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Heme, an iron-containing porphyrin derivative, holds great promise in fields like medicine, food production and chemicals. Here, we developed an engineered Corynebacterium glutamicum strain for efficient heme production by combining modular engineering and RBS engineering. The whole heme biosynthetic pathway was methodically divided into 5-ALA synthetic module, uroporphyrinogen III (UPG III) synthetic module and heme synthetic module for further construction and optimization. Three heme synthetic modules were compared and the siroheme-dependent (SHD) pathway was identified to be optimal in C. glutamicum for the first time. To further improve heme production, the expression of genes in UPG III synthetic module and heme synthetic module was coordinated optimized through RBS engineering, respectively. Subsequently, heme oxygenase was knocked out to reduce heme degradation. The engineered strain HS12 showed a maximum iron-containing porphyrin derivatives titer of 1592 mg/L with the extracellular secretion rate of 45.5% in fed-batch fermentation. Our study constructed a C. glutamicum chassis strain for efficient heme accumulation, which was beneficial for the advancement of efficient heme and other porphyrins production.

Abstract Background Studies of the associations between soft drinks and the risk of cancer showed inconsistent results. No previous published systematic reviews and meta-analysis has investigated a dose–response association between exposure dose and cancer risk or assessed the certainty of currently available evidence. Therefore, we aim to demonstrate the associations and assessed the certainty of the evidence to show our confidence in the associations. Methods We searched Embase, PubMed, Web of Science, and the Cochrane Library from inception to Jun 2022, to include relevant prospective cohort studies. We used a restricted cubic spline model to conduct a dose–response meta-analysis and calculated the absolute effect estimates to present the results. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence. Results Forty-two articles including on 37 cohorts enrolled 4,518,547 participants were included. With low certainty evidence, increased consumption of sugar-sweetened beverages (SSBs) per 250 mL/day was significantly associated with a 17% greater risk of breast cancer, a 10% greater risk of colorectal cancer, a 30% greater risk of biliary tract cancer, and a 10% greater risk of prostate cancer; increased consumption of artificially sweetened beverages (ASBs)re per 250 mL/day was significantly associated with a 16% greater risk of leukemia; increased consumption of 100% fruit juice per 250 mL/day was significantly associated with a 31% greater risk of overall cancer, 22% greater risk of melanoma, 2% greater risk of squamous cell carcinoma, and 29% greater risk of thyroid cancer. The associations with other specific cancer were no significant. We found linear dose–response associations between consumption of SSBs and the risk of breast and kidney cancer, and between consumption of ASBs and 100% fruit juices and the risk of pancreatic cancer. Conclusions An increment in consumption of SSBs of 250 mL/day was positively associated with increased risk of breast, colorectal, and biliary tract cancer. Fruit juices consumption was also positively associated with the risk of overall cancer, thyroid cancer, and melanoma. The magnitude of absolute effects, however, was small and mainly based on low or very low certainty of evidence. The association of ASBs consumption with specific cancer risk was uncertain. Trial registration PROSPERO: CRD42020152223

Abstract The trip mechanism is a weakness in circuit breakers. Traditional fault identification based on the coil current is difficult to report early mechanical defects such as coil‐plunger jam. Here, the vibration signal during the trip process was extracted. Based on the coil current signal and vibration signal, the characteristics of the trip mechanism are analyzed. The phase space reconstruction (PSR) method is used to extract features from the vibration signal. Combined with the features from the coil current waveform, the feature set representing the health condition of the trip mechanism is proposed. The fault simulation tests are carried out and the variation of current vibration characteristics under fault conditions is studied. The fault identification model based on a support vector machine (SVM) is proposed and compared with the identification results when features are extracted from a single signal. When the power supply voltage is dispersed, the prediction accuracy of fault identification is 83.3% considering only the features of the current waveform or vibration signal. And the identification accuracy rises to 96.7% while using the feature set of current and vibration signals. On basis of the current signal, the method further combines the vibration signal so that the robustness of defect identification improves.

Backgrounds: Spontaneous preterm birth (SPB) is a global problem. Early screening, identification, and prevention in asymptomatic pregnant women with risk factors for preterm birth can help reduce the incidence and mortality of preterm births. Therefore, this study systematically reviewed prediction models for spontaneous preterm birth, summarised the model characteristics, and appraised their quality to identify the best-performing prediction model for clinical decision-making. Methods: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, VIP Database, and Wanfang Data were searched up to September 27, 2021. Prediction models for spontaneous preterm births in singleton asymptomatic pregnant women with risk factors were eligible for inclusion. Six independent reviewers selected the eligible studies and extracted data from the prediction models. The findings were summarised using descriptive statistics and visual plots. Results: Twelve studies with twelve developmental models were included. Discriminative performance was reported in 11 studies, with an Area Under the Curve (AUC) ranging from 0.75 to 0.95. The AUCs of the seven models were greater than 0.85. Cervical length (CL) is the most commonly used predictor of spontaneous preterm birth. A total of 91.7% of the studies had a high risk of bias in the analysis domain, mainly because of the small sample size and lack of adjustment for overfitting. Conclusion: The accuracy of the models for spontaneous preterm births in singleton asymptomatic women with risk factors was good. However, these models are not widely used in clinical practice because they lack replicability and transparency. Future studies should transparently report methodological details and consider more meaningful predictors with new progress in research on preterm birth.

BackgroundThe evidence from observational studies on the association between the use of aspirin and the risk of hayfever or allergic rhinitis is conflicting, with a dearth of high-quality randomized controlled trials.ObjectiveThis study aims to investigate the causal relationship between aspirin use and the risk of hayfever or allergic rhinitis.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We utilized publicly available summary statistics datasets from genome-wide association studies (GWAS) meta-analyses on aspirin use in individuals of European descent (n = 337,159) as the exposure variable, and a GWAS on doctor-diagnosed hayfever or allergic rhinitis in individuals from the UK Biobank (n = 83,529) as the outcome variable.ResultsWe identified 7 single nucleotide polymorphisms (SNPs) at genome-wide significance from the GWASs associated with aspirin use as instrumental variables (P

Background: Hyperemesis gravidarum is a serious pregnancy complication that affects approximately 1% of pregnancies worldwide.Objective: To determine whether the use of ondansetron during pregnancy is associated with abnormal pregnancy outcomes.Search strategy: PubMed, Cochrane Library, CINAHL, Embase, CNKI, CBM, WANFANG, and ClinicalTrials.gov were searched for citations published in any language from inception to 15 December 2021.Selection criteria: Eligible studies included any observational study.Data collection and analysis: Odds ratio (OR) and 95% confidence interval (CI) were used as indicators to examine the association between ondansetron and abnormal pregnancy outcomes.Main results: Twenty articles from 1,558 citations were included. Our preliminary analysis showed that compared with the unexposed group, the use of ondansetron during pregnancy may be associated with an increased incidence of cardiac defects (OR = 1.06, 95% CI: 1.01–1.10), neural tube defects (OR = 1.12, 95% CI: 1.05–1.18), and chest cleft (OR = 1.21, 95% CI: 1.07–1.37). Further sensitivity analysis showed no significant association between ondansetron and cardiac defects (OR = 1.15,95% CI: 0.94–1.40) or neural tube defects (OR = 0.87,95% CI: 0.46–1.66). When controversial studies were eliminated, the results for the chest defects disappeared. Simultaneously, we found that the use of ondansetron was associated with a reduced incidence of miscarriage (OR = 0.53, 95% CI: 0.31–0.89). Ondansetron was not associated with orofacial clefts (OR = 1.09,95% CI: 0.95–1.25), spinal limb defects (OR = 1.14,95% CI: 0.89–1.46), urinary tract deformities (OR = 1.06,95% CI: 0.97–1.15), any congenital malformations (OR = 1.03,95% CI: 0.98–1.09), stillbirth (OR = 0.97,95% CI: 0.83–1.15), preterm birth (OR = 1.22,95% CI: 0.80–1.85), neonatal asphyxia (OR = 1.05,95% CI: 0.72–1.54), or neonatal development (OR = 1.18,95% CI: 0.96–1.44) in our primary analysis.Conclusion: In our analysis, using ondansetron during pregnancy was not associated with abnormal pregnancy outcomes. Although our study did not find sufficient evidence of ondansetron and adverse pregnancy outcomes, future studies including the exposure period and dose of ondansetron, as well as controlling for disease status, may be useful to truly elucidate the potential risks and benefits of ondansetron.

Al2O3-bonded SiAlON ceramic with self-coating was prepared using aluminum dross and silicon solid waste as starting materials under ambient air conditions. The changes in phase, microstructure, and physical properties of the ceramic with temperature were analyzed and the formation mechanism of the SiAlON phase was elucidated. The results showed that higher temperature was more suitable for the preparation of SiAlON ceramics. As the temperature increased from 1400 to 1600 °C, the main phases in the ceramic transformed from mullite, Al2O3, and SiAlON to Al2O3 and SiAlON. An Al2O3-rich layer spontaneously coated the surface of the porous ceramic as Al melted and oxidized at high temperature. The thickness of this layer decreased as the temperature increased. The presence of Al2O3-rich coating layer impeded air flow, allowing nitriding of Si and Al, and the formation of the SiAlON phase in ambient air conditions. This study not only presents a strategy to successfully recycle aluminum dross and silicon solid waste but also offers a straightforward approach to preparing SiAlON material in air atmosphere.

Heme b, which is characterized by a ferrous ion and a porphyrin macrocycle, acts as a prosthetic group for many enzymes and contributes to various physiological processes. Consequently, it has wide applications in medicine, food, chemical production, and other burgeoning fields. Due to the shortcomings of chemical syntheses and bio-extraction techniques, alternative biotechnological methods have drawn increasing attention. In this review, we provide the first systematic summary of the progress in the microbial synthesis of heme b. Three different pathways are described in detail, and the metabolic engineering strategies for the biosynthesis of heme b via the protoporphyrin-dependent and coproporphyrin-dependent pathways are highlighted. The UV spectrophotometric detection of heme b is gradually being replaced by newly developed detection methods, such as HPLC and biosensors, and for the first time, this review summarizes the methods used in recent years. Finally, we discuss the future prospects, with an emphasis on the potential strategies for improving the biosynthesis of heme b and understanding the regulatory mechanisms for building efficient microbial cell factories.

IntroductionSeveral clinical practice guidelines (CPGs) for cancer pain have been published; however, the quality of these guidelines has not been evaluated so far. The purpose of this study was to evaluate the quality of CPGs for cancer pain and identify gaps limiting knowledge.MethodsWe systematically searched seven databases and 12 websites from their inception to July 20, 2021, to include CPGs related to cancer pain. We used the validated Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist to assess the methodology and reporting quality of eligible CPGs. The overall agreement among reviewers with the intraclass correlation coefficient (ICC) was calculated. The development methods of CPGs, strength of recommendations, and levels of evidence were determined.ResultsEighteen CPGs published from 1996 to 2021 were included. The overall consistency of the reviewers in each domain was acceptable (ICC from 0.76 to 0.95). According to the AGREE II assessment, only four CPGs were determined to be recommended without modifications. For reporting quality, the average reporting rates for all seven domains of CPGs was 57.46%, with the highest domain in domain 3 (evidence, 68.89%) and the lowest domain in domain 5 (review and quality assurance, 33.3%).ConclusionThe methodological quality of cancer pain CPGs fluctuated widely, and the complete reporting rate in some areas is very low. Researchers need to make greater efforts to provide high-quality guidelines in this field to clinical decision-making.

ABSTRACT The gut microbiota has been shown to be associated with multiple cardiovascular diseases, but there is little research on the gut microbiota and atrial fibrillation (AF); thus, how the gut microbiota and metabolites change in AF patients after catheter ablation is unclear. In this study, we used 16S rRNA high-throughput sequencing and nontargeted metabolomic detection to conduct horizontal and longitudinal analyses of the gut microbiota and metabolites of AF patients. Compared with a control group, species richness and diversity increased significantly in AF patients. Among them, opportunistic pathogenic bacteria, such as Klebsiella, Haemophilus, Streptococcus, and Enterococcus, were significantly increased, and symbiotic bacteria, such as Agathobacter and Butyrivibrio, were significantly reduced. After catheter ablation, intestinal symbiotic bacteria (Lactobacillus, Agathobacter, Lachnospira, etc.) were increased in most AF patients, while pathogenic bacteria (Ruminococcus, etc.) were reduced. Moreover, in AF patients, caffeine, which was negatively correlated with Klebsiella, was downregulated, and estradiol and ascorbic acid, which were positively correlated with Agathobacter, were also downregulated. After catheter ablation, citrulline, which was positively correlated with Ralstonia and Lactobacillus, was increased. Oleanolic acid, which was negatively correlated with Ralstonia was downregulated. In conclusion, our results not only show overall changes in the gut microbiota and metabolites in AF patients but also indicate their changes in the short term after catheter ablation. These data will provide novel possibilities for the future clinical diagnosis and treatment of AF. IMPORTANCE Gut microbiota and metabolites play a very important role in human health and can not only assess human health but also treat and prevent diseases. We analyzed the characteristics of the microbiota and metabolites in the human gut and found the effect of disease on gut microbiota and metabolites, which may be of important value in the pathogenesis of atrial fibrillation. At the same time, we also observed dynamic changes in gut microbiota and metabolites with the intervention of catheter ablation, which was not available in previous studies.

Background: Qingfei Paidu decoction (QFPD) has been widely used in treating COVID-19 in China. However, there is still a lack of comprehensive and systematic evidence to demonstrate the effectiveness and safety of QFPD. This study aims to evaluate the efficacy and safety of QFPD in patients with COVID-19.Methods: We searched seven databases up to 5 March 2021. Two reviewers independently screened studies, extracted data of interest, and assessed risk of bias. The Cochrane risk of bias tool was used to assess the risk of bias of randomized controlled trials. The Newcastle–Ottawa scale was used to assess the risk of bias of cohort and non-randomized trials. The “Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group” was adopted for controlled pre–post studies. We used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of evidence. We carried out a random effect meta-analysis using RevMan 5.3. For outcomes that could not be meta-analyzed, we performed a descriptive analysis.Results: We identified 16 studies with 11,237 patients, including one RCT, six non-randomized trials, two cohort studies, and seven pre–post studies. The certainty of evidence was low to very low because of the observational study design. QFPD combined with conventional treatment might decrease the time for nucleic acid conversion (MD = −4.78 days, 95% CI: −5.79 to −3.77), shorten the length of hospital stay (MD = −7.95 days, 95% CI: −14.66 to −1.24), shorten the duration of symptoms recovery of fever (MD = −1.51 days, 95% CI: −1.92 to −1.09), cough (MD = −1.64 days, 95% CI: −1.91 to −1.36) and chest CT (MD = −2.23 days, 95% CI: −2.46 to −2.00), improve the overall traditional Chinese medicine symptom scores (MD = 41.58 scores, 95% CI: 32.67 to 50.49), and change the laboratory indexes, such as WBC, AST, and CRP.Conclusion: QFPD combined with conventional treatment might be effective for patients with COVID-19. No serious adverse reactions related to QFPD were observed. Further high-quality studies are still needed in the future.

Abstract Background Oxidative stress and neuroinflammation are considered the major central events in the process of Parkinson’s disease (PD). Nrf2 is a key regulator of endogenous defense systems. New finds have contacted activation of Nrf2 signaling with anti-inflammatory activities. Therefore, the outstanding inhibition of neuroinflammation or potent Nrf2 signaling activation holds a promising strategy for PD treatment. Icariin (ICA), a natural compound derived from Herba Epimedii, presents a number of pharmacological properties, including anti-oxidation, anti-aging and anti-inflammatory actions. Recent studies have confirmed ICA exerted neuroprotection against neurodegenerative disorders. However, the underlying mechanisms were not fully elucidated. Methods In the present study, mouse nigral stereotaxic injection of 6-hydroxydopamine (6-OHDA)-induced PD model was performed to investigate ICA-conferred dopamine (DA) neuroprotection. In addition, adult Nrf2 knockout mice and primary rat midbrain neuron-glia co-culture was applied to elucidate whether ICA-exerted neuroprotection was through an Nrf2-dependent mechanism. Results Results indicated that ICA attenuated 6-OHDA-induced DA neurotoxicity and glial cells-mediated neuroinflammatory response. Furtherly, activation of Nrf2 signaling pathway in glial cells participated in ICA-produced neuroprotection, as revealed by the following observations. First, ICA enhanced Nrf2 signaling activation in 6-OHDA-induced mouse PD model. Second, ICA failed to generate DA neuroprotection and suppress glial cells-mediated pro-inflammatory factors production in Nrf2 knockout mice. Third, ICA exhibited neuroprotection in primary neuron-glia co-cultures but not in neuron-enriched cultures (without glial cells presence). Either, ICA-mediated neuroprotection was not discerned after Nrf2 siRNA treatment in neuron-glia co-cultures. Conclusions Our findings identify that ICA attenuated glial cells-mediated neuroinflammation and evoked DA neuroprotection via an Nrf2-dependent manner.

This paper aims at presenting a novel approach for the analysis of vibration signals detected from circuit breaker (CB) opening or closing operations and to mechanical fault identification. An adaptive signal decomposition approach and chaotic nonlinear dynamic technique are used for extracting fault sensitive features of CB. The fault sensitive frequency band is derived using variational mode decomposition (VMD) combining with Hilbert marginal spectrum (HMS). The obtained sensitive frequency band(s) are employed for the reconstruction of the dynamical attractor (chaotic dynamics viewed from a phase space perspective, namely, the attractor-based perspective) following the Taken's embedding theorem. The invariant measures and ergodic quantities such as the largest Lyapunov exponent, correlation dimension, and Kolmogorov entropy which can be estimated on the reconstructed attractor are presented as the fault sensitive features. The CB fault is estimated in a chaotic space using these sensitive features. The effectiveness of the developed method is evaluated by using data sets recorded from several vacuum CBs with the same type.

On-line monitoring and the diagnosis of the high-voltage circuit breaker (HVCB) have been discussed and investigated significantly in the past few decades. The vibration analysis is a noninvasive and advanced diagnostic technique suitable for the detection of mechanical conditions during the HVCB operation, which plays an important role in improving the operating reliability of HVCB and reduces maintenance costs. However, due to the very complicated mechanical system and extremely short operation time of HVCB, the vibration signal has the characteristics of highly nonlinear, non-stationary, and corrupted by heavy garbage noise, which makes it very difficult to precisely extract effective features for machinery fault diagnosis. To address this issue, an energy entropy of Hilbert marginal spectrum (HMS) based on variational mode decomposition (VMD) is presented to analyze the vibration signals of HVCB in this paper. The VMD is used to decompose the vibration signal into a set of intrinsic mode functions (IMFs) reflecting its local characteristics, and then, the energy entropy of IMF's HMS, which varies from different failure modes of HVCB, is obtained by Hilbert transform and entropy-information theory. The characteristics of IMF's HMS, which reveal the variation of vibration signals, under different failure modes of HVCB, are practically analyzed and examined to illustrate the advantage of the proposed method in feature extraction. The IMF that best reflects the mechanical anomaly information of HVCB is ascertained from IMF's HMS, and its Hilbert marginal spectrum energy entropy (HMSEE), namely, IMF-HMSEE, which synthetically reflects the variations of vibration signal's amplitude, phase, and frequency, is turned out to have excellent classification performance for some mechanical anomalies of HVCB. The effectiveness of the proposed approaches is substantiated by experiments carried out in a 12-kV vacuum HVCB.

Neurodegenerative diseases are characterized by progressive loss of selectively vulnerable neuronal populations, which contrasts with selectively static loss of neurons due to toxic or metabolic disorders. The mechanisms underlying their progressive nature remain unknown. To date, a timely and well-controlled peripheral inflammatory reaction is verified to be essential for neurodegenerative diseases remission. The influence of peripheral inflammation on the central nervous system is closely related to immune cells activation in peripheral blood. The immune cells activation participated in the uncontrolled and prolonged inflammation that drives the chronic progression of neurodegenerative diseases. Thus, the dynamic modulation of this peripheral inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases. This review focused on the role of peripheral immune cells on the pathological progression of neurodegenerative diseases.

The hybrid high-voltage direct current (HVDC) breaker combines mechanical and power electronics switching that enables it to interrupt power flows within a few milliseconds. Mechanical switch is a key component of hybrid HVDC breaker and has a number of serially connected interrupter units which ideally would divide the voltage equally. The static voltage distribution characteristics and voltage sharing design of a multi-break mechanical switch were discussed in this study. A finite-element model was developed to study the static voltage distribution characteristics and capacitance parameters of multi-break mechanical switch (which actually consists of resistance and capacitance parameters under direct current) as a preliminary study. Comparisons were made under the simulation of vertical and U-shaped arrangement forms. The results indicate that the static voltage distribution of the high-voltage terminal is at least more than 65%, whereas the severe non-uniform voltage distribution can be well improved by means of the method proposed in this study.

The aim of this study was to evaluate the antioxidant activities of extracts from olive leaves (EOL). The main contents of EOL were determined by colorimetric methods. The antioxidant activities were assessed by measuring the scavenging free radicals in vitro. To investigate the antioxidant activity in vivo, we detected the survival of Caenorhabditis elegans, under thermal stress. Subsequently the reactive oxygen species (ROS) level, activities of antioxidant enzymes, the expression of HSP-16.2 and the translocation of daf-16 were measured. The results showed that, polyphenols was the main component. EOL could well scavenge DPPH and superoxide anion radicals in vitro. Compared to the control group, the survival rate of C. elegans treated with EOL was extended by 10.43%, under heat stress. The ROS level was reduced, while the expression of hsp-16.2 was increased to protect the organism against the increasing ROS. The level of malondialdehyde (MDA) also decreased sharply. The activities of inner antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) were potentiated, which might have had a correlation with the DAF-16 transcription factor that was induced-turned into the nuclear. Therefore, EOL showed a strong antioxidant ability in vitro and in vivo. Hence, it could be a potential candidate when it came to medicinal and edible plants.

处理由偏微分方程描述的新的平面曲线流:，χ(μ,0）= χ0(μ).当初始曲线χ0(μ)是凸的Jordan曲线和β(κ)满足适当的条件时,应用偏微分方程中的最大值原理和先验估计,证明了发展曲线的周长和面积同时收缩,最终它们都收缩到一点.