Copy number variation and expression of exportin-4 associates with severity of fibrosis in metabolic associated fatty liver disease

Background Liver fibrosis risk is a heritable trait, the outcome of which is the net deposition of extracellular matrix by hepatic stellate cell-derived myofibroblasts. Whereas nucleotide sequence variations have been extensively studied in liver fibrosis, the role of copy number variations (CNV) in which genes exist in abnormal numbers of copies (mostly due to duplication or deletion) has had limited exploration. Methods The impact of the XPO4 CNV on histological liver damage was examined in a cohort comprised 646 Caucasian patients with biopsy-proven MAFLD and 170 healthy controls. XPO4 expression was modulated and function was examined in human and animal models. Findings Here we demonstrate in a cohort of 816 subjects, 646 with biopsy-proven metabolic associated liver disease (MAFLD) and 170 controls, that duplication in the exportin 4 (XPO4) CNV is associated with the severity of liver fibrosis. Functionally, this occurs via reduced expression of hepatic XPO4 that maintains sustained activation of SMAD3/SMAD4 and promotes TGF-β1-mediated HSC activation and fibrosis. This effect was mediated through termination of nuclear SMAD3 signalling. XPO4 demonstrated preferential binding to SMAD3 compared to other SMADs and led to reduced SMAD3-mediated responses as shown by attenuation of TGFβ1 induced SMAD transcriptional activity, reductions in the recruitment of SMAD3 to target gene promoters following TGF-β1, as well as attenuation of SMAD3 phosphorylation and disturbed SMAD3/SMAD4 complex formation. Interpretation We conclude that a CNV in XPO4 is a critical mediator of fibrosis severity and can be exploited as a therapeutic target for liver fibrosis

Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study

Background & Aims Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. Methods We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. Results During a mean follow-up time of 5.5 years (range, 2.7–8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%–99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%–89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%–29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%–60% vs 6%, 95% CI, 2%–13%) or hepatocellular carcinoma (17%; 95% CI, 8%–31% vs 2.3%, 95% CI, 1%–12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%–18%) than cirrhosis (2%; 95% CI, 0%–6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%–23%) than cirrhosis (6%; 95% CI, 2%–15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis. Conclusions Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events

Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype- and context-dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.Peer reviewe

IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis

The International Liver Disease Genetics Consortium (ILDGC).Genetic variation in the IFNL3–IFNL4 (interferon-λ3–interferon-λ4) region is associated with hepatic inflammation and fibrosis1,2,3,4. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3–IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4–Ser70) and those encoding fully active IFN-λ4–Pro70. The two proposed functional variants (rs368234815 and rs4803217)5,6 were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis.M.E., M.D., and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, and by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1053206) and NHMRC Project Grants (APP1107178 and APP1108422). G.D. is supported by an NHMRC Fellowship (1028432)

Role of novel genetic variations on tissue fibrosis

Tissue fibrosis is a highly heritable complex phenotype that has both core and disease-specific pathways and is responsible for nearly half of all deaths worldwide. There are no approved therapies for tissue fibrosis. Non-alcoholic fatty liver disease (NAFLD) is a primary cause of liver disease that affects around a quarter of the global population. Adverse outcomes in NAFLD and in many other chronic liver diseases are in large part secondary to the consequences of liver fibrosis. However, our understanding of the genetic basis of tissue fibrosis and of fibrosis in NAFLD is limited, with known variants explaining only a small proportion of the heritability. This suggests that there is a substantial burden of yet to be identified “missing heritability”. Furthermore, most existing studies have focused on single nucleotide polymorphisms that account for genetic variation between individuals, with less information on other types of genetic variation, such as copy number variation (CNV). In the latter, genes exist in abnormal numbers of copies, mostly due to duplication or deletion. The studies in this thesis within the larger context of tissue fibrosis and more specifically in regard to liver and lung fibrosis, were designed to clarify the role of: a) Variants in FNDC5 on the histological severity of NAFLD b) Variants in IFNL3 on lung fibrosis (previous extensive work in our laboratory had confirmed that variants in IFNL3 impact hepatic inflammation and fibrosis in a variety of chronic liver diseases), and c) CNV in the XPO4 gene and the histological severity of NAFLD. The major outcomes of the research were: a) In 987 Caucasian patients with NAFLD, we demonstrated that the FNDC5 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 through a microRNA-mediated mechanism controlling FNDC5 mRNA stability. This effect was independent but additive to that of variants in PNPLA3 and TM6SF2. Elevated serum irisin was associated with reduced steatosis, and an improved metabolic profile. b) In a cohort of Caucasian patients with systemic sclerosis (SSc) (n=733), we observed an association of the IFNL3 polymorphism with pulmonary fibrosis, but not worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with pulmonary fibrosis compared to those unaffected (P<0.0001). Lung Ifnl3 mRNA expression was higher in mice with bleomycin-induced PF compared to controls (P<0.05). c) In a cohort of 920 Caucasian subjects; including 646 adults and 104 children with biopsy-proven NAFLD, and 170 controls, we observed that duplication in XPO4 CNVs is associated with the severity of liver fibrosis. Functionally, XPO4 regulated TGF- β/SMAD3 signalling during hepatic stellate cell (HSC) activation. This data identifies a novel target that can be exploited for treating liver fibrosis. The studies contained in this thesis augment our understanding of three important aspects, in the post-GWAS era: 1) The role of hitherto overlooked genetic variants in filling the missing heritability observed in NAFLD and in liver fibrosis. 2) The role of shared common pathophysiological mechanisms and pathways that mediate fibrosis across different organs, and 3) The potential pivotal contribution of CNVs, in modulating liver fibrosis. We contend that better understanding of the genetic basis of tissue fibrosis could have farreaching implications for the personalization of medicine and for the elucidation of novel therapeutic targets

Unimodal‐Bio‐GAN: Keyless biometric salting scheme based on generative adversarial network

Abstract Cancellable biometrics enabled us to develop robust authentication systems by replacing the storage of the original biometric template with another secured version. A technique called biometric salting uses a parameter (key) and an invertible function to transform the human biometrics features into a secured format that can be protected and stored securely in a biometric database system. The salting key plays a main role in the success of this transformation, which makes it robust or vulnerable to many security attacks. One of the main challenges that faces biometrics' researchers currently is how to design and protect such a salting key considering two basic measures: security and recognition accuracy. In this article, we propose unimodal‐Bio‐GAN, a reliable keyless biometric salting technique based on standard generative adversarial network (GAN). In unimodal‐Bio‐GAN, a random permuted version of the human biometric data is implicitly considered as a salting key and required only during the enrolment stage, which increases the system reliability to overcome different security attacks. The experimental results of unimodal‐Bio‐GAN using the CASIA Iris‐V3‐Internal database outperform the previous methods and its security efficiency is analysed using different attack types

Ant Lion Optimization algorithm for kidney exchanges.

The kidney exchange programs bring new insights in the field of organ transplantation. They make the previously not allowed surgery of incompatible patient-donor pairs easier to be performed on a large scale. Mathematically, the kidney exchange is an optimization problem for the number of possible exchanges among the incompatible pairs in a given pool. Also, the optimization modeling should consider the expected quality-adjusted life of transplant candidates and the shortage of computational and operational hospital resources. In this article, we introduce a bio-inspired stochastic-based Ant Lion Optimization, ALO, algorithm to the kidney exchange space to maximize the number of feasible cycles and chains among the pool pairs. Ant Lion Optimizer-based program achieves comparable kidney exchange results to the deterministic-based approaches like integer programming. Also, ALO outperforms other stochastic-based methods such as Genetic Algorithm in terms of the efficient usage of computational resources and the quantity of resulting exchanges. Ant Lion Optimization algorithm can be adopted easily for on-line exchanges and the integration of weights for hard-to-match patients, which will improve the future decisions of kidney exchange programs. A reference implementation for ALO algorithm for kidney exchanges is written in MATLAB and is GPL licensed. It is available as free open-source software from: https://github.com/SaraEl-Metwally/ALO_algorithm_for_Kidney_Exchanges

Translation Reprogramming as a Novel Therapeutic Target in MAFLD

Approved pharmacotherapies for metabolic-dysfunction-associated fatty liver disease (MAFLD) are lacking. Novel approaches and therapeutic targets that are likely to translate to clinical benefit are required. Targeting components of the translation machinery hold promise as a novel therapeutic approach that can overcome the well-known disease heterogeneity, as dysregulation of mRNA translation is a common feature independent of the MAFLD drivers. In this perspective, recent advances in understanding the role of mRNA translation in MAFLD are discussed, with a particular focus on the potential implications and challenges to “translate” these findings to the clinic, and an overview of similar recent efforts in other diseases is provided

A NEAD exchange graph.

<p>A chain starts with an altruistic donor and ends with a bridge donor assigned to the first compatible patient on the next round.</p