Catalytic asymmetric carbenoid α-C-H insertion of ether.

Significant advancements have been made in catalytic asymmetric α-C-H bond functionalization of ethers via carbenoid insertion over the past decade. Effective asymmetric catalytic systems, featuring a range of chiral metal catalysts, have been established for the enantioselective synthesis of diverse ether substrates. This has led to the generation of various enantioenriched, highly functionalized oxygen-containing structural motifs, facilitating their application in the asymmetric synthesis of bioactive natural products.

In vivo Labeling and Intravital Imaging of Bacterial Infection using a Near-infrared Fluorescent D-Amino Acid Probe.

Bacterial infections still pose a severe threat to public health, necessitating novel tools for real-time analysis of microbial behaviors in living organisms. While genetically engineered strains with fluorescent or luminescent reporters are commonly used in tracking bacteria, their in vivo uses are often limited. Here, we report a near-infrared fluorescent D-amino acid (FDAA) probe, Cy7ADA, for in situ labeling and intravital imaging of bacterial infections in mice. Cy7ADA probe effectively labels various bacteria in vitro and pathogenic Staphylococcus aureus in mice after intraperitoneal injection. Because of Cy7's high tissue penetration and the quick excretion of free probes via urine, real-time visualization of the pathogens in a liver abscess model via intravital confocal microscopy is achieved. The biodistributions, including their intracellular localization within Kupffer cells, are revealed. Monitoring bacterial responses to antibiotics also demonstrates Cy7ADA's capability to reflect the bacterial load dynamics within the host. Furthermore, Cy7ADA facilitates three-dimensional pathogen imaging in tissuecleared liver samples, showcasing its potential for studying the biogeography of microbes in different organs. Integrating nearinfrared FDAA probes with intravital microscopy holds promise for wide applications in studying bacterial infections in vivo.

Efficacy of early administration of sacubitril/valsartan after coronary artery revascularization in patients with acute myocardial infarction complicated by moderate-to-severe mitral regurgitation: a randomized controlled trial.

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12 months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12 months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1 month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12 months (MRJA: - 3.21 ± 2.18 cm2 vs. - 1.83 ± 2.81 cm2, P < 0.05; MRV: - 27.22 ± 15.22 mL vs. - 13.67 ± 21.02 mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12-3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021.

Discovery of a Meisoindigo-Derived PROTAC as the ATM Degrader: Revolutionizing Colorectal Cancer Therapy via Synthetic Lethality with ATR Inhibitors.

Meisoindigo (Mei) has long been recognized in chronic myeloid leukemia (CML) treatment. To elucidate its molecular target and mechanisms, we embarked on designing and synthesizing a series of Mei-derived PROTACs. Through this endeavor, VHL-type PROTAC 9b was identified to be highly cytotoxic against SW620, SW480, and K562 cells. Employing DiaPASEF-based quantitative proteomic analysis, in combination with extensive validation assays, we unveiled that 9b potently and selectively degraded ATM across SW620 and SW480 cells in a ubiquitin-proteasome-dependent manner. 9b-induced selective ATM degradation prompted DNA damage response cascades, thereby leading to the cell cycle arrest and cell apoptosis. This pioneering discovery renders the advent of ATM degradation for anti-cancer therapy. Notably, 9b-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both in vitro and in vivo. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.

Leveraging multimodal MRI-based radiomics analysis with diverse machine learning models to evaluate lymphovascular invasion in clinically node-negative breast cancer.

Objective: This study aimed to investigate and validate the effectiveness of diverse radiomics models for preoperatively differentiating lymphovascular invasion (LVI) in clinically node-negative breast cancer (BC). Methods: This study included 198 patients diagnosed with clinically node-negative bc and pathologically confirmed LVI status from January 2018-July 2023. The training dataset consisted of 138 patients, while the validation dataset included 60. Radiomics features were extracted from multimodal magnetic resonance imaging obtained from T1WI, T2WI, DCE, DWI, and ADC sequences. Dimensionality reduction and feature selection techniques were applied to the extracted features. Subsequently, machine learning approaches, including logistic regression, support vector machine, classification and regression trees, k-nearest neighbors, and gradient boosting machine models (GBM), were constructed using the radiomics features. The best-performing radiomic model was selected based on its performance using the confusion matrix. Univariate and multivariable logistic regression analyses were conducted to identify variables for developing a clinical-radiological (Clin-Rad) model. Finally, a combined model incorporating both radiomics and clinical-radiological model features was created. Results: A total of 6195 radiomic features were extracted from multimodal magnetic resonance imaging. After applying dimensionality reduction and feature selection, seven valuable radiomics features were identified. Among the radiomics models, the GBM model demonstrated superior predictive efficiency and robustness, achieving area under the curve values (AUC) of 0.881 (0.823,0.940) and 0.820 (0.693,0.947) in the training and validation datasets, respectively. The Clin-Rad model was developed based on the peritumoral edema and DWI rim sign. In the training dataset, it achieved an AUC of 0.767 (0.681, 0.854), while in the validation dataset, it achieved an AUC of 0.734 (0.555-0.913). The combined model, which incorporated radiomics and the Clin-Rad model, showed the highest discriminatory capability. In the training dataset, it had an AUC value of 0.936 (0.892, 0.981), and in the validation dataset, it had an AUC value of 0.876 (0.757, 0.995). Additionally, decision curve analysis of the combined model revealed its optimal clinical efficacy. Conclusion: The combined model, integrating radiomics and clinical-radiological features, exhibited excellent performance in distinguishing LVI status. This non-invasive and efficient approach holds promise for aiding clinical decision-making in the context of clinically node-negative BC.

Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus Vaccine in Infants 6-7 Months of age: A Phase 1/2 Randomized Trial.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants. This phase 1/2, observer-blind, randomized, controlled study assessed the safety and immunogenicity of an investigational chimpanzee-derived adenoviral vector RSV vaccine (ChAd155-RSV, expressing RSV F, N, and M2-1) in infants. METHODS: Healthy 6- to 7-month-olds were 1:1:1-randomized to receive 1 low ChAd155-RSV dose (1.5 × 1010 viral particles) followed by placebo (RSV_1D); 2 high ChAd155-RSV doses (5 × 1010 viral particles) (RSV_2D); or active comparator vaccines/placebo (comparator) on days 1 and 31. Follow-up lasted approximately 2 years. RESULTS: Two hundred one infants were vaccinated (RSV_1D: 65; RSV_2D: 71; comparator: 65); 159 were RSV-seronaive at baseline. Most solicited and unsolicited adverse events after ChAd155-RSV occurred at similar or lower rates than after active comparators. In infants who developed RSV infection, there was no evidence of vaccine-associated enhanced respiratory disease (VAERD). RSV-A neutralizing titers and RSV F-binding antibody concentrations were higher post-ChAd155-RSV than postcomparator at days 31, 61, and end of RSV season 1 (mean follow-up, 7 months). High-dose ChAd155-RSV induced stronger responses than low-dose, with further increases post-dose 2. CONCLUSIONS: ChAd155-RSV administered to 6- to 7-month-olds had a reactogenicity/safety profile like other childhood vaccines, showed no evidence of VAERD, and induced a humoral immune response. Clinical Trials Registration. NCT03636906.

Assessment of Lymphovascular Invasion in Breast Cancer Using a Combined MRI Morphological Features, Radiomics, and Deep Learning Approach Based on Dynamic Contrast-Enhanced MRI.

BACKGROUND: Assessment of lymphovascular invasion (LVI) in breast cancer (BC) primarily relies on preoperative needle biopsy. There is an urgent need to develop a non-invasive assessment method. PURPOSE: To develop an effective model to assess the LVI status in patients with BC using magnetic resonance imaging morphological features (MRI-MF), Radiomics, and deep learning (DL) approaches based on dynamic contrast-enhanced MRI (DCE-MRI). STUDY TYPE: Cross-sectional retrospective cohort study. POPULATION: The study included 206 BC patients, with 136 in the training set [97 LVI(-) and 39 LVI(+) cases; median age: 51.5 years] and 70 in the test set [52 LVI(-) and 18 LVI(+) cases; median age: 48 years]. FIELD STRENGTH/SEQUENCE: 1.5 T/T1-weighted images, fat-suppressed T2-weighted images, diffusion-weighted imaging (DWI), and DCE-MRI. ASSESSMENT: The MRI-MF model was developed with conventional MR features using logistic analyses. The Radiomic feature extraction process involved collecting data from categorized DCE-MRI datasets, specifically the first and second post-contrast images (A1 and A2). Next, a DL model was implemented to determine LVI. Finally, we established a joint diagnosis model by combining the MRI-MF, Radiomics, and DL approaches. STATISTICAL TESTS: Diagnostic performance was compared using receiver operating characteristic curve analysis, confusion matrix, and decision curve analysis. RESULTS: Rim sign and peritumoral edema features were used to develop the MRI-MF model, while six Radiomics signature from the A1 and A2 images were used for the Radiomics model. The joint model (MRI-MF + Radiomics + DL models) achieved the highest accuracy (area under the curve [AUC] = 0.857), being significantly superior to the MRI-MF (AUC = 0.724), Radiomics (AUC = 0.736), or DL (AUC = 0.740) model. Furthermore, it also outperformed the pairwise combination models: Radiomics + MRI-MF (AUC = 0.796), DL + MRI-MF (AUC = 0.796), or DL + Radiomics (AUC = 0.826). DATA CONCLUSION: The joint model incorporating MRI-MF, Radiomics, and DL approaches can effectively determine the LVI status in patients with BC before surgery. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Rapid access to icetexane diterpenes: Their protective effects against lipopolysaccharides-induced acute lung injury via PI3K/AKT/NF-κB axis in macrophages.

Acute lung injury (ALI) is a life-threatening disease with limited therapeutic options available in clinic. Development of novel strategies and drugs for anti-ALI therapy are urgently needed. In this study, a facile synthesis of 21 icetexane diterpenes and derivatives with widely-varied oxidation states, particularly the taxamairins that are otherwise challenging to access, were developed from the readily available carnosic acid. Further explorations of their biological implications led to the identification of taxamairin B (6) as a potent anti-inflammatory agent by decreasing the gene expressions of proinflammatory cytokines (TNF-α, IL-1ß and IL-6), as well as mitigating NO and ROS production, within LPS-induced RAW264.7 cells. Taxamairin B (6, 25 mg/kg) also exerted significant protective effects against in LPS-induced ALI in mice. Mechanistic insights drawn from the transcriptomic analysis revealed that taxamairin B (6) down-regulated the PI3K-AKT pathway, along with the suppression of the nuclear translocation of NF-κB. This study not only paves a new pathway to taxamairins, but also provides novel drug leads for the development of anti-inflammatory agents with unique mode of actions.

Auricularia auricula-judae (Bull.) polysaccharides improve obesity in mice by regulating gut microbiota and TLR4/JNK signaling pathway.

Obesity has emerged as a crucial factor impacting people's lives, and gut microbiota disorders contribute to its development and progression. Auricularia auricula-judae (Bull.) polysaccharides (AAPs), a traditional functional food in Asia, exhibit potential anti-obesity effects. However, the specific mechanism still needs to be further confirmed. This study investigated the beneficial effects and specific mechanisms of AAPs on obesity. Firstly, AAPs showed significant improvements in overweight, insulin resistance, glucose and lipid metabolism disorders, and liver damage in obese mice. Additionally, AAPs ameliorated gut microbiota disorders, promoting the proliferation of beneficial bacteria like Lactobacillus and Roseburia, resulting in increased levels of SCFAs, folate, and cobalamin. Simultaneously, AAPs inhibited the growth of harmful bacteria, thereby protecting intestinal barrier function, improving endotoxemia, and decreasing the levels of inflammatory factors such as TNF-α and IL-6. Furthermore, AAPs can inhibit the TLR4/JNK signaling pathway while promoting the activation of AKT and AMPK. Importantly, our study underscored the pivotal role of gut microbiota in the anti-obesity effects of AAPs, as evidenced by fecal microbiota transplantation experiments. In conclusion, our findings elucidated that AAPs improve obesity by regulating gut microbiota and TLR4/JNK signaling pathway, offering novel perspectives for further conclusion the anti-obesity potential of AAPs.

Optimization of fermentation conditions for surfactin production by B. subtilis YPS-32.

BACKGROUND: Surfactin produced by microbial fermentation has attracted increasing attention because of its low toxicity and excellent antibacterial activity. However, its application is greatly limited by high production costs and low yield. Therefore, it is important to produce surfactin efficiently while reducing the cost. In this study, B. subtilis strain YPS-32 was used as a fermentative strain for the production of surfactin, and the medium and culture conditions for the fermentation of B. subtilis YPS-32 for surfactin production were optimized. RESULTS: First, Landy 1 medium was screened as the basal medium for surfactin production by B. subtilis strain YPS-32. Then, using single-factor optimization, the optimal carbon source for surfactin production by B. subtilis YPS-32 strain was determined to be molasses, nitrogen sources were glutamic acid and soybean meal, and inorganic salts were KCl, K2HPO4, MgSO4, and Fe2(SO4)3. Subsequently, using Plackett-Burman design, MgSO4, time (h) and temperature (°C) were identified as the main effect factors. Finally, Box-Behnken design were performed on the main effect factors to obtain optimal fermentation conditions: temperature of 42.9 °C, time of 42.8 h, MgSO4 = 0.4 g·L- 1. This modified Landy medium was predicted to be an optimal fermentation medium: molasses 20 g·L- 1, glutamic acid 15 g·L- 1, soybean meal 4.5 g·L- 1, KCl 0.375 g·L- 1, K2HPO4 0.5 g·L- 1, Fe2(SO4)3 1.725 mg·L- 1, MgSO4 0.4 g·L- 1. Using the modified Landy medium, the yield of surfactin reached 1.82 g·L- 1 at pH 5.0, 42.9 ℃, and 2% inoculum for 42.8 h, which was 2.27-fold higher than that of the Landy 1 medium in shake flask fermentation. Additionally, under these optimal process conditions, further fermentation was carried out at the 5 L fermenter level by foam reflux method, and at 42.8 h of fermentation, surfactin reached a maximum yield of 2.39 g·L- 1, which was 2.96-fold higher than that of the Landy 1 medium in 5 L fermenter. CONCLUSION: In this study, the fermentation process of surfactin production by B. subtilis YPS-32 was improved by using a combination of single-factor tests and response surface methodology for test optimization, which laid the foundation for its industrial development and application.

Solid-state fermentation of Apocynum venetum L. by Aspergillus niger: Effect on phenolic compounds, antioxidant activities and metabolic syndrome-associated enzymes.

This study aimed to evaluate the effect of solid-state fermentation (SSF) with Aspergillus niger on the total phenolic content (TPC), the total flavonoid content (TFC), individual phenolic contents, and antioxidant and inhibitory activities against metabolic syndrome-associated enzymes in an ethanol extract from Apocynum venetum L. (AVL). TPC, TFC, and the contents of quercetin and kaempferol during SSF were 1.52-, 1.33-, 3.64-, and 2.22-fold higher than those of native AVL in the ethyl acetate (EA) subfraction of the ethanol extract. The ABTS·+, DPPH· scavenging, and inhibitory activities against α-glucosidase and pancreatic lipase were found to be highest in the EA subfraction. Fermentation significantly increased the ABTS radical cation, DPPH radical scavenging, and pancreatic lipase inhibitory activities by 1.33, 1.39, and 1.28 times, respectively. TPC showed a significantly positive correlation with antioxidant activities or inhibition against metabolic syndrome-associated enzymes. This study provides a theoretical basis for producing tea products with enhanced antioxidant, antidiabetic, and antihyperlipidemic activities.

Liquid hot water pretreatment combined with high-solids enzymatic hydrolysis and fed-batch fermentation for succinic acid sustainable processed from sugarcane bagasse.

In order to sustainable process of bio-succinic acid (SA), response surface methodology (RSM) was applied to optimize liquid hot water pretreatment pretreatment of sugarcane bagasse (SCB), followed by high-solids enzymatic hydrolysis of pretreated residual that without washing, then the hydrolysates and partial pretreatment liquid were used as carbon sources for SA fermentation. Results showed that the highest sugars yield could be achieved at pretreatment conditions of temperature 186 °C, time 25 min and solid-to-liquid ratio 0.08; enzymatic digestion the pretreated residuals at 20 % (w/v) solid content via enzymes reconstruction and fed-batch strategy, the obtained sugars reached to 121 g/L; by controlling the nutrition and conditions of the fermentation process, most of the C5 and C6 sugars in the hydrolysate and pretreatment liquid were converted into SA with a conversion rate high to 280 mg/g SCB. This study can provide a novel clue for clean and efficient biorefining of chemicals.

Impairment of ovarian follicular development caused by titanium dioxide nanoparticles exposure involved in the TGF-ß/BMP/Smad pathway.

Titanium dioxide nanoparticles (TiO2 NPs) have been shown to induce reproductive system damages in animals. To better underline how TiO2 NPs act in reproductive system, female mice were exposed to 2.5, 5, or 10 mg/kg TiO2 NPs by gavage administration for 60 days, the ovary injuries, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels as well as ovarian follicular development-related molecule expression were investigated. The results showed that TiO2 NPs exposure resulted in reduction of ovary weight and inhibition of ovarian follicular development. Furthermore, the suppression of follicular development was demonstrated to be closely related to higher FSH and LH levels, and higher expression of activin, follistatin, BMP2, BMP4, TGF-ß1, Smad2, Smad3, and Smad4 as well as decreased inhibin-α expression in mouse ovary in a dose-dependent manner. It implies that the impairment of ovarian follicular development caused by TiO2 NPs exposure may be mediated by TGF-ß signal pathway.

Divergent synthesis of bis(indolyl)methanes via FeIII-catalysed regioselective dehydrogenative coupling reactions: a biomimetic approach to 6,6'-bis-(debromo)-gelliusine F.

The divergent dehydrogenative coupling reactions of tryptamines with the catalysis of nontoxic FeIII salts in the presence of DDQ as the co-oxidant have been developed. Remarkably, the transformations feature a rapid and regioselective assembly of diverse 2,8'- and N1,8'-bis(indolyl) methane derivatives from readily-available starting materials by simply changing the FeIII salt and reaction temperature. Besides, the fast reaction rate, mild reaction conditions, low catalyst cost and easy operations make this methodology quite useful. The synthetic utility was further demonstrated in the biomimetic synthesis of 6,6'-bis-(debromo)-gelliusine F.

Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus (RSV) Vaccine in Healthy RSV-Seropositive Children 12-23 Months of Age.

BACKGROUND: Safe and effective respiratory syncytial virus (RSV) vaccines remain elusive. This was a phase I/II trial (NCT02927873) of ChAd155-RSV, an investigational chimpanzee adenovirus-RSV vaccine expressing 3 proteins (fusion, nucleoprotein, and M2-1), administered to 12-23-month-old RSV-seropositive children followed up for 2 years after vaccination. METHODS: Children were randomized to receive 2 doses of ChAd155-RSV or placebo (at a 1:1 ratio) (days 1 and 31). Doses escalated from 0.5 × 1010 (low dose [LD]) to 1.5 × 1010 (medium dose [MD]) to 5 × 1010 (high dose [HD]) viral particles after safety assessment. Study end points included anti-RSV-A neutralizing antibody (Nab) titers through year 1 and safety through year 2. RESULTS: Eighty-two participants were vaccinated, including 11, 14, and 18 in the RSV-LD, RSV-MD, and RSV-HD groups, respectively, and 39 in the placebo groups. Solicited adverse events were similar across groups, except for fever (more frequent with RSV-HD). Most fevers were mild (≤38.5°C). No vaccine-related serious adverse events or RSV-related hospitalizations were reported. There was a dose-dependent increase in RSV-A Nab titers in all groups after dose 1, without further increase after dose 2. RSV-A Nab titers remained higher than prevaccination levels at year 1. CONCLUSIONS: Three ChAd155-RSV dosages were found to be well tolerated. A dose-dependent immune response was observed after dose 1, with no observed booster effect after dose 2. Further investigation of ChAd155-RSV in RSV-seronegative children is warranted. CLINICAL TRIALS REGISTRATION: NCT02927873.

Respiratory syncytial virus (RSV) is among the main causes of bronchiolitis and pneumonia regularly leading to hospitalization in children. A safe and effective vaccine to prevent RSV infection in this age group has not yet been found, despite great efforts over several decades. This study tested a new candidate RSV vaccine, expressing 3 important pieces of the virus, in toddlers who already had a previous RSV infection. The vaccine was generally well tolerated. Vaccination triggered antibodies against RSV that were able to block the virus in laboratory tests and that persisted for 1 year.

Mendelian randomization study supports the causal association between serum cystatin C and risk of diabetic nephropathy.

Aims: Cystatin C, an inhibitor of cysteine protease, has been used as a biomarker for estimating glomerular filtration rate. However, the causal relation between cystatin C and diabetic nephropathy remains uncertain. Methods: We assessed the causal effect of cystatin C together with other five serum biomarkers including KIM-1, GDF-15, TBIL, uric acid, and Scr on diabetic nephropathy by Mendelian randomization (MR) analysis. 234 genetic variants were selected as instrumental variables to evaluate the causal effect of cystatin C (NGWAS=361194) on diabetic nephropathy (Ncase/Ncontrol up to 3283/210463). Multivariable MR (MVMR) was performed to assess the stability of cystatin C's causal relationship. Two-step MR was used to assess the mediation effect of BMI and SBP. Results: Among the six serum biomarkers, only cystatin C causally associated with diabetic nephropathy (IVW OR: 1.36, 95%CI [1.15, 1.61]). After adjusting for the potential confounders BMI and SBP, cystatin C maintained its causal effect on the DN (OR: 1.17, 95%CI [1.02, 1.33]), which means that the risk of DN increased by 17% with an approximate 1 standard deviation (SD) increment of serum cystatin C level. Two-step MR results indicated that BMI might mediate the causal effect of cystatin C on diabetic nephropathy. Interpretation: Our findings discovered that cystatin C was a risk factor for diabetic nephropathy independent of BMI and SBP in diabetes mellitus patients. Future research is required to illustrate the underlying mechanism and prove targeting circulating cystatin C could be a potential therapy method.

Probiotic assessment and antioxidant characterization of Lactobacillus plantarum GXL94 isolated from fermented chili.

Oxidative stress is caused by an imbalance between prooxidants and antioxidants, which is the cause of various chronic human diseases. Lactic acid bacteria (LAB) have been considered as an effective antioxidant to alleviate oxidative stress in the host. To obtain bacterium resources with good antioxidant properties, in the present study, 113 LAB strains were isolated from 24 spontaneously fermented chili samples and screened by tolerance to hydrogen peroxide (H2O2). Among them, Lactobacillus plantarum GXL94 showed the best antioxidant characteristics and the in vitro antioxidant activities of this strain was evaluated extensively. The results showed that L. plantarum GXL94 can tolerate hydrogen peroxide up to 22 mM, and it could normally grow in MRS with 5 mM H2O2. Its fermentate (fermented supernatant, intact cell and cell-free extract) also had strong reducing capacities and various free radical scavenging capacities. Meanwhile, eight antioxidant-related genes were found to up-regulate with varying degrees under H2O2 challenge. Furthermore, we evaluated the probiotic properties by using in vitro assessment. It was showed that GXL94 could maintain a high survival rate at pH 2.5% or 2% bile salt or 8.0% NaCl, live through simulated gastrointestinal tract (GIT) to colonizing the GIT of host, and also show higher abilities of auto-aggregation and hydrophobicity. Additionally, the usual antibiotic susceptible profile and non-hemolytic activity indicated the safety of the strain. In conclusion, this study demonstrated that L. plantarum GXL94 could be a potential probiotic candidate for producing functional foods with antioxidant properties.

Improving saccharification of ramie stalks by synergistic effect of in-house cellulolytic enzymes consortium.

The high cost of cellulase is one of the main obstacles hindering the large-scale biorefining of lignocellulosic biomass. Therefore, developing efficient method for preparation of cellulase is promising. In the present study, the production of cellulase by Trichoderma reesei, Trichoderma harzianum, and Aspergillus niger was optimized, and the synergistic effect of these cellulase on enzymatic hydrolysis of pretreated ramie stalks was also evaluated. The maximum CMCase (Carboxymethyl Cellulase) and filter paper activity (FPA) produced by T. reesei reached to 3.12 IU/mL and 0.13 IU/mL, respectively. The maximum activities of CMCase (3.68 IU/mL), FPA (0.04 IU/mL) and ß-glucosidase (8.44 IU/mL) were obtained from A. niger. The results also showed that under the premise of the same FPA activity, the contribution of ß-glucosidase activity to yield of reducing sugar was greater than that of CMCase. Besides, cellulase produced by T. reesei and A. niger had the best synergistic effect on enzymatic hydrolysis of pretreated ramie stalks. The highest reducing sugars yield (417 mg/g dry substrate) was achieved when enzyme cocktail was prepared at the ratio of 1:1, which was 1.36-3.35 folds higher than that of different single enzymes. The present research has provided a novel method for efficient preparation of enzymes consortium for enzymatic hydrolysis of ramie stalks.

Construction of Pulmonary Nodule CT Radiomics Random Forest Model Based on Artificial Intelligence Software for STAS Evaluation of Stage IA Lung Adenocarcinoma.

Objective: Spread through air space (STAS) is an invasive characterization of lung adenocarcinoma and is regarded as a risk factor for poor prognosis. The aim of this study is to develop a random forest model for preoperative prediction of spread through air spaces (STAS) in stage IA lung adenocarcinoma. Methods: 92 patients with stage IA lung adenocarcinoma, who underwent computed tomography (CT) scan and surgical resection, were retrospectively reviewed. Each pulmonary nodule was automatically segmented by artificial intelligence (AI) software, and its CT-based radiomics were extracted. All patients were pathologically classified into STAS-negative and STAS-positive cohorts; then, clinical pathological and CT-based radiomics were compared between the two cohorts. Finally, a prediction model for evaluating STAS status in stage IA lung adenocarcinoma was established by a random forest model. Results: Among 92 patients with stage IA lung adenocarcinoma, STAS positive was identified in 19 patients. The random forest classification model identified predictive features, including CT maximum value, consolidation to tumor ratio (CTR), 3D diameter, CT mean value, entropy, and CT minimum value. The misclassification rate of the random forest model is only 7.69%. Conclusion: The risk factors of STAS in stage IA lung adenocarcinoma can be effectively identified based on the random forest model, and the hierarchical management of characteristic risk can be effectively realized. A random forest model for predicting STAS in IA lung adenocarcinoma is simple and practical.

Chrysin improves diabetic nephropathy by regulating the AMPK-mediated lipid metabolism in HFD/STZ-induced DN mice.

Diabetic nephropathy (DN) is a highly prevalent and severe diabetic complication. It is urgent to explore high efficiency and minor side effects therapy for DN. Chrysin is a natural flavonoid with various biological activities found in honey and propolis, and has considerable potential to improve DN. The study was designed to explore the effects and the specific underlying mechanism of chrysin for DN in high-fat-diet (HFD) and streptozotocin (STZ) induced DN mice. Firstly, the study revealed that chrysin effectively improved obesity, insulin resistance (IR), renal function, and pathological injury in DN mice. Secondly, the study found that chrysin improved the key indices and markers of lipid accumulation, oxidative stress, and inflammation which are closely related to the development or progression of DN. Moreover, chrysin markedly modulated lipid metabolism by regulating Adenosine 5' monophosphate-activated protein kinase (AMPK) and essential downstream proteins. Furthermore, AMPK inhibitor (Dorsomorphin) intervention partially suppressed the positive effects of chrysin on all testing indicators, indicating that activated AMPK is crucial for chrysin action on DN. The present study demonstrated that chrysin may improve DN by regulating lipid metabolism, and activated AMPK plays a critical role in the regulation of chrysin. PRACTICAL APPLICATIONS: The study verified the positive effects of chrysin on obesity, insulin resistance, kidney injury, renal function, lipid accumulation, inflammation, and oxidative stress, which are closely related to the development or progression of diabetic nephropathy (DN). Moreover, we explored that chrysin improves DN by regulating AMPK-mediated lipid metabolism. Furthermore, the AMPK inhibitor was used to confirm that activated AMPK plays a critical role in the effects of chrysin. These results could offer a full explanation and a potential option for adjuvant therapy of DN diabetes with chrysin.