Physical Model of Inclusions Removal at Static Steel-Slag Interface.

Inclusions are one of the important factors affecting the cleanliness of molten steel. The current optimization of inclusion removal methods mainly focuses on promoting inclusions to float to the slag-steel interface so that the inclusions can be absorbed and removed by the refining slag. However, the research on the floating removal of inclusions cannot be carried out directly in the ladle, so methods such as mathematical models and physical models were developed. This article uses silicone oil to simulate the slag layer; polypropylene particles; and aluminum oxide particles to simulate inclusions to establish a water model experiment. By changing the viscosity of silicone oil and the diameter of particles, the factors affecting the movement of inclusions at the slag-steel interface were explored. Based on the water model, a mathematical model of the floating behavior of inclusions at the slag-steel interface was constructed, and parameters such as particle diameter and interfacial tension in the water model experiment were studied by the mathematical model for calculation. Both the mathematical model and the water model experimental results show that after the viscosity of silicone oil increases from 0.048 Pa·s to 0.096 Pa·s, the dimensionless displacement and terminal velocity of the particles decreases. When the diameter of the same particle increases, the dimensionless displacement and terminal velocity increases. The dimensionless displacement of polypropylene particles of the same diameter is larger than that of aluminum oxide particles, and the terminal velocity is smaller than that of aluminum oxide particles. This is attributed to the better overall three-phase wettability of polypropylene particle. When the liquid level increases, the dimensionless displacement and terminal velocity of particles under the same conditions show only slight differences (less than 10%).

Designing and preparing supramolecular encapsulation systems based on fraxetin and cyclodextrins for highly selective detection of nicotine.

Herein, a series of water-soluble supramolecular inclusion complexes (ICs) probes were prepared using cyclodextrins (CDs) and fraxetin (FRA) to detect nicotine (NT) with high selectivity in vitro and in vivo. The FRA/CD ICs prepared through the saturated solution method exhibited excellent water solubility, stability, and biocompatibility. A clear host-guest inclusion model was provided by the theoretical calculations. The investigation revealed that NT was able to enter into the cavities of FRA/ß-CD IC and FRA/γ-CD IC, and further formed charge transfer complexes with FRA in the CD cavities, resulting in a rapid and highly selective fluorescence-enhanced response with the lowest detection limits of 1.9 × 10-6 M and 9.7 × 10-7 M, and the linear response ranged from 0.02 to 0.3 mM and 0.01-0.05 mM, respectively. The IC probes showed good anti-interference performance to common interferents or different pH environments, with satisfactory reproducibility and repeatability of response to NT. Furthermore, the potentiality of the probes was confirmed through fluorescence imaging experiments using human lung cancer cells and the lung tissue of mice. This study offers a fresh perspective for detecting NT in environmental and biomedical analysis.

The effect of luteinizing hormone changes in GnRH antagonist protocol on the outcome of controlled ovarian hyperstimulation and embryo transfer.

BACKGROUD: To investigate the effect of Luteinizing hormone (LH) level changes on the outcomes of controlled ovarian hyperstimulation (COH) and embryo transfer (ET) in gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. METHODS: A total of 721 patients undergoing GnRH-ant protocol COH for the first IVF/ICSI cycles were retrospectively analyzed. COH process were divided into 2 stages, before (stage 1) and after (stage 2) the GnRH-ant initiation, and each with 5 groups basing on LH levels: LH decreased more than 50% (groups A1, A2), decreased 25-50% (groups B1, B2), change less than 25% (groups C1, C2), increased 25-50% (groups D1, D2), and increased more than 50% (groups E1, E2). RESULTS: There were no significant differences among groups of stage1 regarding COH and ET outcomes. For stage 2, the more obvious the decrease of LH level, the more the number of oocytes retrieved, mature oocytes, fertilized oocytes, embryos cleavaged and the numbers of embryo available (P < 0.05), but without significant differences regarding ET outcomes. We also found the freeze-all rate in Group A2 was higher (P < 0.001). CONCLUSION: LH level changes before GnRH-ant addition were not related to COH and ET outcomes. LH level changes after the addition of GnRH-ant were related to the outcome of COH, and no significant differences were found relating to ET outcomes.

Induced Pluripotent Stem Cells for Tissue-Engineered Skeletal Muscles.

Skeletal muscle, which comprises a significant portion of the body, is responsible for vital functions such as movement, metabolism, and overall health. However, severe injuries often result in volumetric muscle loss (VML) and compromise the regenerative capacity of the muscle. Tissue-engineered muscles offer a potential solution to address lost or damaged muscle tissue, thereby restoring muscle function and improving patients' quality of life. Induced pluripotent stem cells (iPSCs) have emerged as a valuable cell source for muscle tissue engineering due to their pluripotency and self-renewal capacity, enabling the construction of tissue-engineered artificial skeletal muscles with applications in transplantation, disease modelling, and bio-hybrid robots. Next-generation iPSC-based models have the potential to revolutionize drug discovery by offering personalized muscle cells for testing, reducing reliance on animal models. This review provides a comprehensive overview of iPSCs in tissue-engineered artificial skeletal muscles, highlighting the advancements, applications, advantages, and challenges for clinical translation. We also discussed overcoming limitations and considerations in differentiation protocols, characterization methods, large-scale production, and translational regulations. By tackling these challenges, iPSCs can unlock transformative advancements in muscle tissue engineering and therapeutic interventions for the future.

Metabolic Signature of Healthy Lifestyle and Risk of Rheumatoid Arthritis: Observational and Mendelian Randomization Study.

BACKGROUND: Although substantial evidence reveals that healthy lifestyle behaviors are associated with a lower risk of rheumatoid arthritis (RA), the underlying metabolic mechanisms remain unclear. OBJECTIVES: This study aimed to identify the metabolic signature reflecting a healthy lifestyle and investigate its observational and genetic linkage with RA risk. METHODS: This study included 87,258 UK Biobank participants (557 cases with incident RA) aged 37-73 y with complete lifestyle, genotyping, and nuclear magnetic resonance (NMR) metabolomics data. A healthy lifestyle was assessed based on 5 factors: healthy diet, regular exercise, not smoking, moderate alcohol consumption, and normal body mass index. The metabolic signature was developed by summing the selected metabolites' concentrations weighted by the coefficients using elastic net regression. We used the multivariate Cox model to assess the associations between metabolic signatures and RA risk, and examined the mediating role of the metabolic signature in the impact of a healthy lifestyle on RA. We performed genome-wide association analysis (GWAS) to obtain genetic variants associated with the metabolic signature and then conducted Mendelian randomization (MR) analyses to detect causality. RESULTS: The metabolic signature comprised 81 metabolites, robustly correlated with a healthy lifestyle (r = 0.45, P = 4.2 × 10-15). The metabolic signature was inversely associated with RA risk (HR per standard deviation (SD) increment: 0.76; 95% CI: 0.70-0.83), and largely explained the protective effects of healthy lifestyle on RA with 64% (95% CI: 50.4-83.3) mediation proportion. 1- and 2-sample MR analyses also consistently showed the associations of genetically inferred per SD increment in metabolic signature with a reduction in RA risk (HR: 0.84; 95% CI: 0.75-0.94; and P = 0.002 and OR: 0.84; 95% CI: 0.73-0.97; and P = 0.02, respectively). CONCLUSIONS: Our findings implicate that the metabolic signature reflecting healthy lifestyle is a potential causal mediator in the development of RA, highlighting the importance of early lifestyle intervention and metabolic status tracking for precise prevention of RA.

A promising prognostic model for predicting survival of patients with HIV-related diffuse large B-cell lymphoma in the cART era.

BACKGROUND: Optimization of risk stratification is important for facilitating prognoses and therapeutic decisions regarding diffuse large B-cell lymphoma (DLBCL). However, a simple and applicable prognostic tool is lacking for individuals with human immunodeficiency virus (HIV)-related DLBCL in the era of combined antiretroviral therapy (cART). METHODS: This retrospective multicenter observational study included 147 HIV-related DLBCL patients with histologically confirmed DLBCL from 2013 to 2020. The total group was divided into training (n = 78) and validation (n = 69) cohorts to derive the best prognostic score. Clinicopathological and characteristic biomarkers correlated with clinical outcomes were analyzed. RESULTS: Age, Ann Arbor stage, lactate dehydrogenase (LDH) ratio, bulky disease, and red blood cell distribution width (RDW) ratio retained robust independent correlations with overall survival (OS) in multivariate analysis. A new and practical prognostic model was generated and externally validated, classifying patients into three categories with significantly different survival rates. Moreover, the new index outperformed the International Prognostic Index (IPI) score (area under the curve values of 0.94 vs. 0.81 in the training cohort and 0.85 vs. 0.74 in the validation cohort, C-indices of 0.80 vs. 0.70 in the training cohort and 0.74 vs. 0.70 in the validation cohort, and integrated discrimination improvement values of 0.203 in the training cohort and 0.175 in the validation cohort) and was better at defining intermediate- and high-risk groups. The calibration curves performed satisfactorily for predicting 3-year OS in the training and validation cohorts. CONCLUSIONS: We developed and validated a simple and feasible prognostic model for patients with HIV-related DLBCL that had more discriminative and predictive accuracy than the IPI score for risk stratification and individualized treatment in the cART era.

Structures of the human Wilson disease copper transporter ATP7B.

The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-Pi state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD.

Nicotine in Complex Samples: Recent Updates on the Pretreatment and Analysis Method.

Nicotine is a significant evaluation index of tobacco and its related products' quality, but nicotine overdose can pose serious health hazards and cause addiction and dependence, thus it can be seen that it is necessary to find suitable and efficient detection methods to precisely detect nicotine in diverse samples and complex matrices. In this review, an updated summary of the latest trends in pretreatment and analytical techniques for nicotine is provided. We reviewed various sample pretreatment methods, such as solid phase extraction, solid phase microextraction, liquid phase microextraction, QuEChERS, etc., and diverse nicotine assay methods including liquid chromatography, gas chromatography, electrochemical sensors, etc., focusing on the developments since 2015. Furthermore, the recent progress in the applications and applicability of these techniques as well as our prospects for future developments are discussed.HighlightsUpdated pretreatment and analysis methods of nicotine were systematically summarized.Microextraction and automation were main development trends of nicotine pretreatment.The introduction of novel materials added luster to nicotine pretreatment.The evolutions of ion source and mass analyzer were emphasized.

Comparative transcriptome analysis of Monascus purpureus at different fermentation times revealed candidate genes involved in exopolysaccharide biosynthesis.

Exopolysaccharides (EPS), metabolites of the medicinal edible fungus Monascus purpureus, have antioxidant, immunomodulatory, and anti-inflammatory effects. However, the biosynthetic mechanism of EPS from M. purpureus is still unclear, which hinders its utilization. In this study, the fermentation conditions of M. purpureus were optimized and comparative transcriptomic analysis was performed to understand the mechanisms and effects of fermentation on EPS synthesis. The optimal medium composition was 40 g/L mannose, 4 g/L yeast powder, 1 g/L MgSO4·7H2O, 0.8 g/L KH2PO4, 1.6 g/L K2HPO4·3H2O, and 2 mL/L Tween 80, and the optimal cultivation conditions were an inoculum of 7 %, culture temperature 30 °C, initial pH 6.0, and 180 rpm for 4 d. A total of 8095 unigenes were obtained, and 17 key enzymes for EPS synthesis were identified. Interestingly, 12 carbohydrate metabolism subcategories were enriched in the group with 4 days of fermentation compared to 2 days, with most of the differentially expressed genes (DEGs) being upregulated, but only nine carbohydrate metabolism subcategories were enriched with longer fermentation time, with all DEGs being downregulated. This study provides a theoretical basis for enhancing the EPS content and reveals the dynamics of EPS synthesis in M. purpureus, providing important targets for future EPS molecular modifications and gene knockdown studies.

Efficacy of ω-3 Polyunsaturated Fatty Acids in Patients with Lung Cancer Undergoing Radiotherapy and Chemotherapy: A Meta-Analysis.

Background: Radiotherapy and chemotherapy in patients with lung cancer can lead to a series of problems such as malnutrition and inflammatory reaction. Some studies have shown that ω-3 polyunsaturated fatty acids (PUFAs) could improve malnutrition and regulate inflammatory reaction in these patients, but no relevant meta-analysis exists. Methods: We systematically searched randomized controlled trials of ω-3 PUFAs in the adjuvant treatment of lung cancer in the PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang databases. Relevant outcomes were extracted, and we pooled standardized mean differences (SMDs) using a random or fixed-effects model. The risk of bias was evaluated according to the Cochrane Handbook (version 15.1). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: A total of 7 studies were included. The SMDs (95% CI) of body weight change, albumin change, energy intake, and protein intake at the end of intervention were 1.15 (0.50, 1.80), 0.60 (0.11, 1.09), 0.39 (-0.10, 0.89), and 0.27 (-0.04, 0.58), respectively. The SMDs (95% CI) of CRP change and TNF-α change were -3.44 (-6.15, -0.73) and -1.63 (-2.53, -0.73), respectively. Conclusions: ω-3 PUFAs can improve nutritional status and regulate indicators of inflammation in patients with lung cancer undergoing radiotherapy and chemotherapy. This study was registered in the PROSPERO (registration number: CRD42022307699).

Multiplexed site-specific genome engineering in Mycolicibacterium neoaurum by Att/Int system.

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

PpybZIP43 contributes to sucrose synthesis in pear fruits by activating PpySPS3 expression and interacts with PpySTOP1.

Sucrose is an important factor affecting sweetness and flavor in pear fruits, but the molecular mechanism of sucrose synthesis regulation is relatively unknown. Here, we characterized a transcription factor gene from pear (Pyrus pyrifolia Nakai cv. "Hosui") fruits, PpybZIP43, and found that the transient overexpression of PpybZIP43 in pear fruits significantly increased the sucrose content and the relative expression level of sucrose phosphate synthase genes (PpySPS3 and PpySPS8). Subcellular localization analysis in tobacco leaves showed that PpybZIP43 was localized in the nucleus. Yeast one-hybrid, electrophoretic mobility shift assay (EMSA), and dual-luciferase reporter assays indicated that PpybZIP43 was able to activate the expression of PpySPS3 by binding specifically to the G-box (CACGTG) element in the promoter. The protein-protein interaction assays using yeast two-hybrid, bimolecular fluorescence complementation (BiFC), firefly luciferase complementation imaging (LCI), and glutathione S-transferase (GST) pull-down demonstrated that PpybZIP43 could directly interact with PpySTOP1 to form a transcription complex. This study is helpful for understanding the molecular basis of sucrose synthesis and accumulation in pear fruits and provides candidate genes for breeding.

ExpressVis: a biologist-oriented interactive web server for exploring multi-omics data.

In the era of life-omics, huge amounts of multi-omics data have been generated and widely used in biomedical research. It is challenging for biologists with limited programming skills to obtain biological insights from multi-omics data. Thus, a biologist-oriented platform containing visualization functions is needed to make complex omics data digestible. Here, we propose an easy-to-use, interactive web server named ExpressVis. In ExpressVis, users can prepare datasets; perform differential expression analysis, clustering analysis, and survival analysis; and integrate expression data with protein-protein interaction networks and pathway maps. These analyses are organized into six modules. Users can use each module independently or use several modules interactively. ExpressVis displays analysis results in interactive figures and tables, and provides comprehensive interactive operations in each figure and table, between figures or tables in each module, and among different modules. It is freely accessible at https://omicsmining.ncpsb.org.cn/ExpressVis and does not require login. To test the performance of ExpressVis for multi-omics studies of clinical cohorts, we re-analyzed a published hepatocellular carcinoma dataset and reproduced their main findings, suggesting that ExpressVis is convenient enough to analyze multi-omics data. Based on its complete analysis processes and unique interactive operations, ExpressVis provides an easy-to-use solution for exploring multi-omics data.

Diagnosis of Cardiac Amyloidosis Using a Radiomics Approach Applied to Late Gadolinium-Enhanced Cardiac Magnetic Resonance Images: A Retrospective, Multicohort, Diagnostic Study.

Objectives: To assess the potential of a radiomics approach of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) in the diagnosis of cardiac amyloidosis (CA). Materials and Methods: This retrospective study included 200 patients with biopsy-proven light-chain (AL) amyloidosis. CA was diagnosed on the basis of systemic amyloidosis confirmed with evidence of cardiac involvement by imaging and clinical biomarkers. A total of 139 patients [54 ± 8 years, 75 (54%) men] in our institution were divided into training cohort [n = 97, mean age of 53 ± 8 years, 54 (56%) men] and internal validation cohort [n = 42, mean age: 56 ± 8 years, 21 (50%) men] with a ratio of 7:3, while 61 patients [mean age: 60 ± 9 years, 42 (69%) men] from the other two institutions were enrolled for external validation. Radiomics features were extracted from global (all short-axis images from base-to-apex) left ventricular (LV) myocardium and three different segments (basal, midventricular, and apex) on short-axis LGE images using the phase-sensitive reconstruction (PSIR) sequence. The Boruta algorithm was used to select the radiomics features. This model was built using the XGBoost algorithm. The two readers performed qualitative and semiquantitative assessment of the LGE images based on the visual LGE patterns, while the quantitative assessment was measured using a dedicated semi-automatic CMR software. The diagnostic performance of the radiomics and other qualitative and quantitative parameters were compared by a receiver operating characteristic (ROC) curve analysis. A correlation between radiomics and the degree of myocardial involvement by amyloidosis was tested. Results: A total of 1,906 radiomics features were extracted for each LV section. No statistical significance was indicated between any two slices for diagnosing CA, and the highest area under the curve (AUC) was found in basal section {0.92 [95% confidence interval (CI), 0.86-0.97] in the LGE images in the training set, 0.89 (95% CI, 0.79-1.00) in the internal validation set, and 0.92 (95% CI, 0.85-0.99) in the external validation set}, which was superior to the visual assessment and quantitative LGE parameters. Moderate correlations between global or basal radiomics scores (Rad-scores) and Mayo stage in all patients were reported (Spearman's Rho = 0.61, 0.62; all p < 0.01). Conclusion: A radiomics analysis of the LGE images provides incremental information compared with the visual assessment and quantitative parameters on CMR to diagnose CA. Radiomics was moderately correlated with the severity of CA. Further studies are needed to assess the prognostic significance of radiomics in patients with CA.

The concordance rates of an initial trophectoderm biopsy with the rest of the embryo using PGTseq, a targeted next-generation sequencing platform for preimplantation genetic testing-aneuploidy.

OBJECTIVE: To determine how often the results of a single trophectoderm (TE) biopsy tested by PGTseq, a targeted next-generation sequencing preimplantation genetic testing for aneuploidy technology, reflect the biology of the rest of the embryo. DESIGN: Blinded prospective cohort study. SETTING: University-affiliated private practice. PATIENT(S): A total of 300 blastocysts were donated; 113 of these embryos were euploid; 163 embryos possessed at least one whole chromosome aneuploidy; and 24 embryos were negative for whole chromosome aneuploidy but possessed at least one secondary finding on initial TE biopsy. INTERVENTION(S): All blastocysts underwent rebiopsy and preimplantation genetic testing for aneuploidy on the PGTseq platform. MAIN OUTCOME MEASURE(S): Partial concordance rate per embryo, total concordance rate per embryo, and total concordance rate per chromosomal event. RESULT(S): An initial TE biopsy result of euploidy or whole chromosome aneuploidy was reconfirmed in >99% of rebiopsied samples, affirming that meiotic errors are manifested in almost the entire embryo. In contrast, results of whole chromosome or segmental mosaicism were confirmed in 15%-18% of subsequent rebiopsies, suggesting that mitotic events are only sporadically seen throughout the embryo. Segmental aneuploidy was confirmed in 56.6% of rebiopsied samples, identifying a mixed meiotic and mitotic etiology for such abnormalities. CONCLUSION(S): A euploid or aneuploid result on the PGTseq platform is highly concordant with the rest of the embryo's ploidy status. The rarer confirmation of whole chromosome mosaic and segmental mosaic results suggest that these mosaics are suitable for embryo transfer. Segmental aneuploidy, with higher concordance rates throughout the embryo, may represent a different biologic etiology compared to mosaic embryos.

Radiomics from Primary Tumor on Dual-Energy CT Derived Iodine Maps can Predict Cervical Lymph Node Metastasis in Papillary Thyroid Cancer.

RATIONALE AND OBJECTIVES: To develop and validate 2 iodine maps based radiomics nomograms for preoperatively predicting cervical lymph node metastasis (LNM) and central lymph node metastasis (CLNM) in papillary thyroid cancer (PTC). MATERIALS AND METHODS: A total of 346 patients with PTC were enrolled and allocated to training (242) and validation (104) sets. Radiomics features were extracted from arterial and venous phase iodine maps, respectively. Aggregated machine-learning strategy was applied for features selection and construction of 2 radiomics scores (LN rad-score; CLN rad-score). Logistic regression model was employed to establish two radiomics nomograms (nomogram 1: predicting LNM; nomogram 2: predicting CLNM) after incorporating LN or CLN rad-score with clinical predictors. Nomograms performance was determined by discrimination, calibration and clinical usefulness. RESULTS: Nomogram 1 incorporated LN rad-score, age (categorized by 55) and CT reported LN status; Nomogram 2 incorporated CLN rad-score, capsule contact >25% and CT reported CLN status. 2 nomograms both showed good discrimination and calibration in the training (AUC = 0.847; AUC = 0.837) and validation cohorts (AUC = 0.807; AUC = 0.795). Significant improved AUC, net reclassification index (NRI) and integrated discriminatory improvement (IDI) confirmed additional great predictive value of 2 rad-scores, compared with clinical models without radiomics. Decision curve analysis indicated clinical utility of nomograms. 2 nomograms both demonstrated favorable predictive efficacy in CT reported LN or CLN negative subgroup (AUC = 0.766; AUC = 0.744). CONCLUSION: The presented 2 radiomics nomograms are useful tools for preoperative prediction of LNM and CLNM in PTC.

Structure-guided engineering of a flavin-containing monooxygenase for the efficient production of indirubin.

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

Physical Therapies for Psychosomatic Symptoms and Quality of Life Induced by Aromatase Inhibitors in Breast Cancer Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the effects of Physical Therapies (PTs) on improvement in psychosomatic symptoms and quality of life (QOL) in breast cancer patients. DATA SOURCES: Seven databases (MEDLINE, EMBASE, Cochrane CENTRAL, China National Knowledge Infrastructure, Wangfang, VIP, and China Biology Medicine disc databases) were systematically searched from the database inception through May 18, 2021. STUDY SELECTION: Randomized controlled trials (RCTs) which compared acupuncture or exercise with a sham control or usual care for the treatment of aromatase inhibitors (AIs)-related psychosomatic symptoms and QOL. DATA EXTRACTION AND SYNTHESIS: Data were screened and extracted independently using predesigned forms. The quality of RCTs was assessed with the Cochrane Handbook for Systematic Reviews of Interventions. The effect size was calculated via random-effects modeling. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. MAIN OUTCOMES AND MEASURES: The score of pain was measured with BPI scale and Western Ontario and the McMaster Universities Index (WOMAC) scale. Emotional state was measured with Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS-A), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). The QOL score was measured by self-reported measurements, including the Functional Assessment of Cancer Therapy-General (FACT-G) scale and 36-Item Short Form Survey (SF-36) scale. RESULTS: Eleven RCTs (with 830 patients) were included in the systematic review, and data from 10 RCTs (with 798 patients) were used in the meta-analysis. Results showed acupuncture significantly reduced worst pain scores (P < 0.00001, I 2 = 83.5%) [SMD = -0.81, 95% CI (-1.51, -0.11)], but the effect of exercise therapies was not significant in overall change in worst pain scores (P =0.006, I 2 = 72.3%) [SMD = -0.30, 95% CI (-0.76, 0.16)]. Both acupuncture and exercise resulted in little to no difference in overall change in HADS-A subscale (P = 0.026<0.05, I 2 = 79.8%) [WMD = -0.21, 95% CI (-3.44, 3.03)], PSQI subscale (P = 0.488, I 2 = 0%) [WMD = 0.98, 95% CI (-0.57, 2.53)], and FACIT-Fatigue subscale (P = 0.022<0.05, I 2 = 81.0%) [WMD = 1.6, 95% CI (-5.75, 8.94)]. Exercise (compared with usual care) was associated with improving overall change in health-related QOL (subscales of SF-36 tool) (P = 0, I 2 = 72.1%) [WMD = 7.97, 95% CI (5.68, 10.25)] and cancer-specific QOL (subscales of FACT-G tool) (P = 0.304, I 2 = 16%) [WMD = 1.16, 95% CI (0.34, 1.97)]. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis suggested that based on moderate-level evidence, acupuncture was associated with significant reductions in pain intensity, and exercise might improve QOL in breast cancer patients treated with AIs. However, in psychosomatic symptoms such as anxiety, sleep disturbance, and fatigue, acupuncture and exercise training did not result in significant improvements.

Analysis of right ventricular flow with 4-dimensional flow cardiovascular magnetic resonance imaging in patients with pulmonary arterial hypertension.

BACKGROUND: Cardiac flow closely interact with function, however, the correlation of right ventricular (RV) flow and function remains unknown, thus our objective is to observe right ventricular flow with four-dimensional phase-contrast cardiovascular magnetic resonance imaging (4D flow CMR) in patients with pulmonary arterial hypertension (PAH) and to analyze flow components with RV function and hemodynamics. METHODS: This study retrospectively enrolled 30 patients with PAH (mean age: 49±13 years, 16 females) and 14 age- and sex-matched healthy volunteers as controls (mean age: 44±12 years, 9 females). All patients who underwent CMR and right heart catheterization (RHC) within 1 week between January 2019 and July 2020 were included. Hemodynamics were measured with RHC. RV flow components, including the percentages of direct flow (RVPDF), retained inflow (RVPRI), delayed ejection flow (RVPDEF) and residual volume (RVPRVo) were quantified using 4D flow CMR. The associations between RV flow components and other CMR metrics, clinical data, and hemodynamics were analyzed by Spearman's correlation analysis. RESULTS: In patients with PAH, RVPDF was decreased and RVPRVo was increased compared with the normal control group. The sum of RVPDF and RVPDEF RV was significantly correlated with RV ejection fraction (RVEF) (r=0.802, P<0.001), and there was no notable difference between RVEF and the sum of RVPDF and RVPDEF (t=0.251, P=0.831). Both RVPDF and RVPRVo were correlated (in opposite directions) with the RV end-diastolic volume index, RV end-systolic volume index, RV global longitudinal strain, and RVEF. RVPDF was negatively correlated with pulmonary vascular resistance (PVR), and positively correlated with cardiac output and cardiac index. RVPRVo was positively correlated with PVR and negatively correlated with cardiac output and cardiac index. CONCLUSIONS: RV blood flow components qualified with 4D flow CMR is a valuable noninvasive method for the assessment of RV function and hemodynamics in patients with PAH.

Feasibility study of using virtual non-contrast images derived from dual-energy CT to replace true non-contrast images in patients diagnosed with papillary thyroid carcinoma.

OBJECTIVE: To assess the feasibility of using virtual non-contrast (VNC) images derived from dual-energy computed tomography (DECT) to replace true non-contrast (TNC) images of papillary thyroid carcinoma (PTC) patients. METHODS: Images of 96 PTC patients were retrospectively analyzed. TNC images were acquired under the single-energy mode of DECT after the plain scanning. The arterial and venous phase VNC (VNC-a and VNC-v) images were generated by the post-processing algorithm from the arterial phase and venous phase of contrast-enhanced CT images, respectively. Mean attenuation values, image noise, number and length of calcification were measured. Radiation dose was also calculated. Last, subjective score of image quality was evaluated by a 5-point scale. RESULTS: Signal-to-noise ratio (SNR) of each tissue in TNC images is significantly higher than that of VNC images (p<0.050). Contrast-to-noise ratio (CNR) of fat, muscle, thyroid nodules and internal carotid artery in TNC images is significantly higher than that of VNC images, while CNR in TNC images is lower for cervical vertebra (p<0.001). Calcification is detected on TNC images of 44 patients, while it is omitted on VNC images of 14 patients (31.8%). The subjective score of TNC images is higher than VNC images (p<0.001). The effective dose reduction is 47.6% by avoiding plain scanning. CONCLUSIONS: Considering the different attenuation value, SNR, CNR and especially reduced detection rate of calcification, we deem that VNC images cannot be directly used to replace TNC images in PTC patients, despite the reduced radiation dose.