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Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 35282

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Prof. Dr. Hiroshi Fukui

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Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Japan
Interests: gut microbiome; liver disease; metagenomics; metabolomics; alcoholic liver disease; nonalcoholic steatohepatitis (NASH); liver cirrhosis and hepatocellular carcinoma
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Dear Colleagues,

The etiologies of liver disease are variable, including viral hepatitis, autoimmune hepatitis, and alcoholic liver disease. Recently, metabolic-dysfunction-associated fatty liver has become the most common cause of liver disease in the world. In addition, the liver is closely associated with other major organs, such as the kidneys, heart, and brain. The pathophysiology of these complications is very complicated. Portal blood containing the gut microbiome and its products, such as endotoxin and bacterial products, flows into the liver. The liver acts to initially detoxify these products. In the so-called “leaky gut”, the increased intestinal permeability to bacteria and their products is an important pathogenetic factor in major complications in patients with liver diseases. Prolonged gut transit may induce intestinal bacterial overgrowth, a condition in which colonic bacteria translocate into the small gut. Pathological bacterial translocation (BT) is another factor contributing to the development of various complications. Bile acids (BAs) undergo extensive enterohepatic circulation and play vital roles in the so-called gut–liver axis. BT-induced inflammation prevents the synthesis of bile acids (BAs) in the liver through the inhibition of BA-synthesizing enzyme. A lower abundance of 7α-dehydroxylating gut bacteria leads to the decreased conversion of primary to secondary BAs. Decreases in total and secondary BAs may play an important role in gut dysbiosis, characterized by a proinflammatory and toxic gut microbiome inducing BT and endotoxemia. Selective intestinal decontamination by various antimicrobial drugs for the management of complications has a lengthy history. Lactobacillus GG decreasing endotoxemia is known to improve the microbiome, leading to beneficial changes in amino acid, vitamins, and secondary BA metabolism. In this Special Issue, we aim to explore important aspects of cellular signaling and cellular dysfunction in the pathophysiology and drug effects of various liver diseases. These approaches may help to shed further light on the future management of hepatology.

Prof. Dr. Hiroshi Fukui
Guest Editor

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Keywords

viral hepatitis
autoimmune liver diseases
alcoholic liver diseaes
metabolic-associated fatty liver
liver cirrhosis
hepatocellular carcinoma
gut–liver axis
leaky gut
portal hypertension

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Published Papers (12 papers)

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19 pages, 10382 KiB

Open AccessArticle

Proteomic Analysis of Dysfunctional Liver Sinusoidal Endothelial Cells Reveals Substantial Differences in Most Common Experimental Models of Chronic Liver Diseases

by Mar Gil, Mikel Azkargorta, Carla Fuster, María Martínez-Gómez, Imma Raurell, Aurora Barberá, Juan Manuel Pericàs, Diana Hide, Felix Elortza, Joan Genescà and María Martell

Int. J. Mol. Sci. 2023, 24(15), 11904; https://doi.org/10.3390/ijms241511904 - 25 Jul 2023

Cited by 2 | Viewed by 2033

Abstract

Molecular markers of dedifferentiation of dysfunctional liver sinusoidal endothelial cells (LSEC) have not been fully elucidated. We aimed at deciphering the molecular profile of dysfunctional LSEC in different pathological scenarios. Flow cytometry was used to sort CD11b⁻/CD32b⁺ and CD11b⁻/CD32b⁻ LSEC from three rat models of liver disease (bile duct ligation-BDL; inhaled carbon tetrachloride-CCl4; and high fat glucose/fructose diet-HFGFD). A full proteomic profile was performed applying nano-scale liquid chromatography tandem mass spectrometry (nLC-MS) and analyzed with PEAKS software. The percentage of CD32b⁻ LSEC varied across groups, suggesting different capillarization processes. Both CD32⁺ and CD32b⁻ LSEC from models are different from control LSEC, but differently expressed proteins in CD32b⁻ LSEC are significantly higher. Heatmaps evidenced specific protein expression patterns for each model. Analysis of biological significance comparing dysfunctional CD32b⁻ LSEC with specialized CD32b⁺ LSEC from controls showed central similarities represented by 45 common down-regulated proteins involved in the suppression of the endocytic machinery and 63 common up-regulated proteins associated with the actin-dependent cytoskeleton reorganization. In summary; substantial differences but also similarities in dysfunctional LSEC from the three most common models of liver disease were found, supporting the idea that LSEC may harbor different protein expression profiles according to the etiology or disease stage. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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17 pages, 4573 KiB

Open AccessArticle

Hepatocyte-Specific Triggering of Hepatic Stellate Cell Profibrotic Activation by Apoptotic Bodies: The Role of Hepatoma-Derived Growth Factor, HIV, and Ethanol

by Moses New-Aaron, Siva Sankar Koganti, Murali Ganesan, Sharma Kanika, Vikas Kumar, Weimin Wang, Edward Makarov, Kusum K. Kharbanda, Larisa Y. Poluektova and Natalia A. Osna

Int. J. Mol. Sci. 2023, 24(6), 5346; https://doi.org/10.3390/ijms24065346 - 10 Mar 2023

Cited by 5 | Viewed by 2162

Abstract

Liver disease is one of the leading comorbidities in HIV infection. The risk of liver fibrosis development is potentiated by alcohol abuse. In our previous studies, we reported that hepatocytes exposed to HIV and acetaldehyde undergo significant apoptosis, and the engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) potentiates their pro-fibrotic activation. However, in addition to hepatocytes, under the same conditions, ABs can be generated from liver-infiltrating immune cells. The goal of this study is to explore whether lymphocyte-derived ABs trigger HSC profibrotic activation as strongly as hepatocyte-derived ABs. ABs were generated from Huh7.5-CYP2E1 (RLW) cells and Jurkat cells treated with HIV+acetaldehyde and co-culture with HSC to induce their pro-fibrotic activation. ABs cargo was analyzed by proteomics. ABs generated from RLW, but not from Jurkat cells activated fibrogenic genes in HSC. This was driven by the expression of hepatocyte-specific proteins in ABs cargo. One of these proteins is Hepatocyte-Derived Growth Factor, for which suppression attenuates pro-fibrotic activation of HSC. In mice humanized with only immune cells but not human hepatocytes, infected with HIV and fed ethanol, liver fibrosis was not observed. We conclude that HIV+ABs of hepatocyte origin promote HSC activation, which potentially may lead to liver fibrosis progression. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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22 pages, 7812 KiB

Open AccessArticle

HBV Enhances Sorafenib Resistance in Hepatocellular Carcinoma by Reducing Ferroptosis via SRSF2-Mediated Abnormal PCLAF Splicing

by Lijuan Liu, Zhao Lv, Miao Wang, Dongyan Zhang, Dongying Liu and Fan Zhu

Int. J. Mol. Sci. 2023, 24(4), 3263; https://doi.org/10.3390/ijms24043263 - 7 Feb 2023

Cited by 21 | Viewed by 3723

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. Hepatitis B virus (HBV) infection accounts for nearly 50% of HCC cases. Recent studies indicate that HBV infection induces resistance to sorafenib, the first-line systemic treatment for advanced HCC for more than a decade, from 2007 to 2020. Our previous research shows that variant 1 (tv1) of proliferating cell nuclear antigen clamp-associated factor (PCLAF), overexpressed in HCC, protects against doxorubicin-induced apoptosis. However, there are no reports on the relevance of PCLAF in sorafenib resistance in HBV-related HCC. In this article, we found that PCLAF levels were higher in HBV-related HCC than in non-virus-related HCC using bioinformatics analysis. Immunohistochemistry (IHC) staining of clinical samples and the splicing reporter minigene assay using HCC cells revealed that PCLAF tv1 was elevated by HBV. Furthermore, HBV promoted the splicing of PCLAF tv1 by downregulating serine/arginine-rich splicing factor 2 (SRSF2), which hindered the inclusion of PCLAF exon 3 through a putative cis-element (116–123), “GATTCCTG”. The CCK-8 assay showed that HBV decreased cell susceptibility to sorafenib through SRSF2/PCLAF tv1. HBV reduced ferroptosis by decreasing intracellular Fe²⁺ levels and activating GPX4 expression via the SRSF2/PCLAF tv1 axis, according to a mechanism study. Suppressed ferroptosis, on the other hand, contributed to HBV-mediated sorafenib resistance through SRSF2/PCLAF tv1. These data suggested that HBV regulated PCLAF abnormal alternative splicing by suppressing SRSF2. HBV caused sorafenib resistance by reducing ferroptosis via the SRSF2/PCLAF tv1 axis. As a result, the SRSF2/PCLAF tv1 axis may be a prospective molecular therapeutic target in HBV-related HCC, as well as a predictor of sorafenib resistance. The inhibition of the SRSF2/PCLAF tv1 axis may be crucial in the emergence of systemic chemotherapy resistance in HBV-associated HCC. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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15 pages, 2496 KiB

Open AccessArticle

Increased Hepatic ATG7 mRNA and ATG7 Protein Expression in Nonalcoholic Steatohepatitis Associated with Obesity

by Andrea Barrientos-Riosalido, Monica Real, Laia Bertran, Carmen Aguilar, Salomé Martínez, David Parada, Margarita Vives, Fàtima Sabench, David Riesco, Daniel Del Castillo, Cristóbal Richart and Teresa Auguet

Int. J. Mol. Sci. 2023, 24(2), 1324; https://doi.org/10.3390/ijms24021324 - 10 Jan 2023

Cited by 2 | Viewed by 2546

Abstract

The autophagy gene ATG7 has been shown to be essential for the induction of autophagy, a process that used to be suppressed in nonalcoholic fatty liver disease (NAFLD). However, the specific role of ATG7 in NAFLD remains unclear. The aim of this study was to analyze hepatic ATG7 mRNA and ATG7 protein expression regarding obesity-associated NAFLD. Patients included women classified into normal weight (NW, n = 6) and morbid obesity (MO, n = 72). The second group was subclassified into normal liver (NL, n = 11), simple steatosis (SS, n= 29), and nonalcoholic steatohepatitis (NASH, n = 32). mRNA expression was analyzed by RT–qPCR and protein expression was evaluated by Western blotting. Our results showed that NASH patients presented higher ATG7 mRNA and ATG7 protein levels. ATG7 mRNA expression was increased in NASH compared with SS, while ATG7 protein abundance was enhanced in NASH compared with NL. ATG7 mRNA correlated negatively with the expression of some hepatic lipid metabolism-related genes and positively with endocannabinoid receptors, adiponectin hepatic expression, and omentin levels. These results suggest that ATG7-mediated autophagy may play an important role in the pathogenesis of NAFLD, especially in NASH, perhaps playing a possible protective role. However, this is a preliminary study that needs to be further studied. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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21 pages, 6150 KiB

Open AccessArticle

Protective Role of Hepassocin against Hepatic Endoplasmic Reticulum Stress in Mice

by Yang Yang, Hui Chen, Yue Wan, Diandian Dong, Xiaofang Wang, Songhui Yao, Pengjun Wang, Shensi Xiang, Xiaoming Yang and Miao Yu

Int. J. Mol. Sci. 2022, 23(21), 13325; https://doi.org/10.3390/ijms232113325 - 1 Nov 2022

Cited by 3 | Viewed by 1998

Abstract

Hepassocin (HPS) is a hepatokine that has multiple proposed physiological functions. Some of the biological processes in which it is involved are closely related to endoplasmic reticulum (ER) stress, but the role of HPS in the regulation of ER stress remains unclear. Here, we demonstrated that HPS transcription is induced by the protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4) cascade upon ER stress in hepatocytes. Additionally, fasting/refeeding also induced HPS expression in mice liver. The loss of HPS sensitizes hepatocytes to ER stress-related cytotoxicity in vitro, whereas HPS treatment altered these phenotypes. HPS deficiency exacerbates fasting/refeeding-induced ER stress in vivo. The preliminary administration of HPS ameliorates liver steatosis, cell death, and inflammation in mice injected with tunicamycin (TM). The improvement of HPS can be observed even if HPS protein is injected after TM treatment. Furthermore, the administration of an ER stress inhibitor alleviated steatohepatitis in methionine- and choline-deficient (MCD) diet-fed HPS-deficient mice. These results suggest that HPS protects hepatocytes from physiological and pathological ER stress, and that the inactivation of HPS signaling aggravating ER stress may be a novel mechanism that drives the development of steatohepatitis. The protective mechanism of HPS against ER stress in hepatocytes was associated with the regulation of ER calcium handling, and the suppression of calcium influx release from ER upon stressor treatment. Collectively, our findings indicate that HPS may act in a negative feedback fashion to regulate hepatic ER stress and protect hepatocytes from ER stress-related injury. HPS has the potential to be a candidate drug for the treatment of ER stress-related liver injury. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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17 pages, 5986 KiB

Open AccessArticle

FOXM1 Is a Novel Molecular Target of AFP-Positive Hepatocellular Carcinoma Abrogated by Proteasome Inhibition

by Ru Li, Hikari Okada, Taro Yamashita, Kouki Nio, Han Chen, Yingyi Li, Tetsuro Shimakami, Hajime Takatori, Kuniaki Arai, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda and Shuichi Kaneko

Int. J. Mol. Sci. 2022, 23(15), 8305; https://doi.org/10.3390/ijms23158305 - 27 Jul 2022

Cited by 9 | Viewed by 2512

Abstract

Alpha-fetoprotein (AFP) is an oncofetal protein that is elevated in a subset of hepatocellular carcinoma (HCC) with poor prognosis, but the molecular target activated in AFP-positive HCC remains elusive. Here, we demonstrated that the transcription factor forkhead box M1 (FOXM1) is upregulated in AFP-positive HCC. We found that FOXM1 expression was highly elevated in approximately 40% of HCC cases, and FOXM1-high HCC was associated with high serum AFP levels, a high frequency of microscopic portal vein invasion, and poor prognosis. A transcriptome and pathway analysis revealed the activation of the mitotic cell cycle and the inactivation of mature hepatocyte metabolism function in FOXM1-high HCC. The knockdown of FOXM1 reduced AFP expression and induced G2/M cell cycle arrest. We further identified that the proteasome inhibitor carfilzomib attenuated FOXM1 protein expression and suppressed cell proliferation in AFP-positive HCC cells. Carfilzomib in combination with vascular endothelial growth factor receptor 2 (VEGFR2) blockade significantly prolonged survival by suppressing AFP-positive HCC growth in a subcutaneous tumor xenotransplantation model. These data indicated that FOXM1 plays a pivotal role in the proliferation of AFP-positive liver cancer cells. Carfilzomib can effectively inhibit FOXM1 expression to inhibit tumor growth and could be a novel therapeutic option in patients with AFP-positive HCC who receive anti-VEGFR2 antibodies. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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Review

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22 pages, 1100 KiB

Open AccessReview

COVID-19, Possible Hepatic Pathways and Alcohol Abuse—What Do We Know up to 2023?

by Agata Michalak, Tomasz Lach, Karolina Szczygieł and Halina Cichoż-Lach

Int. J. Mol. Sci. 2024, 25(4), 2212; https://doi.org/10.3390/ijms25042212 - 12 Feb 2024

Viewed by 1756

Abstract

The pandemic period due to coronavirus disease 2019 (COVID-19) revolutionized all possible areas of global health. Significant consequences were also related to diverse extrapulmonary manifestations of this pathology. The liver was found to be a relatively common organ, beyond the respiratory tract, affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple studies revealed the essential role of chronic liver disease (CLD) in the general outcome of coronavirus infection. Present concerns in this field are related to the direct hepatic consequences caused by COVID-19 and pre-existing liver disorders as risk factors for the severe course of the infection. Which mechanism has a key role in this phenomenon—previously existing hepatic disorder or acute liver failure due to SARS-CoV-2—is still not fully clarified. Alcoholic liver disease (ALD) constitutes another not fully elucidated context of coronavirus infection. Should the toxic effects of ethanol or already developed liver cirrhosis and its consequences be perceived as a causative or triggering factor of hepatic impairment in COVID-19 patients? In the face of these discrepancies, we decided to summarize the role of the liver in the whole picture of coronavirus infection, paying special attention to ALD and focusing on the pathological pathways related to COVID-19, ethanol toxicity and liver cirrhosis. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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32 pages, 2034 KiB

Open AccessReview

Endothelial Cells and Mitochondria: Two Key Players in Liver Transplantation

by Alessandro Parente, Mauricio Flores Carvalho and Andrea Schlegel

Int. J. Mol. Sci. 2023, 24(12), 10091; https://doi.org/10.3390/ijms241210091 - 13 Jun 2023

Cited by 4 | Viewed by 2722

Abstract

Building the inner layer of our blood vessels, the endothelium forms an important line communicating with deeper parenchymal cells in our organs. Previously considered passive, endothelial cells are increasingly recognized as key players in intercellular crosstalk, vascular homeostasis, and blood fluidity. Comparable to other cells, their metabolic function strongly depends on mitochondrial health, and the response to flow changes observed in endothelial cells is linked to their mitochondrial metabolism. Despite the direct impact of new dynamic preservation concepts in organ transplantation, the impact of different perfusion conditions on sinusoidal endothelial cells is not yet explored well enough. This article therefore describes the key role of liver sinusoidal endothelial cells (LSECs) together with their mitochondrial function in the context of liver transplantation. The currently available ex situ machine perfusion strategies are described with their effect on LSEC health. Specific perfusion conditions, including perfusion pressure, duration, and perfusate oxygenation are critically discussed considering the metabolic function and integrity of liver endothelial cells and their mitochondria. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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18 pages, 815 KiB

Open AccessReview

Nanoparticle-Based Interventions for Liver Transplantation

by Joseph Sushil Rao, Robert Ivkov and Anirudh Sharma

Int. J. Mol. Sci. 2023, 24(8), 7496; https://doi.org/10.3390/ijms24087496 - 19 Apr 2023

Cited by 1 | Viewed by 2360

Abstract

Liver transplantation is the only treatment for hepatic insufficiency as a result of acute and chronic liver injuries/pathologies that fail to recover. Unfortunately, there remains an enormous and growing gap between organ supply and demand. Although recipients on the liver transplantation waitlist have significantly higher mortality, livers are often not allocated because they are (i) classified as extended criteria or marginal livers and (ii) subjected to longer cold preservation time (>6 h) with a direct correlation of poor outcomes with longer cold ischemia. Downregulating the recipient’s innate immune response to successfully tolerate a graft having longer cold ischemia times or ischemia-reperfusion injury through induction of immune tolerance in the graft and the host would significantly improve organ utilization and post-transplant outcomes. Broadly, technologies proposed for development aim to extend the life of the transplanted liver through post-transplant or recipient conditioning. In this review, we focus on the potential benefits of nanotechnology to provide unique pre-transplant grafting and recipient conditioning of extended criteria donor livers using immune tolerance induction and hyperthermic pre-conditioning. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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19 pages, 1425 KiB

Open AccessReview

The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

by Chaoqun Yu, Peng Chen, Longyu Miao and Guohu Di

Int. J. Mol. Sci. 2023, 24(4), 3067; https://doi.org/10.3390/ijms24043067 - 4 Feb 2023

Cited by 25 | Viewed by 4440

Abstract

Acute liver injury (ALI) is a globally important public health issue that, when severe, rapidly progresses to acute liver failure, seriously compromising the life safety of patients. The pathogenesis of ALI is defined by massive cell death in the liver, which triggers a cascade of immune responses. Studies have shown that the aberrant activation of the nod-like receptor protein 3 (NLRP3) inflammasome plays an important role in various types of ALI and that the activation of the NLRP3 inflammasome causes various types of programmed cell death (PCD), and these cell death effectors can in turn regulate NLRP3 inflammasome activation. This indicates that NLRP3 inflammasome activation is inextricably linked to PCD. In this review, we summarize the role of NLRP3 inflammasome activation and PCD in various types of ALI (APAP, liver ischemia reperfusion, CCl₄, alcohol, Con A, and LPS/D-GalN induced ALI) and analyze the underlying mechanisms to provide references for future relevant studies. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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19 pages, 376 KiB

Open AccessReview

Could Alcohol Abuse and Dependence on Junk Foods Inducing Obesity and/or Illicit Drug Use Represent Danger to Liver in Young People with Altered Psychological/Relational Spheres or Emotional Problems?

by Giovanni Tarantino, Mauro Cataldi and Vincenzo Citro

Int. J. Mol. Sci. 2022, 23(18), 10406; https://doi.org/10.3390/ijms231810406 - 8 Sep 2022

Cited by 14 | Viewed by 5020

Abstract

Recent data show that young people, mainly due to the pressure of some risk factors or due to disrupted interpersonal relationships, utilise greater reward value and display greater sensitivity to the reinforcing properties of “pleasurable stimuli”, specifically in those situations in which an enhanced dopamine release is present. Alcoholic beverages, foods rich in sugar and fat, and illicit drug use are pleasurable feelings associated with rewards. Research shows that there is a link between substance abuse and obesity in brain functioning. Still, alcohol excess is central in leading to obesity and obesity-related morbidities, such as hepatic steatosis, mainly when associated with illicit drug dependence and negative eating behaviours in young people. It is ascertained that long-term drinking causes mental damage, similarly to drug abuse, but also affects liver function. Indeed, beyond the pharmacokinetic interactions of alcohol with drugs, occurring in the liver due to the same metabolic enzymes, there are also pharmacodynamic interactions of both substances in the CNS. To complicate matters, an important noxious effect of junk foods consists of inducing obesity and obesity-related NAFLD. In this review, we focus on some key mechanisms underlying the impact of these addictions on the liver, as well as those on the CNS. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

12 pages, 861 KiB

Open AccessReview

The Role of Hydrogen Sulfide Regulation of Autophagy in Liver Disorders

by Xueqin Lu, Yueming Ding, Huiyang Liu, Mengyao Sun, Chaoran Chen, Yihan Yang and Honggang Wang

Int. J. Mol. Sci. 2022, 23(7), 4035; https://doi.org/10.3390/ijms23074035 - 6 Apr 2022

Cited by 11 | Viewed by 2836

Abstract

Autophagy is a complex process of degradation of senescent or dysfunctional organelles in cells. Dysfunctional autophagy is associated with many diseases such as cancers, immune dysfunction, and aging. Hydrogen sulfide (H₂S) is considered to be the third gas signal molecule after nitrous oxide and carbon monoxide. In recent years, H₂S has been found to have a variety of important biological functions, and plays an important role in a variety of physiological and pathological processes. In this review, we review the recent role and mechanism of H₂S in regulating autophagy in liver disorders, in order to provide a basis for further research in the future. Full article

(This article belongs to the Special Issue Mechanism of Cellular Signaling, Dysfunction and Drug Effects on Liver Diseases)

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