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Abstract Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations.

Abstract Background The Cumberland Ankle Instability Tool (CAIT) is used to screen patients with chronic ankle instability (CAI) and to quantify the severity of ankle instability. Neuromuscular deficits are common in CAI, including proprioception, strength, and balance issues. The relationship between CAIT scores and neuromuscular factors is unclear. The purpose of this study was to investigate the correlation between ankle instability and ankle muscle strength, proprioception, and dynamic balance. Methods Thirty-four individuals with chronic ankle instability were included in this study. The participants’ CAIT scores, muscle strength (isokinetic) and proprioception in plantarflexion (PF), dorsiflexion (DF), inversion (IV), and eversion (EV), and dynamic balance (Star Excursion Balance Test in anterior, posteromedial, and posterolateral directions) were assessed. Bivariate correlations were used to determine the relationship between CAIT scores and ankle muscle strength, proprioception, and dynamic balance. Results In terms of muscle strength, ankle PF (r = 0.378, 95%CI: 0.046–0.635, P = 0.027) and IV (r = 0.527, 95%CI: 0.233–0.736, P = 0.001) strength were positively correlated with CAIT Score, whereas ankle DF and EV strength had no significant correlation with CAIT Score. In terms of proprioception, ankle IV proprioception (r = -0.340, 95%CI: -0.608–0.002, P = 0.027) was negatively correlated with CAIT Score, while ankle PF, DF, and EV proprioception had no significant correlation with CAIT Score. In terms of dynamic balance, the SEBT posteromedial (r = 0.444, 95%CI: 0.124–0.680, P = 0.001) was positively correlated with CAIT Score. The SEBT anterior and posterolateral were not significantly correlated with the CAIT Score. Conclusion This study found that increasing ankle plantarflexion and inversion muscle strength, improving dynamic balance in the posteromedial direction, and decreasing ankle inversion proprioceptive thresholds may help improve the subjective stability of CAI. This provides data support for targeted ankle neuromuscular function rehabilitation training for patients. Trial registration Chinese Clinical Trial Registry ChiCTR2100044089. Registered on 10 March 2021.

Abstract The role of circulating metabolome in cognitive impairment is inconclusive, and whether the associations are in the severity-dependent manner remains unclear. We aimed to identify plasma metabolites associated with cognitive impairment and evaluate the added predictive capacity of metabolite biomarkers on incident cognitive impairment beyond traditional risk factors. In the Rugao Longevity and Ageing Study (RuLAS), plasma metabolome was profiled by nuclear magnetic resonance spectroscopy. Participants were classified into the cognitively normal, moderately impaired, and severely impaired groups according to their performance in two objective cognitive tests. A two-step strategy of cross-sectional discovery followed by prospective validation was applied. In the discovery stage, we included 1643 participants (age: 78.9 ± 4.5 years) and conducted multinomial logistic regression. In the validation stage, we matched 68 incident cases of cognitive impairment (moderately-to-severely impaired) during the 2-year follow-up with 204 cognitively normal controls by age and sex at a 1:3 ratio, and conducted conditional logistic regression. We identified 28 out of 78 metabolites cross-sectionally related to severely impaired cognition, among which IDL particle number, ApoB in IDL, leucine, and valine were prospectively associated with 28%, 28%, 29%, and 33% lower risk of developing cognitive impairment, respectively. Incorporating 13 metabolite biomarkers selected through Lasso regression into the traditional risk factors-based prediction model substantially improved the ability to predict incident cognitive impairment (AUROC: 0.839 vs. 0.703, P

Introduction: Previous lipidomics studies have identified various lipid predictors for cardiovascular risk, however, with limited predictive increment, sometimes using too many predictor variables at the expense of practical efficiency. Objectives: To search for lipid predictors of future coronary heart disease (CHD) with stronger predictive power and efficiency to guide primary intervention. Methods: We conducted a prospective nested case-control study involving 1,621 incident CHD cases and 1:1 matched controls. Lipid profiling of 161 lipid species for baseline fasting plasma was performed by liquid chromatography-mass spectrometry. Results: In search of CHD predictors, seven lipids were selected by elastic-net regression during over 90% of 1000 cross-validation repetitions, and the derived composite lipid score showed an adjusted odds ratio of 3.75 (95% confidence interval: 3.15, 4.46) per standard deviation increase. Addition of the lipid score into traditional risk model increased c-statistic to 0.736 by an increment of 0.077 (0.063, 0.092). From the seven lipids, we found mediation of CHD risk from baseline diabetes through sphingomyelin (SM) 41:1b with a considerable mediation proportion of 36.97% (P

Abstract Identifying tropical cyclone (TC) signatures in paleoclimate records enhances our understanding of long-term TC activity trends and the climatic factors influencing TC evolution. Stalagmites are considered promising archives for recording TC activity. However, despite the western North Pacific being the most TC-active ocean basin globally, it lacks stalagmite-based TC reconstructions. Here, we present a seasonally resolved stalagmite δ18O record from XRY cave in Southeast China, covering the period from 1951 to 2018 CE, to identify annual signals of strong TC activity. We propose that the minimum seasonal XRY δ18O value of each year can reconstruct regional TC activity, achieving an identification rate of 86% for strong TC years in study area. This demonstrates the feasibility of using stalagmites for TC reconstruction in Southeast China. Moreover, our research shows that inland stalagmites can still capture TC activity signals, which will promote the use of stalagmites in obtaining long-term records of post-landfall TC activity and inland impacts.

Background Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid‐lowering therapy. Methods and Results We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid‐lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2‐sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow‐up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low‐density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low‐density lipoprotein cholesterol marker. In large high‐density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score–based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018–1.295]) independent of demographic factors, medication use, and disease status. Conclusions Our findings highlight the potential of nuclear magnetic resonance–based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.

Abstract Background The relationship between circulating bile acids (BAs) and kidney function among patients with type 2 diabetes is unclear. We aimed to investigate the associations of circulating concentrations of BAs, particularly individual BA subtypes, with chronic kidney disease (CKD) in patients of newly diagnosed type 2 diabetes. Methods In this cross-sectional study, we included 1234 newly diagnosed type 2 diabetes who participated in an ongoing prospective study, the Dongfeng-Tongji cohort. Circulating primary and secondary unconjugated BAs and their taurine- or glycine-conjugates were measured using ultraperformance liquid chromatography-tandem mass spectrometry. CKD was defined as eGFR

Acylcarnitines are metabolic intermediates of fatty acids and branched-chain amino acids having vital biofunctions and pathophysiological significances. Here, we developed a high-throughput method for quantifying hundreds of acylcarnitines in one run using ultrahigh performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). This enabled simultaneous quantification of 1136 acylcarnitines (C0–C26) within 10-min with good sensitivity (limit of detection 0.992), accuracy (relative error < 20%), precision (coefficient of variation (CV), CV 0.998) for predicting retention time (tR) of acylcarnitines with no standards and built a database of their multiple reaction monitoring parameters (tR, ion-pairs, and collision energy). Furthermore, we quantified 514 acylcarnitines in human plasma and urine, mouse kidney, liver, heart, lung, and muscle. This provides a rapid method for quantifying acylcarnitines in multiple biological matrices.

Bile acids are the main body of enterohepatic circulation in vivo. They have essential functions such as emulsifying fat, bacteriostasis and regulating multiple metabolic pathways as signal molecules. However, the assignments of NMR signals for some low-concentration bile acids are still needed. This study combined 1D nuclear magnetic resonance (NMR) and 2D NMR techniques including 1H–1H correlation spectroscopy (COSY), 1H–1H total correlation spectroscopy (TOCSY), 1H J-resolved spectroscopy (J-Res), 1H–13C heteronuclear single quantum coherence spectroscopy (HSQC), and 1H–13C heteronuclear multiple bond correlation spectroscopy (HMBC) to assign the 1H and 13C signals of six bile acids in aqueous solution at physiological pH (∼7.4) and nine bile acids in methanol. These data are of importance to the NMR-based studies on lipid digestion, absorption, and metabolism.

ContextEstrogen receptor α (ERα) is a key regulator of reproductive function, particularly in ovarian development and function, yet the specifics of its role at the molecular level remain unclear.AimsThe study aims to elucidate the molecular mechanisms of ERα-regulated transcriptional dynamics in ovarian cells using ERα knockout (αERKO) mice created via CRISPR/Cas9.MethodsSingle-cell RNA sequencing (scRNA-seq) was used to compare transcriptomes from individual ovarian cells in both wild type and αERKO mice. Bioinformatics analyses identified distinct cell populations and their transcriptional profiles post ERα deletion.Key resultsDistinct oocyte and granulosa cell populations were identified, with ERα deletion disrupting the regulation of genes linked to ovarian infertility, the ovulation cycle, and steroidogenesis. Greb1 expression in granulosa cells was found to be ERα-dependent.ConclusionsERα deletion significantly alters the transcriptional landscape of ovarian cells, affecting genes and pathways central to ovarian function and the ovulation process.ImplicationsThe findings provide an in-depth, single-cell view of ERα's role in the reproductive system, offering insights that may lead to novel treatments for ovarian disorders.

The extra copy of the methyl-CpG-binding protein 2 (MeCp2) gene causes MeCP2 duplication syndrome (MDS), a neurodevelopmental disorder characterized by intellectual disability and autistic phenotypes. However, the disturbed microbiome and metabolic profiling underlying the autistic-like behavioral deficits of MDS are rarely investigated. Here we aimed to understand the contributions of microbiome disruption and associated metabolic alterations, especially the disturbed neurotransmitters in MDS employing a transgenic mouse model with MeCP2 overexpression. We analyzed metabolic profiles of plasma, urine, and cecum content and microbiome profiles by both 16 s RNA and shotgun metagenomics sequence technology. We found the decreased levels of Firmicutes and increased levels of Bacteroides in the single MeCP2 gene mutation autism-like mouse model, demonstrating the importance of the host genome in a selection of microbiome, leading to the heterogeneity characteristics of microbiome in MDS. Furthermore, the changed levels of several neurotransmitters (such as dopamine, taurine, and glutamate) implied the excitatory-inhibitory imbalance caused by the single gene mutation. Concurrently, a range of microbial metabolisms of aromatic amino acids (such as tryptophan and phenylalanine) were identified in different biological matrices obtained from MeCP2 transgenic mice. Our investigation revealed the importance of genetic variation in accounting for the differences in microbiomes and confirmed the bidirectional regulatory axis of microbiota-gut-brain in studying the role of microbiome on MDS, which could be useful in deeply understanding the microbiome-based treatment in this autistic-like disease.

Abstract Triple-negative breast cancers (TNBC) frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. However, less than 15% of TNBC patients were found to carry BRCA1 mutation, indicating that there are other mechanisms regulating BRCA1-deficient in TNBC. In the current study, we shown that overexpression of TRIM47 correlates with progression and poor prognosis in triple-negative breast cancer. Moreover, we demonstrated that TRIM47 directly interacts with BRCA1 and induces ubiquitin-ligase-mediated proteasome turnover of BRCA1, subsequently leads to a decrease of BRCA1 protein levels in TNBC. Moreover, the downstream gene expression of BRCA1, such as p53, p27, p21 was significantly reduced in the overexpression of TRIM47 cell lines but increased in TRIM47-deleted cells. Functionally, we found that overexpression of TRIM47 in TNBC cells confers an exquisite sensitivity to olaparib, an inhibitor of poly-(ADP-ribose)-polymerase (PARP), but TRIM47 inhibition significantly confers TNBC cells resistance to olaparib both in vitro and in vivo. Furthermore, we showed that overexpression of BRCA1 significant increase the olaparib resistance in TRIM47-overexpression-induced PARP inhibitions sensitivity. Taken together, our results uncover a novel mechanism for BRCA1-deficient in TNBC and targeting TRIM47/BRCA1 axis may be a promising prognostic factor and a valuable therapeutic target for TNBC.

Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid and cholesterol metabolism is linked together with type I interferon (IFN‐I) signaling in the regulation of the pathogenesis of SLE. Here, a metabonomic analysis is performed and increased plasma concentrations of oxysterols, especially 7α, 25‐dihydroxycholesterol (7α, 25‐OHC), are identified in SLE patients. The authors find that 7α, 25‐OHC binding to its receptor Epstein–Barr virus‐induced gene 2 (EBI2) in macrophages can suppress STAT activation and the production of IFN‐β, chemokines, and cytokines. Importantly, monocytes/macrophages from SLE patients and mice show significantly reduced EBI2 expression, which can be triggered by IFN‐γ produced in activated T cells. Previous findings suggest that EBI2 enhances immune cell migration. Opposite to this effect, the authors demonstrate that EBI2‐deficient macrophages produce higher levels of chemokines and cytokines, which recruits and activates myeloid cells,T and B lymphocytes to exacerbate tetramethylpentadecane‐induced SLE. Together, via sensing the oxysterol 7α, 25‐OHC, EBI2 in macrophages can modulate innate and adaptive immune responses, which may be used as a potential diagnostic marker and therapeutic target for SLE.

Glycerol dialkyl glycerol tetraethers (GDGTs), which are derived from microbial membranes, occur widely in soils, peats, lake sediments, marine sediments, hot springs, and other environments. GDGTs respond sensitively to environmental changes and have become an important tool in paleoenvironmental reconstruction. However, their application in speleothems, one of the most important archives of the study of past climates, has been quite limited. In this paper, we review the recent progress in the study of GDGTs in speleothems, from their sources to their distribution characteristics and paleoenvironmental applications. GDGTs in speleothems have been shown to come from dripping water, and cave systems. The distribution of GDGTs in speleothems shows that archaeal isoprenoid GDGTs (isoGDGTs) dominate over bacterial branched GDGTs (brGDGTs). The proxies based on isoGDGTs (TEX86) and brGDGTs (MBT/CBT) are correlated with temperature, which may offer promising potential methods for reconstructing terrestrial palaeotemperature. Ultimately, we discuss the difficulties and problems to be solved in studying speleothem GDGTs and the possible future directions for this field.

Purpose: This study aimed to investigate the lower limb inter-joint coordination and variability during Tai Chi movements compared with normal walking in older adults.Methods: A total of 30 female Tai Chi practitioners (70.9 ± 5.2 years) were recruited in this study. Herein, each participant performed three trials of the normal walking and Tai Chi movements. The lower limb kinematics data were collected with Vicon 3D motion capture system. The continuous relative phase (CRP) includes both spatial and temporal information of two adjacent joints, which was calculated to assess the inter-joint coordination of lower limbs. Coordination amplitude and coordination variability were assessed with mean absolute relative phase (MARP) and deviation phase (DP). MANOVOA was used to analyze inter-joint coordination parameters between different movements.Results: The CRP values of hip-knee and knee-ankle segments in the sagittal plane of the Tai Chi movements changed frequently. The MARP values of the hip-knee (p < 0.001) and knee-ankle segments (p = 0.032) as well as the DP values of the hip-knee segment (p < 0.001) were significantly lower in Tai Chi than in normal walking.Conclusion: More consistent and stable inter-joint coordination patterns of Tai Chi movements found in this study may be one of the critical factors that Tai Chi could be a suitable coordinated exercise for older adults.

Paraquat is a cost-effective herbicide, widely used in many countries, that can induce severe oxidative stress in photosynthetic tissues. Studying plant herbicide resistance or antioxidant stress mechanisms requires determining the cellular paraquat level when plants are treated by paraquat. The traditional isotopic labeling method has the potential risk to cause problems to both human health and the environment. For radioisotope manipulation, special operation spaces and strict environmental inspection are also required. In addition, the radiolabeled paraquat is increasingly hard to buy due to the extended production cycle. Here, we describe a nonradioactive method to determine the paraquat level in a small number of Arabidopsis tissues or protoplasts, using a high resolution ultra-high-performance liquid chromatography (UHPLC)-mass spectrometry (MS)/MS method. This method is highly selective and sensitive, and more environmentally compatible and technically feasible than the isotope detection method.

Background: Cryopreservation of ovarian tissue is a promising method for preserving fertility. Transmission electron microscopy (TEM) is an evaluation system for cryo-injury during the cooling and warming process which is very laborious and needs to be optimized. Objective: In this study, we evaluated that serum 17β-oestradiol (E2) may be used as an indicator of vitrified ovarian tissue. Methods: Immunodeficient nude mice were used as hosts for xenografting of vitrified-warmed human ovarian tissues. A total of 54 mice were divided into two group: vitrified ovarian xenotransplant (VOX) group (n ​= ​45) and non-transplant control group (n ​= ​9). The transplanted mice were grouped into vitrified/warmed grafted-4 weeks (VOX-4w, n ​= ​15), vitrified/warmed grafted-6weeks (VOX-6w n ​= ​15) and vitrified/warmed grafted-12 weeks (VOX-12w n ​= ​15) according to the time after transplantation.The viable and functional recovery of grafted ovarian tissue was assessed by light microscopy, transmission electron microscopy, and hormone (E2) assays. Results: Serum E2 concentration was significantly higher in VOX-6w (group (21.07 ​pg/ml) than that of VOX-12w group (15.59 ​pg/ml). VOX-12w group showed a lower value (12.61 ​pg/ml) for E2 concentration. The trend for E2 concentration was consistent with the morphological identification of the grafts. Conclusion: In vivo serum hormone E2 released by cortical biopsies can be used as a functional marker for xenotransplanted vitrified-warmed human ovarian tissue reserve.

Abstract Background Ankle instability limits physical activities and undermines a person’s quality of life. Tai Chi’s health benefits have been reported in different population groups. However, the effects of Tai Chi on neuromuscular function among young adults with functional ankle instability (FAI) remain unclear. Therefore, we aim to investigate the effect of Tai Chi on young adults with FAI. Methods This study will be conducted as a randomized controlled trial with blinded assessors. A total of 104 young adults with FAI will be recruited and randomly assigned to intervention and control groups. The participants in the simplified Tai Chi exercise program (STCEP) group will receive a 12-week Tai Chi training. The participants in the control group will receive a low-intensity exercise program and health education for 12 weeks. The primary and secondary outcomes will be assessed at baseline, 4th, 8th, and 12th weeks. Primary outcome measures will include the Cumberland Ankle Instability Tool (CAIT) score, kinematics/kinetics data, electromyography during single-leg landing tasks, and the modified Star Excursion Balance Test (mSEBT). Secondary outcome measures will include the total time of Dynamic Leap and Balance Test (DLBT), ankle muscle strength, and ankle proprioception. Discussion This study will investigate the effects of Tai Chi exercise on the neuromuscular function of patients with FAI, as indicated by ankle joint biomechanics, ankle proprioception, balance, ankle muscle strength, and ankle muscle activation. Results will demonstrate that Tai Chi can be an effective exercise for young adults with FAI. Trial registration Chinese Clinical Trial Registry ChiCTR2100044089 . Registered on 10 March 2021

Temperature affects seed germination and seedling growth, which is a critical and complex stage in plant life cycle. However, comprehensive metabolic basis on temperature implicating seed germination and seedling growth remains less known. Here, we applied the high-throughput untargeted metabolomic and advanced shotgun lipidomic approaches to profile the Arabidopsis 182 metabolites and 149 lipids under moderate (22°C, 28°C) and extreme high (34°C, 40°C) temperatures. Our results showed that a typical feature of the metabolism related to organic acids/derivates and amines was obviously enriched at the moderate temperature, which was implicated in many cellular responses towards tricarboxylic acid cycle (TCA), carbohydrates and amino acids metabolism, peptide biosynthesis, phenylpropanoid biosynthesis and indole 3-acetate (IAA) biosynthetic pathway. Whereas, under extreme high temperatures, there was no seed germination, but 148 out of total 182 metabolites were highly enriched, involving in the galactose metabolism, fatty acid degradation, tryptophan/phenylalanine metabolism, and shikimic acid-mediated pathways especially including alkaloids metabolism and glucosinolate/flavone/flavonol biosynthesis. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) also exhibited the gradually increased tendency from moderate temperatures to extreme high temperatures; whereas phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylglycerol (PG), monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and sulfoquinovosyldiacylglycerol (SQDG) were contrary to decrease. Another typical feature of the distinguished metabolites between 22°C and 28°C, the TCA, disaccharides, nucleotides, polypeptides, SQDG and the biosynthesis of fatty acids and glucobrassicin-mediated IAA were obviously decreased at 28°C, while amino acids, trisaccharides, PE, PC, PA, PS, MGDG, DGDG and diacylglycerol (DAG) preferred to enrich at 28°C, which characterized the alteration of metabolites and lipids during fast seedling growth. Taking together, our results provided the comprehensive metabolites phenotyping, revealed the characteristics of metabolites necessary for seed germination and/or seedling growth under different temperatures, and provided insights into the different metabolic regulation of metabolites and lipid homeostasis for seed germination and seedling growth.

Mesenchymal stem/stromal cells (MSCs) show tremendous potential for regenerative medicine due to their self-renewal, multi-differentiation and immunomodulatory capabilities. Largely studies had indicated conventional tissue-derived MSCs have considerable limited expandability and donor variability which hinders further application. Induced pluripotent stem cell (iPSCs)-derived MSCs (iMSCs) have created exciting source for standardized cellular therapy. However, the cellular and molecular differences between iMSCs and the cognate tissue-derived MSCs remains poorly explored. In this study, we first successfully reprogrammed human umbilical cords-derived mesenchymal stem/stromal cells (UMSCs) into iPSCs by using the cocktails of mRNA. Subsequently, iPSCs were further differentiated into iMSCs in xeno-free induction medium. Then, iMSCs were compared with the donor matched UMSCs by assessing proliferative state, differentiation capability, immunomodulatory potential through immunohistochemical analysis, flow cytometric analysis, transcriptome sequencing analysis, and combine with coculture with immune cell population. The results showed that iMSCs exhibited high expression of MSCs positive-makers CD73, CD90, CD105 and lack expression of negative-maker cocktails CD34, CD45, CD11b, CD19, HLA-DR; also successfully differentiated into osteocytes, chondrocytes and adipocytes. Further, the iMSCs were similar with their parental UMSCs in cell proliferative state detected by the CCK-8 assay, and in cell rejuvenation state assessed by β-Galactosidase staining and telomerase activity related mRNA and protein analysis. However, iMSCs exhibited similarity to resident MSCs in Homeobox (Hox) genes expression profile and presented better neural differentiation potential by activation of NESTIN related pathway. Moreover, iMSCs owned enhanced immunosuppression capacity through downregulation pools of pro-inflammatory factors, including IL6, IL1B etc. and upregulation anti-inflammatory factors NOS1, TGFB etc. signals. In summary, our study provides an attractive cell source for basic research and offers fundamental biological insight of iMSCs-based therapy.

Abstract Itaconic acid is produced by immune responsive gene 1 (IRG1)-coded enzyme in activated macrophages and known to play an important role in metabolism and immunity. In this study, mechanism of itaconic acid functioning as an anti-inflammatory metabolite was investigated with molecular biology and immunology techniques, by employing IRG1-null (prepared with CRISPR) and wild-type macrophages. Experimental results showed that itaconic acid significantly promoted the pentose phosphate pathway (PPP), which subsequently led to significantly higher NADPH oxidase activity and more reactive oxygen species (ROS) production. ROS production increased the expression of anti-inflammatory gene A20, which in turn decreased the production of inflammatory cytokines IL-6, IL-1β and TNF-α. NF-κB, which can up-regulate A20, was also vital in controlling IRG1 and itaconic acid involved immune-modulatory responses in LPS-stimulated macrophage in this study. In addition, itaconic acid inhibited the growth of Salmonella typhimurium in cell through increasing ROS production from NADPH oxidase and the hatching of Schistosoma japonicum eggs in vitro. In short, this study revealed an alternative mechanism by which itaconic acid acts as an anti-inflammatory metabolite and confirmed the inhibition of bacterial pathogens with itaconic acid via ROS in cell. These findings provide the basic knowledge for future biological applications of itaconic acid in anti-inflammation and related pathogens control.

Background: The perturbation of fatty acid metabolism in heart failure (HF) has been a critical issue. It is unclear whether the amounts of circulating carnitines will benefit primary etiology diagnosis and prognostic prediction in HF. This study was designed to assess the diagnostic and prognostic values of serum carnitine profiles between ischemic and non-ischemic derived heart failure. Methods: HF patients (non-ischemic dilated cardiomyopathy: DCM-HF, n = 98; ischemic heart disease: IHD-HF, n = 63) and control individuals (n = 48) were enrolled consecutively. The serum carnitines were quantitatively measured using the UHPLC-MS/MS method. All patients underwent a median follow-up of 28.3 months. Multivariate Cox regression analysis was performed during the prognosis evaluation. Results: Amongst 25 carnitines measured, all of them were increased in HF patients, and 20 acylcarnitines were associated with HF diagnosis independently. Seven acylcarnitines were confirmed to increase the probability of DCM diagnosis independently. The addition of isobutyryl-L-carnitine and stearoyl-L-carnitine to conventional clinical factors significantly improved the area under the receiver operating characteristic curve (ROC) from 0.771 to 0.832 (p = 0.023) for DCM-HF diagnosis (calibration test for the composite model: Hosmer-Lemeshow χ2 = 7.376, p = 0.497 > 0.05). Using a multivariate COX survival analysis adjusted with clinical factors simultaneously, oleoyl L-carnitine >300 nmol/L (HR = 2.364, 95% CI = 1.122–4.976, p = 0.024) and isovaleryl-L-carnitine p = 0.026) increased the prediction of all-cause mortality independently, while linoleoyl-L-carnitine >420 nmol/L, succinyl carnitine >60 nmol/L and isovaleryl-L-carnitine

Objective: To investigate the clinical features and outcome of recurrent endometrial cancer (EC) or atypical endometrial hyperplasia (AEH) patients who underwent hysterectomy after fertility-sparing therapy. Methods: Clinical data was retrospectively collected for 15 recurrent endometrial cancer or atypical endometrial hyperplasia patients who underwent hysterectomy in six hospitals from 2003 to 2019. According to the indicators of hysterectomy, patients were divided into four groups: 7 patients who underwent direct hyesterectomy after the first relapse, 4 due to re-treatment failure, 1 after full term live birth, and 3 because of multiple recurrence. Clinical coexisting conditions, regimen and outcome of fertility-sparing therapy, pre- and post-operative pathological results, and prognosis were analyzed. Results: (1) Fertility-spraring treatment was given to a total of 15 eligible patients, including 6 with EC and 9 with AEH. Median time interval from remission to recurrence was 12 months (range 3–92). Oral progestin-based medicine was the main fertility-sparing therapy in both primary treatment and re-treatment after recurrence. Six (6/8) patients received progestin combined with gonadotrophin releasing hormone agonist or metformin in three re-treatment groups. (2) Nine patients underwent hysterectomy and 6 staging surgery. Three patients had pathological upgrade after surgery. Five (5/10) EC patients had superficial myometrial invasion in postoperative pathology. All patients showed no evidence of disease in the median follow-up of 17 months (range 3–118). (3) Among seven patients who failed to re-treatment and had multiple recurrence, six were overweight/obesity and six had insulin resistance. Two of these patients had synchronous ovarian cancer in the postoperative pathology. Conclusion: For the patients with recurrent EC or AEH after primary fertility-sparing therapy, overweight/obesity and insulin resistance might be the risk factors for re-treatment failure. Hysterectomy is recommended when patients had re-treatment failure or multiple recurrence; and generally the prognosis is favorable.

Abstract Endometriosis (EMS) is a multifactorial disease that affects 10%–15% women of reproductive age and is associated with chronic pelvic pain and infertility. The pathogenesis of EMS has not been consistently explained until now. In this study, we involved 36 endometriosis patients and 14 control subjects who performed laparoscopic surgery due to gynecological benign tumor. The samples from lower third of vagina (CL), posterior vaginal fornix (CU), cervical mucus (CV), endometrium (ET) and peritoneal fluid (PF), were collected and sequenced by 16S rRNA amplicon. The continuous change of the microbiota distribution was identified along the reproductive tract. The flora in lower reproductive tract (CL, CU) were dominated by Lactobacillus. Significant difference of the community diversity began showing in the CV of EMS patients and gradually increased upward the reproductive tract. It indicates the microbiota in cervical samples is expected to be an indicator for the risk of EMS. This study also highlights the decreasing of Lactobacillus in vaginal flora and the increasing of signature Operational Taxonomic Units (OTUs) in transaction zone (CV) and upper reproductive tract (ET, PF) of EMS patients, which reflect the alteration of microbial community associated with EMS, participation of specific colonized bacteria in the EMS pathogenesis and relationship between microbiota and development of disease.

Pimacao is a traditional Chinese folk medicine and is the main component of the famous Chinese herbal remedy “Yunnan Baiyao” for its significant analgesic activity in the treatment of wounds. Due to increases in consumption, its wild population is now difficult to find, and adulterant from the same genus has occurred. However, this is challenging to distinguish the species of Veratrum in Pimacao using dried roots and rhizomes or medicinal powder. ITS2 sequences and steroidal alkaloids by the non-targeted and pseudo-targeted metabolomics methods were taken advantage of establishing an effective identification method. Based on the ITS2 sequence, metabolite profiling of steroidal alkaloids and morphological characteristics, the classification of two distinct subspecies in V. mengzeanum has been reinforced. In addition, the new subspecies V. mengzeanum subsp. phuwae was collected in China for the first time. The ITS2 sequence could be used in the identification of V. taliense, V. mengtzeanum, V. stenophyllum, and V. nigrum, but is insufficient for intraspecific identification. Simultaneously, 147 variables were labeled by non-targeted analysis accomplished utilizing an ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry (UPLC-ESI-QE-Orbitrap-MS) system consisting of an Orbitrap QE HF-X. Followed by a pseudo-targeted analysis method developed for the Qtrap 6500-plus mass spectrometry system coupled with an ESI source, 29 labeled steroidal alkaloids detected by the MRM mode could distinguish between four species. Notably, 25 labeled steroidal alkaloids could distinguish between three closely related species. These have the potential to be used as markers for identification. Furthermore, there were several variables with statistical differences between two subspecies of V. mengtzeanum and populations of V. taliense, V. mengtzeanum, and V. stenophyllum.

ObjectiveTo evaluate the effect of maintenance therapy for patients with atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) after successful fertility-preserving management on prognosis and pregnancy outcome.MethodsWe performed a retrospectively analysis of 109 young women with atypical endometrial hyperplasia and early endometrioid endometrial cancer who had received complete response after fertility-preserving treatment at 5centers between May 2005 and March 2021. Maintenance therapy regimes included low-dose oral progesterone, levonorgestrel intrauterine device(LNG-IUD) and combination oral contraceptive (COC). The patients were divided into two groups, maintenance therapy group and non-maintenance therapy group. Clinical characteristics, treatment regimens, prognosis, and pregnancy outcome were compared between the two groups.ResultsThe overall disease recurrence rate of the maintenance therapy group was significantly lower than that of the non-maintenance therapy group (P < 0.001). The recurrence rate of atypical endometrial hyperplasia and endometrial cancer in the maintenance therapy group were significantly lower than those in the non-maintenance group (P < 0.001). Maintenance therapy can reduce pregnancy rates and live birth rates. Maintenance therapy can protect the endometrium in patients treated with assisted reproductive technology (ART), greatly reducing the recurrence rate after ART (P

Summary: Plant-nectar-derived sugar is the major energy source for mosquitoes, but its influence on vector competence for malaria parasites remains unclear. Here, we show that Plasmodium berghei infection of Anopheles stephensi results in global metabolome changes, with the most significant impact on glucose metabolism. Feeding on glucose or trehalose (the main hemolymph sugars) renders the mosquito more susceptible to Plasmodium infection by alkalizing the mosquito midgut. The glucose/trehalose diets promote proliferation of a commensal bacterium, Asaia bogorensis, that remodels glucose metabolism in a way that increases midgut pH, thereby promoting Plasmodium gametogenesis. We also demonstrate that the sugar composition from different natural plant nectars influences A. bogorensis growth, resulting in a greater permissiveness to Plasmodium. Altogether, our results demonstrate that dietary glucose is an important determinant of mosquito vector competency for Plasmodium, further highlighting a key role for mosquito-microbiota interactions in regulating the development of the malaria parasite.

Human urine is traditionally considered to be sterile, and whether the urine harbours distinct microbial communities has been a matter of debate. Potential links between female urine and reproductive tract microbial communities is currently not clear. Here, we collected urine samples from 147 Chinese women of reproductive age and explored the nature of colonization by 16S rRNA gene amplicon sequencing, quantitative real-time PCR, and live bacteria culture. To demonstrate the utility of this approach, the intra-individual Spearman’s correlation was used to explore the relationship between urine and multiple sites of the female reproductive tract. PERMANOVA was also performed to explore potential correlations between the lifestyle and various clinical factors and urinary bacterial communities. Our data demonstrated distinct bacterial communities in urine, indicative of a non-sterile environment. Streptococcus-dominated, Lactobacillus-dominated, and diverse type were the three most common urinary bacterial community types in the cohort. Detailed comparison of the urinary microbiota with multiple sites of the female reproductive tract microbiota demonstrated that the urinary microbiota were more similar to the microbiota in the cervix and uterine cavity than to those of the vagina in the same women. Our data demonstrate the potential connectivity among microbiota in the female urogenital system and provide insight and resources for exploring diseases of the urethra and genital tract.

Carbonyl-containing metabolites widely exist in biological samples and have important physiological functions. Thus, accurate and sensitive quantitative analysis of carbonyl-containing metabolites is crucial to provide insight into metabolic pathways as well as disease mechanisms. Although reversed phase liquid chromatography electrospray ionization mass spectrometry (RPLC-ESI-MS) is widely used due to the powerful separation capability of RPLC and high specificity and sensitivity of MS, but it is often challenging to directly analyze carbonyl-containing metabolites using RPLC-ESI-MS due to the poor ionization efficiency of neutral carbonyl groups in ESI. Modification of carbonyl-containing metabolites by a chemical derivatization strategy can overcome the obstacle of sensitivity; however, it is insufficient to achieve accurate quantification due to instrument drift and matrix effects. The emergence of stable isotope-coded derivatization (ICD) provides a good solution to the problems encountered above. Thus, LC-MS methods that utilize ICD have been applied in metabolomics including quantitative targeted analysis and untargeted profiling analysis. In addition, ICD makes multiplex or multichannel submetabolome analysis possible, which not only reduces instrument running time but also avoids the variation of MS response. In this review, representative derivatization reagents and typical applications in absolute quantification and submetabolome profiling are discussed to highlight the superiority of the ICD strategy for detection of carbonyl-containing metabolites.

Whether the female reproductive tract harbours distinct microbiomes beyond the vagina has been a matter of debate. Here, the authors show a subject-specific continuity in microbial communities at six sites along the female reproductive tract, indicative of a non-sterile environment.

Abstract Background The aim of this study was to determine whether brain abundant membrane attached signal protein 1 (BASP1) is a valuable prognostic biomarker for cervical cancer and whether BASP1 regulates the progression of cervical cancer. Methods Quantitative real-time PCR, western blotting, and immunohistochemistry were used to determined BASP1 levels. Statistical analyses were used to examine whether BASP1 was a prognostic factor for patients with cervical cancer. The MTT assay, colony formation assay, cell cycle assay, anchorage-independent growth assay, and a tumor xenograft model were used to determine the role of BASP1 in the proliferation and tumorigenicity of cervical cancer. Results Brain abundant membrane attached signal protein 1 was upregulated in cervical cancer tissues and cells, and BASP1 expression levels were higher in patients that had died during follow-up compared with those that survived. There was a positive correlation between BASP1 expression and clinical stage (p

Abstract Coinfection of microorganisms is a common phenomenon in humans and animals. In order to further our understanding of the progress of coinfection and the possible interaction between different pathogens, we have built a coinfection mouse model with Schistosoma japonicum and Salmonella typhimurium, and used this model to investigate the systemic metabolic and immune responses using NMR-based metabonomics and immunological techniques. Our results show that Salmonella typhimurium (ATCC14028) infection reduces the number of adult schistosomal worms and eggs, relieves symptoms of schistosomiasis and also abates the mortality of mice infected by Schistosoma japonicum. In addition, Salmonella typhimurium infection counteracts the metabolic disturbances associated with schistosomiasis, which was reflected by the reverted levels of metabolites in coinfected mice, compared with the Schistosoma japonicum infected mice. Furthermore, immune analyses also indicate that shift of the immune response to different pathogens is a result of indirect interactions between Schistosoma japonicum and Salmonella typhimurium within the host. Salmonella typhimurium infection can ameliorate Schistosoma japonicum-caused schistosomiasis in BALB/c mice, which is most likely due to inverse immune polarization. Our work provides an insight into coinfection between Schistosoma japonicum and Salmonella typhimurium, and may further contribute to the development of new tools for controlling Schistosoma japonicum-associated diseases.

Abstract Metabolites containing amino groups cover multiple pathways and play important roles in redox homeostasis and biosyntheses of proteins, nucleotides and neurotransmitters. Here, we report a new method for simultaneous quantification of 124 such metabolites. This is achieved by derivatization-assisted sensitivity enhancement with 5-aminoisoquinolyl-N-hydroxysuccinimidyl carbamate (5-AIQC) followed with comprehensive analysis using ultra-high performance liquid chromatography and electrospray ionization tandem mass spectrometry (UHPLC-MS/MS). In an one-pot manner, this quantification method enables simultaneous coverage of 20 important metabolic pathways including protein biosynthesis/degradation, biosyntheses of catecholamines, arginine and glutathione, metabolisms of homocysteine, taurine-hypotaurine etc. Compared with the reported ones, this method is capable of simultaneously quantifying thiols, disulfides and other oxidation-prone analytes in a single run and suitable for quantifying aromatic amino metabolites. This method is also much more sensitive for all tested metabolites with LODs well below 50 fmol (at sub-fmol for most tested analytes) and shows good precision for retention time and quantitation with inter-day and intra-day relative standard deviations (RSDs) below 15% and good recovery from renal cancer tissue, rat urine and plasma. The method was further applied to quantify the amino metabolites in silkworm hemolymph from multiple developmental stages showing its applicability in metabolomics and perhaps some clinical chemistry studies.

Despite the broad-spectrum antimicrobial activities of silver, its internal usage is restricted, owing to the toxicity. Strategies to enhance its efficacy are highly desirable but rely heavily on the understanding of its molecular mechanism of action. However, up to now, no direct silver-targeting proteins have been mined at a proteome-wide scale, which hinders systemic studies on the biological pathways interrupted by silver. Herein, we build up a unique system, namely liquid chromatography gel electrophoresis inductively coupled plasma mass spectrometry (LC-GE-ICP-MS), allowing 34 proteins directly bound by silver ions to be identified in Escherichia coli. By using integrated omic approaches, including metalloproteomics, metabolomics, bioinformatics, and systemic biology, we delineated the first dynamic antimicrobial actions of silver (Ag+) in E. coli, i.e., it primarily damages multiple enzymes in glycolysis and tricarboxylic acid (TCA) cycle, leading to the stalling of the oxidative branch of the TCA cycle and an adaptive metabolic divergence to the reductive glyoxylate pathway. It then further damages the adaptive glyoxylate pathway and suppresses the cellular oxidative stress responses, causing systemic damages and death of the bacterium. To harness these novel findings, we coadministrated metabolites involved in the Krebs cycles with Ag+ and found that they can significantly potentiate the efficacy of silver both in vitro and in an animal model. Our study reveals the comprehensive and dynamic mechanisms of Ag+ toxicity in E. coli cells and offers a novel and general approach for deciphering molecular mechanisms of metallodrugs in various pathogens and cells to facilitate the development of new therapeutics.

Amomum tsaoko is a perennial herb belonging to Zingiberaceae. Its dried ripe fruit is an important food additive, spice and materia medicai in Southeast Asia. For hundreds of years of cultivation, morphological variations have existed. The essential oil is one of the major active products of the A. tsaoko fruit and seed. In this study, we collected 12 populations in Yunnan province, and the correlation analysis of compounds was focused on the essential oil of A. tsaoko seed and its fruit morphological characteristics, geographical conditions, and locality of growth. The results showed that the difference in morphological characteristics between populations is greater than the difference within the population. High altitude areas are beneficial for biomass accumulation. Another interesting finding is that selecting specific functional or odor type materials could reference the morphologies of A. tsaoko fruit and seed. Furthermore, the qualitative and quantitative analysis of compounds in essential oil could be used to distinguish the producing area of the A. tsaoko fruit. These results are crucial in realizing the determination of botanical origin and evaluating the quality of A. tsaoko fruit. Meanwhile, it makes clear that various other studies on this plant deserve more attention.

The human microbiota is an aggregate of microorganisms residing in the human body, mostly in the gastrointestinal tract (GIT). Our gut microbiota evolves with us and plays a pivotal role in human health and disease. In recent years, the microbiota has gained increasing attention due to its impact on host metabolism, physiology, and immune system development, but also because the perturbation of the microbiota may result in a number of diseases. The gut microbiota may be linked to malignancies such as gastric cancer and colorectal cancer. It may also be linked to disorders such as nonalcoholic fatty liver disease (NAFLD); obesity and diabetes, which are characterized as “lifestyle diseases” of the industrialized world; coronary heart disease; and neurological disorders. Although the revolution in molecular technologies has provided us with the necessary tools to study the gut microbiota more accurately, we need to elucidate the relationships between the gut microbiota and several human pathologies more precisely, as understanding the impact that the microbiota plays in various diseases is fundamental for the development of novel therapeutic strategies. Therefore, the aim of this review is to provide the reader with an updated overview of the importance of the gut microbiota for human health and the potential to manipulate gut microbial composition for purposes such as the treatment of antibiotic-resistant Clostridium difficile (C. difficile) infections. The concept of altering the gut community by microbial intervention in an effort to improve health is currently in its infancy. However, the therapeutic implications appear to be very great. Thus, the removal of harmful organisms and the enrichment of beneficial microbes may protect our health, and such efforts will pave the way for the development of more rational treatment options in the future.

Valeriana jatamansi Jones is an aromatic medicinal herb and important alternative to V. officinalis, which is utilized for medicinal purposes in China and India and also as spices in India. Bioactive ingredients of V. jatamansi vary in different regions. However, no information is currently available on influence of genotype and environmental factors in the volatile compounds, especially when germplasms and planting locations need to be selected. Based on the results of SNP and volatile constituents from GC-MS analysis, this study found various genotypes and chemotypes of V. jatamansi for wild plants from seven regions in China and common-garden samples; correlations between genotype and chemotype were revealed for the plants. Two distinct populations (PX, FY) were distinguishable from five others (GJ, YL, SY, DD, DY) according to their genotypes and volatile profiles, the consistency of which was observed showing that genotype could significantly influence chemotype. Wild populations and common-garden samples were also separated in their volatile profiles, demonstrating that environmental factors strongly affected their chemotypes. Compounds contributing to the discrimination were identified as discriminatory compounds. This investigation has explored and provided essential information concerning the correlation between genotype and chemotype as well as environmental factors and chemotype of V. jatamansi in some regions of China. Feasible plantation and conservation strategies of V. jatamansi could be further explored based on these results.

Obesity has been linked to many health problems, such as diabetes. However, there is no drug that effectively treats obesity. Here, we reveal that miR-378 transgenic mice display reduced fat mass, enhanced lipolysis, and increased energy expenditure. Notably, administering AgomiR-378 prevents and ameliorates obesity in mice. We also found that the energy deficiency seen in miR-378 transgenic mice was due to impaired glucose metabolism. This impairment was caused by an activated pyruvate-PEP futile cycle via the miR-378-Akt1-FoxO1-PEPCK pathway in skeletal muscle and enhanced lipolysis in adipose tissues mediated by miR-378-SCD1. Our findings demonstrate that activating the pyruvate-PEP futile cycle in skeletal muscle is the primary cause of elevated lipolysis in adipose tissues of miR-378 transgenic mice, and it helps orchestrate the crosstalk between muscle and fat to control energy homeostasis in mice. Thus, miR-378 may serve as a promising agent for preventing and treating obesity in humans.

Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader–Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

Fusarium head blight disease resulting from Fusarium graminearum (FG) infection causes huge losses in global production of cereals and development of FG-resistant plants is urgently needed. To understand biochemistry mechanisms for FG resistance, here, we have systematically investigated the plant metabolomic phenotypes associated with FG resistance for transgenic Arabidopsis thaliana expressing a class-I chitinase (Chi), a Fusarium-specific recombinant antibody gene (CWP2) and fused Chi-CWP2. Plant disease indices, mycotoxin levels, metabonomic characteristics, and expression levels of several key genes were measured together with their correlations. We found that A. thaliana expressing Chi-CWP2 showed higher FG resistance with much lower disease indices and mycotoxin levels than the wild-type and the plants expressing Chi or CWP2 alone. The combined metabonomic and quantitative RT-PCR analyses revealed that such FG-resistance was closely associated with the promoted biosynthesis of secondary metabolites (phenylpropanoids, alkanoids) and organic osmolytes (proline, betaine, glucose, myo-inositol) together with enhanced TCA cycle and GABA shunt. These suggest that the concurrently enhanced biosyntheses of the shikimate-mediated secondary metabolites and organic osmolytes be an important strategy for A. thaliana to develop and improve FG resistance. These findings provide essential biochemical information related to FG resistance which is important for developing FG-resistant cereals.

Bile acids are the main body of enterohepatic circulation in vivo. They have essential functions such as emulsifying fat, bacteriostasis and regulating multiple metabolic pathways as signal molecules. However, the assignments of NMR signals for some lowconcentration bile acids are still needed. This study combined 1D nuclear magnetic resonance (NMR) and 2D NMR techniques including ¹H-¹H correlation spectroscopy (COSY), ¹H-¹H total correlation spectroscopy (TOCSY), ¹H J-resolved spectroscopy (J-Res), ¹H-13C heteronuclear single quantum coherence spectroscopy (HSQC), and ¹H-13C heteronuclear multiple bond correlation spectroscopy (HMBC) to assign the ¹H and 13C signals of six bile acids in aqueous solution at physiological pH (~7.4) and nine bile acids in methanol. These data are of importance to the NMR-based studies on lipid digestion, absorption, and metabolism. [ABSTRACT FROM AUTHOR]