Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron.

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population1. Although recent reports reveal that the Omicron variant robustly escapes vaccine-associated and therapeutic neutralization antibodies2-10, the pathogenicity of the virus remains unknown. Here we show that the replication of Omicron is substantially attenuated in human Calu3 and Caco2 cells. Further mechanistic investigations reveal that Omicron is inefficient in its use of transmembrane serine protease 2 (TMPRSS2) compared with wild-type SARS-CoV-2 (HKU-001a) and previous variants, which may explain its reduced replication in Calu3 and Caco2 cells. The replication of Omicron is markedly attenuated in both the upper and lower respiratory tracts of infected K18-hACE2 mice compared with that of the wild-type strain and Delta (B.1.617.2) variant, resulting in its substantially ameliorated lung pathology. Compared with wild-type SARS-CoV-2 and the Alpha (B.1.1.7), Beta (1.351) and Delta variants, infection by Omicron causes the lowest reduction in body weight and the lowest mortality rate. Overall, our study demonstrates that the replication and pathogenicity of the Omicron variant of SARS-CoV-2 in mice is attenuated compared with the wild-type strain and other variants.

Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways.

Interferons (IFNs) are critical for immune defense against pathogens. While type-I and -III IFNs have been reported to inhibit SARS-CoV-2 replication, the antiviral effect and mechanism of type-II IFN against SARS-CoV-2 remain largely unknown. Here, we evaluate the antiviral activity of type-II IFN (IFNγ) using human lung epithelial cells (Calu3) and ex vivo human lung tissues. In this study, we found that IFNγ suppresses SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Moreover, IFNγ treatment does not significantly modulate the expression of SARS-CoV-2 entry-related factors and induces a similar level of pro-inflammatory response in human lung tissues when compared with IFNß treatment. Mechanistically, we show that overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts the replication of ancestral SARS-CoV-2 and the Alpha and Delta variants. Meanwhile, loss-of-function study reveals that IDO1 knockdown restores SARS-CoV-2 replication restricted by IFNγ in Calu3 cells. We further found that the treatment of l-tryptophan, a substrate of IDO1, partially rescues the IFNγ-mediated inhibitory effect on SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Collectively, these results suggest that type-II IFN potently inhibits SARS-CoV-2 replication through IDO1-mediated antiviral response.

ß-Cyclodextrin molecularly imprinted solid-phase microextraction coatings for selective recognition of polychlorophenols in water samples.

A series of ß-cyclodextrin derivatives were designed and synthesized. The derivatives were investigated as functional monomers in molecularly imprinted polymeric solid-phase microextraction (MIP-SPME) fiber coatings. The coatings, with a layer thickness of 250 µm, were immobilized onto stainless steel using a capillary tube as a mold. This study employed a simple, easy, and reproducible method to prepare uniform coatings for polychlorophenols extraction. The combination of molecular inclusion effects and the molecular imprinting sites was expected to enhance the molecular recognition ability for polychlorophenols. Compared with non-imprinted polymer coatings and MIP coatings with methacrylic acid as the functional monomer, the ß-cyclodextrin MIP-SPME coatings exhibited significantly higher extraction amounts and excellent selectivity to the template of triclosan. The MIP-SPME coatings exhibited a favorable synergistic extraction capacity resulting from the ß-cyclodextrin cavity and molecularly imprinted binding sites. The method of ß-cyclodextrin MIP-SPME coupled with high performance liquid chromatography (HPLC) for triclosan and polychlorophenols analysis in real water samples was developed. The limit of quantification was 1 µg/L for the three polychlorophenols. The recovery for three analytes ranged from 83.71% to 109.98%, with the relative standard deviation (RSD) of 2.83% to 12.19%. The ß-cyclodextrin MIP-SPME fiber coatings could be used for at least 100 cycles. Graphical Abstract Synergistic effects in ß-cyclodextrin MIP-SPME.

The resistance effect of vegetation stem diameter on overland runoff under different slope gradients.

Vegetation is an important part of the natural environment and has resistance effects on overland runoff, which can effectively reduce hydraulic erosion. The effect of vegetation stem diameter and slope gradient on flow resistance is thus worthy of further study. The influence of three different slope gradients (s), three vegetation stem diameters (d) and 12 levels of unit discharge (q) on the flow resistance of a slope was simulated to systematically study the effect of vegetation stem diameter and slope gradient on overland runoff. The diameter of the vegetation stem and the slope gradient were found to have a significant resistance effect on overland runoff. Under the same slope gradient, the Darcy-Weisbach resistance factor (f) increased with an increase in the vegetation stem diameter. Under experimental conditions, the rate of change of f was analysed by linear regression, and as d increased by 1 mm, f increased by an average of 49.9%. For a given vegetation stem diameter and vegetation distribution pattern, the greater the slope gradient, the smaller the value of f, and as S increased by 1.0%, f decreased by an average of 24.5%. These results are important to optimize the slope vegetation distribution in farmland conservation.

Effect of telemedicine on glycated hemoglobin in diabetes: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Telemedicine, the use of telecommunications to deliver health services, expertise and information, is a promising but unproven tool for improving the quality of diabetes care. We summarized the effectiveness of different methods of telemedicine for the management of diabetes compared with usual care. METHODS: We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials databases (to November 2015) and reference lists of existing systematic reviews for randomized controlled trials (RCTs) comparing telemedicine with usual care for adults with diabetes. Two independent reviewers selected the studies and assessed risk of bias in the studies. The primary outcome was glycated hemoglobin (HbA1C) reported at 3 time points (≤ 3 mo, 4-12 mo and > 12 mo). Other outcomes were quality of life, mortality and episodes of hypoglycemia. Trials were pooled using randomeffects meta-analysis, and heterogeneity was quantified using the I2 statistic. RESULTS: From 3688 citations, we identified 111 eligible RCTs (n = 23 648). Telemedicine achieved significant but modest reductions in HbA1C in all 3 follow-up periods (difference in mean at ≤ 3 mo: -0.57%, 95% confidence interval [CI] -0.74% to -0.40% [39 trials]; at 4-12 mo: -0.28%, 95% CI -0.37% to -0.20% [87 trials]; and at > 12 mo: -0.26%, 95% CI -0.46% to -0.06% [5 trials]). Quantified heterogeneity (I2 statistic) was 75%, 69% and 58%, respectively. In meta-regression analyses, the effect of telemedicine on HbA1C appeared greatest in trials with higher HbA1C concentrations at baseline, in trials where providers used Web portals or text messaging to communicate with patients and in trials where telemedicine facilitated medication adjustment. Telemedicine had no convincing effect on quality of life, mortality or hypoglycemia. INTERPRETATION: Compared with usual care, the addition of telemedicine, especially systems that allowed medication adjustments with or without text messaging or a Web portal, improved HbA1C but not other clinically relevant outcomes among patients with diabetes.

Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis.

IMPORTANCE: Numerous glucose-lowering drugs are used to treat type 2 diabetes. OBJECTIVE: To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. DATA SOURCES: Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016. STUDY SELECTION: Randomized clinical trials of 24 weeks' or longer duration. DATA EXTRACTION AND SYNTHESIS: Random-effects network meta-analysis. MAIN OUTCOMES AND MEASURES: The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A1c (HbA1C) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight. RESULTS: A total of 301 clinical trials (1,417,367 patient-months) were included; 177 trials (56,598 patients) of drugs given as monotherapy; 109 trials (53,030 patients) of drugs added to metformin (dual therapy); and 29 trials (10,598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, -22% [-27% to -18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, -10% [95% CI, -18% to -2%]). CONCLUSIONS AND RELEVANCE: Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.

Divergent trajectory of replication and intrinsic pathogenicity of SARS-CoV-2 Omicron post-BA.2/5 subvariants in the upper and lower respiratory tract.

BACKGROUND: Earlier Omicron subvariants including BA.1, BA.2, and BA.5 emerged in waves, with a subvariant replacing the previous one every few months. More recently, the post-BA.2/5 subvariants have acquired convergent substitutions in spike that facilitated their escape from humoral immunity and gained ACE2 binding capacity. However, the intrinsic pathogenicity and replication fitness of the evaluated post-BA.2/5 subvariants are not fully understood. METHODS: We systemically investigated the replication fitness and intrinsic pathogenicity of representative post-BA.2/5 subvariants (BL.1, BQ.1, BQ.1.1, XBB.1, CH.1.1, and XBB.1.5) in weanling (3-4 weeks), adult (8-10 weeks), and aged (10-12 months) mice. In addition, to better model Omicron replication in the human nasal epithelium, we further investigated the replication capacity of the post-BA.2/5 subvariants in human primary nasal epithelial cells. FINDINGS: We found that the evaluated post-BA.2/5 subvariants are consistently attenuated in mouse lungs but not in nasal turbinates when compared with their ancestral subvariants BA.2/5. Further investigations in primary human nasal epithelial cells revealed a gained replication fitness of XBB.1 and XBB.1.5 when compared to BA.2 and BA.5.2. INTERPRETATION: Our study revealed that the post-BA.2/5 subvariants are attenuated in lungs while increased in replication fitness in the nasal epithelium, indicating rapid adaptation of the circulating Omicron subvariants in the human populations. FUNDING: The full list of funding can be found at the Acknowledgements section.

Altered host protease determinants for SARS-CoV-2 Omicron.

Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While the role of the host transmembrane protease serine 2 in SARS-CoV-2 infection is widely recognized, the involvement of other proteases capable of facilitating SARS-CoV-2 entry remains incompletely explored. Here, we show that multiple members from the membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin and metalloproteinase families can mediate SARS-CoV-2 entry. Inhibition of MT-MMPs significantly reduces SARS-CoV-2 replication in vitro and in vivo. Mechanistically, we show that MT-MMPs can cleave SARS-CoV-2 spike and angiotensin-converting enzyme 2 and facilitate spike-mediated fusion. We further demonstrate that Omicron BA.1 has an increased efficiency on MT-MMP usage, while an altered efficiency on transmembrane serine protease usage for virus entry compared with that of ancestral SARS-CoV-2. These results reveal additional protease determinants for SARS-CoV-2 infection and enhance our understanding on the biology of coronavirus entry.

The viral fitness and intrinsic pathogenicity of dominant SARS-CoV-2 Omicron sublineages BA.1, BA.2, and BA.5.

BACKGROUND: Among the Omicron sublineages that have emerged, BA.1, BA.2, BA.5, and their related sublineages have resulted in the largest number of infections. While recent studies demonstrated that all Omicron sublineages robustly escape neutralizing antibody response, it remains unclear on whether these Omicron sublineages share any pattern of evolutionary trajectory on their replication efficiency and intrinsic pathogenicity along the respiratory tract. METHODS: We compared the virological features, replication capacity of dominant Omicron sublineages BA.1, BA.2 and BA.5 in the human nasal epithelium, and characterized their pathogenicity in K18-hACE2, A129, young C57BL/6, and aged C57BL/6 mice. FINDINGS: We found that BA.5 replicated most robustly, followed by BA.2 and BA.1, in the differentiated human nasal epithelium. Consistently, BA.5 infection resulted in higher viral gene copies, infectious viral titres and more abundant viral antigen expression in the nasal turbinates of the infected K18-hACE2 transgenic mice. In contrast, the Omicron sublineages are continuously attenuated in lungs of infected K18-hACE2 and C57BL/6 mice, leading to decreased pathogenicity. Nevertheless, lung manifestations remain severe in Omicron sublineages-infected A129 and aged C57BL/6 mice. INTERPRETATION: Our results suggested that the Omicron sublineages might be gaining intrinsic replication fitness in the upper respiratory tract, therefore highlighting the importance of global surveillance of the emergence of hyper-transmissive Omicron sublineages. On the contrary, replication and intrinsic pathogenicity of Omicron is suggested to be further attenuated in the lower respiratory tract. Effective vaccination and other precautions should be in place to prevent severe infections in the immunocompromised populations at risk. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Generic imprinted fiber array strategy for high-throughput and ultrasensitive simultaneous determination of multiple neonicotinoids.

Herein, a new generic fiber array based on molecular imprinting solid-phase microextraction (MIP-SPME) technology, was described to enrich trace multiple neonicotinoids with high flux from the food matrix. To begin with adsorption experiments coupled with theoretical calculations provided universal means for selecting the preferred template molecule clothianidin (CLT). Results demonstrated that the CLT-MIP fiber array exhibited significantly superior enrichment ability of 1189-2356-folds for six neonicotinoids compared with two kinds of commercial fiber arrays. Furthermore, the practicability of the CLT-MIP fiber array was verified by simultaneously determining multiple neonicotinoids in tea and honey samples. The CLT-MIP fiber array showed a limit of detection (LOD) of 0.03-0.58 µg/L for six neonicotinoids. The method also exhibited satisfactory recoveries ranging from 85.4% to 116.8% with RSD (n = 3) less than 8.8%. The imprinted fiber array has the advantages of high-throughput, predominant reproducibility, and accurate quantitation multi-component, and it may open up a new mean to efficiently enrich high-throughput and simultaneously detect multiple compounds from food samples.

Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2.

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating SARS-CoV-2 variant globally. Omicron BA.1 contains more than 30 mutations in the spike protein, which contribute to its altered virological features when compared to the ancestral SARS-CoV-2 or previous SARS-CoV-2 variants. Recent studies by us and others demonstrated that Omicron BA.1 is less dependent on transmembrane serine protease 2 (TMPRSS2), less efficient in spike cleavage, less fusogenic, and adopts an altered propensity to utilize the plasma membrane and endosomal pathways for virus entry. Ongoing studies suggest that these virological features of Omicron BA.1 are in part retained by the subsequent Omicron sublineages. However, the exact spike determinants that contribute to these altered features of Omicron remain incompletely understood. In this study, we investigated the spike determinants for the observed virological characteristics of Omicron. By screening for the individual changes on Omicron BA.1 and BA.2 spike, we identify that 69-70 deletion, E484A, and H655Y contribute to the reduced TMPRSS2 usage while 25-27 deletion, S375F, and T376A result in less efficient spike cleavage. Among the shared spike mutations of BA.1 and BA.2, S375F and H655Y reduce spike-mediated fusogenicity. Interestingly, the H655Y change consistently reduces serine protease usage while increases the use of endosomal proteases. In keeping with these findings, the H655Y substitution alone reduces plasma membrane entry and facilitates endosomal entry when compared to SARS-CoV-2 WT. Overall, our study identifies key changes in Omicron spike that contributes to our understanding on the virological determinant and pathogenicity of Omicron.

Targeting ACLY efficiently inhibits SARS-CoV-2 replication.

The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets. In this study, we dissected the metabolome derived from COVID-19 patients to identify key host factors that are required for efficient SARS-CoV-2 replication. Through a series of metabolomic analyses, in vitro, and in vivo investigations, we identified ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. ACLY should be further explored as a novel intervention target for COVID-19.

Virological features and pathogenicity of SARS-CoV-2 Omicron BA.2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 was a dominant circulating SARS-CoV-2 variant worldwide. Recent reports hint that BA.2 is similarly potent regarding antibody evasion but may be more transmissible than BA.1. The pathogenicity of BA.2 remains unclear and is of critical public health significance. Here we investigated the virological features and pathogenicity of BA.2 with in vitro and in vivo models. We show that BA.2 is less dependent on transmembrane protease serine 2 (TMPRSS2) for virus entry in comparison with BA.1 in vitro. In K18-hACE2 mice, BA.2 replicates more efficiently than BA.1 in the nasal turbinates and replicates marginally less efficiently in the lungs, leading to decreased body weight loss and improved survival. Our study indicates that BA.2 is similarly attenuated in lungs compared with BA.1 but is potentially more transmissible because of its better replication at the nasal turbinates.

Ultra-durable, multi-template molecularly imprinted polymers for ultrasensitive monitoring and multicomponent quantification of trace sulfa antibiotics.

Traditional analysis methods are susceptible to interference caused by the complexity of sample matrices, and detector surface fouling arising from nonspecific adsorption of microorganisms (in biological samples) which leads in particular to a gradual loss of sensitivity. Imprinted materials can be used to effectively reduce interference originating in the matrices. However, the poor reproducibility and multicomponent quantification of trace antibiotics represent significant challenges to the detection process. Meanwhile, the high biological risk presented by bacterial antibiotic immunity and the persistence of antibiotics in foodstuffs, especially meat, both caused by the overuse of sulfonamide antibiotics, remain urgent issues. Here, we present the first example of a method for the accurate quantification of trace sulfa antibiotics (SAs) based on multi-template imprinted polymers (MMIPs). Levels of multiple SAs have been simultaneously successfully quantified by applying MMIP extraction coupled with UPLC-MS/MS analysis. This method shows excellent linearity of detection in the range of 0.1-500 µg L-1, and ultrasensitivity with low limits of detection of 0.03 µg L-1. The maximum SA residue recovered from sample tissues by using MMIPs was 5.48 µg g-1. MMIP-coupled UPLC-MS/MS quantification of SAs is an accurate and repeatable method for the monitoring of SA accumulation in mouse tissue samples. It also provides an effective strategy for the tracking and quantification of drugs in other biological samples.

Interaction of mercury ion (Hg2+) with blood and cytotoxicity attenuation by serum albumin binding.

Blood mercury reflects the amount available from tissues, which is an indication of the exposure level. Here we confirm that Hg2+ caused hemolytic effects at high concentrations; while at light concentrations, most of the ions were bound to human serum albumin (HSA). The binding mechanism of Hg2+ to HSA has been investigated, which indicated that the presence of Hg2+ significantly perturbed the structure of HSA and quenched the fluorescence of protein in a hybrid dynamic and static mode. Hg2+ was preferably bound to cysteine and cystine, where the R‒S‒S‒R structure is responsible for maintaining the protein's structure by stabilizing the α-helical bundles. The metal-protein interaction mitigated the cellular toxicity as concealed by A498 cell lines. The fundamental and comprehensive data in this work is beneficial to elucidating and understanding the identification and binding mechanisms of heavy metals with proteins, as well as possible risks on human beings and the environment.

Mass spectrometry-based metabolomics investigation on two different indica rice grains (Oryza sativa L.) under cadmium stress.

Cadmium is a toxic environmental pollutant that is readily absorbed by rice grains and poses serious threats to human health. The selection and breeding of rice varieties with low cadmium accumulation is one of the most economical and ecological methods to reduce cadmium exposure. In this study, two different indica rice grains under cadmium stress were subjected to mass spectrometry-based metabolomics analysis for the first time. When the cadmium concentration increased in rice grains, most carbohydrates and amino acids were down-regulated, except myoinositol that can prevent cadmium toxicity, which was up-regulated. d-Mannitol and l-cysteine were up-regulated with the increase of cadmium concentration in low-cadmium-accumulating rice. Also, organic acids were activated especially 13-(S)-hydroperoxy-9(Z),11(E),15(Z)-octadecatrienoicacid that is related to the alpha-linolenic acid metabolism and jasmonic acid production. The determination of biomarkers and characterization of metabolic pathways might be helpful for the selection of rice varieties with low cadmium accumulation.

Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. DESIGN: Network meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. MAIN OUTCOME MEASURES: Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. RESULTS: 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes. CONCLUSIONS: In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019153180.

Metabolomics and lipidomics study unveils the impact of polybrominated diphenyl ether-47 on breast cancer mice.

Polybrominated diphenyl ether-47 (BDE-47) is a congener of polybrominated diphenyl ethers (PBDEs) and relates to different health risks. However, in vivo study of the association between BDE-47 and breast cancer was scarce. In this study, we performed in vivo exposure of BDE-47 to breast cancer nude mice and conducted mass spectrometry-based metabolomics and lipidomics analysis to investigate the metabolic changes in mice. Results showed that the tumor sizes were positively associated with the dosage of BDE-47. Metabolomics and lipidomics profiling analysis indicated that BDE-47 induced significant alterations of metabolic pathways in livers, including glutathione metabolism, ascorbate and aldarate metabolism, and lipids metabolism, etc. The upregulations of phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) suggested the membrane remodeling, and the downregulations of Lyso-PCs and Lyso-PEs might be associated with the tumor growth. Targeted metabolomics analysis revealed that BDE-47 inhibited fatty acid ß-oxidation (FAO) and induced incomplete FAO. The inhibition of FAO and downregulation of PPARγ would contribute to inflammation, which could promote tumor growth. In addition, BDE-47 elevated the expression of the cytokines TNFRSF12A, TNF-α, IL-1ß and IL-6, and lowered the cytokines SOCS3 and the nuclear receptor PPARα. The changes of cytokines and receptor may contribute to the tumor growth of mice.

Chiral molecularly imprinted polymeric stir bar sorptive extraction for naproxen enantiomer detection in PPCPs.

Chiral micropollutant analysis in pharmaceuticals and personal care products (PPCPs) is interesting but challenging. We firstly developed a series of chiral molecularly imprinted polymeric (CMIP) stir bar sorptive extraction coatings by combining a chiral template with chiral functional monomers via a click reaction for naproxen enantiomer analysis in PPCPs. Heterochiral selectivity was observed in the molecule recognition of the CMIP coatings, which demonstrated good adsorption capability for the chiral template and its structurally similar chiral compounds. The coatings also exhibited excellent enrichment capability for chiral analytes in an aqueous matrix. The surface morphology and pore structure of the CMIP coatings were characterized. The molecular interactions between the chiral template and chiral functional monomer were investigated through UV-vis spectroscopy and theoretical calculations to prove the effective interactions existing in the heterochiral MIPs. The CMIP coatings were used to enrich naproxen enantiomers in chiral drug and environmental water samples, and satisfactory recoveries (83.98 %-118.88 %) with a relative standard deviation of 3.49 %-13.08 % were achieved. The heterochiral imprinted coating-based method provided a sensitive, selective, and effective enrichment strategy for chiral micropollutant analysis in PPCPs. This technique is critical for chiral molecule recognition and enantiomer analysis in complex samples.

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.