, −0.49, −0.27, −0.37, −0.37, and −0.60) with Cu, Cd, Fe, Ni, Zn and Pb respectively in winter, but only with Zn (r = −0.46) in summer season. As a result, ALP activity can possibly be used as a predictor and sensitive indicator of heavy metals bioavailability in marine sediments.

A one-year-old baby girl with one-month history of recurrent pus fluid exuding from her left preauricular sinus orifice, who failed multiple courses of surgical drainage of the abscess and persistent debridement for the wound, presented with MRSA infection. The patient was treated with linezolid for three days. Her pain and paresthesia resolved, and C-reactive protein decreased to normal.

This paper presents an adaptive probabilistic recurrent Takagi-Sugeno-Kang fuzzy neural PID controller for handling the problems of uncertainties in nonlinear systems. The proposed controller combines probabilistic processing with a Takagi-Sugeno-Kang fuzzy neural system to proficiently address stochastic uncertainties in controlled systems. The stability of the controlled system is ensured through the utilization of Lyapunov function to adjust the controller parameters. By tuning the probability parameters of the controller design, an additional level of control is achieved, leading to enhance the controller performance. Furthermore, it can operate without relying on the system's mathematical model. The proposed control approach is employed in nonlinear dynamical plants and compared to other existing controllers to validate its applicability in engineering domains. Simulation and experimental investigations demonstrate that the proposed controller surpasses alternative controllers in effectively managing external disturbances, random noise, and a broad spectrum of system uncertainties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 ISA. Published by Elsevier Ltd. All rights reserved.)

Some heterocycles bearing a benzo[h]quinoline moiety were synthesized through treating a 3-((2-chlorobenzo[h]quinolin-3-yl)methylene)-5-(p-tolyl)furan-2(3H)-one with four nitrogen nucleophiles comprising ammonium acetate, benzylamine, dodecan-1-amine, and 1,2-diaminoethane. Also, thiation reactions of furanone and pyrrolinone derivatives were investigated. The insecticidal activity of these compounds against mosquito larvae (Culex pipiens L.) was evaluated. All tested compounds exhibited significant larvicidal activity, surpassing that of the conventional insecticide chlorpyrifos. In silico docking analysis revealed that these compounds may act as acetyl cholinesterase (AChE) inhibitors, potentially explaining their larvicidal effect. Additionally, interactions with other neuroreceptors, such as nicotinic acetylcholine receptor and sodium channel voltage-gated alpha subunit were also predicted. The results obtained from this study reflected the potential of benzo[h]quinoline derivatives as promising candidates for developing more effective and sustainable mosquito control strategies. The ADME (absorption, distribution, metabolism, and excretion) analyses displayed their desirable drug-likeness and oral bioavailability properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Non-alcoholic steatohepatitis (NASH) is the second most frequent cause of liver transplantation following alcoholic liver disease. With longer follow-up and increased survival rates, the occurrence rate of the metabolic syndrome is increasing with time among liver transplant recipients. Reappearances of non-alcoholic fatty liver disease after transplantation, both as recurring cases and new instances, are prevalent; nonetheless, the recurrence of fibrosis is minimal. Recognizing populations at elevated risk and enhancing the management of metabolic-related conditions are crucial for maintaining a healthy transplanted organ, particularly considering the prolonged utilization of immunosuppressive treatments. Furthermore, NASH-related cirrhosis patients who had transplant are at a greater risk of cardiovascular, renal events and increased incidence of cancer, necessitating a unique care strategy. This review discusses post-transplant metabolic syndrome, risk factors, pathogenesis, diagnosis, prevention strategy, recurrent and de novo NAFLD and customized immunosuppression., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC 50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC 50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A novel optical sensor has been fabricated for highly accurate, simple and selective determination of nanomolar levels of cadmium ions. The sensor depends on the interaction of 6-{4-(2,4-dihydroxyphenyl)diazenyl)phenyl}-2-oxo-4-phenyl-1,2-dihydropyri-dine-3-carbonitrile (DDPODC) with Cd(II) in plasticized (2-nitrophenyloctyl ether) (o-NPOE) polyvinylchloride (PVC) membrane incorporating chromoionophore V as a lipophilic H + -selective indicator. It would seem that the higher Cd(II) concentration, the lower absorbance of chromoionophore V in the membrane at 668 nm, whereas the absorbance at 586 nm increased. The developed sensor at pH 4.7 has a linear range of 5.0 × 10 -12 - 2.5 × 10 -5  M with limits of detection and quantification of 1.62 × 10 -12 and 4.95 × 10 -12  M, respectively. The relative standard deviation (RSD) for eight determination of 1.0 × 10 -7  M Cd(II) was 1.67%. Finally, the proposed sensor gives good results for applications in the direct determination of cadmium ions in water, food, and biological samples. Additionally, we compared the obtained results with the data obtained from the flame atomic absorption spectrometry (FAAS)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The attenuating effect of 150 mg/kg of N-acetylcysteine (NAC) against the oral administration of 7.88 and 202.07 mg/kg/day for 14 days of either chlropyrifos-ethyl (CPE-E) or chlropyrifos-methyl (CPF-M), respectively, in male rat was investigated using biochemical and genetic markers. Biomarkers such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), paraoxonase (PON), adenosine 5'-triphosphatase (ATP-ase), glutathione-S-transferase (GST), catalase (CAT), glutathione reduced (GSH) in serum showed a significant decline in their levels, while calcium (Ca +2 ), cytochrome C reduction (CYC-R), lipid peroxidation (LPO), nitric oxide (NO) levels showed a significant increase in serum of treated rats. Regarding the genotoxic parameters, when rats are treated either with CPE-E or CPF-M, liver DNA, chromosomal aberration (CA), and micronucleated polychromatic erythrocytes (MnPCE) significantly increased, while the mitotic index (MI) and polychromatic erythrocytes (PCE)/ normochromatic erythrocytes (NCE) ratio were significantly decreased. However, the administration of NAC following the intoxication of CPF-E or CPF-M attenuated the tested biochemical and genotoxic markers. It can be concluded that NAC can be used to ameliorate the toxicity of certain organophosphorus compounds such as CPF-E and CPF-M., (Copyright © 2021 Elsevier B.V. All rights reserved.)

BRAF V600E mutation has been detected in various malignant tumours. Developing of potent BRAF V600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC 50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC 50 values of 2.4 µM and 3.6 µM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14h and 16e. The mean IC 50 values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAF V600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAF V600E with IC 50 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types., (Copyright © 2020 Elsevier Inc. All rights reserved.)

As an extension for our earlier effort in the field of discovery of anticancer agents acting on DNA and Topo II, eighteen quinoxaline derivatives were designed and synthesized. Such members were designed to possess the main essential pharmacophoric features of DNA intercalators. The cytotoxic potential of the synthesized compounds was assessed against a group of human cancer cell lines (HCT-116, HepG2, and MCF-7). Doxorubicin as potential intercalative Topo II inhibitor, was used as a positive reference. In general, compounds 12, 15, 19, 21, and 22 showed promising anti-proliferative activities against the three cell lines with IC 50 values ranging from 2.81 to 10.23 µM. The cytotoxicities of the most active compounds against normal human cells (WI-38) were evaluated, and the results revealed that these compounds have low toxicity. Further examination for the most active anti-proliferative members as Topo II inhibitors was also performed, showing a narrow range of the inhibitory activities (from 0.45 to 1.06 µM). In addition, DNA/methyl green assay was carried out to evaluate DNA-binding potential of such compounds. The results indicated that these compounds have strong to moderate DNA-binding affinities ranging from 33.48 to 51.23 µM. Further studies exhibited the capability of compound 22 to induce apoptosis in HepG2 cells and can arrest growth of such cells at G2/M phase. Also, compound 22 produced a significant increase in the level of caspase- 3 (10 folds) and caspase-9 (7 folds) compared to the control cells. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the DNA-Topo II complex., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BRAF mutation is commonly known in a number of human cancer types. It is counted as a potential component in treating cancer. In this study, based on structural optimization of previously reported inhibitors (3-fluro substituted derivatives of imidazo[2,1-b]thiazole-based scaffold), we designed and synthesized sixteen new imidazo[2,1-b]thiazole derivatives with m-nitrophenyl group at position 6. The electron withdrawing properties was reserved while the polarity was modified compared to previously synthesized compounds (-F). Furthermore, the new substituted group (-NO 2 ) provided an additional H-bond acceptor(s) which may bind with the target enzyme through additional interaction(s). In vitro cytotoxicity evaluation was performed against human cancer cell line (A375). In addition, in vitro enzyme assay was performed against mutated B-Raf (B-Raf V600E). Compounds 13a, 13g and 13f showed highest activity on mutated B-Raf with IC 50 0.021, 0.035 and 0.020 µM. All target compounds were tested for in vitro cytotoxicity against NCI 60 cell lines. Compounds 13a and 13g were selected for 5 doses test mode. Moreover, in silico molecular simulation was explored in order to explore the possible interactions between the designed compounds and the B-Raf V600E active site., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, "positive criteria" to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

In the present work, a novel series of B-RAF kinase inhibitors having imidazo[2,1-b]oxazole scaffold was designed and synthesized based on the structures of the well-known B-RAF inhibitors. The twenty two final compounds were tested over A375 and SKMEL28 cell lines to determine the primary cytotoxic activity of these compounds, and their activities were compared with that of sorafenib as a standard. Compounds 11c, 11e, 11o, 11q, 11r, and 11u exhibited higher cellular activity compared to sorafenib with IC 50 values of 7.25, 8.03, 9.81, 8.47, 4.70, and 9.04 µM, respectively and 10.38 µM for sorafenib. In addition, the target compounds were screened for their anticancer activity by the NCI-60 cell line assay. Compounds 11v and 11u were the most active compounds with percent inhibition reached 95.99% for 11v and 87.03% for 11u over K562 cell line at 10 µM concentration. Compound 11v was selected for 5-dose test mode. Furthermore, the kinase inhibitory activities of 11a, 11c, 11e, 11i, 11o, 11q, 11r, 11u, and 11v were determined against wild-type B-RAF, V600E-B-RAF, and RAF1. Compound 11o was the most potent against V600E-B-RAF with IC 50 34 nM followed by 11q and 11u with IC 50 92 and 93 nM, respectively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Micro-RNAs (miRNAs) are evolving as biological markers for multiple sclerosis (MS) both in activity and remission. miR-96 is associated with remission, however, the exact mechanism through which it contributes to the anti-inflammatory pathway is not clear., Objective: To study the expression of miR-96 and IL-10 (anti-inflammatory mediator) in relapsing remitting (RR) MS., Subjects and Methods: A case control study including 32 RRMS patients from Kasr Al-Ainy MS clinic, Cairo University, Egypt, and 26 healthy controls (HC). Assessment of serum IL-10 by ELISA, and miR-96 via real time PCR was done during relapse and remission in patients, and in HC., Results: IL-10 was higher in RRMS patients during remission and in HC compared with relapse (P ˂ 0.001). miR-96 expression was higher in RRMS patients during remission compared with relapse and HC, and was higher in HC than in relapse (P ˂ 0.001). IL-10 level in remission correlated positively with disease duration (r = 0.41; P = 0.02). Otherwise, no correlation was found between IL-10 and relapse number or EDSS (P>0.05). miR-96 in relapse negatively correlated with EDSS in relapse (r=-0.47; P=0.007), but no correlation was found with disease duration or relapse number, whereas, miR-96 in remission did not correlate with any clinical parameters (P>0.05). No correlation was found between IL-10 and miR-96 either in relapse or remission (P>0.05)., Conclusion: IL-10 and miR-96 are associated with MS quiescence, however, the lack of a significant correlation between them implicates that the influence of miR-96 may be exhibited through some pathway other than IL-10., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background & Aims: Natural killer (NK) cells are known to exert strong antiviral activity. Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is expressed by terminally differentiated NK cells and KLRG1-expressing lymphocytes are known to expand following chronic viral infections. We aimed to elucidate the previously unknown role of KLRG1 in the pathogenesis of chronic hepatitis B (CHB)., Methods: KLRG1+ NK cells were taken from the blood and liver of healthy individuals and patients with CHB. The phenotype and function of these cells was assessed using flow cytometry and in vitro stimulation., Results: Patients with CHB had a higher frequency of KLRG1+ NK cells compared to healthy controls (blood 13.4 vs. 2.3%, p <0.0001 and liver 23.4 vs. 2.6%, p <0.01). KLRG1+ NK cells were less responsive to K562 and cytokine stimulation, but demonstrated enhanced cytotoxicity (9.0 vs. 4.8%, p <0.05) and IFN-γ release (8.0 vs. 1.5%, p <0.05) via antibody dependent cellular cytotoxicity compared to their KLRG1- counterparts. KLRG1+ NK cells possessed a mature phenotype, demonstrating stronger cytolytic activity and IFN-γ secretion against hepatic stellate cells (HSCs) than KLRG1- NK cells. Moreover, KLRG1+ NK cells more effectively induced primary HSC apoptosis in a TRAIL-dependent manner. Increased KLRG1+ NK cell frequency in the liver and blood was associated with lower fibrosis stage (F0/F1) in patients with CHB. Finally, the expression of CD44, degranulation and IFN-γ production were all increased in KLRG1+ NK cells following stimulation with osteopontin, the CD44 ligand, suggesting that HSC-derived osteopontin may cause KLRG1+ NK cell activation., Conclusions: KLRG1+ NK cells likely play an antifibrotic role during the natural course of CHB infection. Harnessing this antifibrotic function may provide a novel therapeutic approach to treat liver fibrosis in patients with CHB., Lay Summary: Individuals that are chronically infected with hepatitis B virus (HBV) possess an increased number of immune cells, called natural killer (NK) cells expressing the surface marker KLRG1 in the blood and liver. Here, we demonstrate that these specific NK cells are able to kill activated stellate cells in the liver. Because activated stellate cells contribute to liver scarring, i.e. fibrosis, and subsequent liver dysfunction in individuals with chronic HBV infection, KLRG1+ NK cells are a novel immune cell type that can limit liver scarring., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Irisin, the cleaved extra-cellular fragment of the Fibronectin type III domain-containing protein 5 (FNDC5) is a myokine that is proposed to have favorable metabolic activity. We aimed to elucidate the currently undefined role of variants in the FNDC5 gene in non-alcoholic fatty liver disease (NAFLD)., Methods: We prioritized single nucleotide polymorphisms in FNDC5 on the basis of their putative biological function and identified rs3480 in the 3' untranslated region (3'UTR). We studied the association of rs3480 with liver disease severity and the metabolic profile of 987 Caucasian patients with NAFLD. Functional investigations were undertaken using luciferase reporter assays of the 3'UTR of human FNDC5, pyrosequencing for allele-specific expression of FNDC5 in liver, measurement of serum irisin, and bioinformatics analysis., Results: The rs3480 (G) allele was associated with advanced steatosis (OR 1.29; 95% CI 1.08-1.55; p = 0.004), but not with other histological features. This effect was independent but additive to PNPLA3 and TM6SF2. The rs3480 polymorphism influenced FNDC5 mRNA stability and the binding of miR-135a-5P. Compared with controls, hepatic expression of this microRNA was upregulated while FNDC5 expression was downregulated. Elevated serum irisin was associated with reduced steatosis, and an improved metabolic profile., Conclusions: Carriage of the FNDC5 rs3480 minor (G) allele is associated with more severe steatosis in NAFLD through a microRNA-mediated mechanism controlling FNDC5 mRNA stability. Irisin is likely to have a favorable metabolic impact on NAFLD., Lay Summary: Irisin is a novel protein produced mainly by muscle, which is known to be released into the circulation, with an unclear role in liver fat deposition. This study demonstrates that genetic variants in the gene encoding the irisin protein modulate the risk of liver fat in patients with fatty liver disease. Interestingly, these effects are independent of, but additive to those of other recently described genetic variants that contribute to liver fat. In functional studies, we have deciphered the detailed molecular mechanisms by which this genetic variant mediates its effects., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The extent of liver fibrosis predicts long-term outcomes, and hence impacts management and therapy. We developed a non-invasive algorithm to stage fibrosis using non-parametric, machine learning methods designed for predictive modeling, and incorporated an invariant genetic marker of liver fibrosis risk., Methods: Of 4277 patients with chronic liver disease, 1992 with chronic hepatitis C (derivation cohort) were analyzed to develop the model, and subsequently validated in an independent cohort of 1242 patients. The model was assessed in cohorts with chronic hepatitis B (CHB) (n=555) and non-alcoholic fatty liver disease (NAFLD) (n=488). Model performance was compared to FIB-4 and APRI, and also to the NAFLD fibrosis score (NFS) and Forns' index, in those with NAFLD., Results: Significant fibrosis (⩾F2) was similar in the derivation (48.4%) and validation (47.4%) cohorts. The FibroGENE-DT yielded the area under the receiver operating characteristic curve (AUROCs) of 0.87, 0.85 and 0.804 for the prediction of fast fibrosis progression, cirrhosis and significant fibrosis risk, respectively, with comparable results in the validation cohort. The model performed well in NAFLD and CHB with AUROCs of 0.791, and 0.726, respectively. The negative predictive value to exclude cirrhosis was>0.96 in all three liver diseases. The AUROC of the FibroGENE-DT performed better than FIB-4, APRI, and NFS and Forns' index in most comparisons., Conclusion: A non-invasive decision tree model can predict liver fibrosis risk and aid decision making., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Single nucleotide polymorphisms (SNPs) near the interferon lambda 3 (IFNL3, previously known as IL28B) region are the strongest baseline predictors of sustained virologic response (SVR) to pegylated interferon and ribavirin therapy in hepatitis C virus (HCV) genotype 1 infection. Whether IFNL3 SNPs influence treatment response in genotype 2 and 3 (HCV-2/3) infection remains controversial. This study sought to clarify in a large cohort, whether SNPs in the IFNL3 region are associated with treatment response in HCV-2/3 patients., Methods: The cohort comprised 1002 HCV-2/3 Caucasians patients treated with pegylated interferon-alpha and ribavirin who underwent genotyping for the SNPs rs12979860 and rs8099917., Results: Overall, 736 (73.5%) patients achieved SVR (81.9%, 67.9%, and 57.8% for rs12979860 CC, CT, and TT [p = 0.0001]; 78%, 68.7%, and 46.3% for rs8099917 TT, TG, and GG [p = 0.0001]). By logistic regression, both rs12979860 CC and rs8099917 TT were independent predictors of SVR with an odds ratio (OR) of 2.39 (1.19-3.81) p = 0.0001 and OR 1.85 (1.15-2.23) p = 0.0001, respectively. IFNL3 responder genotypes were more frequent in relapsers than null-responders (p = 0.0001 for both SNPs). On-treatment rapid virological response (RVR) was predictive of SVR only in those individuals with IFNL3 non-responder genotypes (rs12979860 CT/TT and rs8099917 TG/GG)., Conclusions: This adequately powered study in patients with HCV genotypes 2 or 3 infection clearly demonstrates that IFNL3 genotypes are the strongest baseline predictor of SVR, in keeping with the known association for genotype 1 infection. IFNL3 genotyping can aid in therapeutic decision making for these patients., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections., (Copyright © 2010 European Association for the Study of the Liver. All rights reserved.)