Understanding vermicompost and organic manure interactions: impact on toxic elements, nitrification activity, comammox Nitrospira inopinata, and archaea/bacteria.

Vermicompost is a substantial source of nutrients, promotes soil fertility, and maintains or increases soil organic matter levels. Potentially toxic elements (PTEs) in vermicompost impact on nitrification activity. However, it is yet unknown how vermicompost affects nitrifying bacteria and archaea, comammox Nitrospira inopinata (complete ammonia oxidizers), net nitrification rates (NNRs), and PTEs. The effects of vermicompost application on NNRs, potential nitrification rates (NPs), PTEs, and the abundances of comammox N. inopinata bacteria, nitrite-oxidizing bacteria (NOB), and ammonia-oxidizing bacteria (AOB)/archaea (AOA) were studied. NNRs and NPs were significantly higher (p < 0.05) in fresh cow-dung vermicompost (stored for 40 days) as compared with other organic manure. The level of PTEs (Cu2+, Fe2+, Pb2+, Cd2+, and Zn2+) was significantly lower (p < 0.05) in vermicompost as compared with compost of waste material with Trichoderma and cow dung. Comammox N. inopinata, NOB, AOB, and AOA were significantly higher (p < 0.05) in stored cow-dung vermicompost (more than 1 year) as compared with other organic manure. The results of the scatterplot matrix analysis suggested that Fe2+, total nitrogen (TN), soil organic carbon (SOC), and total carbon (TC) were linearly correlated (p < 0.001) with NNRs and NPs in vermicompost and organic manure. Similarly, comammox N. inopinata bacteria, NOB, AOB, and AOA were linearly correlated (p < 0.001) with NNR and NP. These results indicated that vermicompost promoted nitrification activity by increasing microbial diversity and abundance, supplying nutrients and organic matter for microbial growth, and facilitating complex microbial interactions. It may be concluded that the influence of vermicompost, which played a great role in PTE concentration reduction, increased chemical, and biological properties, increased the growth rate of nitrifying bacteria/archaea and the nitrogen cycle.

FK-binding protein 5: Possible relevance to the pathogenesis of metabolic dysfunction and alcohol-associated liver disease.

The FK506-binding protein (FKBP5) plays significant roles in mediating stress responses by interacting with glucocorticoids, participating in adipogenesis, and influencing various cellular pathways throughout the body. In this review, we described the potential role of FKBP5 in the pathogenesis of two common chronic liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). We provided an overview of the FK-binding protein family and elucidated their roles in cellular stress responses, metabolic diseases, and adipogenesis. We explored how FKBP5 may mechanistically influence the pathogenesis of MASLD and ALD and provided insights for further investigation into the role of FKBP5 in these two diseases.

HMGB2 is a potential diagnostic marker and therapeutic target for liver fibrosis and cirrhosis.

BACKGROUND: High mobility group proteins 1 and 2 (HMGB1 and HMGB2) are 80% conserved in amino acid sequence. The function of HMGB1 in inflammation and fibrosis has been extensively characterized. However, an unaddressed central question is the role of HMGB2 on liver fibrosis. In this study, we provided convincing evidence that the HMGB2 expression was significantly upregulated in human liver fibrosis and cirrhosis, as well as in several mouse liver fibrosis models. METHODS: The carbon tetrachloride (CCl4) induced liver fibrosis mouse model was used. AAV8-Hmgb2 was utilized to overexpress Hmgb2 in the liver, while Hmgb2-/- mice were used for loss of function experiments. The HMGB2 inhibitor inflachromene and liposome-shHMGB2 (lipo-shHMGB2) were employed for therapeutic intervention. RESULTS: The serum HMGB2 levels were also markedly elevated in patients with liver fibrosis and cirrhosis. Deletion of Hmgb2 in Hmgb2-/- mice or inhibition of HMGB2 in mice using a small molecule ICM slowed the progression of CCl4-induced liver fibrosis despite constant HMGB1 expression. In contrast, AAV8-mediated overexpression of Hmgb2 enchanced CCl4-incuded liver fibrosis. Primary hepatic stellate cells (HSCs) isolated from Hmgb2-/- mice showed significantly impaired transdifferentiation and diminished activation of α-SMA, despite a modest induction of HMGB1 protein. RNA-seq analysis revealed the induction of top 45 CCl4-activated genes in multiple signaling pathways including integrin signaling and inflammation. The activation of these genes by CCl4 were abolished in Hmgb2-/- mice or in ICM-treated mice. These included C-X3-C motif chemokine receptor 1 (Cx3cr1) associated with inflammation, cyclin B (Ccnb) associated with cell cycle, DNA topoisomerase 2-alpha (Top2a) associated with intracellular component, and fibrillin (Fbn) and fibromodulin (Fmod) associated with extracellular matrix. CONCLUSION: We conclude that HMGB2 is indispensable for stellate cell activation. Therefore, HMGB2 may serve as a potential therapeutic target to prevent HSC activation during chronic liver injury. The blood HMGB2 level may also serve as a potential diagnostic marker to detect early stage of liver fibrosis and cirrhosis in humans.

Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease.

Ca2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca2+-channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD.

A comprehensive review on the diverse pharmacological perspectives of Terminalia chebula Retz.

Terminalia chebula Retz, commonly known as 'Haritaki/Myrobalan,' has been utilised as a traditional medicine for a long time. It has been extensively exercised in various indigenous medicine practices like Unani, Tibb, Ayurveda, and Siddha to remedy human ailments such as bleeding, carminative, dysentery, liver tonic, digestive, antidiarrheal, analgesic, anthelmintic, antibacterial and helpful in skin disorders. Studies on the pharmacological effects of T. chebula and its phytoconstituents documented between January, 1996 and December, 2021 were explored using various electronic databases. During the time mentioned above, several laboratory approaches revealed the biological properties of T. chebula, including antioxidative, antiproliferative, anti-microbial, proapoptotic, anti-diabetic, anti-ageing, hepatoprotective, anti-inflammatory, and antiepileptic. It is also beneficial in glucose and lipid metabolism and prevents atherogenesis and endothelial dysfunction. Different parts of T. chebula such as fruits, seeds, galls, barks extracted with various solvent systems (aqueous, ethanol, methanol, chloroform, ethyl-acetate) revealed major bioactive compounds like chebulic acid, chebulinic acid, and chebulaginic acid, which in turn proved to have valuable pharmacological properties through broad scientific investigations. There is a common link between chebulagic acid and chebulanin with its antioxidant property, antiaging activity, antiinflammatory, antidiabetic activity, and cardioprotective activity. The actions may be through neutralizing the free radicals responsible for producing tissue damage alongside interconnecting many other diseases. The current review summarises the scientifically documented literature on pharmacological potentials and chemical compositions of T. chebula, which is expected to investigate further studies on this subject.

Biosynthesis and chemical composition of nanomaterials in agricultural soil bioremediation: a review.

Nanomaterials (NMs) are currently being used in agricultural soils as part of a new bioremediation (BR) process. In this study, we reviewed the biosynthesis of NMs, as well as their chemical composition and prospective strategies for helpful and sustainable agricultural soil bioremediation (BR). Different types of NMs, such as nanoparticles, nanocomposites, nanocrystals, nano-powders, and nanotubes, are used in agricultural soil reclamation, and they reflect the toxicity of NMs to microorganisms. Plants (Sargassum muticum, Dodonaea viscose, Aloe Vera, Rosemarinus officinalis, Azadirachta indica, Green tea, and so on) and microorganisms (Escherichia coli, Shewanella oneidensis, Pleurotus sp., Klebsiella oxytoca, Aspergillus clavatus, and so on) are the primary sources for the biosynthesis of NMs. By using the BR process, microorganisms, such as bacteria and plants, can immobilize metals and change both inorganic and organic contaminants in the soil. Combining NMs with bioremediation techniques for agricultural soil remediation will be a valuable long-term solution.

Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure.

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neuhi), but low levels of CD8+ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neuhi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.

Effect of pesticides on nitrification activity and its interaction with chemical fertilizer and manure in long-term paddy soils.

Effect of pesticides on nitrification activity and its interaction among heavy metal concentrations (HMCs), antibiotic resistance genes (ARGs), and ammonia monooxygenase (amoA) genes of long-term paddy soils is little known. The aim was to study the effect of pesticides on net nitrification rate (NR), potential nitrification rate (NP), HMCs, ARGs (sulI, sulII, tetO, and tetQ), and amoA (amoA-AOA, amoA-AOB, and amoA-NOB) genes in long-term treated paddy soils. NR and NP were significantly decreased (p < 0.05), whereas HMCs (Pb2+, Cu2+, Zn2+, and Fe3+) were a significantly increased (p < 0.05) in chemical fertilizer with pesticide treated paddy soils as compared with chemical fertilizer treated paddy soils. The scatter plot matrix indicated that total carbon (TC), soil organic carbon (SOC), total nitrogen (TN), and Fe were linearly correlated with NR and NP in long-term treated paddy soils. ARGs and amoA genes were significantly decreased (p < 0.05) in chemical fertilizer and manure with pesticide treated paddy soils. Overall, the result indicated the response of pesticide and their combination of manure with pesticide interaction present in long-term paddy soils, which will play a great role in the control uses of pesticides, manure, and chemical fertilizers in paddy soils and protect the nitrogen cycle as well as environment.

Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.

BACKGROUND & AIMS: Cellular senescence frequently is present in injured livers. The induction mechanism and the pathologic role are not always clear. We aimed to understand the dynamics of senescence induction and progression, and the mechanism responsible for the pathology using a mouse model that disables the essential process of autophagy. METHODS: Mice deficient in key autophagy genes Atg7 or Atg5 in the liver were used. Senescence was measured using established cellular and molecular signatures. The mechanistic roles of nuclear factor erythroid 2 (NRF2), forkhead box K1, and C-C motif chemokine receptor 2 (CCR2) were assessed using mouse genetic models. Liver functions, pathology, and tumor development were measured using biochemical and histologic approaches. RESULTS: Inducible deletion of Atg7 rapidly up-regulated cyclin-dependent kinase inhibitors independently of injury and induced senescence-associated ß-galactosidase activities and senescence-associated secretory phenotype (SASP). Sustained activation of NRF2 was the major factor causing senescence by mediating oxidative DNA damage and up-regulating C-C motif chemokine ligand 2, a key component of autophagy-related SASP, via the NRF2-forkhead box K1 axis. Senescence was responsible for hepatic inflammation through CCR2-mediated recruitment of CD11b+ monocytes and CD3+ T cells. The CCR2-mediated process in turn enhanced senescence and SASP by up-regulating cyclin-dependent kinase inhibitors and chemokines. Thus, senescence and inflammation can mutually augment each other, forming an amplification loop for both events. The CCR2-mediated process also modulated liver injury and tumor progression at the later stage of autophagy deficiency-related pathology. CONCLUSIONS: These results provide the insight that hepatic senescence can occur early in the disease process, triggers inflammation and is enhanced by inflammation, and has long-term effects on liver injury and tumor progression.

Waste battery disposal and recycling behavior: a study on the Australian perspective.

Consumer behavior is a critical consideration for the development of sustainable waste management systems, including waste batteries, which pose a serious threat to human health and the environment if disposed of improperly. This study investigates the consumers' perspective on the waste battery collection and recycling behaviors in Australia, and analyses their implications for the development of recycling schemes. The results show that, although general awareness exists among consumers about the negative impacts of improper disposal, this awareness was not reflected during the disposal of waste batteries among the participants. Insufficient knowledge about the waste battery collection points and convenience were the most important factors affecting the inappropriate disposal behavior from most of the consumers. Over 50% of participants were unaware of the collection points for waste batteries. The most-preferred battery collection systems involved a deposit return system similar to that used for bottle recycling in the state of New South Wales (NSW) or collection at supermarkets/retailers. The most preferred methods for providing an incentive to recycle batteries were "old-for-new" battery swaps, "vouchers that could be used for other items in a store," and "cash payments." Several policy implications have been highlighted from this pioneering study that could shape the future development of sustainable waste battery management systems in Australia.

Telomere length in patients with alcohol-associated liver disease: a brief report.

The intact telomere structure is essential for the prevention of the chromosome end-to-end fusions and maintaining genomic integrity. The maintenance of telomere length is critical for cellular homeostasis. The shortening of telomeres has been reported in patients with chronic liver diseases. The telomere length has not been systemically studied in patients with alcohol-associated liver disease (ALD) at different stages, such as alcoholic hepatitis and alcoholic cirrhosis. In this brief report, we observed evidence of telomere shortening without changes in the telomerase activity in the liver of patients with alcoholic hepatitis and alcoholic cirrhosis when compared with controls. The alterations in the genes associated with telomere binding proteins were only observed in patients with alcoholic cirrhosis. Future studies are required to determine the mechanism of how alcohol affects the length of the telomere and if the shortening impacts the disease progression in ALD.

Transcriptomic Analysis Reveals the Messenger RNAs Responsible for the Progression of Alcoholic Cirrhosis.

Alcohol-associated liver disease is the leading cause of chronic liver disease. We hypothesized that the expression of specific coding genes is critical for the progression of alcoholic cirrhosis (AC) from compensated to decompensated states. For the discovery phase, we performed RNA sequencing analysis of 16 peripheral blood RNA samples, 4 healthy controls (HCs) and 12 patients with AC. The DEGs from the discovery cohort were validated by quantitative polymerase chain reaction in a separate cohort of 17 HCs and 48 patients with AC (17 Child-Pugh A, 16 Child-Pugh B, and 15 Child-Pugh C). We observed that the numbers of differentially expressed messenger RNAs (mRNAs) were more pronounced with worsening disease severity. Pathway analysis for differentially expressed genes for patients with Child-Pugh A demonstrated genes involved innate immune responses; those in Child-Pugh B belonged to genes related to oxidation and alternative splicing; those in Child-Pugh C related to methylation, acetylation, and alternative splicing. We found significant differences in the expression of heme oxygenase 1 (HMOX1) and ribonucleoprotein, PTB binding 1 (RAVER1) in peripheral blood of those who died during the follow-up when compared to those who survived. Conclusion: Unique mRNAs that may implicate disease progression in patients with AC were identified by using a transcriptomic approach. Future studies to confirm our results are needed, and comprehensive mechanistic studies on the implications of these genes in AC pathogenesis and progression should be further explored.

What drives WEEE recycling? A comparative study concerning legislation, collection and recycling.

Waste electrical and electronic equipment (WEEE) has been rising worldwide, and its improper management incurs in economic losses and environmental damage. To provide a better understanding of the forces that drive the management of WEEE, economic and political roles are discussed by comparing the WEEE recycling system of Brazil and Australia. Additional insights about the recycling systems were gathered from interviews with recyclers of both countries (in-loco visits and online/phone surveys). Previous studies show that both countries act as first stage recyclers, dismantling WEEE to ship their valuable components for international recyclers (such as printed circuit boards) while keeping less valuable material (such as polymeric and ferrous pieces). Australia has defined the responsibilities of most agents involved in the WEEE management and recycling setup, while Brazil inadvertently has left the system to be defined through free market regulation. As Brazil recently signed a reverse logistic agreement, there is an important opportunity to channel WEEE into formal routes and implement improvements in the entire recycling system (some suggestions are provided). Australian recyclers were found more organised in their disassembly lines, and some characteristics of the Australian model can be adapted for the Brazilian benefit. In conclusion, economic factors will drive first stage recycling (where labour wages are a small fraction of the total costs) and international downstream recycling, while a political framework is necessary to establish a comprehensive collection system, first stage recycling (where wages are representative) and domestic downstream recycling, given these are generally non-profitable activities in the short term.

Serum metabolomic analysis reveals several novel metabolites in association with excessive alcohol use - an exploratory study.

Appropriate screening tool for excessive alcohol use (EAU) is clinically important as it may help providers encourage early intervention and prevent adverse outcomes. We hypothesized that patients with excessive alcohol use will have distinct serum metabolites when compared to healthy controls. Serum metabolic profiling of 22 healthy controls and 147 patients with a history of EAU was performed. We employed seemingly unrelated regression to identify the unique metabolites and found 67 metabolites (out of 556), which were differentially expressed in patients with EAU. Sixteen metabolites belong to the sphingolipid metabolism, 13 belong to phospholipid metabolism, and the remaining 38 were metabolites of 25 different pathways. We also found 93 serum metabolites that were significantly associated with the total quantity of alcohol consumption in the last 30 days. A total of 15 metabolites belong to the sphingolipid metabolism, 11 belong to phospholipid metabolism, and 7 metabolites belong to lysolipid. Using a Venn diagram approach, we found the top 10 metabolites with differentially expressed in EAU and significantly associated with the quantity of alcohol consumption, sphingomyelin (d18:2/18:1), sphingomyelin (d18:2/21:0,d16:2/23:0), guanosine, S-methylmethionine, 10-undecenoate (11:1n1), sphingomyelin (d18:1/20:1, d18:2/20:0), sphingomyelin (d18:1/17:0, d17:1/18:0, d19:1/16:0), N-acetylasparagine, sphingomyelin (d18:1/19:0, d19:1/18:0), and 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1). The diagnostic performance of the top 10 metabolites, using the area under the ROC curve, was significantly higher than that of commonly used markers. We have identified a unique metaboloic signature among patients with EAU. Future studies to validate and determine the kinetics of these markers as a function of alcohol consumption are needed.

Scope and cost-effectiveness of fermented corn straw roughage-based buffalo fattening approach.

OBJECTIVE: This experiment was undertaken to assess the scope and cost-effectiveness of the fermented corn mixture (FCM)-based buffalo fattening approach compared to urea molasses straw (UMS) and silage-based approach. MATERIALS AND METHODS: A completely comparative randomized design experiment was conducted for 90 days with three treatments and five buffalo bulls in each. UMS, silage, and FCM roughage-based fattening diets were attributed as T1, T2, and T3, respectively. Two types of protein supplements, i.e., Type 1 (Bangladesh Livestock Research Institute-developed) for T1 and T2 and Type 2 (prescribed by farmers) for T3 treatments, were used. All the parameters were analyzed through Statistical Package for the Social Sciences, 20 software. RESULTS: Dry matter intake (kg, %live weight) was significantly higher in T1 (2.65), followed by T2 (2.34) and T3 (2.00), respectively. The crude protein intake, digestible crude protein intake, and digestible dry matter intake (kg/d) significantly (p < 0.05) differed between T1 and T3, but not T2. The digestibility of acid detergent fiber (65.97) was significantly higher for T3 than T1 and T2 (54.44 and 58.73, respectively). Neutral detergent fiber digestibility of T3 (70.35) also differed (p < 0.05) with T1 (60.97) but not T2 (64.78). No difference was observed in the case of growth, but feed conversion ration was found to be significantly (p < 0.05) better in T2 (7.10) than T1 (8.35), where T3 (7.24) was neutral. The significantly (p < 0.001) highest expense [216.37 Bangladesh taka (BDT)/kg gain] was required for T1, followed by T2 and T3 (174.47 and 126.33 BDT/kg gain, respectively). Net profit from T3 and T2 (15,877 and 15,175 BDT, respectively) gained significantly (p < 0.05) higher than T1 (11,265 BDT). CONCLUSION: The FCM-based diet was suitable and cost-effective as a buffalo fattening approach.

The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease.

Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp-/- mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp-/- mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα-/- hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.

Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol-Associated Hepatitis.

BACKGROUND AND AIMS: We conducted a comprehensive serum transcriptomic analysis to explore the roles of microRNAs (miRNAs) in alcohol-associated hepatitis (AH) pathogenesis and their prognostic significance. APPROACH AND RESULTS: Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, expression of miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell-cycle progression pathways, including ribonucleotide reductase regulatory subunit M2 (RRM2), cyclin D1 (CCND1), cyclin D2 (CCND2), MYC proto-oncogene (MYC), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1). We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1, in AH patients who underwent liver transplantation; miR-26b-5p and miR-30b-5p inhibited the 3'-UTR (untranslated region) luciferase activity of RRM2 and CCND2, and miR-20a-5p reduced the 3'-UTR luciferase activity of CCND1 and CCND2. During a median follow-up of 346 days, 21% of AH patients died; these patients had higher body mass index (BMI), Model for End-Stage Liver Disease (MELD), and serum miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p than those who survived. Cox regression analysis showed that BMI, MELD score, miR-20a-5p, miR-146a-5p, and miR-26b-5p predicted mortality. CONCLUSIONS: Patients with AH attempt to deal with hepatocyte injury by down-regulating specific miRNAs and up-regulating genes responsible for DNA synthesis and cell-cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short-term mortality in AH patients.

Stress-Responsive Gene FK506-Binding Protein 51 Mediates Alcohol-Induced Liver Injury Through the Hippo Pathway and Chemokine (C-X-C Motif) Ligand 1 Signaling.

BACKGROUND AND AIMS: Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. APPROACH AND RESULTS: We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. CONCLUSIONS: We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.

Long noncoding RNA H19 - a new player in the pathogenesis of liver diseases.

The liver is a vital organ that controls glucose and lipid metabolism, hormone regulation, and bile secretion. Liver injury can occur from various insults such as viruses, metabolic diseases, and alcohol, which lead to acute and chronic liver diseases. Recent studies have demonstrated the implications of long noncoding RNAs (lncRNAs) in the pathogenesis of liver diseases. These newly discovered lncRNAs have various functions attributing to many cellular biological processes via distinct and diverse mechanisms. LncRNA H19, one of the first lncRNAs being identified, is highly expressed in fetal liver but not in adult normal liver. Its expression, however, is increased in liver diseases with various etiologies. In this review, we focused on the roles of H19 in the pathogenesis of liver diseases. This comprehensive review is aimed to provide useful perspectives and translational applications of H19 as a potential therapeutic target of liver diseases.

Reverse logistics network design for waste solar photovoltaic panels: A case study of New South Wales councils in Australia.

Waste solar photovoltaic (PV) panels are considered as one of the fastest-growing future waste streams under the category of large electronic waste (e-waste). The lifespan of solar panels varies from 20 to 30 years, and an appropriate reverse logistics network design is essential to manage the waste stream efficiently once their lifetime expires. Mixed-integer programming-based RL model is proposed in this paper for New South Wales, Australia that minimizes the overall cost by identifying optimal locations and sizing of the collection points while determining optimal capacities for recycling facilities. Using the historical data (2001-2017) on the installed capacity of solar panels in the state, the potential waste generation (at council-level) is estimated and optimized solutions are proposed for the year 2047. The results of the study show that the highest waste solar PV will be generated at Murrumbidgee, Berrigan, Balranald, and Bogan councils. Out of 129 councils in the state, the model identifies 78 optimized-locations of the collection points that would be required in the councils. In the councils of Newcastle, Narrandera and Wagga Wagga, three major recycling facilities would need to be established. This is the first systematic attempt in designing an optimized RL network in Australia focusing on waste solar PV. Policy-makers will find this research highly valuable in decision-making on local recycling infrastructure development.