Integrated transcriptomics and histopathology approach identifies a subset of rejected donor livers with potential suitability for transplantation.

BACKGROUND: Liver transplantation is an effective treatment for liver failure. There is a large unmet demand, even as not all donated livers are transplanted. The clinical selection criteria for donor livers based on histopathological evaluation and liver function tests are variable. We integrated transcriptomics and histopathology to characterize donor liver biopsies obtained at the time of organ recovery. We performed RNA sequencing as well as manual and artificial intelligence-based histopathology (10 accepted and 21 rejected for transplantation). RESULTS: We identified two transcriptomically distinct rejected subsets (termed rejected-1 and rejected-2), where rejected-2 exhibited a near-complete transcriptomic overlap with the accepted livers, suggesting acceptability from a molecular standpoint. Liver metabolic functional genes were similarly upregulated, and extracellular matrix genes were similarly downregulated in the accepted and rejected-2 groups compared to rejected-1. The transcriptomic pattern of the rejected-2 subset was enriched for a gene expression signature of graft success post-transplantation. Serum AST, ALT, and total bilirubin levels showed similar overlapping patterns. Additional histopathological filtering identified cases with borderline scores and extensive molecular overlap with accepted donor livers. CONCLUSIONS: Our integrated approach identified a subset of rejected donor livers that are likely suitable for transplantation, demonstrating the potential to expand the pool of transplantable livers.

Standardized Pre-clinical Surgical Animal Model Protocol to Investigate the Cellular and Molecular Mechanisms of Ischemic Flap Healing.

BACKGROUND: Some of the most complex surgical interventions to treat trauma and cancer include the use of locoregional pedicled and free autologous tissue transfer flaps. While the techniques used for these reconstructive surgery procedures have improved over time, flap complications and even failure remain a significant clinical challenge. Animal models are useful in studying the pathophysiology of ischemic flaps, but when repeatability is a primary focus of a study, conventional in-vivo designs, where one randomized subset of animals serves as a treatment group while a second subset serves as a control, are at a disadvantage instigated by greater subject-to-subject variability. Our goal was to provide a step-by-step methodological protocol for creating an alternative standardized, more economical, and transferable pre-clinical animal research model of excisional full-thickness wound healing following a simulated autologous tissue transfer which includes the primary ischemia, reperfusion, and secondary ischemia events with the latter mimicking flap salvage procedure. RESULTS: Unlike in the most frequently used classical unilateral McFarlane's caudally based dorsal random pattern skin flap model, in the herein described bilateral epigastric fasciocutaneous advancement flap (BEFAF) model, one flap heals under normal and a contralateral flap-under perturbed conditions or both flaps heal under conditions that vary by one within-subjects factor. We discuss the advantages and limitations of the proposed experimental approach and, as a part of model validation, provide the examples of its use in laboratory rat (Rattus norvegicus) axial pattern flap healing studies. CONCLUSIONS: This technically challenging but feasible reconstructive surgery model eliminates inter-subject variability, while concomitantly minimizing the number of animals needed to achieve adequate statistical power. BEFAFs may be used to investigate the spatiotemporal cellular and molecular responses to complex tissue injury, interventions simulating clinically relevant flap complications (e.g., vascular thrombosis) as well as prophylactic, therapeutic or surgical treatment (e.g., flap delay) strategies in the presence or absence of confounding risk factors (e.g., substance abuse, irradiation, diabetes) or favorable wound-healing promoting activities (e.g., exercise). Detailed visual instructions in BEFAF protocol may serve as an aid for teaching medical or academic researchers basic vascular microsurgery techniques that focus on precision, tremor management and magnification.

Photo-oxidation of Micro- and Nanoplastics: Physical, Chemical, and Biological Effects in Environments.

Micro- and nanoplastics (MNPs) are attracting increasing attention due to their persistence and potential ecological risks. This review critically summarizes the effects of photo-oxidation on the physical, chemical, and biological behaviors of MNPs in aquatic and terrestrial environments. The core of this paper explores how photo-oxidation-induced surface property changes in MNPs affect their adsorption toward contaminants, the stability and mobility of MNPs in water and porous media, as well as the transport of pollutants such as organic pollutants (OPs) and heavy metals (HMs). It then reviews the photochemical processes of MNPs with coexisting constituents, highlighting critical factors affecting the photo-oxidation of MNPs, and the contribution of MNPs to the phototransformation of other contaminants. The distinct biological effects and mechanism of aged MNPs are pointed out, in terms of the toxicity to aquatic organisms, biofilm formation, planktonic microbial growth, and soil and sediment microbial community and function. Furthermore, the research gaps and perspectives are put forward, regarding the underlying interaction mechanisms of MNPs with coexisting natural constituents and pollutants under photo-oxidation conditions, the combined effects of photo-oxidation and natural constituents on the fate of MNPs, and the microbiological effect of photoaged MNPs, especially the biotransformation of pollutants.

Appearance of Recalcitrant Dissolved Black Carbon and Dissolved Organic Sulfur in River Waters Following Wildfire Events.

Increasing wildfire frequency, a consequence of global climate change, releases incomplete combustion byproducts such as aquatic pyrogenic dissolved organic matter (DOM) and black carbon (DBC) into waters, posing a threat to water security. In August 2022, a series of severe wildfires occurred in Chongqing, China. Samples from seven locations along the Yangtze and Jialing Rivers revealed DBC, quantified by the benzene poly(carboxylic acid) (BPCA) method, comprising 9.5-19.2% of dissolved organic carbon (DOC). High concentrations of BPCA-DBC with significant polycondensation were detected near wildfire areas, likely due to atmospheric deposition driven by wind. Furthermore, Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) revealed that wildfires were associated with an increase in condensed aromatics, proteins, and unsaturated hydrocarbons, along with a decrease in lignins. The condensed aromatics primarily consisted of dissolved black nitrogen (DBN), contributing to abundant high-nitrogen-containing compounds in locations highly affected by wildfires. Meanwhile, wildfires potentially induced the input of recalcitrant sulfur-containing protein-like compounds, characterized by high oxidation, aliphatic nature, saturation, and low aromaticity. Overall, this study revealed the appearance of recalcitrant DBC and dissolved organic sulfur in river waters following wildfire events, offering novel insights into the potential impacts of wildfires on water quality and environmental biogeochemistry.

Human health risk assessment framework for new water resource recovery-based bio-composite materials.

A new type of bio-composite material is being produced from water-recovered resources such as cellulose fibres from wastewater, calcite from the drinking water softening process, and grass and reed from waterboard sites. These raw materials may be contaminated with pathogens and chemicals such as Escherichia coli, heavy metals, and resin compounds. A novel risk assessment framework is proposed here, addressing human health risks during the production of new bio-composite materials. The developed framework consists of a combination of existing risk assessment methods and is based on three main steps: hazard identification, qualitative risk mapping, and quantitative risk assessment. The HAZOP and Event Tree Analysis methodologies were used for hazard identification and risk mapping stages. Then, human health risks were quantitatively assessed using quantitative chemical risk assessment, evaluating cancer and non-cancer risk, and quantitative microbial risk assessment. The deterministic and the stochastic approaches were performed for this purpose. The contamination of raw materials may pose human health concerns, resulting in cancer risk above the threshold. Microbial risk is also above the safety threshold. Additional analysis would be significant as future research to better assess the microbial risk in biocomposite production. The framework has been effectively used for chemical and microbial risk assessment.

Assessing the Mass Concentration of Microplastics and Nanoplastics in Wastewater Treatment Plants by Pyrolysis Gas Chromatography-Mass Spectrometry.

The level of microplastics (MPs) in wastewater treatment plants (WWTPs) has been well evaluated by the particle number, while the mass concentration of MPs and especially nanoplastics (NPs) remains unclear. In this study, pyrolysis gas chromatography-mass spectrometry was used to determine the mass concentrations of MPs and NPs with different size ranges (0.01-1, 1-50, and 50-1000 µm) across the whole treatment schemes in two WWTPs. The mass concentrations of total MPs and NPs decreased from 26.23 and 11.28 µg/L in the influent to 1.75 and 0.71 µg/L in the effluent, with removal rates of 93.3 and 93.7% in plants A and B, respectively. The proportions of NPs (0.01-1 µm) were 12.0-17.9 and 5.6-19.5% in plants A and B, respectively, and the removal efficiency of NPs was lower than that of MPs (>1 µm). Based on annual wastewater effluent discharge, it is estimated that about 0.321 and 0.052 tons of MPs and NPs were released into the river each year. Overall, this study investigated the mass concentration of MPs and NPs with a wide size range of 0.01-1000 µm in wastewater, which provided valuable information regarding the pollution level and distribution characteristics of MPs, especially NPs, in WWTPs.

Identification and Quantification of Nanoplastics in Surface Water and Groundwater by Pyrolysis Gas Chromatography-Mass Spectrometry.

Nanoplastics (NPs) are currently considered an environmental pollutant of concern, but the actual extent of NP pollution in environmental water bodies remains unclear and there is not enough quantitative data to conduct proper risk assessments. In this study, a pretreatment method combining ultrafiltration (UF, 100 kDa) with hydrogen peroxide digestion and subsequent detection with pyrolysis gas chromatography-mass spectrometry (Py-GC/MS) was developed and used to identify and quantify six selected NPs in surface water (SW) and groundwater (GW), including poly(vinylchloride) (PVC), poly(methyl methacrylate) (PMMA), polypropylene (PP), polystyrene (PS), polyethylene (PE), and poly(ethylene terephthalate) (PET). The results show that the proposed method could detect NPs in environmental water samples. Nearly all selected NPs could be detected in the surface water at all locations, while PVC, PMMA, PS, and PET NPs were frequently below the detection limit in the groundwater. PP (32.9-69.9%) and PE (21.3-44.3%) NPs were the dominant components in both surface water and groundwater, although there were significant differences in the pollution levels attributed to the filtration efficiency of riverbank, with total mass concentrations of 0.283-0.793 µg/L (SW) and 0.021-0.203 µg/L (GW). Overall, this study quantified the NPs in complex aquatic environments for the first time, filling in gaps in our knowledge about NP pollution levels and providing a useful methodology and important reference data for future research.

Life Cycle Environmental Impacts of Wastewater-Derived Phosphorus Products: An Agricultural End-User Perspective.

Recovering phosphorus from wastewater in more concentrated forms has potential to sustainably recirculate phosphorus from cities to agriculture. The environmental sustainability of wastewater-based phosphorus recovery processes or wastewater-derived phosphorus products can be evaluated using life cycle assessment (LCA). Many LCA studies used a process perspective to account for the impacts of integrating phosphorus recovery processes at wastewater treatment plants, while some used a product perspective to assess the impacts of producing wastewater-derived phosphorus products. We demonstrated the application of an end-user perspective by assessing life cycle environmental impacts of substituting half of the conventional phosphorus rock-based fertilizers used in three crop production systems with wastewater-derived phosphorus products from six recovery pathways (RPs). The consequential LCA results show that the substitution reduces global warming potential, eutrophication potential, ecotoxicity potential, and acidification potential of the assessed crop production systems in most RPs and scenarios. The end-user perspective introduced in this study can (i) complement with the process perspective and the product perspective to give a more holistic picture of environmental impacts along the "circular economy value chains" of wastewater-based resource recovery, (ii) enable systemwide assessment of wide uptake of wastewater-derived products, and (iii) draw attention to understanding the long-term environmental impacts of using wastewater-derived products.

Dysregulation of miR-21-associated miRNA regulatory networks by chronic ethanol consumption impairs liver regeneration.

Impaired liver regeneration has been considered as a hallmark of progression of alcohol-associated liver disease. Our previous studies demonstrated that in vivo inhibition of the microRNA (miRNA) miR21 can restore regenerative capacity of the liver in chronic ethanol-fed animals. The present study focuses on the role of microRNA regulatory networks that are likely to mediate the miR-21 action. Rats were chronically fed an ethanol-enriched diet along with pair-fed control animals and treated with AM21 (anti-miR-21), a locked nucleic acid antisense to miR-21. Partial hepatectomy (PHx) was performed and miRNA expression profiling over the course of liver regeneration was assessed. Our results showed dynamic expression changes in several miRNAs after PHx, notably with altered miRNA expression profiles between ethanol and control groups. We found that in vivo inhibition of miR-21 led to correlated differential expression of miR-340-5p and anticorrelated expression of miR-365, let-7a, miR-1224, and miR-146a across all sample groups after PHx. Gene set enrichment analysis identified a miRNA signature significantly associated with hepatic stellate cell activation within whole liver tissue data. We hypothesized that at least part of the PHx-induced miRNA network changes responsive to miR-21 inhibition is localized to hepatic stellate cells. We validated this hypothesis using AM21 and TGF-ß treatments in LX-2 human hepatic stellate cells in culture and measured expression levels of select miRNAs by quantitative RT-PCR. Based on the in vivo and in vitro results, we propose a hepatic stellate cell miRNA regulatory network as contributing to the restoration of liver regenerative capacity by miR-21 inhibition.

Changes in biofilm composition and microbial water quality in drinking water distribution systems by temperature increase induced through thermal energy recovery.

Drinking water distribution systems (DWDSs) have been thoroughly studied, but the concept of thermal energy recovery from DWDSs is very new and has been conceptualized in the past few years. Cold recovery results in a temperature increase of the drinking water. Its effects on drinking water quality and biofilm development are unclear. Hence, we studied both bulk water and biofilm phases for 232 days in two parallel pilot scale distribution systems with two temperature settings after cold recovery, 25 °C and 30 °C, and compared these with a reference pilot system without cold recovery. In all three pilot distributions systems (DSs) our results showed an initial increase in biomass (ATP) in the biofilm phase, along with occurrence of primary colonizers (Betaproteobacteriales) and subsequently a decrease in biomass and an increasing relative abundance of other microbial groups (amoeba resisting groups; Xanthobacteraceae, Legionellales), including those responsible for EPS formation in biofilms (Sphingomonadaceae). The timeline for biofilm microbial development was different for the three pilot DSs: the higher the temperature, the faster the development took place. With respect to the water phase within the three pilot DSs, major microbial contributions came from the feed water (17-100%) and unkown sources (2-80%). Random contributions of biofilm (0-70%) were seen between day 7-77. During this time period six-fold higher ATP concentration (7-11 ng/l) and two-fold higher numbers of high nucleic acid cells (5.20-5.80 × 104 cells/ml) were also observed in the effluent water from all three pilot DSs, compared to the feed water. At the end of the experimental period the microbial composition of effluent water from three pilot DSs revealed no differences, except the presence of a biofilm related microbial group (Sphingomonadaceae), within all three DSs compared to the feed water. In the biofilm phase higher temperatures initiated the growth of primary colonizing bacteria but this did not lead to differences in microbial diversity and composition at the end of the experimental period. Hence, we propose that the microbiological water quality of DWDSs with cold recovery should be monitored more frequently during the first 2-3 months of operation.

Model development for evidence-based prioritisation of policy action on emerging chemical and microbial drinking water risks.

While the burden of disease from well-studied drinking water contaminants is declining, risks from emerging chemical and microbial contaminants arise because of social, technological, demographic and climatological developments. At present, emerging chemical and microbial drinking water contaminants are not assessed in a systematic way, but reactively and incidence based. Furthermore, they are assessed separately despite similar pollution sources. As a result, risks might be addressed ineffectively. Integrated risk assessment approaches are thus needed that elucidate the uncertainties in the risk evaluation of emerging drinking water contaminants, while considering risk assessors' values. This study therefore aimed to (1) construct an assessment hierarchy for the integrated evaluation of the potential risks from emerging chemical and microbial contaminants in drinking water and (2) develop a decision support tool, based on the agreed assessment hierarchy, to quantify (uncertain) risk scores. A multi-actor approach was used to construct the assessment hierarchy, involving chemical and microbial risk assessors, drinking water experts and members of responsible authorities. The concept of value-focused thinking was applied to guide the problem-structuring and model-building process. The development of the decision support tool was done using Decisi-o-rama, an open-source Python library. With the developed decision support tool (uncertain) risk scores can be calculated for emerging chemical and microbial drinking water contaminants, which can be used for the evidence-based prioritisation of actions on emerging chemical and microbial drinking water risks. The decision support tool improves existing prioritisation approaches as it combines uncertain indicator levels with a multi-stakeholder approach and integrated the risk assessment of chemical and microbial contaminants. By applying the concept of value-focused thinking, this study addressed difficulties in evidence-based decision-making related to emerging drinking water contaminants. Suggestions to improve the model were made to guide future research in assisting policy makers to effectively protect public health from emerging drinking water risks.

Low-Carbon Urban Water Systems: Opportunities beyond Water and Wastewater Utilities?

The provision of urban water and wastewater services contributes to greenhouse gas (GHG) emissions. Urban water supply and wastewater utilities can potentially achieve low-carbon or carbon-neutral operation through many "utility opportunities". Outside the jurisdiction of water utilities, many water-related "wider opportunities" can also contribute to GHG emissions abatement for cities. This study aims to explore the GHG emissions abatement potential, cost effectiveness, and enabling factors of implementing wider opportunities in cities. Using Amsterdam as a case study, we developed a marginal abatement cost curve to compare the abatement potential and cost effectiveness of both utility and wider opportunities. The results show that many wider opportunities related to thermal energy, water end use, and life cycle are cost-effective with significant abatement potential, compared to utility opportunities. This case study and emerging worldwide examples show that the water industry has a role to play to support wider water-related opportunities in cities. This vision can be supported by developing mechanisms to credit utilities for wider opportunity initiatives, building inter- and intrasectoral partnerships for utilities, accounting for scope 3 emissions of utilities, and being open to extend utilities' role beyond water and wastewater services providers.

Thermal energy recovery from chlorinated drinking water distribution systems: Effect on chlorine and microbial water and biofilm characteristics.

Thermal energy recovery from drinking water has a high potential in the application of sustainable building and industrial cooling. However, drinking water and biofilm microbial qualities should be concerned because the elevated water temperature after cold recovery may influence the microbial activities in water and biofilm phases in drinking water distribution systems (DWDSs). In this study, the effect of cold recovery on microbial qualities was investigated in a chlorinated DWDS. The chlorine decay was slight (1.1%-15.5%) due to a short contact time (~60 s) and was not affected by the cold recovery (p > 0.05). The concentrations of cellular ATP and intact cell numbers in the bulk water were partially inactivated by the residual chlorine, with the removal rates of 10.1%-16.2% and 22.4%-29.4%, respectively. The chlorine inactivation was probably promoted by heat exchangers but was not further enhanced by higher temperatures. The higher water temperature (25 °C) enhanced the growth of biofilm biomass on pipelines. Principle coordination analysis (PCoA) showed that the biofilms on the stainless steel plates of HEs and the plastic pipe inner surfaces had totally different community compositions. Elevated temperatures favored the growth of Pseudomonas spp. and Legionella spp. in the biofilm after cold recovery. The community functional predictions revealed more abundances of five human diseases (e.g. Staphylococcis aureus infection) and beta-lactam resistance pathways in the biofilms at higher temperature. Compared with a previous study with a non-chlorinated DWDS, chlorine dramatically reduced the biofilm biomass growth but raised the relative abundances of the chlorine-resistant genera (i.e. Pseudomonas and Sphingomonas) in bacterial communities.

Effects of cold recovery technology on the microbial drinking water quality in unchlorinated distribution systems.

Drinking water distribution systems (DWDSs) are used to supply hygienically safe and biologically stable water for human consumption. The potential of thermal energy recovery from drinking water has been explored recently to provide cooling for buildings. Yet, the effects of increased water temperature induced by this "cold recovery" on the water quality in DWDSs are not known. The objective of this study was to investigate the impact of cold recovery from DWDSs on the microbiological quality of drinking water. For this purpose, three pilot distribution systems were operated in parallel for 38 weeks. System 1 has an operational heat exchanger, mimicking the cold recovery system by maintaining the water temperature at 25 °C; system 2 operated with a non-operational heat exchanger and system 3 run without heat exchanger. The results showed no significant effects on drinking water quality: cell numbers and ATP concentrations remained around 3.5 × 105 cells/ml and 4 ng ATP/l, comparable observed operational taxonomic units (OTUs) (~470-490) and similar Shannon indices (7.7-8.9). In the system with cold recovery, a higher relative abundance of Pseudomonas spp. and Chryseobacterium spp. was observed in the drinking water microbial community, but only when the cold recovery induced temperature difference (ΔT) was higher than 9 °C. In the 38 weeks' old biofilm, higher ATP concentration (475 vs. 89 pg/cm2), lower diversity (observed OTUs: 88 vs. ≥200) and a different bacterial community composition (e.g. higher relative abundance of Novosphingobium spp.) were detected, which did not influence water quality. No impacts were observed for the selected opportunisitic pathogens after introducing cold recovery. It is concluded that cold recovery does not affect bacterial water quality. Further investigation for a longer period is commended to understand the dynamic responses of biofilm to the increased temperature caused by cold recovery.

Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease.

Inflammation has been recognized as essential for restorative regeneration. Here, we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function, and regeneration. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl4 (2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl4 intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl4-induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.

Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity.

Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardiomyocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction with matrix-targeted photoactivatable GFP and confocal microscopy. Imaging in whole rat hearts indicated mitochondrial network formation and fusion activity in ventricular cardiomyocytes. Promptly after isolation, cardiomyocytes showed extensive mitochondrial connectivity and fusion, which decayed in culture (at 24-48 h). Fusion manifested both as rapid content mixing events between adjacent organelles and slower events between both neighboring and distant mitochondria. Loss of fusion in culture likely results from the decline in calcium oscillations/contractile activity and mitofusin 1 (Mfn1), because (i) verapamil suppressed both contraction and mitochondrial fusion, (ii) after spontaneous contraction or short-term field stimulation fusion activity increased in cardiomyocytes, and (iii) ryanodine receptor-2-mediated calcium oscillations increased fusion activity in HEK293 cells and complementing changes occurred in Mfn1. Weakened cardiac contractility in vivo in alcoholic animals is also associated with depressed mitochondrial fusion. Thus, attenuated mitochondrial fusion might contribute to the pathogenesis of cardiomyopathy.

Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin.

The extracellular matrix is a master regulator of tissue homeostasis in health and disease. Here we examined how the small, leucine-rich, extracellular matrix proteoglycan decorin regulates cardiomyocyte metabolism during fasting in vivo First, we validated in Dcn-/- mice that decorin plays an essential role in autophagy induced by fasting. High-throughput metabolomics analyses of cardiac tissue in Dcn-/- mice subjected to fasting revealed striking differences in the hexosamine biosynthetic pathway resulting in aberrant cardiac O-ß-N-acetylglycosylation as compared with WT mice. Functionally, Dcn-/- mice maintained cardiac function at a level comparable with nonfasted animals whereas fasted WT mice showed reduced ejection fraction. Collectively, our results suggest that reduced sensing of nutrient deprivation in the absence of decorin preempts functional adjustments of cardiac output associated with metabolic reprogramming.

Lipid Synthesis Is Required to Resolve Endoplasmic Reticulum Stress and Limit Fibrotic Responses in the Lung.

Endoplasmic reticulum (ER) stress is evident in the alveolar epithelium of humans and mice with pulmonary fibrosis, but neither the mechanisms causing ER stress nor the contribution of ER stress to fibrosis is understood. A well-recognized adaptive response to ER stress is that affected cells induce lipid synthesis; however, we recently reported that lipid synthesis was downregulated in the alveolar epithelium in pulmonary fibrosis. In the present study, we sought to determine whether lipid synthesis is needed to resolve ER stress and limit fibrotic remodeling in the lung. Pharmacologic and genetic manipulations were performed to assess whether lipid production is required for resolving ER stress and limiting fibrotic responses in cultured alveolar epithelial cells and whole-lung tissues. Concentrations of ER stress markers and lipid synthesis enzymes were also measured in control and idiopathic pulmonary fibrosis lung tissues. We found that chemical agents that induce ER stress (tunicamycin or thapsigargin) enhanced lipid production in cultured alveolar epithelial cells and in the mouse lung. Moreover, lipid production was found to be dependent on the enzyme stearoyl-coenzyme A desaturase 1, and when pharmacologically inhibited, ER stress persisted and lung fibrosis ensued. Conversely, lipid production was reduced in mouse and human fibrotic lung, despite there being an increase in the magnitude of ER stress. Furthermore, augmenting lipid production effectively reduced ER stress and mitigated fibrotic remodeling in the mouse lung after exposure to silica. Augmenting lipid production reduces ER stress and attenuates fibrotic remodeling in the mouse lung, suggesting that similar approaches might be effective for treating human fibrotic lung diseases.

An exploration of disinfection by-products formation and governing factors in chlorinated swimming pool water.

This paper investigates disinfection by-products (DBPs) formation and their relationship with governing factors in chlorinated swimming pools. The study compares concentrations of DBPs with WHO guidelines for drinking water quality recommended to screen swimming pool water quality. The statistical analysis is based on a global database of 188 swimming pools accumulated from 42 peer-reviewed journal publications from 16 countries. The mean and standard deviation of dichloroacetic acid and trichloroacetic acid were estimated as 282 ± 437 and 326 ± 517 µg L-1, respectively, which most often surpassed the WHO guidelines. Similarly, more than half of the examined pools had higher values of chloral hydrate (102 ± 128 µg L-1). The concentration of total chloramines (650 ± 490 µg L-1) was well above the WHO guidelines in all reported cases. Nevertheless, the reported values remained below the guidelines for most of the studied pools in the case of total trihalomethanes (134 ± 160 µg L-1), dichloroacetonitrile (12 ± 12 µg L-1) and dibromoacetonitrile (8 ± 11 µg L-1). Total organic carbon, free residual chlorine, temperature, pH, total nitrogen and bromide ions play a pivotal role in DBPs formation processes. Therefore, proper management of these governing factors could significantly reduce DBPs formation, thereby, contributing towards a healthy swimming pool environment.

Pattern analysis uncovers a chronic ethanol-induced disruption of the switch-like dynamics of C/EBP-ß and C/EBP-α genome-wide binding during liver regeneration.

Chronic ethanol intake impairs liver regeneration through a system-wide alteration in the regulatory networks driving the response to injury. Our study focused on the initial phase of response to 2/3rd partial hepatectomy (PHx) to investigate how adaptation to chronic ethanol intake affects the genome-wide binding profiles of the transcription factors C/EBP-ß and C/EBP-α. These factors participate in complementary and often opposing functions for maintaining cellular differentiation, regulating metabolism, and governing cell growth during liver regeneration. We analyzed ChIP-seq data with a comparative pattern count (COMPACT) analysis, which exhaustively enumerates temporal patterns of discretized binding profiles to identify dominant as well as subtle patterns that may not be apparent from conventional clustering analyses. We found that adaptation to chronic ethanol intake significantly alters the genome-wide binding profile of C/EBP-ß and C/EBP-α before and following PHx. A subset of these ethanol-induced changes include C/EBP-ß binding to promoters of genes involved in the profibrogenic transforming growth factor-ß pathway, and both C/EBP-ß and C/EBP-α binding to promoters of genes involved in the cell cycle, apoptosis, homeostasis, and metabolic processes. The shift in C/EBP binding loci, coupled with an ethanol-induced increase in C/EBP-ß binding at 6 h post-resection, indicates that ethanol adaptation may change both the amount and nature of C/EBP binding postresection. Taken together, our results suggest that chronic ethanol consumption leads to a spatially and temporally reorganized activity at many genomic loci, resulting in a shift in the dynamic balance and coordination of cellular processes underlying regenerative response.