An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

Using a DNA mini-barcode within the ITS region to identify toxic Amanita in mushroom poisoning cases.

Mushroom poisoning contributes significantly to global foodborne diseases and related fatalities. Amanita mushrooms frequently cause such poisonings; however, identifying these toxic species is challenging due to the unavailability of fresh and intact samples. It is often necessary to analyze residues, vomitus, or stomach extracts to obtain DNA sequences for the identification of species responsible for causing food poisoning. This usually proves challenging to obtain usable DNA sequences that can be analyzed using conventional molecular biology techniques. Therefore, this study aimed to develop a DNA mini-barcoding method for the identification of Amanita species. Following the evaluation and optimization of universal primers for DNA mini-barcoding in Amanita mushrooms, we found that the internal transcribed spacer (ITS) gene sequence primer ITS-a was the most suitable DNA barcode primer for identifying Amanita species. Forty-three Amanita samples were subsequently amplified and sequenced. The sequences obtained were analyzed for intra- and inter-species genetic distances, and a phylogenetic tree was constructed. The findings indicated that the designed primers had strong universality among the Amanita samples and could accurately identify the target gene fragment with a length of 290 bp. Notably, the DNA mini-barcode accurately identified the 43 Amanita samples, demonstrating high consistency with the conventional DNA barcode. Furthermore, it effectively identified DNA from digested samples. In summary, this DNA mini-barcode is a promising tool for detecting accidental ingestion of toxic Amanita mushrooms. It may be used as an optimal barcode for species identification and traceability in events of Amanita-induced mushroom poisoning. KEY POINTS: • Development of a DNA mini-barcoding method for Amanita species identification without fresh samples. • The ITS-a primer set was optimized for robust universality in Amanita samples. • The mini-barcode is suitable for screening toxic mushroom species in mushroom poisoning cases.

Divergent Energy-Climate Nexus in the Global Fuel Combustion Processes.

Fuel combustion provides basic energy for the society but also produces CO2 and incomplete combustion products that threaten human survival, climate change, and global sustainability. A variety of fuels burned in different facilities expectedly have distinct impacts on climate, which remains to be quantitatively assessed. This study uses updated emission inventories and an earth system model to evaluate absolute and relative contributions in combustion emission-associated climate forcing by fuels, sectors, and regions. We showed that, from 1970 to 2014, coal burned in the energy sector and oil used in the transportation sector contributed comparable energies consumed (24 and 20% of the total) but had distinct climate forcing (1 and 40%, respectively). Globally, coal burned for energy production had negative impacts on climate forcing but positive effects in the residential sector. In many developing countries, coal combustion in the energy sector had negative radiative forcing (RF) per unit energy consumed due to insufficient controls on sulfur and scattering aerosol levels, but oils in the transportation sector had high positive RF values. These results had important implications on the energy transition and emission reduction actions in response to climate change. Distinct climate efficiencies of energies and the spatial heterogeneity implied differentiated energy utilization strategies and pollution control policies by region and sector.

Interpreting Highly Variable Indoor PM2.5 in Rural North China Using Machine Learning.

Household air pollution associated with solid fuel use is a long-standing public concern. The global population mainly using solid fuels for cooking remains large. Besides cooking, large amounts of coal and biomass fuels are burned for space heating during cold seasons in many regions. In this study, a wintertime multiple-region field campaign was carried out in north China to evaluate indoor PM2.5 variations. With hourly resolved data from ∼1600 households, key influencing factors of indoor PM2.5 were identified from a machine learning approach, and a random forest regression (RFR) model was further developed to quantitatively assess the impacts of household energy transition on indoor PM2.5. The indoor PM2.5 concentration averaged at 120 µg/m3 but ranged from 16 to ∼400 µg/m3. Indoor PM2.5 was ∼60% lower in families using clean heating approaches compared to those burning traditional coal or biomass fuels. The RFR model had a good performance (R2 = 0.85), and the interpretation was consistent with the field observation. A transition to clean coals or biomass pellets can reduce indoor PM2.5 by 20%, and further switching to clean modern energies would reduce it an additional 30%, suggesting many significant benefits in promoting clean transitions in household heating activities.

Identification of Factors Determining Household PM2.5 Variations at Regional Scale and Their Implications for Pollution Mitigation.

Indoor PM2.5, particulate matter no more than 2.5 µm in aerodynamic equivalent diameter, has very high spatiotemporal variabilities; and exploring the key factors influencing the variabilities is critical for purifying air and protecting human health. Here, we conducted a longer-term field monitoring campaign using low-cost sensors and evaluated inter- and intra-household PM2.5 variations in rural areas where energy or stove stacking is common. Household PM2.5 varied largely across different homes but also within households. Using generalized linear models and dominance analysis, we estimated that outdoor PM2.5 explained 19% of the intrahousehold variation in indoor daily PM2.5, whereas factors like the outdoor temperature and indoor-outdoor temperature difference that was associated with energy use directly or indirectly, explained 26% of the temporal variation. Inter-household variation was lower than intrahousehold variation. The inter-household variation was strongly associated with distinct internal sources, with energy-use-associated factors explaining 35% of the variation. The statistical source apportionment model estimated that solid fuel burning for heating contributed an average of 31%-55% of PM2.5 annually, whereas the contribution of sources originating from the outdoors was ≤10%. By replacing raw biomass or coal with biomass pellets in gasifier burners for heating, indoor PM2.5 could be significantly reduced and indoor temperature substantially increased, providing thermal comforts in addition to improved air quality.

Indoor exposure to polycyclic aromatic hydrocarbons associated with solid fuel use in rural China.

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants associated with various health risks including lung cancer. Indoor exposure to PAHs, particularly from the indoor burning of fuels, is significant; however, long-term large-scale assessments of indoor PAHs are hampered by high costs and time-consuming in field sampling and laboratory experiments. A simple fuel-based approach and statistical regression models were developed as a trial to predict indoor BaP, as a typical PAH, in China, and consequently spatiotemporal variations in indoor BaP and indoor exposure contributions were discussed. The results show that the national population-weighted indoor BaP concentration has decreased substantially from 46.1 ng/m3 in 1992 to 6.60 ng/m3 in 2017, primarily due to the increased use of clean energies for cooking and heating. Indoor BaP exposure contributed to > 70% of the total inhalation exposure in most cities, particularly in regions where solid fuels are widely utilized. With limited experimental observation data in building statistical models, quantitative results of the study are associated with high uncertainties; however, the study undoubtedly supports effective countermeasures on indoor PAHs from solid fuel use and the importance of promoting clean household energy usage to improve household air quality.

Variabilities in Primary N-Containing Aromatic Compound Emissions from Residential Solid Fuel Combustion and Implications for Source Tracers.

Nitroaromatic compounds (NACs) not only are strongly absorbing chromophores but also adversely affect human health. NACs can be emitted from incomplete combustions and can derive secondarily through photochemical reactions. Here, emission experiments were conducted for 31 fuel-stove combinations to elucidate variations in, and influencing factors of, NAC emission factors (EF∑NACs) and to explore potential tracers for different combustion sources. EF∑NACs varied by 2 orders of magnitude among different combinations. Differences in fuel type contributed more than the stove difference to the observed variation. EF∑NACs for biomass pellets was approximately 66% lower than that for raw biomass, although the bulk organic and brown carbon EFs were 95% lower. 2-Nitro-1-naphthol was the most abundant individual compound, followed by 4-nitrocatechol, while acid compounds (salicylic acid and benzoic acid) were low in abundance (<1%). Substantially different profiles were observed between coal and biomass burning emissions. Biomass burning had more single-ring-based phenolic compounds with more 4-nitrocatechol, while in coal combustion, more two-ring products were produced. This study demonstrated much lower ratios of 2-nitro-1-naphthol/4-nitrocatechol for biomass in both traditional (2.0 ± 3.5) and improved stoves (3.0 ± 2.1) than for coals (15 ± 6). Coal and biomass burning differed in not only EF∑NACs but also compound profile, consequently leading to distinct health and climate impacts; moreover, the ratio of 2-nitro-1-naphthol/4-nitrocatechol may be used in source apportionment of NACs.

Infection deteriorating hepatitis B virus related acute-on-chronic liver failure: a retrospective cohort study.

BACKGROUND: Infection is common in acute-on-chronic liver failure (ACLF), which may worsen the clinical condition and prognosis. However, the characteristics of infection and its influence on prognosis in hepatitis B virus related ACLF (HBV-ACLF) as defined by the European Association for the Study of the Liver (EASL) have not been clarified. We aimed to investigate the characteristics of infection and its influence on mortality in patients with HBV-ACLF defined by EASL in China. METHODS: We performed a retrospective cohort study in patients with HBV-ACLF defined by EASL in a single center from January 2015 to December 2017. These patients were divided into two groups with and without infection. The incidence, sites of infection, isolated strains, and risk factors associated with mortality were evaluated. RESULTS: A total of 289 patients were included, among them 185 (64.0%) were diagnosed with an infection. The most common type of infection was pneumonia (55.7%), followed by spontaneous bacterial peritonitis (47.6%) and others. The gram-negative bacteria were the most frequent (58.3%). Patients with one, two, and three or more infection sites had a gradually increasing incidence of sepsis (P < 0.01), septic shock (P < 0.001), and ACLF-3 (P < 0.05). Also, patients with infection isolated one, two, and three or more strains showed a growing incidence of sepsis (P < 0.01) and septic shock (P < 0.001). Patients with infection showed a significantly higher 28-day mortality than those without (P < 0.01), especially in patients with ACLF-3. Infection was identified as an independent risk factor for 28-day mortality in all HBV-ACLF patients. Pneumonia and sepsis were identified as independent predictors of 28-day mortality for patients with infection. CONCLUSIONS: Infection is associated with severe clinical course and high mortality in HBV-ACLF defined by EASL. The increased number of infection sites or isolated strains was associated with the occurrence of sepsis and septic shock. Pneumonia and sepsis were independent predictors for mortality in HBV-ACLF patients with infection.

Cadmium-induced genome-wide DNA methylation changes in growth and oxidative metabolism in Drosophila melanogaster.

BACKGROUND: Cadmium (Cd)-containing chemicals can cause serious damage to biological systems. In animals and plants, Cd exposure can lead to metabolic disorders or death. However, for the most part the effects of Cd on specific biological processes are not known. DNA methylation is an important mechanism for the regulation of gene expression. In this study we examined the effects of Cd exposure on global DNA methylation in a living organism by whole-genome bisulfite sequencing (WGBS) using Drosophila melanogaster as model. RESULTS: A total of 71 differentially methylated regions and 63 differentially methylated genes (DMGs) were identified by WGBS. A total of 39 genes were demethylated in the Cd treatment group but not in the control group, whereas 24 showed increased methylation in the former relative to the latter. In most cases, demethylation activated gene expression: genes such as Cdc42 and Mekk1 were upregulated as a result of demethylation. There were 37 DMGs that overlapped with differentially expressed genes from the digital expression library including baz, Act5C, and ss, which are associated with development, reproduction, and energy metabolism. CONCLUSIONS: DNA methylation actively regulates the physiological response to heavy metal stress in Drosophila in part via activation of apoptosis.

A systematic analysis strategy for accurate detection of anthocyanin pigments in red wines.

RATIONALE: To develop a reliable and accurate method for the identification of anthocyanins and their subsequent derivatives formed during red grape fermentation and wine maturation. METHODS: By using a Poroshell 120 EC-C18 column in a high-performance liquid chromatography/triple-quadrupole tandem mass spectrometry (HPLC/QqQ-MS/MS) system, combined with multiple reaction monitoring (MRM), it was possible to establish and validate a method for the determination of anthocyanin and a range of complex reaction products. A selected range of six 3-O-glucosidic anthocyanins were used as standards. A database was established from these results. Then various red wines were examined and quantified by this method. RESULTS: With the range of accuracy and precision being 86.97-111.39% and 0.09-4.32%, respectively, the HPLC/QqQ-MS/MS method was found to be a reliable method for anthocyanin detection. By using this HPLC/QqQ-MS/MS method combined with the inclusive database, accurate identification of 95 anthocyanin compounds of different families from various wine samples was systematically achieved in 29 min. CONCLUSIONS: By combining this analytical system with an inclusive database, it was possible to determine a wide range of anthocyanins and related complex derivatives for the first time. We consider that it should be possible to extend this method further to include more complex anthocyanins, and to other complex compounds. Copyright © 2016 John Wiley & Sons, Ltd.

Impact of different types of stoppers on sensorial and phenolic characteristics evolution during a bottle storage time of a white wine from Chardonnay grape variety.

The objective of this work was to study the correlation between the variation of phenolic compounds and sensory characteristics in white wine during bottle storage and to explore the compounds that affected sensory evolution. Chardonnay (Vitis vinifera L. cv.) dry white wines were bottled under six types of stoppers and stored for 18 months. The composition of phenolic compounds was analyzed, and the sensory attributes of these wines were evaluated by professional panel. Multivariate statistical analysis demonstrated that bottle aging period exhibited a more important effect on phenolic compound evolution than stopper type. Most of the phenolic compounds disappeared after 18 months of bottle storage, whereas the wine sensory attributes were significantly improved after 15-month of bottle aging. No strong correlation existed between the phenolic variation and the dissolved oxygen content. Wine color characteristics developed towards better quality accompanying with the reduction of detectable hydroxycinnamic acid derivatives and flavan-3-ols, while the wine mouth-feel was related mainly to gallic acid and ferulic acid ester. This work provided some references for wine producers to select appropriate storage duration for bottled white wine.

Macrophage inhibitory factor 1 acts as a potential biomarker in patients with esophageal squamous cell carcinoma and is a target for antibody-based therapy.

Macrophage inhibitory factor 1 (MIC1) is frequently altered in various cancers. The aim of this study was to investigate the clinical significance of MIC1 for esophageal squamous cell carcinoma (ESCC). Serum MIC1 of 286 ESCC and 250 healthy subjects was detected, the diagnostic performance was assessed and compared with SCC, CEA, CA199 and CA724, and the value as a prognostic indicator was also evaluated. The expression of MIC1 in ESCC cell lines, tissues were detected, and the inhibition of MIC1 antibody on ESCC was carried out in vitro and in vivo. The results showed that the serum MIC1 of ESCC was significantly higher than normal groups (P < 0.001), and was positively associated with tumor invasion (P = 0.030) as well as lymph node metastasis (P = 0.007). The sensitivity of MIC1 was significantly better than SCC, CEA, CA199 and CA724, especially for stage I ESCC. Patients with higher serum MIC1 also had a poorer prognosis in relapse-free (P = 0.050) and tumor-specific survival (P = 0.005). In vitro studies showed that the expression of MIC1 was upregulated in 37.5% (3/8) ESCC cell lines and 45% (18/40) tissues, and the transcription of MIC1 in tumor tissues was significantly higher than paired adjacent normal tissues (P = 0.001). The antibody of MIC1 inhibited the tumor growth (P < 0.001), and showing preference for tumor tissues in xenograft model. The decreased formation of neovascularization lumen may be involved in the mechanism. We conclude that MIC1 plays an important role in the progression of ESCC and can serve as a potential biomarker and therapeutic target for ESCC.

Characterization of the IncA/C plasmid pSCEC2 from Escherichia coli of swine origin that harbours the multiresistance gene cfr.

OBJECTIVES: To determine the complete nucleotide sequence of the multidrug resistance plasmid pSCEC2, isolated from a porcine Escherichia coli strain, and to analyse it with particular reference to the cfr gene region. METHODS: Plasmid pSCEC2 was purified from its E. coli J53 transconjugant and then sequenced using the 454 GS-FLX System. After draft assembly, predicted gaps were closed by PCR with subsequent sequencing of the amplicons. RESULTS: Plasmid pSCEC2 is 135 615 bp in size and contains 200 open reading frames for proteins of ≥100 amino acids. Analysis of the sequence of pSCEC2 revealed two resistance gene segments. The 4.4 kb cfr-containing segment is flanked by two IS256 elements in the same orientation, which are believed to be involved in the dissemination of the rRNA methylase gene cfr. The other segment harbours the resistance genes floR, tet(A)-tetR, strA/strB and sul2, which have previously been found on other IncA/C plasmids. Except for these two resistance gene regions, the pSCEC2 backbone displayed >99% nucleotide sequence identity to that of other IncA/C family plasmids isolated in France, Chile and the USA. CONCLUSIONS: The cfr gene was identified on an IncA/C plasmid, which is well known for its broad host range and transfer and maintenance properties. The location on such a plasmid will further accelerate the dissemination of cfr and co-located resistance genes among different Gram-negative bacteria. The genetic context of cfr on plasmid pSCEC2 underlines the complexity of cfr transfer events and confirms the role that insertion sequences play in the spread of cfr.

Design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents.

Tuberculosis remains a global public health problem in recent years. To develop novel type of potential antitubercular agents, twelve novel dihydroartemisinin-fluoroquinolone (DHA-FQ) conjugates (three types of molecules) were gradually designed and conveniently synthesized. All the newly synthesized conjugates were well characterized and evaluated against different Mycobacterium tuberculosis strains in vitro. The screening results showed that five DHA-FQ conjugates were active toward M. tuberculosis H37Rv, and compound 3a exhibited the strongest inhibitory activity (MIC=0.0625 µg/mL), which was comparable to the positive control Moxifloxacin and even stronger than Ofloxacin. Conjugates 2a and 3a also displayed comparable activities against various clinically isolated sensitive and resistant M. tuberculosis strains (MIC=0.125-16 µg/mL) to Moxifloxacin. All target compounds possessed selective anti-M. tuberculosis ability. Preliminary structure-activity relationship demonstrated that short linker between DHA and FQ was favorable for strong antitubercular activity. This study provides a new clue for the development of novel antitubercular lead molecules.

Household fuel and direct carbon emission disparity in rural China.

Universal access to clean fuels in household use is one explicit indicator of sustainable development while currently still billions of people rely on solid fuels for daily cooking. Despite of the recognized clean transition trend in general, disparities in household energy mix in different activities (e.g. cooking and heating) and historical trends remain to be elucidated. In this study, we revealed the historical changing trend of the disparity in household cooking and heating activities and associated carbon emissions in rural China. The study found that the poor had higher total direct energy consumption but used less modern energy, especially in cooking activities, in which the poor consumed 60 % more energy than the rich. The disparity in modern household energy use decreased over time, but conversely the disparity in total residential energy consumption increased due to the different energy elasticities as income increases. Though per-capita household CO2 and Black Carbon (BC) emissions were decreasing under switching to modern energies, the disparity in household CO2 and BC deepened over time, and the low-income groups emitted âˆ¼ 10 kg CO2 more compared to the high-income population. Relying solely on spontaneous clean cooking transition had limited impacts in reducing disparities in household energy and carbon emissions, whereas improving access to modern energy had substantial potential to reduce energy consumption and carbon emissions and its disparity. Differentiated energy-related policies to promote high-efficiency modern heating energies affordable for the low-income population should be developed to reduce the disparity, and consequently benefit human health and climate change equally.

Estimated health effects from domestic use of gaseous fuels for cooking and heating in high-income, middle-income, and low-income countries: a systematic review and meta-analyses.

BACKGROUND: Exposure to household air pollution from polluting domestic fuel (solid fuel and kerosene) represents a substantial global public health burden and there is an urgent need for rapid transition to clean domestic fuels. Gas for cooking and heating might possibly affect child asthma, wheezing, and respiratory health. The aim of this review was to synthesise the evidence on the health effects of gaseous fuels to inform policies for scalable clean household energy. METHODS: In this systematic review and meta-analysis, we summarised the health effects from cooking or heating with gas compared with polluting fuels (eg, wood or charcoal) and clean energy (eg, electricity and solar energy). We searched PubMed, Scopus, Web of Science, MEDLINE, Cochrane Library (CENTRAL), Environment Complete, GreenFile, Google Scholar, Wanfang DATA, and CNKI for articles published between Dec 16, 2020, and Feb 6, 2021. Studies eligible for inclusion had to compare gas for cooking or heating with polluting fuels (eg, wood or charcoal) or clean energy (eg, electricity or solar energy) and present data for health outcomes in general populations. Studies that reported health outcomes that were exacerbations of existing underlying conditions were excluded. Several of our reviewers were involved in screening studies, data extraction, and quality assessment (including risk of bias) of included studies; 20% of studies were independently screened, extracted and quality assessed by another reviewer. Disagreements were reconciled through discussion with the wider review team. Included studies were appraised for quality using the Liverpool Quality Assessment Tools. Key health outcomes were grouped for meta-analysis and analysed using Cochrane's RevMan software. Primary outcomes were health effects (eg, acute lower respiratory infections) and secondary outcomes were health symptoms (eg, respiratory symptoms such as wheeze, cough, or breathlessness). This study is registered with PROSPERO, CRD42021227092. FINDINGS: 116 studies were included in the meta-analysis (two [2%] randomised controlled trials, 13 [11%] case-control studies, 23 [20%] cohort studies, and 78 [67%] cross-sectional studies), contributing 215 effect estimates for five grouped health outcomes. Compared with polluting fuels, use of gas significantly lowered the risk of pneumonia (OR 0·54, 95% CI 0·38-0·77; p=0·00080), wheeze (OR 0·42, 0·30-0·59; p<0·0001), cough (OR 0·44, 0·32-0·62; p<0·0001), breathlessness (OR 0·40, 0·21-0·76; p=0·0052), chronic obstructive pulmonary disease (OR 0·37, 0·23-0·60; p<0·0001), bronchitis (OR 0·60, 0·43-0·82; p=0·0015), pulmonary function deficit (OR 0·27, 0·17-0·44; p<0·0001), severe respiratory illness or death (OR 0·27, 0·11-0·63; p=0·0024), preterm birth (OR 0·66, 0·45-0·97; p=0·033), and low birth weight (OR 0·70, 0·53-0·93; p=0·015). Non-statistically significant effects were observed for asthma in children (OR 1·04, 0·70-1·55; p=0·84), asthma in adults (OR 0·65, 0·43-1·00; p=0·052), and small for gestational age (OR 1·04, 0·89-1·21; p=0·62). Compared with electricity, use of gas significantly increased risk of pneumonia (OR 1·26, 1·03-1·53; p=0·025) and chronic obstructive pulmonary disease (OR 1·15, 1·06-1·25; p=0·0011), although smaller non-significant effects were observed for higher-quality studies. In addition, a small increased risk of asthma in children was not significant (OR 1·09, 0·99-1·19; p=0·071) and no significant associations were found for adult asthma, wheeze, cough, and breathlessness (p>0·05). A significant decreased risk of bronchitis was observed (OR 0·87, 0·81-0·93; p<0·0001). INTERPRETATION: Switching from polluting fuels to gaseous household fuels could lower health risk and associated morbidity and mortality in resource-poor countries where reliance on polluting fuels is greatest. Although gas fuel use was associated with a slightly higher risk for some health outcomes compared with electricity, gas is an important transitional option for health in countries where access to reliable electricity supply for cooking or heating is not feasible in the near term. FUNDING: WHO.

Early administration of Wumei Wan inhibit myeloid-derived suppressor cells via PI3K/Akt pathway and amino acids metabolism to prevent colitis-associated colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Wumei Wan (WMW), a traditional Chinese medicine prescription, has been proved to be effective in treating Colitis-associated colorectal cancer (CAC), but it has not been proven to be effective in different stages of CAC. AIM OF THE STUDY: The purpose of our study is to investigate the therapeutic effect and mechanism of WMW on the progression of CAC. MATERIALS AND METHODS: Azioximethane (AOM) and dextran sulfate sodium (DSS) were used to treat mice for the purpose of establishing CAC models. WMW was administered in different stages of CAC. The presentative chemical components in WMW were confirmed by LC-MS/MS under the optimized conditions. The detection of inflammatory cytokines in the serum and colon of mice were estimated by qRT-PCR and ELISA. The changes of T cells and myeloid-derived suppressor cells (MDSCs) in each group were detected by flow cytometry. The metabolic components in serum of mice were detected by UPLC-MS/MS. Expression of genes and proteins were detected by eukaryotic transcriptomics and Western blot to explore the key pathway of WMW in preventing CAC. RESULTS: WMW had significant effect on inhibiting inflammatory responses and tumors during the early development stage of CAC when compared to other times. WMW increased the length of mice's colons, reduced the level of IL-1ß, IL-6, TNF-α in colon tissues, and effectively alleviated colonic inflammation, and improved the pathological damage of colon tissues. WMW could significantly reduce the infiltration of MDSCs in the spleen, increase CD4+ T cells and CD8+ T cells in the spleen of CAC mice, and effectively reform the immune microenvironment in CAC mice. Transcriptomics analysis revealed that 2204 genes had different patterns of overlap in the colon tissues of mice between control group, AOM + DSS group, and early administration of WMW group. And KEGG enrichment analysis showed that PI3K/Akt signaling pathway, ECM-receptor interaction, IL-17 signaling pathway, MAPK signaling pathway, pancreatic secretion, thermogenesis, and Rap1 signaling pathway were all involved. The serum metabolomics results of WMW showed that the metabolic compositions of the control group, AOM + DSS group and the early stage of WMW were different, and 42 differential metabolites with the opposite trends of changes were screened. The metabolic pathways mainly included pyrimidine metabolism, glycine, serine and threonine metabolism, tryptophan metabolism, and purine metabolism. And amino acids and related metabolites may play an important role in WMW prevention of CAC. CONCLUSION: WMW can effectively prevent the occurrence and development of CAC, especially in the initial stage. WMW can reduce the immune infiltration of MDSCs in the early stage. Early intervention of WMW can improve the metabolic disorder caused by AOM + DSS, especially correct the amino acid metabolism. PI3K/Akt signaling pathway was inhabited in early administration of WMW, which can regulate the amplification and function of MDSCs.

Phytoplankton in headwater streams: spatiotemporal patterns and underlying mechanisms.

Phytoplankton are key members of river ecosystems wherein they influence and regulate the health of the local environment. Headwater streams are subject to minimal human activity and serve as the sources of rivers, generally exhibiting minimal pollution and strong hydrodynamic forces. To date, the characteristics of phytoplankton communities in headwater streams have remained poorly understood. This study aims to address this knowledge gap by comparing phytoplankton communities in headwater streams with those in plain rivers. The results demonstrated that within similar watershed sizes, lower levels of spatiotemporal variability were observed with respect to phytoplankton community as compared to plain rivers. Lower nutrient levels and strong hydrodynamics contribute to phytoplankton growth limitation in these streams, thereby reducing the levels of spatiotemporal variation. However, these conditions additionally contribute to greater phytoplankton diversity and consequent succession towards Cyanophyta. Overall, these results provide new insights into the dynamics of headwater stream ecosystems and support efforts for their ecological conservation.

Trends in air pollutants emissions in the Qinghai-Tibet Plateau and its surrounding areas under different socioeconomic scenarios.

The Qinghai-Tibetan Plateau (QTP) and its surrounding areas are undergoing rapid changes in socioeconomic conditions, activity sectors, and emission levels. These changes underscore the significance of conducting local environmental assessments in the future and generating air pollutant emission forecasts necessary for effective evaluation. Current pollutants emissions pathways exhibit regional limitation since their based historical inventory could not accurately reflect the emission characteristics in QTP. This study constructed a high spatial resolution (0.1° × 0.1°) atmospheric pollutant emissions dataset in the Qinghai-Tibet Plateau and its surrounding Areas (QTPA) based on updated emission inventory and various socioeconomic scenarios. We found that the pollutant emissions levels are distinct among different social development scenarios, with SSP3-7.0 demonstrating the highest magnitude of emissions. Regional and sectoral contributions exhibit substantial variations. Notably, solid fuel combustion originating from residential sectors in Northeast India and open fires in Myanmar are identified as high-density sources of PM2.5 emissions. Current pollutant emission patterns in the QTPA are more akin to SSP2-4.5, however, specific regions such as Qinghai and Tibet have exhibited more pronounced trends of emission reduction. The comparison with previous datasets reveals that the predicted pollutant emissions in this study are lower than Scenario Model Intercomparison Project (SMIP) dataset but higher than Asian-Pacific Integrated Model (AIM) dataset due to the revised inventory data and model variations, in which the latter might be the main obstacle to accurate emissions prediction.

Pyroptotic MAITs link microbial translocation with severity of alcohol-associated liver disease.

BACKGROUND: Mucosal-associated invariant T cells (MAITs) are markedly reduced in patients with alcohol-associated liver disease (ALD); however, the potential mechanism underlying MAITs' loss remains elusive. Hence, we aimed to explore what induced MAITs' loss and its clinical significance. METHODS: The characteristics of pyroptotic MAITs were evaluated in a cohort of patients with ALD, including 41 patients with alcohol-associated liver cirrhosis (ALC) and 21 patients with ALC complicated with severe alcoholic hepatitis (ALC + SAH). RESULTS: In patients with ALD, blood MAITs were significantly decreased, hyperactivated, and displayed enhanced cell death through pyroptosis. The frequencies of pyroptotic MAITs increased with disease severity in patients with ALC and patients with ALC + SAH. These frequencies were negatively associated with the frequencies of MAITs and positively correlated with the levels of MAITs' activation, plasma levels of intestinal fatty acid-binding protein (a marker of intestinal enterocyte damage), soluble CD14, lipopolysaccharide-binding protein, and peptidoglycan recognition proteins (surrogate markers of microbial translocation). Pyroptotic MAITs were also found in the liver of patients with ALD. Interestingly, MAITs underwent further activation and pyroptosis in vitro under stimulation by Escherichia coli or direct bilirubin. Notably, blocking IL-18 signaling reduced the activation and frequencies of pyroptotic MAITs. CONCLUSIONS: The loss of MAITs in patients with ALD is, at least in part, due to cell death from pyroptosis and is associated with the severity of ALD. Such increased pyroptosis may be affected by dysregulated inflammatory responses to intestinal microbial translocation or direct bilirubin.