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Coproporphyrin III (CP III), a natural porphyrin derivative, has extensive applications in the biomedical and material industries. S. cerevisiae has previously been engineered to highly accumulate the CP III precursor 5-aminolevulinic acid (ALA) through the C4 pathway. In this study, a combination of cytoplasmic metabolic engineering and mitochondrial compartmentalization was used to enhance CP III production in S. cerevisiae. By integrating pathway genes into the chromosome, the CP III titer gradually increased to 32.5 ± 0.5 mg/L in shake flask cultivation. Nevertheless, increasing the copy number of pathway genes did not consistently enhance CP III synthesis. Hence, the partial synthesis pathway was compartmentalized in mitochondria to evaluate its effectiveness in increasing CP III production. Subsequently, by superimposing the mitochondrial compartmentalization strategy on cytoplasmic metabolic engineered strains, the CP III titer was increased to 64.3 ± 1.9 mg/L. Furthermore, augmenting antioxidant pathway genes to reduce reactive oxygen species (ROS) levels effectively improved the growth of engineered strains, resulting in a further increase in the CP III titer to 82.9 ± 1.4 mg/L. Fed-batch fermentations in a 5 L bioreactor achieved a titer of 402.8 ± 9.3 mg/L for CP III. This study provides a new perspective on engineered yeast for the microbial production of porphyrins.

Abstract Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome‐wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment‐resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation‐relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein‐coding region of HLA‐DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA‐DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin‐6 (IL‐6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA‐DRB1 polymorphism, and enhanced IL‐6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.

PurposeTo evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRASG12C mutation from the China and United States’social perspective.Materials and MethodsA Markov model that included three states (progression-free survival, post-progression survival, and death) was developed. Incremental cost-effectiveness ratio (ICER), quality-adjusted life-year (QALY), and incremental QALY were calculated for the two treatment strategies. One-way sensitivity analysis was used to investigate the factors that had a greater impact on the model results, and tornado diagrams were used to present the results. Probabilistic sensitivity analysis was performed with 1,000 Monte Carlo simulations. Assume distributions based on parameter types and randomly sample all parameter distributions each time., The results were presented as cost-effectiveness acceptable curves.ResultsThis economic evaluation of data from the CodeBreak 200 randomized clinical trial. In China, sotorasib generated 0.44 QAYL with a total cost of $84372.59. Compared with docetaxel, the ICER value of sotorasib was $102701.84/QALY, which was higher than willingness to pay (WTP), so sotorasib had no economic advantage. In the US, sotorasib obtained 0.35 QALY more than docetaxel, ICER was $15,976.50/QALY, which was more than 1 WTP but less than 3 WTP, indicating that the increased cost of sotorasib was acceptable. One-way sensitivity analysis showed that the probability of sotorasib having economic benefits gradually increased when the cost of follow-up examination was reduced in China. And there was no influence on the conclusions within the range of changes in China. When the willingness to pay (WTP) exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.ConclusionSotorasib had a cost effect from the perspective in the United States. However, sotorasib had no cost effect from the perspective in China, and only when the WTP exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.

Mounting evidence has shown that the gut microbiota plays a key role in human health. The homeostasis of the gut microbiota could be affected by many factors, including environmental chemicals. Aldicarb is a carbamate insecticide used to control a variety of insects and nematode pests in agriculture. Aldicarb is highly toxic and its wide existence has become a global public health concern. In our previous study, we have demonstrated that aldicarb disturbed the gut microbial community structure and composition. However, the impacts of aldicarb on gut microbiota-derived metabolites, bile acids, remain elusive. In present study, we performed targeted metabolomics analysis to explore the effects of aldicarb exposure on bile acids, as well as steroid hormones and oxylipins in the serum, feces and liver of C57BL/6 J mice. Our results showed that aldicarb exposure disturbed the level of various bile acids, steroid hormones and oxylipins in the serum and feces of C57BL/6 J mice. In the liver, the level of cortisol was decreased, meanwhile 15,16-dihydroxyoctadeca-9,12-dienoic acid was increased in aldicarb-treated mice. Metagenomic sequencing analysis showed that the relative abundance of a bile salt hydrolase, choloylglycine hydrolase (EC:3.5.1.24) and a sulfatase enzyme involved in steroid hormone metabolism, arylsulfatase, was significantly increased by aldicarb exposure. Furthermore, correlations were found between gut microbiota and various serum metabolites. The results from this study are helpful to improve the understanding of the impact of carbamate insecticides on host and microbial metabolism.

Abstract Background Harnessing engineered Mycolicibacteria to convert cheap phytosterols into valuable steroid synthons is a basic way in the industry for the production of steroid hormones. Thus, C-19 and C-22 steroids are the two main types of commercial synthons and the products of C17 side chain degradation of phytosterols. During the conversion process of sterols, C-19 and C-22 steroids are often produced together, although one may be the main product and the other a minor byproduct. This is a major drawback of the engineered Mycolicibacteria for industrial application, which could be attributed to the co-existence of androstene-4-ene-3,17-dione (AD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (HBC) sub-pathways in the degradation of the sterol C17 side chain. Since the key mechanism underlying the HBC sub-pathway has not yet been clarified, the above shortcoming has not been resolved so far. Results The key gene involved in the putative HBC sub-pathway was excavated from the genome of M. neoaurum by comparative genomic analysis. Interestingly, an aldolase- encoding gene, atf1, was identified to be responsible for the first reaction of the HBC sub-pathway, and it exists as a conserved operon along with a DUF35-type gene chsH4, a reductase gene chsE6, and a transcriptional regulation gene kstR3 in the genome. Subsequently, atf1 and chsH4 were identified as the key genes involved in the HBC sub-pathway. Therefore, an updated strategy was proposed to develop engineered C-19 or C-22 steroid-producing strains by simultaneously modifying the AD and HBC sub-pathways. Taking the development of 4-HBC and 9-OHAD-producing strains as examples, the improved 4-HBC-producing strain achieved a 20.7 g/L production titer with a 92.5% molar yield and a 56.4% reduction in byproducts, and the improved 9-OHAD producing strain achieved a 19.87 g/L production titer with a 94.6% molar yield and a 43.7% reduction in byproduct production. Conclusions The excellent performances of these strains demonstrated that the primary operon involved in the HBC sub-pathway improves the industrial strains in the conversion of phytosterols to steroid synthons.

China's efforts to mitigate air pollution from its large-scale coal-fired power plants (CFPPs) have involved the widespread use of air pollution control devices (APCDs). However, the operation of these devices relies on substantial electricity generated by CFPPs, resulting in indirect CO2 emissions. The extent of CO2 emissions caused by APCDs in China remains uncertain. Here, using a plant-level dataset, we quantified the CO2 emissions associated with electricity consumption by APCDs in China's CFPPs. Our findings reveal a significant rise in CO2 emissions attributed to APCDs, increasing from 1.48 Mt in 2000 to 51.7 Mt in 2020. Moreover, the contribution of APCDs to total CO2 emissions from coal-fired power generation escalated from 0.12% to 1.19%. Among the APCDs, desulfurization devices accounted for approximately 80% of the CO2 emissions, followed by dust removal and denitration devices. Scenario analysis indicates that the lifespan of CFPPs will profoundly impact future emissions, with Nei Mongol, Shanxi, and Shandong provinces projected to exhibit the highest emissions. Our study emphasizes the urgent need for a comprehensive assessment of environmental policies and provides valuable insights for the integrated management of air pollutants and carbon emissions in CFPPs.

Abstract Background Polycyclic triterpenoids (PTs) are common in plants, and have attracted considerable interest due to their remarkable biological activities. Currently, engineering the ergosterol synthesis pathway in Saccharomyces cerevisiae is a safe and cost-competitive way to produce triterpenoids. However, the strict regulation of ERG1 involved in the epoxidation of squalene limits the triterpenoid production. Results In this study, we found that the decrease in ERG7 protein level could dramatically boost the epoxidation of squalene by improving the protein stability of ERG1. We next explored the potential factors that affected the degradation process of ERG1 and confirmed that ERG7 was involved in the degradation process of ERG1. Subsequently, expression of four different triterpene cyclases utilizing either 2,3-oxidosqualene or 2,3:22,23-dioxidosqualene as the substrate in ERG7-degraded strains showed that the degradation of ERG7 to prompt the epoxidation of squalene could significantly increase triterpenoid production. To better display the potential of the strategy, we increased the supply of 2,3-oxidosqualene, optimized flux distribution between ergosterol synthesis pathway and β-amyrin synthesis pathway, and modified the GAL-regulation system to separate the growth stage from the production stage. The best-performing strain ultimately produced 4216.6 ± 68.4 mg/L of β-amyrin in a two-stage fed-fermentation (a 47-fold improvement over the initial strain). Conclusions This study showed that deregulation of the native restriction in ergosterol pathway was an effective strategy to increase triterpenoid production in yeast, which provided a new insight into triterpenoids biosynthesis.

This study presents a stress testing operation conducted using a wireline formation tester in a newly discovered gas hydrate prospect located offshore in Japan. The campaign, which spanned from December 2021 to January 2022, involved drilling a well using logging-while-drilling technology. Subsequently, wireline formation testing and stress testing were successfully conducted at three different depths within a gas hydrate-concentrated zone. The testing was accomplished in a single riserless descent, with the primary goal of obtaining crucial data such as mobility, formation pressure, and fracture gradient for one of the prospects. This operation marked the first stress testing job performed with dual packers in an open water and deepwater environment specifically for gas hydrate reservoirs. The study also provides a comprehensive interpretation of the data gathered during the operation. Moreover, it evaluates various properties such as formation mobility, formation pressure, initial breakdown pressure, closure pressure, fracture propagation pressure, and instantaneous shut-in pressure.

The wide spread of microplastics has fueled growing public health concern globally. Due to their porous structure and large surface area, microplastics can serve as carriers for other environmental pollutants, including heavy metals. Although the toxic effects of microplastics or heavy metals have been reported previously, investigations into the sex-differential health effects of combined exposure to microplastics and heavy metals are lacking. In the present study, the effects of polystyrene microplastics and lead(II) co-exposure on the gut microbiome, intestinal permeability, and fecal metabolome were examined in both male and female mice. Combined exposure of polystyrene microplastics and lead(II) increased intestinal permeability in both male and female mice. Sex-specific responses to the co-exposure were found in gut bacteria, fungi, microbial metabolic pathways, microbial genes encoding antibiotic resistance and virulence factors, as well as fecal metabolic profiles. In particular, Shannon and Simpson indices of gut bacteria were reduced by the co-exposure only in female mice. A total of 34 and 13 fecal metabolites were altered in the co-exposure group in female and male mice, respectively, among which only three metabolites were shared by both sexes. These sex-specific responses to the co-exposure need to be taken into consideration when investigating the combined toxic effects of microplastics and heavy metals on the gut microbiota.

Genomic integration of genes and pathway-sized DNA cassettes is often an indispensable way to construct robust and productive microbial cell factories. For some uncommon microbial hosts, such as Mycolicibacterium and Mycobacterium species, however, it is a challenge. Here, we present a multiplexed integrase-assisted site-specific recombination (miSSR) method to precisely and iteratively integrate genes/pathways with controllable copies in the chromosomes of Mycolicibacteria for the purpose of developing cell factories. First, a single-step multi-copy integration method was established in M. neoaurum by a combination application of mycobacteriophage L5 integrase and two-step allelic exchange strategy, the efficiencies of which were ∼100% for no more than three-copy integration events and decreased sharply to ∼20% for five-copy integration events. Second, the R4, Bxb1 and ΦC31 bacteriophage Att/Int systems were selected to extend the available integration toolbox for multiplexed gene integration events. Third, a reconstructed mycolicibacterial Xer recombinases (Xer-cise) system was employed to recycle the selection marker of gene recombination to facilitate the iterative gene manipulation. As a proof of concept, the biosynthetic pathway of ergothioneine (EGT) in Mycolicibacterium neoaurum ATCC 25795 was achieved by remodeling its metabolic pathway with a miSSR system. With six copies of the biosynthetic gene clusters (BGCs) of EGT and pentose phosphate isomerase (PRT), the titer of EGT in the resulting strain in a 30 mL shake flask within 5 days was enhanced to 66 mg/L, which was 3.77 times of that in the wild strain. The improvements indicated that the miSSR system was an effective, flexible, and convenient tool to engineer the genomes of Mycolicibacteria as well as other strains in the Mycobacteriaceae due to their proximate evolutionary relationships.

Abstract Progesterone is one of the classical hormone drugs used in medicine for maintaining pregnancy. However, its manufacturing process, coupled with organic reagents and poisonous catalysts, causes irreversible environmental pollution. Recent advances in synthetic biology have demonstrated that the microbial biosynthesis of natural products, especially difficult-to-synthesize compounds, from building blocks is a promising strategy. Herein, overcoming the heterologous cytochrome P450 enzyme interdependency in Mycolicibacterium neoaurum successfully constructed the CYP11A1 running module to realize metabolic conversion from waste phytosterols to progesterone. Subsequently, progesterone yield was improved through strategies involving electron transfer and NADPH regeneration. Mutant CYP11A1 (mCYP11A1) and adrenodoxin reductase (ADR) were connected by a flexible linker (L) to form the chimera mCYP11A1-L-ADR to enhance electron transfer. The chimera mCYP11A1-L-ADR, adrenodoxin (ADX), and ADR-related homolog ARH1 were expressed in M. neoaurum, showed positive activity and produced 45 mg/L progesterone. This electron transfer strategy increased progesterone production by 3.95-fold compared with M. neoaurum expressing mCYP11A1, ADR, and ADX. Significantly, a novel inorganic–biological hybrid system was assembled by combining engineered M. neoaurum and InP nanoparticles to regenerate NADPH, which was increased 84-fold from the initial progesterone titer to 235 ± 50 mg/L. In summary, this work highlights the green and sustainable potential of obtaining synthetic progesterone from sterols in M. neoaurum. Graphical Abstract

Chronic alcohol use is associated with intestinal bacterial overgrowth and dysbiosis, but the contribution of ethanol is unclear. Here, using mouse models, the authors find that ethanol is not directly metabolized by the gut microbiota, and that induced changes are rather a side effect of elevated acetate levels.

Abstract Indirubin is a bisindole compound for the treatment of chronic myelocytic leukemia. Here, we presented a structure-guided method to improve the activity of a flavin-containing monooxygenase (bFMO) for the efficient production of indirubin in Escherichia coli. A flexible loop interlocked with the active pocket through a helix and the substrate tunnel rather than the active pocket in bFMO were identified to be two reconfigurable structures to improve its activity, resulting in K223R and N291T mutants with enhanced catalytic activity by 2.5- and 2.0-fold, respectively. A combined modification at the two regions (K223R/D317S) achieved a 6.6-fold improvement in catalytic efficiency (k cat/K m) due to enhancing π–π stacking interactions stabilization. Finally, an engineered E. coli strain was constructed by metabolic engineering, which could produce 860.7 mg/L (18 mg/L/h) indirubin, the highest yield ever reported. This work provides new insight into the redesign of FMOs to boost their activities and an efficient approach to produce indirubin. Graphical Abstract

Abstract The introduction of heterologous pathways into microorganisms for high‐level synthesis of valuable compounds would be extremely meaningful. However, the endogenous heterologous pathway conversion point frequently serves as a bottleneck that limits product synthesis. (+)‐Nootkatone is an important functional sesquiterpenoid with a unique grapefruit flavor, which is frequently used as a fragrance. The low catalytic efficiency of the valencene synthase CnVS, the first heterologous enzyme in the biosynthesis of (+)‐nootkatone, is the major challenge that restricts the production of (+)‐nootkatone in Saccharomyces cerevisiae. In this study, we modified CnVS on the basis of the catalytic environment and mechanism of the enzyme. The residue M560 involving in alkyl transfer during substrate cyclization was found to affect activity. By tuning the residue, mutant M560L exhibited a 60% increase in the unit cell yield of (+)‐valencene, which is the precursor of (+)‐nootkatone. Furthermore, multistep strategies of metabolic engineering were employed that transferred the metabolic flux to the target product synthesis pathway and displayed the superimposed effect of metabolic and protein engineering on (+)‐nootkatone yield. Finally, multicopy integration of tHMG1 and ERG20ERG20‐GSG‐CnVSM560L boosted the production of (+)‐nootkatone to 85.43 mg/L in flask and 804.96 mg/L (5.29 mg/[L h]) in bioreactor. In conclusion, this study presents a paradigm for constructing microbial cell factories using a combination of protein and metabolic engineering in S. cerevisiae.

Background and purposeUnderstanding the temporal trends of stroke burden and its attributable risk factors are essential for targeted prevention strategies. We aimed to describe the temporal trends and attributable risk factors of stroke in China.MethodsData on the stroke burden [incidence, prevalence, mortality, and disability-adjusted life years (DALYs)] and the population-attributable fraction for stroke risk factors from 1990 to 2019 were obtained from the Global Burden of Disease Study 2019 (GBD 2019). We analyzed trends in the burden of stroke and its attributable risk factors from 1990 to 2019, and the characteristics of stroke-attributable risk factors by sex, age group, and stroke subtype.ResultsFrom 1990 to 2019, the age-standardized incidence, mortality, and DALY rates for total stroke decreased by 9.3% (3.3, 15.5), 39.8% (28.6, 50.7), and 41.6% (30.7, 50.9) respectively. The corresponding indicators all decreased for intracerebral hemorrhage and subarachnoid hemorrhage. The age-standardized incidence rate of ischemic stroke increased by 39.5% (33.5 to 46.2) for male patients and by 31.4% (24.7 to 37.7) for female patients, and the age-standardized mortality and DALY rates remained almost unchanged. The three leading stroke risk factors were high systolic blood pressure, ambient particulate matter pollution, and smoking. High systolic blood pressure has remained the leading risk factor since 1990. The attributable risk of ambient particulate matter pollution shows a clear upward trend. Smoking and alcohol consumption were important risk factors for men.ConclusionThis study reinforced the findings of an increased stroke burden in China. Precise stroke prevention strategies are needed to reduce the disease burden of stroke.

Microplastic pollution is an emerging threat for marine and terrestrial ecosystems, which has raised global concerns about its implications for human health. Mounting evidence has shown that the gut microbiota plays a key role in human health and diseases. The gut bacteria could be disturbed by many environmental factors, including the microplastic particles. However, the size effect of polystyrene microplastics on mycobiome, as well as gut functional metagenome has not been well studied. In this study, we performed ITS sequencing to explore the size effect of polystyrene microplastics on the fungal composition, in combination with the shotgun metagenomics sequencing to reveal the size effects of polystyrene on the functional metagenome. We found that polystyrene microplastic particles with 0.05–0.1 µm diameter showed greater impact on the bacterial and fungal composition of gut microbiota as well as the metabolic pathways than the polystyrene microplastic particles with 9–10 µm diameter. Our results suggested that size-depended effects should not be ignored in the health risk assessment of microplastics.

Abstract Background 7β-hydroxylated steroids (7β-OHSt) possess significant activities in anti-inflammatory and neuroprotection, and some of them have been widely used in clinics. However, the production of 7β-OHSt is still a challenge due to the lack of cheap 7β-hydroxy precursor and the difficulty in regio- and stereo-selectively hydroxylation at the inert C7 site of steroids in industry. The conversion of phytosterols by Mycolicibacterium species to the commercial precursor, androst-4-ene-3,17-dione (AD), is one of the basic ways to produce different steroids. This study presents a way to produce a basic 7β-hydroxy precursor, 7β-hydroxyandrost-4-ene-3,17-dione (7β-OH-AD) in Mycolicibacterium, for 7β-OHSt synthesis. Results A mutant of P450-BM3, mP450-BM3, was mutated and engineered into an AD producing strain for the efficient production of 7β-OH-AD. The enzyme activity of mP450-BM3 was then increased by 1.38 times through protein engineering and the yield of 7β-OH-AD was increased from 34.24 mg L− 1 to 66.25 mg L− 1. To further enhance the performance of 7β-OH-AD producing strain, the regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) for the activity of mP450-BM3-0 was optimized by introducing an NAD kinase (NADK) and a glucose-6-phosphate dehydrogenase (G6PDH). Finally, the engineered strain could produce 164.52 mg L− 1 7β-OH-AD in the cofactor recycling and regeneration system. Conclusions This was the first report on the one-pot biosynthesis of 7β-OH-AD from the conversion of cheap phytosterols by an engineered microorganism, and the yield was significantly increased through the mutation of mP450-BM3 combined with overexpression of NADK and G6PDH. The present strategy may be developed as a basic industrial pathway for the commercial production of high value products from cheap raw materials.

Abstract Ergothioneine (EGT) represents valuable protective functions for humans, but EGT from the diet cannot meet daily requirements. Although the heterologous synthesis of EGT had been achieved, it is still a challenge to obtain stable and high‐yield EGT‐producing cell factories. Here, after the co‐overexpression of the EGT synthetic gene cluster and hisG, hisC, and allB1 in Mycolicibacterium neoaurum, the natural EGT titer was increased by 7.2‐folds. However, the degradation problem of EGT in large‐scale fermentation needs to be urgently solved. A putative lyase gene Mn_3042 was inactivated, thus inhibiting the product degradation and increasing the EGT titer by 21%. Moreover, the enhancement of S‐adenosyl‐ l‐methionine regeneration further increased EGT titer by 28%. After optimization of fed‐batch fermentation, the yield of EGT was boosted to 1.56 g/L with a productivity of 7.2 mg/L/h. This study provides a systematic engineering strategy for developing EGT‐producing cell factories.

Asthenopia is a syndrome based on the symptoms of eye discomfort that has become a chronic disease that interferes with and harms people’s physical and mental health. Lutein is an internationally recognized “eye nutrient”, and studies have shown that it can protect the retina and relieve visual fatigue. In this study, lutein was extracted from marigold (Tagetes erecta L.) and saponified. The purified lutein concentration measured by HPLC was 50.12 mg/100 g. Then, purified lutein was modified to be water-soluble by nanoscale modification and microencapsulation technology. Water-soluble lutein was then mixed with a leaching solution of Chinese wolfberry and chrysanthemum to make a functional beverage. The effects of this beverage on hepatic antioxidant enzymes and the alleviation of visual fatigue in a rat model of diabetes were investigated for 4 weeks. Lutein intake of 0.72 (medium-lutein beverage group) and 1.44 mg/mL (high-lutein beverage group) relieved visual fatigue, ameliorated turbidity symptoms of impaired crystalline lenses, reduced hepatic MDA concentration, increased hepatic GSH concentration, and significantly increased the activities of the hepatic antioxidant enzymes SOD, CAT, GSH-Px, and GR in rats. These data suggest that a lutein-rich beverage is an effective and harmless way to increase the total anti-oxidation capacity of lenses and alleviate visual fatigue.

Growing evidence has proven that the gut microbiota has a tremendous impact on mammalian health [...]

Syntrichia caninervis is a desiccation tolerant moss and is the dominant bryophyte found in biological soil crusts in the Gurbantunggut desert. In this study, we assessed the transcriptome profiles of S. caninervis gametophytes during the dehydration-rehydration (D-R) process (across 9 time points) using Illumina sequencing. In total, 22489 transcripts were identified, including 5337 novel transcripts, that mapped to the reference genome. A total of 12548 transcripts exhibited significant alterations in the D-R samples compared with the control samples. The differentially expressed transcripts (DETs) possessed several enriched Gene Ontology terms, such as “water stress response”, “oxidation-reduction process”, “membrane metabolism”, “photosynthesis”, and “transcription factor activity”. Moreover, during early dehydration stress, the DETs were significantly enriched in stress-related pathways from the Kyoto Encyclopedia of Genes and Genomes, such as “phenylpropanoid biosynthesis”, “alpha-linolenic acid metabolism”, and “fructose and mannose metabolism”. Photosynthesis-related transcripts (e.g., ScPsa H, ScRubisco, and ScLhcb1) were inhibited during the dehydration treatment and significantly accumulated during the late rehydration period. Most transcripts from the late embryogenesis abundant proteins (LEA) and early light-inducible protein (ELIP) families strongly accumulated at the late dehydration stage. These pathways were positively correlated with the content changes of absolute water content and Fv/Fm values, alongside peroxidase and superoxide dismutase activities. Seven transcription factor families, including AP2-ERF, bHLH, G2-like, MYB, NAC, WRKY, and bZIP, were enriched in DETs during D-R treatment. This study is the first transcriptome analysis using the S. caninervis genome for gene annotation and multigroup D-R treatment points. Our results demonstrated the detailed dynamic changes in the transcriptome of S. caninervis during the D-R process. These results also improve understanding of desiccation tolerant plants’ adaptations to desiccation stress at the transcription level and provide promising gene resources for transgenic crop breeding.

BackgroundThe increased risk of metabolic syndrome (MetS) during the menopausal transition might partly attribute to the changes in follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, few studies were conducted to examine the associations of FSH and LH concentrations with MetS at the full range of reproductive aging, especially in the US population. The aim of this study is to examine the associations of FSH, LH, and LH/FSH ratio with the risk of MetS and severity score in the US women.MethodsData were derived from the National Health and Nutrition Examination Survey. Women aged from 35 to 60 years were eligible. MetS was defined as having at least 3 of the following: a waist circumference ≥ 88 cm, a triglycerides level ≥ 150 mg/dL, a high density lipoprotein < 50 mg/dL, a systolic blood pressure ≥ 130 mm Hg or a diastolic blood pressure ≥ 85 mm Hg or taking hypertension medications, or a fasting plasma glucose level ≥100 mg/dL or taking diabetes medications. The MetS severity score was calculated according to race/ethnicity- specific equation.ResultsThere were 3,831 women included in this study. Increases in serum FSH and LH levels per 1 SD were separately linked to a 22.6% (OR: 0.774; 95% CI: 0.646, 0.929; and P= 0.006) and 18.5% (OR: 0.815; 95% CI: 0.690, 0.962; and P= 0.006) lower risk of MetS only in postmenopausal women. Meanwhile, increases in serum FSH and LH levels per 1SD were associated with a decrease of -0.157 (95% CI :-2.967, -2.034) and -0.078 (95% CI: -2.688, -1.806) MetS severity score in perimenopausal women and -0.195 (95% CI: -2.192, -1.023) and -0.098 (95% CI:-1.884, -0.733) in postmenopausal women. However, LH/FSH ratio had no connections with the risk of MetS and MetS severity score across the menopausal transition.ConclusionsElevated serum FSH and LH levels, but not LH/FSH ratio, were associated with a lower risk of MetS and MetS severity score, especially in postmenopausal women. Therefore, serum FSH and LH levels might be efficient predictors for screening and identifying women at risk of MetS across the menopausal transition.

Abstract Chronic kidney disease is a major public health concern that affects millions of people globally. Alterations in gut microbiota composition have been observed in patients with chronic kidney disease. Nevertheless, the correlation between the gut microbiota and disease severity has not been investigated. In this study, we performed shot-gun metagenomics sequencing and identified several taxonomic and functional signatures associated with disease severity in patients with chronic kidney disease. We noted that 19 microbial genera were significantly associated with the severity of chronic kidney disease. The butyrate-producing bacteria were reduced in patients with advanced stages of chronic kidney diseases. In addition, functional metagenomics showed that two-component systems, metabolic activity and regulation of co-factor were significantly associated with the disease severity. Our study provides valuable information for the development of microbiota-oriented therapeutic strategies for chronic kidney disease.

Although metabolic alterations are observed in many monogenic and complex genetic disorders, the impact of most mammalian genes on cellular metabolism remains unknown. Understanding the effect of mouse gene dysfunction on metabolism can inform the functions of their human orthologues. We investigated the effect of loss-of-function mutations in 30 unique gene knockout (KO) lines on plasma metabolites, including genes coding for structural proteins (11 of 30), metabolic pathway enzymes (12 of 30) and protein kinases (7 of 30). Steroids, bile acids, oxylipins, primary metabolites, biogenic amines and complex lipids were analyzed with dedicated mass spectrometry platforms, yielding 827 identified metabolites in male and female KO mice and wildtype (WT) controls. Twenty-two percent of 23,698 KO versus WT comparison tests showed significant genotype effects on plasma metabolites. Fifty-six percent of identified metabolites were significantly different between the sexes in WT mice. Many of these metabolites were also found to have sexually dimorphic changes in KO lines. We used plasma metabolites to complement phenotype information exemplified for Dhfr, Idh1, Mfap4, Nek2, Npc2, Phyh and Sra1. The association of plasma metabolites with IMPC phenotypes showed dramatic sexual dimorphism in wildtype mice. We demonstrate how to link metabolomics to genotypes and (disease) phenotypes. Sex must be considered as critical factor in the biological interpretation of gene functions.

Abstract Background Medicine purchasing in Chinese public hospitals is decided by the hospital Pharmacy Management Committee (PMC), that is complex, subjective and requires efficient approaches to ensure transparency and consistency for the factors being considered. This study aimed to use the Evidence and Value: Impact on Decision Making (EVIDEM) framework to assess medicine in these hospitals. In this study anti-diabetic drugs DPP-4 inhibitors, which work by inhibiting the activation of the Dipeptidyl Peptidase 4 (DPP-4) inhibitors, were appraised. Methods Following EVIDEM methodology (EVIDEM-10th), we convened an appraisal group and asked each individual to express their perspectives by assigning weights to each criterion. A systematic literature search for information of each criterion of five DPP-4 inhibitors was completed. Then the appraisal group scored for each criterion of the five DPP-4 inhibitors. The estimated value of the five DPP-4 inhibitors was obtained by Multi-Criteria Decision Analysis (MCDA) which combined individual weighting of each criterion with individual scoring for each intervention in each criterion. Results By assigning weights, the most important criterion was the quality of evidence (4.01±0.52), and that the comparative cost consequences-non-medical cost was the least important criterion (2.87±1.03). Criteria included disease severity, size of the affected population, comparative effectiveness, type of therapeutic/preventive benefit and cost of intervention, all of which were assigned the same weight of 3.58. After MCDA, the overall value orders for each DPP-4 inhibitor included Sitagliptin (0.45), Linagliptin (0.44), Vildagliptin (0.43), Alogliptin (0.42) and Saxagliptin (0.40). Conclusions Based on EVIDEM framework and MCDA, we found that overall value of five DPP-4 inhibitors was similar. It is feasible to use the EVIDEM framework and MCDA in purchasing medicine for Chinese public hospitals.

Eremosparton songoricum (Litv.) Vass. is a rare leafless legume shrub endemic to central Asia which grows on bare sand. It shows extreme drought tolerance and is being developed as a model organism for investigating morphological, physiological, and molecular adaptations to harsh desert environments. APETALA2/Ethylene Responsive Factor (AP2/ERF) is a large plant transcription factor family that plays important roles in plant responses to various biotic and abiotic stresses and has been extensively studied in several plants. However, our knowledge on the AP2/ERF family in legume species is limited, and no respective study was conducted so far on the desert shrubby legume E. songoricum. Here, 153 AP2/ERF genes were identified based on the E. songoricum genome data. EsAP2/ERFs covered AP2 (24 genes), DREB (59 genes), ERF (68 genes), and Soloist (2 genes) subfamilies, and lacked canonical RAV subfamily genes based on the widely used classification method. The DREB and ERF subfamilies were further divided into A1–A6 and B1–B6 groups, respectively. Protein motifs and exon-intron structures of EsAP2/ERFs were also examined, which matched the subfamily/group classification. Cis-acting element analysis suggested that EsAP2/ERF genes shared many stress- and hormone-related cis-regulatory elements. Moreover, the gene numbers and the ratio of each subfamily and the intron-exon structures were systematically compared with other model plants ranging from algae to angiosperms, including ten legumes. Our results supported the view that AP2 and ERF evolved early and already existed in algae, whereas RAV and DREB began to appear in moss species. Almost all plant AP2 and Soloist genes contained introns, whereas most DREB and ERF genes did not. The majority of EsAP2/ERFs were induced by drought stress based on RNA-seq data, EsDREBs were highly induced and had the largest number of differentially expressed genes in response to drought. Eight out of twelve representative EsAP2/ERFs were significantly up-regulated as assessed by RT-qPCR. This study provides detailed insights into the classification, gene structure, motifs, chromosome distribution, and gene expression of AP2/ERF genes in E. songoricum and lays a foundation for better understanding of drought stress tolerance mechanisms in legume plants. Moreover, candidate genes for drought-resistant plant breeding are proposed.

Alterations in gut microbiota might contribute to uremic toxicity and immune dysregulation in patients with end-stage renal disease. Hemodialysis patients are prone to infection and higher mortality following sepsis. The virulence factors in the gut metagenome have not been well studied in hemodialysis patients, which could be employed by microorganisms to successfully thrive and flourish in their hosts. In this study, we performed shotgun metagenomics sequencing on fecal DNA collected from 16 control subjects and 24 hemodialysis patients. Our analysis shows that a number of microbial species, metabolic pathways, antibiotic resistance, and virulence factors were significantly altered in hemodialysis patients compared with controls. In particular, erythromycin resistance methylase, pyridoxamine 5-phosphate oxidase, and streptothricin-acetyl-transferase were significantly increased in hemodialysis patients. The findings in our study laid a valuable foundation to further elucidate the causative role of virulence factors in predisposing HD patients to infection and to develop treatment strategies to reduce the genetic capacities of antibiotic resistance and virulence factors in HD patients.

Dietary modulation of the gut microbiota recently received considerable attention, and ligand activation of aryl hydrocarbon receptor (AHR) plays a pivotal role in intestinal immunity. Importantly, black raspberry (BRB, Rubus occidentalis) is associated with a variety of beneficial health effects. We aim to investigate effects of a BRB-rich diet on dextran sulfate sodium (DSS)-induced intestinal inflammation and to determine whether its consequent anti-inflammatory effects are relevant to modulation of the gut microbiota, especially its production of AHR ligands. A mouse model of DSS-induced intestinal inflammation was used in the present study. C57BL/6J mice were fed either AIN-76A or BRB diet. Composition and functions of the gut microbiota were assessed by 16S rRNA sequencing and comparative metagenome analysis. Metabolic profiles of host and the gut microbiome were assessed by serum and fecal metabolomic profiling and identification. BRB diet was found to ameliorate DSS-induced intestinal inflammation and host metabolic perturbation. BRB diet also protected from DSS-induced perturbation in diversity and composition in the gut microbiota. BRB diet promoted AHR ligand production by the gut microbiota, as revealed by increased levels of fecal AHR activity in addition to increased levels of two known AHR ligands, hemin and biliverdin. Accordingly, enrichment of bacterial genes and pathways responsible for production of hemin and biliverdin were found, specific gut bacteria that are highly correlated with abundances of hemin and biliverdin were also identified. BRB dietary intervention ameliorated intestinal inflammation in mice in association with promotion of AHR ligand production by the gut microbiota.

Perfluorooctanoic acid (PFOA) represents an increasing public health concern due to its persistence in the environment and its toxic effects. The gut microbiota is known to produce various metabolites that assist the host to maintain metabolic homeostasis. However, few studies have explored the effects of PFOA on gut-microbiota-related metabolites. In the present study, male C57BL/6J mice were exposed to 1 ppm of PFOA in drinking water for four weeks and integrative analysis of the gut microbiome and metabolome was performed to reveal the health effects of PFOA. Our results showed that PFOA disturbed both the gut microbiota composition and the metabolic profiles of the feces, serum, and liver in mice. A correlation was found between Lachnospiraceae UCG004, Turicibacter, Ruminococcaceae, and different fecal metabolites. Significant alterations of gut-microbiota-related metabolites were induced by PFOA exposure, including bile acids and tryptophan metabolites such as 3-indoleacrylic acid and 3-indoleacetic acid. The findings of this study are helpful to improve the understanding of the health effects of PFOA, which might be mediated through the gut microbiota and its related metabolites.

The check dam is the most important engineering measure in place for controlling water and preventing soil loss in the gully on the Loess Plateau. This study assesses Jiuyuangou, a typical governance watershed of the Loess Plateau, and studies the influence that the check dam system has on the dynamics of sub-storm floods over different return periods by coupling the one-dimensional hydrodynamic MIKE 11 model with the distributed hydrological MIKE SHE model. This research demonstrates the following: The check dam system significantly reduces a flood’s peak flow and total volume in the basin and also increases the flood duration. The former effects are greater than the latter effect. The flood peak’s rate of reduction, the flood volume’s rate of reduction and the flood duration’s rate of increase all increase linearly as the number of check dams increase. Of all dam systems, the check dam has the best linear response to a flood peak’s rate of reduction. The check dam system reduces the flow rate of flood runoff in the basin. After the dam is built, the average flow rate in the basin decreases by 54%. The runoff velocity of the flood is reduced by different degrees over different return periods and the average peak value decreases compared with a scenario lacking any kind of dam. The check dams have a greater impact on the runoff velocity over a shorter return period, with the velocity being 58.56% slower. Finally, the check dam system significantly reduces the intensity of erosion in the middle and lower reaches of the watershed, and it changes the distribution of the intensity compared to the original channel runoff. These findings are expected to provide a scientific basis for guiding the construction and high-quality development of check dams on the Loess Plateau. In addition, check dam construction in basins can trap water, sediment and nutrients, and it can also contribute to ecosystem diversity and maintaining ecosystem imbalances around the world.

Marginal abatement cost (MAC) plays an essential role in pricing pollutants and guiding environmental policies. Considering the heavy polluting nature of China’s coal power industry, this paper aims at providing companies and policymakers with more comprehensive information on the cost of abatement by estimating the MACs of CO2 and SO2 for coal-fired power plants (CFPPs) in China. This study contributes to the literature by considering an interconnected two-stage production system to investigate. The estimation framework is advanced in combining the electricity production and pollution abatement process of CFPPs into a convex quantile regression (CQR) model. The results show that the averages of MAC for CO2 and SO2 are estimated to be 367.56 Yuan/ton and 662.30 Yuan/ton, respectively, indicating that the reduction of such emissions is still costly. The heterogeneous analysis then indicates that large CFPPs, central-government-owned power plants (CGOPPs), and low-regulated CFPPs tend to possess lower MACs for CO2. Regarding SO2, large and medium-sized power plants show significantly larger MACs than small plants. In addition, the MACs of SO2 for CGOPPs and high-regulated CFPPs are more concentrated at high levels. In the second part, the Tobit regression analysis was used to discuss the determinants of MACs for CO2 and SO2. Factors like carbon emission intensity, load, and operating hours can notably decrease MACs for CO2, while MACs for SO2 tend to be positively affected by the total abatement cost and the abatement rate of the FGD equipment. In addition, the MACs for the large CFPPs, CGOPPs, and high-regulated CFPPs are more likely to be affected by the selected influence factors. Based on these results, we conclude with some policy recommendations.

The post-transcriptional regulation of gene expression, in particular alternative splicing (AS) events, substantially contributes to the complexity of eukaryotic transcriptomes and proteomes [...]

Abstract Background Valsa canker is a serious disease in the stem of Malus sieversii, caused by Valsa mali. However, little is known about the global response mechanism in M. sieversii to V. mali infection. Results Phytohormone jasmonic acid (JA) and salicylic acid (SA) profiles and transcriptome analysis were used to elaborate on the dynamic response mechanism. We determined that the JA was initially produced to respond to the necrotrophic pathogen V. mali infection at the early response stage, then get synergistically transduced with SA to respond at the late response stage. Furthermore, we adopted Pacific Biosciences (PacBio) full-length sequencing to identify differentially expressed transcripts (DETs) during the canker response stage. We obtained 52,538 full-length transcripts, of which 8139 were DETs. Total 1336 lncRNAs, 23,737 alternative polyadenylation (APA) sites and 3780 putative transcription factors (TFs) were identified. Additionally, functional annotation analysis of DETs indicated that the wild apple response to the infection of V. mali involves plant-pathogen interaction, plant hormone signal transduction, flavonoid biosynthesis, and phenylpropanoid biosynthesis. The co-expression network of the differentially expressed TFs revealed 264 candidate TF transcripts. Among these candidates, the WRKY family was the most abundant. The MsWRKY7 and MsWRKY33 were highly correlated at the early response stage, and MsWRKY6, MsWRKY7, MsWRKY19, MsWRKY33, MsWRKY40, MsWRKY45, MsWRKY51, MsWRKY61, MsWRKY75 were highly correlated at the late stage. Conclusions The full-length transcriptomic analysis revealed a series of immune responsive events in M. sieversii in response to V. mali infection. The phytohormone signal pathway regulatory played an important role in the response stage. Additionally, the enriched disease resistance pathways and differentially expressed TFs dynamics collectively contributed to the immune response. This study provides valuable insights into a dynamic response in M. sieversii upon the necrotrophic pathogen V. mali infection, facilitates understanding of response mechanisms to canker disease for apple, and provides supports in the identification of potential resistance genes in M. sieversii.

Background & Aims: Fucosyltransferase 2 (Fut2)-mediated intestinal α1- 2-fucosylation is important for host–microbe interactions and has been associated with several diseases, but its role in obesity and hepatic steatohepatitis is not known. The aim of this study was to investigate the role of Fut2 in a Western-style diet–induced mouse model of obesity and steatohepatitis. Methods: Wild-type (WT) and Fut2-deficient littermate mice were used and features of the metabolic syndrome and steatohepatitis were assessed after 20 weeks of Western diet feeding. Results: Intestinal α1-2-fucosylation was suppressed in WT mice after Western diet feeding, and supplementation of α1-2-fucosylated glycans exacerbated obesity and steatohepatitis in these mice. Fut2-deficient mice were protected from Western diet–induced features of obesity and steatohepatitis despite an increased caloric intake. These mice have increased energy expenditure and thermogenesis, as evidenced by a higher core body temperature. Protection from obesity and steatohepatitis associated with Fut2 deficiency is transmissible to WT mice via microbiota exchange; phenotypic differences between Western diet–fed WT and Fut2-deficient mice were reduced with antibiotic treatment. Fut2 deficiency attenuated diet-induced bile acid accumulation by altered relative abundance of bacterial enzyme 7-α-hydroxysteroid dehydrogenases metabolizing bile acids and by increased fecal excretion of secondary bile acids. This also was associated with increased intestinal farnesoid X receptor/fibroblast growth factor 15 signaling, which inhibits hepatic synthesis of bile acids. Dietary supplementation of α1-2-fucosylated glycans abrogates the protective effects of Fut2 deficiency. Conclusions: α1-2-fucosylation is an important host-derived regulator of intestinal microbiota and plays an important role for the pathogenesis of obesity and steatohepatitis in mice.

Abstract Background Autophagy is an evolutionarily conserved system for the degradation of intracellular components in eukaryotic organisms. Autophagy plays essential roles in preventing premature senescence and extending the longevity of vascular plants. However, the mechanisms and physiological roles of autophagy in preventing senescence in basal land plants are still obscure. Results Here, we investigated the functional roles of the autophagy-related gene PpATG3 from Physcomitrella patens and demonstrated that its deletion prevents autophagy. In addition, Ppatg3 mutant showed premature gametophore senescence and reduced protonema formation compared to wild-type (WT) plants under normal growth conditions. The abundance of nitrogen (N) but not carbon (C) differed significantly between Ppatg3 mutant and WT plants, as did relative fatty acid levels. In vivo protein localization indicated that PpATG3 localizes to the cytoplasm, and in vitro Y2H assays confirmed that PpATG3 interacts with PpATG7 and PpATG12. Plastoglobuli (PGs) accumulated in Ppatg3, indicating that the process that degrades damaged chloroplasts in senescent gametophore cells was impaired in this mutant. RNA-Seq uncovered a detailed, comprehensive set of regulatory pathways that were affected by the autophagy mutation. Conclusions The autophagy-related gene PpATG3 is essential for autophagosome formation in P. patens. Our findings provide evidence that autophagy functions in N utilization, fatty acid metabolism and damaged chloroplast degradation under non-stress conditions. We identified differentially expressed genes in Ppatg3 involved in numerous biosynthetic and metabolic pathways, such as chlorophyll biosynthesis, lipid metabolism, reactive oxygen species removal and the recycling of unnecessary proteins that might have led to the premature senescence of this mutant due to defective autophagy. Our study provides new insights into the role of autophagy in preventing senescence to increase longevity in basal land plants.

Alcohol‐related liver disease is a major public health burden, and the gut microbiota is an important contributor to disease pathogenesis. The aim of the present study is to characterize functional alterations of the gut microbiota and test their performance for short‐term mortality prediction in patients with alcoholic hepatitis. We integrated shotgun metagenomics with untargeted metabolomics to investigate functional alterations of the gut microbiota and host co‐metabolism in a multicenter cohort of patients with alcoholic hepatitis. Profound changes were found in the gut microbial composition, functional metagenome, serum, and fecal metabolomes in patients with alcoholic hepatitis compared with nonalcoholic controls. We demonstrate that in comparison with single omics alone, the performance to predict 30‐day mortality was improved when combining microbial pathways with respective serum metabolites in patients with alcoholic hepatitis. The area under the receiver operating curve was higher than 0.85 for the tryptophan, isoleucine, and methionine pathways as predictors for 30‐day mortality, but achieved 0.989 for using the urea cycle pathway in combination with serum urea, with a bias‐corrected prediction error of 0.083 when using leave‐one‐out cross validation. Conclusion: Our study reveals changes in key microbial metabolic pathways associated with disease severity that predict short‐term mortality in our cohort of patients with alcoholic hepatitis.

Abstract Background Auxin response factors (ARFs) have long been a research focus and represent a class of key regulators of plant growth and development. Integrated phylogenomic synteny network analyses were able to provide novel insights into the evolution of the ARF gene family. Results Here, more than 3500 ARFs collected from plant genomes and transcriptomes covering major streptophyte lineages were used to reconstruct the broad-scale family phylogeny, where the early origin and diversification of ARF in charophytes was delineated. Based on the family phylogeny, we proposed a unified six-group classification system for angiosperm ARFs. Phylogenomic synteny network analyses revealed the deeply conserved genomic syntenies within each of the six ARF groups and the interlocking syntenic relationships connecting distinct groups. Recurrent duplication events, such as those that occurred in seed plants, angiosperms, core eudicots and grasses contributed to the expansion of ARF genes which facilitated functional diversification. Ancestral transposition activities in important plant families, including crucifers, legumes and grasses, were unveiled by synteny network analyses. Ancestral gene duplications along with transpositions have profound evolutionary significance which may have accelerated the functional diversification process of paralogues. Conclusions The broad-scale family phylogeny in combination with the state-of-art phylogenomic synteny network analyses not only allowed us to infer the evolutionary trajectory of ARF genes across distinct plant lineages, but also facilitated to generate a more robust classification regime for this transcription factor family. Our study provides insights into the evolution of ARFs which will enhance our current understanding of this important transcription factor family.

Mounting evidence has linked berries to a variety of health benefits. We previously reported that administration of a diet rich in black raspberries (BRBs) impacted arsenic (As) biotransformation and reduced As-induced oxidative stress. To further characterize the role of the gut microbiota in BRB-mediated As toxicity, we utilized the dietary intervention of BRBs combined with a mouse model to demonstrate microbial changes by examining associated alterations in the gut microbiota, especially its functional metabolites. Results showed that BRB consumption changed As-induced gut microbial alterations through restoring and modifying the gut microbiome, including its composition, functions and metabolites. A number of functional metabolites in addition to bacterial genera were significantly altered, which may be linked to the effects of BRBs on arsenic exposure. Results of the present study suggest functional interactions between dietary administration of black raspberries and As exposure through the lens of the gut microbiota, and modulation of the gut microbiota and its functional metabolites could contribute to effects of administration of BRBs on As toxicity.

Alcohol-associated liver disease is a major public health concern globally. Alterations of steroid hormones and gut microbiota were both found in patients with alcohol-associated liver disease. However, their correlation has not been well characterized in these patients. In this study, we measured the level of 30 steroid hormones in serum and fecal samples collected from non-alcoholic controls, patients with alcohol use disorder, and patients with alcohol-associated hepatitis. The profile of serum and fecal steroid hormones was quite different in patients with alcohol-associated hepatitis from that in patients with alcohol use disorder and control subjects. Stronger alterations were observed in male patients than in females. Correlations were found not only between serum steroids and gut bacteria but also between serum steroids and gut fungi. These correlations need to be taken into consideration during the development of treatment strategies for alcohol-associated liver disease.

Enhanced cholesterol biosynthesis is associated with cancer progression. Here the authors identify the nuclear receptor RORγ as a novel master regulator of cholesterol metabolism in triple negative breast cancer (TNBC) and find that RORγ small-molecule antagonists induce tumor regression in patient-derived xenografts and immunocompetent mouse models.

Short bowel syndrome (SBS) is a major cause of intestinal failure (IF) that may require long-term parenteral nutrition (PN) support. However, long-term PN is accompanied by severe complications such as catheter-related blood stream infection (CRBSI) and intestinal failure-associated liver disease (IFALD), and it is associated with high healthcare costs. In this study, we characterized the plasma metabolomic profile and investigated the role of metabolism in predicting long-term PN in pediatric patients with SBS. Untargeted metabolomics was performed in plasma samples from 20 SBS patients with PN support: 6 patients had IFALD and 14 patients had no liver disease. As controls, 18 subjects without liver or intestinal diseases were included for the analysis. SBS patients had distinct plasma metabolomic signatures compared to controls, and several pathways associated with amino acid metabolism and cell death were significantly changed. The presence of IFALD in SBS was associated with alterations of metabolites mainly classified as “amino acids, peptides, and analogues” and “benzene and derivatives”. Serum direct bilirubin levels were negatively correlated with levels of uridine, skatole, and glabrol. Importantly, SBS patients with long-term PN showed significantly increased levels of glutamine compared to those in the short-term PN group. Finally, using multivariate logistic regression analysis, we developed a prediction model including glutamine and creatinine to identify pediatric SBS patients who need long-term PN support. These findings underscore the potential key role of the metabolome in SBS with IF and suggest that metabolomic profiles could be used in long-term PN assessment.

Environmental microbial diversity is often investigated from a molecular perspective using 16S ribosomal RNA (rRNA) gene amplicons and shotgun metagenomics. While amplicon methods are fast, low-cost, and have curated reference databases, they can suffer from amplification bias and are limited in genomic scope. In contrast, shotgun metagenomic methods sample more genomic regions with fewer sequence acquisition biases, but are much more expensive (even with moderate sequencing depth) and computationally challenging. Here, we develop a set of 16S rRNA sequence capture baits that offer a potential middle ground with the advantages from both approaches for investigating microbial communities. These baits cover the diversity of all 16S rRNA sequences available in the Greengenes (v. 13.5) database, with no sequence having 400-fold) and decrease analysis time to obtain consistent community assessments. Furthermore, our study reveals that bioinformatic methods used to analyze sequencing data may have a greater influence on estimates of community composition than library preparation method used, likely due in part to the extent and curation of the reference databases considered. Thus, enriching existing aliquots of shotgun metagenomic libraries and obtaining modest numbers of reads from them offers an efficient orthogonal method for assessment of bacterial community composition.

IntroductionHIV testing is an important strategy for controlling and ultimately ending the global pandemic. Oral rapid HIV testing (ORHT) is an evidence-based strategy and the evidence-based shows is favored over traditional blood tests in many key populations. The dental setting has been found to be a trusted, convenient, and yet untapped venue to conduct ORHT. This study assessed the HIV testing behaviors and willingness to receive ORHT among dental patients in Xi'an, China.MethodsA cross-sectional survey of dental patients from Xi'an was conducted from August to September 2017. Dental patients were recruited using a stratified cluster sampling. A 44-item survey was used to measure HIV/AIDS knowledge, HIV testing behaviors, and willingness to receive ORHT.ResultsNine hundred and nine dental patients completed the survey with a mean HIV/AIDS knowledge score of 10.7/15 (SD 2.8). Eighty-four participants (9.2%) had previously received an HIV test. Participants would have a high rate of HIV testing if they had higher monthly income (OR = 1.982, 95% CI: 1.251-3.140) and a higher HIV/AIDS knowledge score (OR = 1.137, 95% CI: 1.032-1.252). Five hundred and eighty-two participants (64.0%) were willing to receive ORHT before a dental treatment, 198 (21.8%) were not sure, and 129 (14.2%) were unwilling. Logistic regression showed that age (OR = 0.970, 95% CI: 0.959-0.982), HIV/AIDS knowledge score (OR = 1.087, 95% CI: 1.031-1.145), previous HIV test (OR = 2.057, 95% CI: 1.136-3.723), having advanced HIV testing knowledge (OR = 1.570, 95% CI: 1.158-2.128), and having advanced ORHT knowledge (OR = 2.074, 95%: CI 1.469-2.928) were the factors affecting the willingness to receive ORHT.ConclusionsThe majority of dental patients had not previously received an HIV test, although many were receptive to being tested in the dental setting. The dental setting as a venue to screen people for HIV needs further exploration, particularly because many people do not associate dentistry with chairside screenings. Increasing awareness of ORHT and reducing testing price can further improve the patient's willingness to receive ORHT.

The accurate determination of blast-induced ground vibration has an important significance in protecting human activities and the surrounding environment. For evaluating the peak particle velocity resulting from the quarry blast, a robust artificial intelligence system combined with the salp swarm algorithm (SSA) and Gaussian process (GP) was proposed, and the SSA was used to find the optimal hyperparameters of the GP here. In this regard, 88 datasets with 9 variables including the ratio of bench height to burden (H/B) and the ratio of spacing to burden (S/B) were selected as the input variables, while peak particle velocity (PPV) was measured. Then, an ANN model, an SVR model, a GP model, an SSA-GP model, and three empirical models were established, and the predictive performance was evaluated by using the root-mean-square error (RMSE), determination coefficient (R2), value account for (VAF), Akaike Information Criterion (AIC), Schwarz Bayesian Criterion (SBC), and the run time. After comparing, it is found that the proposed SSA-GP yielded a superior performance and the ratio of bench height to burden (H/B) was the most sensitive variable.

Alcohol-related liver disease is a public health care burden globally. Only 10–20% of patients with alcohol use disorder have progressive liver disease. This study aimed to identify lipid biomarkers for the early identification of progressive alcohol-related liver disease, which is a key step for early intervention. We performed untargeted lipidomics analysis in serum and fecal samples for a cohort of 49 subjects, including 17 non-alcoholic controls, 16 patients with non-progressive alcohol-related liver disease, and 16 patients with progressive alcohol-related liver disease. The serum and fecal lipidome profiles in the two patient groups were different from that in the controls. Nine lipid biomarkers were identified that were significantly different between patients with progressive liver disease and patients with non-progressive liver disease in both serum and fecal samples. We further built a random forest model to predict progressive alcohol-related liver disease using nine lipid biomarkers. Fecal lipids performed better (Area Under the Curve, AUC = 0.90) than serum lipids (AUC = 0.79). The lipid biomarkers identified are promising candidates for the early identification of progressive alcohol-related liver disease.

Background Animal data suggest a role of the gut-liver axis in progression of alcoholic liver disease (ALD), but human data are scarce especially for early disease stages. Methods We included patients with alcohol use disorder (AUD) who follow a rehabilitation program and matched healthy controls. We determined intestinal epithelial and vascular permeability (IP) (using urinary excretion of 51Cr-EDTA, fecal albumin content, and immunohistochemistry in distal duodenal biopsies), epithelial damage (histology, serum iFABP, and intestinal gene expression), and microbial translocation (Gram – and Gram + serum markers by ELISA). Duodenal mucosa-associated microbiota and fecal microbiota were analyzed by 16 S rRNA sequencing. ALD was staged by Fibroscan® (liver stiffness, controlled attenuation parameter) in combination with serum AST, ALT, and CK18-M65. Results Only a subset of AUD patients had increased 51Cr-EDTA and fecal albumin together with disrupted tight junctions and vasculature expression of plasmalemma Vesicle-Associated Protein-1. The so-defined increased intestinal permeability was not related to changes of the duodenal microbiota or alterations of the intestinal epithelium but associated with compositional changes of the fecal microbiota. Leaky gut alone did not explain increased microbial translocation in AUD patients. By contrast, duodenal dysbiosis with a dominance shift toward specific potential pathogenic bacteria genera (Streptococcus, Shuttleworthia, Rothia), increased IP and elevated markers of microbial translocation characterized AUD patients with progressive ALD (steato-hepatitis, steato-fibrosis). Conclusion Progressive ALD already at early disease stages is associated with duodenal mucosa-associated dysbiosis and elevated microbial translocation. Surprisingly, such modifications were not linked with increased IP. Rather, increased IP appears related to fecal microbiota dysbiosis.

Background and Aims Alcoholic hepatitis is the most severe form of alcohol-related liver disease. While the gut microbiome is known to play a role in disease development and progression, less is known about specific compositional changes of the gut bacterial microbiome associated with disease severity. Therefore, the aim of our study was to correlate gut microbiota features with disease severity in alcoholic hepatitis patients. Methods We used 16S rRNA gene sequencing on fecal samples from 74 alcoholic hepatitis patients, which were enrolled at 9 centers in Europe, the United States, and Mexico in a multi-center observational study. The relative abundance of gut bacterial taxa on genus level, as well as the microbiome diversity, was correlated to various clinical, laboratory, and histologic parameters. Results We observed a negative correlation between the model for end-stage liver disease score and Shannon diversity, independent of potentially confounding factors (Padjust = 0.046). Alcoholic hepatitis patients with more severe disease had significantly decreased relative abundances of Akkermansia while the relative abundance of Veillonella was increased. We observed a reduction in the Bacteroides abundance (Padjust = 0.048) and Shannon diversity (Padjust = 0.018) in antibiotic-treated patients and patients receiving steroids had an increase in Veillonella abundance (Padjust = 0.005), which was both independent of potentially confounding factors. Conclusion We observed distinct changes in the gut bacterial microbiome of alcoholic hepatitis patients with more severe disease. The gut bacterial microbiome might be an attractive target to prevent and treat this deadly disease.