Multi-omics analysis of attenuated variant reveals potential evaluation marker of host damaging for SARS-CoV-2 variants.

SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination. The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences. Molecular markers for evaluating the pathogenicity of new variants are therefore needed. By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels, six key molecules on the polyamine biosynthesis pathway including putrescine, SAM, dc-SAM, ODC1, SAMS, and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants. To validate our discovery, human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients. Using ODC1 as a proof-of-concept, differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system (RAS) and positively associated with ACE2 activity. Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern (VOCs) and was found to be correlated with each VOCs' pathogenic properties. Particularly, the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models. Our work, therefore, presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.

Ten metabolites-based algorithm predicts the future development of type 2 diabetes in Chinese.

INTRODUCTION: Type 2 diabetes (T2D) is a heterogeneous metabolic disease with large variations in the relative contributions of insulin resistance and ß-cell dysfunction across different glucose tolerance subgroups and ethnicities. A more precise yet feasible approach to categorize risk preceding T2D onset is urgently needed. This study aimed to identify potential metabolic biomarkers that could contribute to the development of T2D and investigate whether their impact on T2D is mediated through insulin resistance and ß-cell dysfunction. METHODS: A non-targeted metabolomic analysis was performed in plasma samples of 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from a long-term prospective Chinese community-based cohort with a follow-up period of âˆ¼ 16 years. RESULTS: Metabolic profiles revealed profound perturbation of metabolomes before T2D onset. Overall metabolic shifts were strongly associated with insulin resistance rather than ß-cell dysfunction. In addition, 188 out of the 578 annotated metabolites were associated with insulin resistance. Bi-directional mediation analysis revealed putative causal relationships among the metabolites, insulin resistance and T2D risk. We built a machine-learning based prediction model, integrating the conventional clinical risk factors (age, BMI, TyG index and 2hG) and 10 metabolites (acetyl-tryptophan, kynurenine, γ-glutamyl-phenylalanine, DG(18:2/22:6), DG(38:7), LPI(18:2), LPC(P-16:0), LPC(P-18:1), LPC(P-20:0) and LPE(P-20:0)) (AUROC = 0.894, 5.6% improvement comparing to the conventional clinical risk model), that successfully predicts the development of T2D. CONCLUSIONS: Our findings support the notion that the metabolic changes resulting from insulin resistance, rather than ß-cell dysfunction, are the primary drivers of T2D in Chinese adults. Metabolomes as a valuable phenotype hold potential clinical utility in the prediction of T2D.

Comparative Metabolomics Combined with Physiological Analysis Revealed Cadmium Tolerance Mechanism in Indica Rice (Oryza sativa L.).

Cadmium (Cd) pollution reduces rice production and quality, putting food security and human health at risk. We conducted comparative physiology and metabolomic analyses in two indica rice ('NH199' and 'NH224') to elucidate the Cd-tolerance mechanism. Cd hampered rice growth, induced oxidative stress, and changed the metabolomics profiling of the root. The biochemical and physiological analysis demonstrated that NH224 exhibited a more potent Cd-tolerance ability than NH199. Cd was primarily distributed in root, and NH224 had a lower Cd translocation factor than NH199 by about 24%. The metabolomic analysis revealed 180 and 177 differentially accumulated metabolites between Cd-stressed seedlings and the controls in NH224 and NH199, respectively. In NH224, amino acids biosynthesis, hormone metabolism, lipids-related metabolism, phenylalanine metabolism, and phenylpropanoid biosynthesis pathways were more active and highly associated with antioxidant defense system, biosynthesis of the cell wall and phytochelatins, and maintenance of plasma membrane stability. These findings provide insights into the metabolic profiles of rice following Cd stress and the screening and breeding of Cd-tolerant rice varieties.

Specific triacylglycerol, diacylglycerol, and lyso-phosphatidylcholine species for the prediction of type 2 diabetes: a ~ 16-year prospective study in Chinese.

BACKGROUND: Bioactive lipids play an important role in insulin secretion and sensitivity, contributing to the pathophysiology of type 2 diabetes (T2D). This study aimed to identify novel lipid species associated with incident T2D in a nested case-control study within a long-term prospective Chinese community-based cohort with a median follow-up of ~ 16 years. METHODS: Plasma samples from 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) were first analyzed using untargeted lipidomics. Potential predictive lipid species selected by the Boruta analysis were then verified by targeted lipidomics. The associations between these lipid species and incident T2D were assessed. Effects of novel lipid species on insulin secretion in mouse islets were investigated. RESULTS: Boruta analysis identified 16 potential lipid species. After adjustment for body mass index (BMI), triacylglycerol/high-density lipoprotein (TG/HDL) ratio and the presence of prediabetes, triacylglycerol (TG) 12:0_18:2_22:6, TG 16:0_11:1_18:2, TG 49:0, TG 51:1 and diacylglycerol (DG) 18:2_22:6 were independently associated with increased T2D risk, whereas lyso-phosphatidylcholine (LPC) O-16:0, LPC P-16:0, LPC O-18:0 and LPC 18:1 were independently associated with decreased T2D risk. Addition of the identified lipid species to the clinical prediction model, comprised of BMI, TG/HDL ratio and the presence of prediabetes, achieved a 3.8% improvement in the area under the receiver operating characteristics curve (AUROC) (p = 0.0026). Further functional study revealed that, LPC O-16:0 and LPC O-18:0 significantly potentiated glucose induced insulin secretion (GSIS) in a dose-dependent manner, whereas neither DG 18:2_22:6 nor TG 12:0_18:2_22:6 had any effect on GSIS. CONCLUSIONS: Addition of the lipid species substantially improved the prediction of T2D beyond the model based on clinical risk factors. Decreased levels of LPC O-16:0 and LPC O-18:0 may contribute to the development of T2D via reduced insulin secretion.

In Vivo Transcranial Acoustoelectric Brain Imaging of Different Steady-State Visual Stimulation Paradigms.

OBJECTIVE: Based on the acoustoelectric (AE) effect, transcranial acoustoelectric brain imaging (tABI) is of potential for brain functional imaging with high temporal and spatial resolution. With nonlinear and non-steady-state, brain electrical signal is microvolt level which makes the development of tABI more difficult. This study demonstrates for the first time in vivo tABI of different steady-state visual stimulation paradigms. METHOD: To obtain different brain activation maps, we designed three steady-state visual stimulation paradigms, including binocular, left eye and right eye stimulations. Then, tABI was implemented with one fixed recording electrode. And, based on decoded signal power spectrum (tABI-power) and correlation coefficient between steady-state visual evoked potential (SSVEP) and decoded signal (tABI-cc) respectively, two imaging methods were investigated. To quantitatively evaluate tABI spatial resolution performance, ECoG was implemented at the same time. Finally, we explored the performance of tABI transient imaging. RESULTS: Decoded AE signal of activation region is consistent with SSVEP in both time and frequency domains, while that of the nonactivated region is noise. Besides, with transcranial measurement, tABI has a millimeter-level spatial resolution (< 3mm). Meanwhile, it can achieve millisecond-level (125ms) transient brain activity imaging. CONCLUSION: Experiment results validate tABI can realize brain functional imaging under complex paradigms and is expected to develop into a brain functional imaging method with high spatiotemporal resolution.

Metabolomics Reveal Nanoplastic-Induced Mitochondrial Damage in Human Liver and Lung Cells.

Plastic debris in the global biosphere is an increasing concern, and nanoplastic (NPs) toxicity in humans is far from being understood. Studies have indicated that NPs can affect mitochondria, but the underlying mechanisms remain unclear. The liver and lungs have important metabolic functions and are vulnerable to NP exposure. In this study, we investigated the effects of 80 nm NPs on mitochondrial functions and metabolic pathways in normal human hepatic (L02) cells and lung (BEAS-2B) cells. NP exposure did not induce mass cell death; however, transmission electron microscopy analysis showed that the NPs could enter the cells and cause mitochondrial damage, as evidenced by overproduction of mitochondrial reactive oxygen species, alterations in the mitochondrial membrane potential, and suppression of mitochondrial respiration. These alterations were observed at NP concentrations as low as 0.0125 mg/mL, which might be comparable to the environmental levels. Nontarget metabolomics confirmed that the most significantly impacted processes were mitochondrial-related. The metabolic function of L02 cells was more vulnerable to NP exposure than that of BEAS-2B cells, especially at low NP concentrations. This study identifies NP-induced mitochondrial dysfunction and metabolic toxicity pathways in target human cells, providing insight into the possibility of adverse outcomes in human health.

Simultaneous determination of methionine cycle metabolites, urea cycle intermediates and polyamines in serum, urine and intestinal tissue by using UHPLC-MS/MS.

Metabolites of methionine cycle, urea cycle and polyamine metabolism play important roles in regulating the metabolic processes and the development of diseases. It is rewarding and interesting to monitor the levels of the above metabolites in biological matrices to investigate pathological mechanisms. However, their quantitation is still unsatisfactory due to the poor retention behavior of the analytes on the traditional reversed-phase column. And never a single analytical method simultaneously quantify these three classes of metabolites. Besides, the concentrations of some metabolites are too low to be detected in the biological samples. In this study, we developed a UHPLC-ESI-MS/MS method to simultaneously determine the levels of 14 metabolites, including 4 methionine metabolism metabolites (methionine, homocysteine, S-adenosylmethionine and S-adenosylhomocysteine), 3 urea cycle intermediates (arginine, citrulline and ornithine) and 7 polyamines (putrescine, spermidine, spermine, N1-acetylputrescine, N1-acetylspermidine, N1-acetylspermine and N1,N12-diacetylspermine). The chromatographic separation was performed on the BEH amide column within 14 min using water and acetonitrile (both with 0.1% formic acid) as the mobile phases. The results of method validation showed good selectivity, linearity (r2 > 0.99), recovery (93.1%-112.1%), inter-day and intra-day precision (RSD < 13.6% and RSD < 11.0%, respectively), stability (RSD < 15.1%) and matrix effect (76.0%-113.2%). The method is simple, quick and sensitive without derivatization processes and the use of ion-pairing reagents. This approach was successfully applied in urine, serum and tissue matrices, as well as in identifying potential biomarkers for hyperthyroidism and hypothyroidism. The method is promising to provide more information on pathophysiological mechanisms in metabolomics study.

Integrated Functional Omics Analysis of Flavonoid-Related Metabolism in AtMYB12 Transcript Factor Overexpressed Tomato.

Genetic engineering (GE) technology is widely used in plant modification. However, the results of modification may not exactly meet the expectations. Herein, we propose a new multi-omics method for GE plant evaluation based on the optimized use of the metID algorithm. Using this method, we found that flavonoid accumulation was at the expense of the great sacrifice of l-phenylalanine in GE tomatoes for the first time. Meanwhile, the ceramide series of sphingolipid is synthesized de novo from l-serine, and ceramides are the primary source of vesicles coated with flavonoids and secreted from the endoplasmic reticulum. Therefore, the accumulation of the ceramide series of sphingolipid changed the cell component of intracellular organelles. Furthermore, the improvement of the method allows us to identify more metabolites related to dysregulated pathways.

Wuchuyuamide V, a new amide alkaloid from the fruits of Tetradium trichotomum.

Tetradium trichotomum Lour., is a plant species endemic to tropical South East Asia with particular medicinal importance. However, very little analysis in this plant has been studied up to now from a phytochemical viewpoint. One new amide alkaloid (wuchuyuamide V, 1), as well as two known amide alkaloids-wuchuyuamide III (2), and wuchuyuamide I (3) were obtained from the fruits of T. trichotomum for the first time. The structures of wuchuyuamide V (1) and wuchuyuamide III (2) were unambiguously elucidated by 1D and 2D-NMR spectra, mass spectrometry, and single-crystal X-ray diffraction.

Three new quinazolines from Evodia rutaecarpa and their biological activity.

In this research, we investigated the profile and bioactivities of quinazoline alkaloids, a class of natural products boasting multiple bioactivities, from the unripe fruit of Evodia rutaecarpa (Juss.) Benth. Three new quinazoline alkaloids, evodiamide A (1), evodiamide B (2), and evodiamide C (3), as well as eight known quinazolines, were isolated from the MeOH extract of E. rutaecarpa. The new compounds are rare quinazolinedione derivatives with linked heterocyclic nuclei. Among these quinazolines, rhetsinine (8) showed potential as a pesticide and exhibited excellent inhibition against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola, and Xanthomonas campestris pv. campestris, with respective EC50 values of 3.13, 14.32, and 32.72 nmol.

Three-Dimensional Ordered Macroporous FePO4 as High-Efficiency Catalyst for Rechargeable Li-O2 Batteries.

The Li-O2 battery is receiving much recent attention because of its superhigh theoretical energy density. However, its performance is limited by the irreversible formation/decomposition of Li2O2 on the cathode and the undesired electrolyte decomposition. In this work, low-cost three-dimensional ordered macroporous (3DOM) FePO4 is synthesized by using polystyrene (PS) spheres template in a facile experimental condition and applied as a high-efficiency catalyst for rechargeable Li-O2 batteries, including good rate performance, high specific capacity, and perfect cycling stability. The superior performances can be attributed to the unique structure of 3DOM FePO4 cathodes, which can provide an efficient buffer space for O2/Li2O2 conversion. In addition, it is demonstrated that the Li+ intercalation/deintercalation behavior of 3DOM FePO4 in ether-based electrolyte can contribute to capacity for Li-O2 batteries over cycling. As a result, when there is no O2 in the environment, the Li-O2 cell can also be operated as a rechargeable Li-FePO4 cell with a perfect cycle capability.

Flexible Aqueous Lithium-Ion Battery with High Safety and Large Volumetric Energy Density.

A flexible and wearable aqueous lithium-ion battery is introduced based on spinel Li1.1 Mn2 O4 cathode and a carbon-coated NASICON-type LiTi2 (PO4 )3 anode (NASICON=sodium-ion super ionic conductor). Energy densities of 63 Wh kg(-1) or 124 mWh cm(-3) and power densities of 3 275 W kg(-1) or 11.1 W cm(-3) can be obtained, which are seven times larger than the largest reported till now. The full cell can keep its capacity without significant loss under different bending states, which shows excellent flexibility. Furthermore, two such flexible cells in series with an operation voltage of 4 V can be compatible with current nonaqueous Li-ion batteries. Therefore, such a flexible cell can potentially be put into practical applications for wearable electronics. In addition, a self-chargeable unit is realized by integrating a single flexible aqueous Li-ion battery with a commercial flexible solar cell, which may facilitate the long-time outdoor operation of flexible and wearable electronic devices.

Addition of all-trans-retinoic acid to omeprazole and sucralfate therapy improves the prognosis of gastric dysplasia.

OBJECTIVE: To investigate the efficacy of all-trans retinoic acid (ATRA) in human gastric dysplasia. METHODS: In this double-blind study, patients with precancerous gastric dysplasia with or without intestinal metaplasia (IM) received either conventional treatment consisting of omeprazole and sucralfate (control group) or conventional treatment plus ATRA. Gastric mucosal biopsies were performed before and after drug treatment and were analysed histologically; expression of retinoblastoma (Rb) protein and HER2 protein in gastric mucosa were measured using immunohistochemistry. RESULTS: A total of 122 patients were included in the study, 63 in the ATRA group and 59 in the control group. In the ATRA group, dysplasia was attenuated in 43 out of 63 patients (68%) compared with 22 out of 59 patients (37%) in the control group; however, IM was not affected by treatment in either group. ATRA treatment was associated with significantly increased Rb expression and decreased HER2 expression in gastric mucosa. CONCLUSIONS: The use of conventional therapy plus ATRA for gastric dysplasia was associated with improved efficacy compared with conventional therapy alone. It was also accompanied by increased Rb expression and decreased HER2 expression in gastric mucosa. The addition of ATRA to conventional therapy for gastritis may improve the prognosis of gastric dysplasia.

Pro variant of TP53 Arg72Pro contributes to gastric cancer risk in Asians: evidence from a meta-analysis.

BACKGROUND: Previous studies investigating the association between TP53 Arg72Pro polymorphism and gastric cancer (GC) risk in Asian population have reported controversial results. Thus, a meta-analysis was performed. METHODS: A comprehensive literature search was conducted and 17 case-control studies were finally included, involving a total of 5,990 GC cases and 6,812 controls. Subgroup analyses were performed by the sample size. RESULTS: Meta-analysis of all 17 studies showed variant genotypes of TP53 Arg72Pro to be associated with an elevated GC risk in three genetic comparison models (OR(Pro vs. Arg)=1.13, 95%CI 1.03-1.25, P(OR)=0.01; OR(Homozygote comparison model)=1.33, 95%CI 1.07-1.64, P(OR)=0.009; OR(Dominant genetic model)=1.13, 95%CI 1.05-1.22, P(OR)=0.002). Besides, a more obvious association was observed after the heterogeneity was decreased (all P values less than 0.001). This association was further identified by both subgroup and sensitivity analyses. CONCLUSIONS: This meta-analysis suggests the Pro variant of TP53 Arg72Pro contributes to gastric cancer risk in Asians.

Hot electron induced cathodic electrochemiluminescence at AuSb alloy electrode for fabricating immunosensor with self-assembled monolayers.

Thin antimony oxide covered AuSb alloy electrode was firstly found to be an excellent cold cathode for generating hot electrons during cathodic pulse polarization. Owing to the injection of hot electrons and the subsequent generation of hydrated electrons, fluorescein iso-thiocyanate (FITC) that cannot be excited in common ECL was cathodically excited at the alloy electrode. Self-assembled thiol monolayers were formed on the electrode surface due to the presence of Au in the alloy, to which strepavidin was covalently bound, and then biotinylated antibody was immobilized through the strepavidin-biotin interaction. As a simple model, an immunosensor for the detection of human IgG (hIgG) using FITC as labeling agent was fabricated. ECL signals were responsive to the amount of hIgG bounded to the immunosensor. The ECL intensity was linearly changed with the logarithm of hIgG concentration in the range of 1.0-1000 ng mL(-1), and the detection limit was ca. 0.3 ng mL(-1) (S/N=3). The proposed immunosensor showed a broad linear range (three magnitudes), good reproducibility and stability, which is promising in detecting FITC-based labels in various types of bioaffinity assays.

Cathodic electrochemiluminescence at C/CxO(1-x) electrodes for the fabrication of label-free biosensors.

Cathodic electrochemiluminescence (ECL) is firstly observed at a carbon oxide covered glassy carbon (C/C(x)O(1-x)) electrode as a large cathodic pulse polarization is applied. This insulating carbon oxide (C(x)O(1-x)) film is constructed on a glassy carbon (GC) substrate by electrochemical oxidization in basic media. The film properties, such as the composition of carbon and oxygen, and the thickness as well, can be controlled by the potential and the duration in the oxidizing process. X-Ray photoelectron spectroscopy (XPS) studies show that carbonyl and carboxyl dominate at the oxidized surface, to which antibodies can be covalently bound. The specific immunoreaction between antigen (Ag) and antibody (Ab) resulted in a decrease in the ECL intensity, thus creating an interesting basis for the development of a label-free cathodic ECL immunosensor. As an example, human IgG (hIgG) was sensitively determined in the concentration range of 0.01-100 ng mL(-1), and the detection limit was ca. 1.0 pg mL (-1) (S/N = 3). In addition, the content of hIgG in human serum has been assayed by the developed immunosensor and a commercially available immune turbidimetry method, respectively, and consistent results were obtained. The prepared immunosensor provides a promising approach for the clinical determination of IgG levels in human serum, because it is simple, rapid, highly sensitive, specific, and without the need of tedious labeling operations.

Catalytic electrogenerated chemiluminescence and nitrate reduction at CdS nanotubes modified glassy carbon electrode.

Electrochemical and electrogenerated chemiluminescence (ECL) properties of a glassy carbon electrode modified with CdS nanotubes (CdS-GCE) are investigated in neutral media. The cyclic voltammogram (CV) shows two cathodic peaks (P(C1) and P(C2)) at -0.76 and -0.97 V and an anodic peak (P(A)) at -0.8 V, while two ECL peaks around -0.76 V are observed. Similar mechanisms of both ECLs are supposed and possibly related to the capture of an electron at a surface trap, that is, the surface sulfide vacancy (V(S)(2+)) of CdS nanotubes and its electrocatalytic reduction to H(2)O(2) generated from the dissolved oxygen. P(C2) and P(A) are ascribed to the two-electron redox at V(S)(2+). Moreover, electrocatalysis to nitrate reduction is also found at P(C2), with a good linear relationship between nitrate concentration and electrocatalytic peak current in CV.