Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.

Effectiveness and Safety of Different Postoperative Adjuvant Regimens in Patients with Low-Grade Gliomas: A Network Meta-Analysis.

OBJECTIVE: This study aimed to investigate the effectiveness and safety of various adjuvant regimens in patients with low-grade gliomas and to further explore the optimal adjuvant treatment for patients with low-grade gliomas and the differences in the efficacy of each treatment regimens in different tumor types. METHODS: A comprehensive search of the PubMed, Cochrane Library, Ovid, Embase, and Web of Science databases was conducted to screen randomized and nonrandomized controlled trials related to adjuvant therapy in patients with low-grade gliomas. The Cochrane quality assessment method and the Newcastle-Ottawa Scale were used to assess the quality of the included randomized and nonrandomized controlled trials, respectively. The data from previous studies were extracted using Excel and GetData Graph Digitizer 2.26 software, and network meta-analysis was performed using RevMan 5.3 and Stata 16.0 statistical software. RESULTS: The specific ranking of 5-year progression-free survival (5-year PFS) for each treatment regimen from the best to the worst in patients with low-grade gliomas was surgery (S) combined with procarbazine, lomustine, and vincristine (S + PCV); surgery combined with standard radiotherapy and PCV multidrug chemotherapy (S + RT + PCV); surgery combined with standard radiotherapy and temozolomide monotherapy (S + RT + TMZ); surgery combined with enhanced radiotherapy (S + H-RT); surgery combined with standard radiotherapy (S + RT); surgery combined with TMZ (S + TMZ); and S. The 5-year overall survival (OS) ranking was S + RT + TMZ, S + RT + PCV, surgery combined with enhanced radiotherapy and TMZ monotherapy (S + H-RT + TMZ), S + H-RT, S + RT, and S. The 2-year progression-free survival ranking was S + RT + TMZ, S + PCV, S + RT, S + RT + PCV, S + TMZ, S + H-RT, and S. The 2-year overall survival ranking was S + RT + TMZ, S + H-RT + TMZ, S + RT, S + RT + PCV, S + H-RT, and S. The incidence of adverse events (≥3) was ranked from highest to lowest as follows: S + RT + PCV, S + RT + TMZ, S + PCV, S + H-RT, S + TMZ, and S + RT. In the isocitrate dehydrogenase 1/2 mutation nonchromosome 1p and 19q chromosome whole arm codeletion (IDHmt/noncoder) group, the S + RT + PCV and S + H-RT regimens had better 5-year PFS and 5-year OS. In the isocitrate dehydrogenase 1/2 mutation and chromosome 1p and 19q chromosome whole arm codeletion (IDHmt/coder) group, the 5-year PFS of each treatment regimen ranked from the best to the worst was S + RT + TMZ, S + RT + PCV, S + H-RT, S + RT, S + TMZ, and S. The order of 5-year OS from the best to the worst was S + H-RT, S + RT + TMZ, S + RT + PCV, S + RT, and S. In the isocitrate dehydrogenase 1/2 wild-type (IDHwt) group, the S + H-RT and S + TMZ regimens had better 5-year PFS. CONCLUSIONS: This study revealed that both the S + RT + TMZ and S + RT + PCV regimens might be effective therapies for treating patients with low-grade gliomas. Among these, the S + RT + TMZ regimen seemed to be safer but might lead to tumor deterioration. In the IDHmt/coder type, the S + RT + TMZ scheme might have a significant advantage. In the IDHmt/noncoder type, the S + RT + PCV scheme might be more dominant, while in the IDHwt type, the S + H-RT and S + TMZ schemes also might be good treatment options.

Glucose status within dark-grown etiolated cotyledons determines seedling de-etiolation upon light irradiation.

Exposure of dark-grown etiolated seedlings to light triggers the transition from skotomorphogenesis/etiolation to photomorphogenesis/de-etiolation. In the life cycle of plants, de-etiolation is essential for seedling development and plant survival. The mobilization of soluble sugars (glucose [Glc], sucrose, and fructose) derived from stored carbohydrates and lipids to target organs, including cotyledons, hypocotyls, and radicles, underpins de-etiolation. Therefore, dynamic carbohydrate biochemistry is a key feature of this phase transition. However, the molecular mechanisms coordinating carbohydrate status with the cellular machinery orchestrating de-etiolation remain largely opaque. Here, we show that the Glc sensor HEXOKINASE 1 (HXK1) interacts with GROWTH REGULATOR FACTOR5 (GRF5), a transcriptional activator and key plant growth regulator, in Arabidopsis (Arabidopsis thaliana). Subsequently, GRF5 directly binds to the promoter of phytochrome A (phyA), encoding a far-red light (FR) sensor/cotyledon greening inhibitor. We demonstrate that the status of Glc within dark-grown etiolated cotyledons determines the de-etiolation of seedlings when exposed to light irradiation by the HXK1-GRF5-phyA molecular module. Thus, following seed germination, accumulating Glc within dark-grown etiolated cotyledons stimulates a HXK1-dependent increase of GRF5 and an associated decrease of phyA, triggering the perception, amplification, and relay of HXK1-dependent Glc signaling, thereby facilitating the de-etiolation of seedlings following light irradiation. Our findings, therefore, establish how cotyledon carbohydrate signaling under subterranean darkness is sensed, amplified, and relayed, determining the phase transition from skotomorphogenesis to photomorphogenesis on exposure to light irradiation.

Photoacoustic spectroscopy-based ppb-level multi-gas sensor using symmetric multi-resonant cavity photoacoustic cell.

In this paper, we propose and experimentally demonstrate a symmetric multi-resonant cavity photoacoustic cell (MR-PAC) with dual microphones detection, based on multi-resonator photoacoustic spectroscopy (MR-PAS). The designed photoacoustic cell contains three interconnected acoustic resonators to facilitate simultaneous control of three lasers for multi-gas sensing. Two microphones are symmetrically located at both sides of photoacoustic cell to implement two-point detection. The length of acoustic resonator is about 50 mm to minimize the photoacoustic cell, and the resonant frequency is around 3000 Hz. Feasibility and performance of the MR-PAC was demonstrated by simultaneous detection of C2H2, NO and CF4 using a near infrared diode laser and two mid infrared quantum cascade lasers. The minimum detection limits (MDLs) of C2H2, NO and CF4 are 480 ppb, 260 ppb and 0.57 ppb respectively with a 1 s integration time at normal atmospheric pressure. This minimized MR-PAS system is promising for the portable multi-gas sensing.

Sugar status in preexisting leaves determines systemic stomatal development within newly developing leaves.

Stomata are pores found in the epidermis of stems or leaves that modulate both plant gas exchange and water/nutrient uptake. The development and function of plant stomata are regulated by a diverse range of environmental cues. However, how carbohydrate status in preexisting leaves might determine systemic stomatal formation within newly developing leaves has remained obscure. The glucose (Glc) sensor HEXOKINASE1 (HXK1) has been reported to decrease the stability of an ethylene/Glc signaling transcriptional regulator, EIN3 (ETHYLENE INSENSITIVE3). EIN3 in turn directly represses the expression of SUC2 (sucrose transporter 2), encoding a master transporter of sucrose (Suc). Further, KIN10, a nuclear regulator involved in energy homeostasis, has been reported to repress the transcription factor SPCH (SPEECHLESS), a master regulator of stomatal development. Here, we demonstrate that the Glc status of preexisting leaves determines systemic stomatal development within newly developing leaves by the HXK1-¦EIN3-¦SUC2 module. Further, increasing Glc levels in preexisting leaves results in a HXK1-dependent decrease of EIN3 and increase of SUC2, triggering the perception, amplification and relay of HXK1-dependent Glc signaling and thereby triggering Suc transport from mature to newly developing leaves. The HXK1-¦EIN3-¦SUC2 molecular module thereby drives systemic Suc transport from preexisting leaves to newly developing leaves. Subsequently, increasing Suc levels within newly developing leaves promotes stomatal formation through the established KIN10⟶ SPCH module. Our findings thus show how a carbohydrate signal in preexisting leaves is sensed, amplified and relayed to determine the extent of systemic stomatal development within newly developing leaves.

Laser Linewidth Analysis and Filtering/Fitting Algorithms for Improved TDLAS-Based Optical Gas Sensor.

Tunable Diode Laser Absorption Spectroscopy (TDLAS) has been widely applied in in situ and real-time monitoring of trace gas concentrations. In this paper, an advanced TDLAS-based optical gas sensing system with laser linewidth analysis and filtering/fitting algorithms is proposed and experimentally demonstrated. The linewidth of the laser pulse spectrum is innovatively considered and analyzed in the harmonic detection of the TDLAS model. The adaptive Variational Mode Decomposition-Savitzky Golay (VMD-SG) filtering algorithm is developed to process the raw data and could significantly eliminate the background noise variance by about 31% and signal jitters by about 12.5%. Furthermore, the Radial Basis Function (RBF) neural network is also incorporated and applied to improve the fitting accuracy of the gas sensor. Compared with traditional linear fitting or least squares method (LSM), the RBF neural network brings along the enhanced fitting accuracy within a large dynamic range, achieving an absolute error of below 50 ppmv (about 0.6%) for the maximum 8000 ppmv methane. The proposed technique in this paper is universal and compatible with TDLAS-based gas sensors without hardware modification, allowing direct improvement and optimization for current optical gas sensors.

An open-label randomized noninferior study of generic name and brand name of propafenone for rhythm control in patients with paroxysmal atrial fibrillation.

BACKGROUND: Propafenone is a class IC antiarrhythmic agent that is commonly used as the first-line therapy for patients with paroxysmal atrial fibrillation (AF) in Taiwan. This study compared the efficacy and safety of generic (Rhynorm) and brand name (Rytmonorm) propafenone for rhythm control of paroxysmal AF in Taiwan. METHODS: This was an open-label randomized multicenter noninferior study conducted in Taiwan. We enrolled 76 patients with AF. To investigate the efficacy of propafenone, we used a wearable electrocardiogram (ECG) event recorder to evaluate the daily burden of AF episodes in patients for 24 weeks. The primary efficacy endpoint was the frequency of AF with clinical significance, which was indicated by AF duration ≥30 seconds. The safety endpoints included proarrhythmic or hemodynamic adverse events. RESULT: To analyze the efficacy and safety of these agents, 71 patients (five patients with screen failure) were randomized to two groups, specifically a Rhynorm group (n = 37) and a Rytmonorm group (n = 34), for 24 weeks of the treatment period. The baseline patient characteristics were comparable between the groups. However, the Rhynorm group was older (65.4 ± 8.40 vs 59.8 ± 10.8 years; p = 0.02). The primary efficacy endpoint at week 24 decreased by 4.76% ± 18.5% (from 24.3% ± 33.9% to 19.0% ± 28.7%; p = 0.13) in the Rhynorm group and by 3.27% ± 15.2% (from 16.9% ± 26.4% to 13.6% ± 19.2%; p = 0.22) in the Rytmonorm group, with an intergroup difference of 1.5% ± 17.0%; p = 0.71. This finding indicates that Rhynorm is not inferior to Rytmonorm ( p = 0.023 for noninferiority). The safety profile of the agents was comparable between the two groups. CONCLUSION: Our results verified that Rhynorm was noninferior to Rytmonorm in terms of efficacy and safety for treating paroxysmal AF in Taiwan ( ClinicalTrials.gov Identifier: NCT03674658).

Antihyperlipidemic effect of Vaccinium dunalianum buds based on biological activity screening and LC-MS.

ETHNOPHARMACOLOGICAL RELEVANCE: The buds of Vaccinium dunalianum Wight are used as folk medicine in the Yi settlement of the Yunnan Province, China. It has long been used as herbal tea in the local area owing to its effects of lowering blood lipids and body weight. However, there are only a few studies on its antihyperlipidemic effects, effective substances and mechanisms, especially its effectiveness in diet-induced hyperlipidemia. AIM OF THE STUDY: This study aimed to elucidate the therapeutic effects, pharmacodynamic material bases, and mechanisms of V. dunalianum buds on diet-induced hyperlipidemia. MATERIALS AND METHODS: A high-fat diet-induced hyperlipidemic Sprague-Dawley (SD) rat model was established. Rats were gavaged with different doses of aqueous extract of V. dunalianum(VDW) for 8 weeks and their sera and organ samples were collected. The antihyperlipidemic effect of VDW on SD rats was evaluated based on the biochemical indices and histopathological outcomes. Liquid chromatography-mass spectrometry(LC-MS) was used to determine the main components in VDW, which were separated and purified using sequential chromatographic methods. Their chemical structures were determined using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. 6'-O-caffeoyl-arbutin, as the principal component of VDW, was also evaluated for its antihyperlipidemic activity using an approach similar to that used for VDW. Lastly, the potential targets of VDW and 6'-O-caffeoyl-arbutin in lowering blood lipids were screened out using network pharmacology, and the selected targets were docked with arbutin derivatives. The expression of target proteins was determined using western blotting to illustrate the antihyperlipidemic mechanisms of VDW and 6'-O-caffeoyl-arbutin. RESULTS: VDW reduced triglyceride, total cholesterol, low-density lipoprotein, alanine transaminase, and aspartate transaminase levels in the serum of modeled rats, and increased high-density lipoprotein levels. There was an improvement in steatoses, and lipid droplet accumulation decreased in vivo after VDW intervention. LC-MS revealed that VDW mainly contained arbutin and chlorogenic acid derivatives. Sixteen compounds were isolated and identified. 6'-O-caffeoyl-arbutin was the main compound of VDW (>21.67%) that showed obvious antihyperlipidemic effect with low hepatic damage at different doses. PTGS2, ADH1C, and MAOB were screened out using network pharmacology and they showed strong correlations with arbutin derivative through molecular docking. Results from WB showed that VDW and 6'-O-caffeoyl-arbutin could reduce blood lipid levels by reducing the protein expression of PTGS2, ADH1C, and MAOB. CONCLUSIONS: 6'-O-caffeoyl-arbutin was the main component of V. dunalianum buds. VDW and 6'-O-caffeoyl-arbutin could regulate blood lipid levels in the high-fat diet-induced rat model of hyperlipidemia without damaging their vital organs. Furthermore, they could regulate the expression of PTGS2, ADH1C, and MAOB proteins and play a role in lowering blood lipids. The findings of this study lay a foundation for the further development of V. dunalianum and 6'-O-caffeoyl-arbutin as health supplements or drugs for the management of hyperlipidemia.

Diseases, health behaviors, psychological health and associated factors among women aged 50-70 years: a cross-sectional study in Hunan Province, China.

This cross-sectional study identified 2, 585 women aged 50-70 with certain diseases, health behaviors and psychological health problems among a representative and community-conducted sample of women in Hunan Province of China. It disclosed their poor health status: 51.0% had chronic diseases, 49.6% had gynecopathy, 23.6% had mastopathy, 57.1% failed to avoid secondhand smoke, less than 50% completed periodic health examinations, and 3.1% were anxious. Chronic diseases are expected to be serious health problems in the next 10 years, emphasizing the importance of women discussing their health status. Common diseases should be managed via public health service projects, and free screening and treatment of common diseases should be provided. To enhance women's health knowledge and awareness, targeted health education is necessary in accordance with their physiological and psychological characteristics.

Regulating the immune response to carbon tetrachloride-induced liver fibrosis in mice by blocking inducible co-stimulatory molecules and interleukin-33 / 中华肝脏病杂志

Objective: To investigate the effects of combined blockade of interleukin-33 (IL-33) and inducible co-stimulatory molecule (ICOS) on carbon tetrachloride-induced chronic liver fibrosis and imbalance of T helper lymphocyte subsets in mice. Methods: There were 40 BALB/c mice in each model and control group. Flow cytometry was used to determine the proportion of Th1/Th2/Th17 cells in the splenic lymphocyte suspension of mice, the expression levels of interferon γ, IL-4, and IL-17 in the splenic lymphocyte suspension of liver fibrosis mice after combined blockade of IL-33 and ICOS, and the pathological changes of liver histopathology in mice with liver fibrosis. Two independent sample t-test was used to compare data between groups. Results: Compared with the non-blocking group, the proportion of Th2 and Th17 cells in the IL-33/ICOS blocking group was significantly down-regulated (Th2: 65.96% ± 6.04% vs. 49.09% ± 7.03%; Th17: 19.17% ± 4.03% vs. 9.56% ± 2.03%), while the proportion of Th1 cells and Th1/Th2 ratio were up-regulated (Th1: 17.14% ± 3.02% vs. 31.93% ± 5.02%; Th1/Th2: 0.28 ± 0.06 vs. 0.62 ± 0.23), and the difference was statistically significant (t = 5.15, 6.03, 7.14, 4.28, respectively, with P < 0.05). After entering the chronic inflammation stage of liver fibrosis in mice (10 weeks), compared with the non-blocking group, the expression levels of IL-4 and IL-17 in the blockade group were significantly down-regulated [IL-4: (84.75 ± 14.35) pg/ ml vs. (77.88 ± 19.61) pg/ml; IL-17: (72.38 ± 15.13) pg/ml vs. (36.38 ± 8.65) pg/ml], while the expression of interferon γ was up-regulated [(37.25 ± 11.51) pg/ml vs. (77.88 ± 19.61) pg/ml], and the difference was statistically significant (t: IL-4: 4.71; IL-17: 5.84; interferon γ: 5.05, respectively, with P < 0.05). Liver histopathological results showed that hepatic necrosis, hepatic lobular structural disorder, and fibrous tissue hyperplasia were significantly lower in the blockade group than those in the non-blocking group at 13 weeks of liver fibrosis. Conclusion: Combined blockade of the ICOS signaling pathway and IL-33 can regulate Th2 and Th17 polarization, down-regulate the inflammatory response, and inhibit or prevent the occurrence and progression of fibrosis.

The consistency and application value of MRI-based ovarian-adnexal reporting and data system in the diagnosis of ovarian adnexal masses / 中华放射学杂志

Objective:To explore the consistency of MRI-based ovarian-adnexal report and data system (O-RADS) score and its diagnostic value for ovarian adnexal masses.Methods:The MRI data of 309 patients with ovarian adnexal masses confirmed by pathology were retrospectively collected from January 2017 to August 2021 in the Second Affiliated Hospital of Soochow University, including 327 lesions consisted of 250 benign lesions, 21 borderline lesions, and 56 malignant lesions confirmed by pathology. Borderline and malignant lesions were classified into the malignant group ( n=77) and benign lesions were classified as benign group ( n=250). Two radiologists scored all lesions according to the MRI-based O-RADS, and scored again after 6 months. The proportion of borderline/malignant lesions in each MRI-based O-RADS score was calculated. The weighted Kappa test was used to assess the intra-reader and inter-reader consistency of the image interpretation results. The receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic efficacy of MRI-based O-RADS classification for distinguishing benign and malignant ovarian adnexal masses. Results:The weighted Kappa value of the MRI-based O-RADS score between the two radiologists was 0.810 (95%CI 0.764-0.855), and the weighted Kappa values of the two radiologists′ scores at different times were 0.848 (95%CI 0.806-0.889) and 0.875 (95%CI 0.835-0.914), respectively. The borderline/malignant lesions accounted for 0/16, 0.8% (1/127), 10.1% (10/99), 76.0% (57/75), 9/10 and 0/17, 0 (0/122), 8.0% (8/100), 76.2% (48/63), and 84.0% (21/25) of the lesions in the two radiologists based on the MRI O-RADS score of 1, 2, 3, 4, and 5, respectively. When adopting O-RADS score>3 as a cut-off value, the area under the ROC curve of the two radiologists for distinguishing benign and malignant ovarian adnexal masses was 0.928 (95%CI 0.895-0.954) and 0.942 (95%CI 0.911-0.965), respectively. The sensitivity was 0.857 and 0.896, the specificity was 0.924 and 0.924, and the accuracy was 0.908 and 0.917 respectively.Conclusion:The MRI-based O-RADS yields high diagnostic efficiency in the evaluation of benign and malignant ovarian adnexal masses, and the intra-reader and inter-reader consistency of the image interpretation is strong.

Comparison of corneal higher order aberration after femtosecond laser-assisted laser in situ keratomileusis and small incision lenticule extraction / 中华实验眼科杂志

Objective:To analyze and compare the corneal higher order aberration (HOA) after femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) and small incision lenticule extraction (SMILE).Methods:A non-randomized controlled study was conducted.Sixty myopic patients (60 eyes) who underwent FS-LASIK or SMILE correction at Shandong Eye Hospital from April 2018 to January 2020 were enrolled and the data from the right eye were collected for analysis.Thirty cases (30 eyes) who received FS-LASIK in FS-LASIK group and 30 cases (30 eyes) who received SMILE in SMILE group had a preoperative equivalent spherical diopter of (-5.36±1.11)D and (-4.93±1.03)D, respectively.The HOA of the 6-mm anterior surface, posterior surface, and whole cornea were measured before surgery and at 1, 3, 6, and 12 months after surgery using Pentacam.The root mean square values (μm) of total corneal HOA, spherical aberration, coma and trefoil were obtained.Differences in the above root mean square values at different time points were compared between the two groups.The study protocol adhered to the Declaration of Helsinki and was approved by the Ethics Committee of Shandong Eye Hospital (No.SDSYKYY20180306). Written informed consent was obtained from each subject.Results:The preoperative and 1-, 3-, 6-, 12-month postoperative total HOA of the anterior corneal surface were (0.428±0.126), (0.775±0.169), (0.811±0.194), (0.759±0.214), (0.704±0.199)μm in the FS-LASIK group and (0.409±0.094), (0.656±0.148), (0.681±0.161), (0.668±0.175), (0.648±0.160)μm in the SMILE group, with a significant overall difference ( Fgroup=5.652, P=0.024; Ftime=107.169, P<0.01). Compared with SMILE group, the postoperative total HOA of anterior corneal surface and spherical aberration at different time points were increased in FS-LASIK group, showing statistically significant differences (all at P<0.05). Compared with before surgery, the postoperative total HOA of the anterior corneal surface and spherical aberration at different time points were increased in both groups, showing statistically significant differences (all at P<0.05). In the two groups, the 6- and 12-month postoperative total HOA of the anterior corneal surface were reduced in comparison with the 3-month postoperative ones of the anterior corneal surface, and the 12-month postoperative spherical aberrations of the anterior corneal surface were significantly reduced in comparison with the 1- and 3-month postoperative ones of the anterior corneal surface, showing statistically significant differences (all at P<0.05). There were significant differences in the coma and trefoil of the anterior corneal surface between before and after the operation (coma: Ftime=47.848, P<0.01; trefoil: Ftime=2.497, P=0.046). Compared with before surgery, the postoperative coma was significantly increased in the two groups (all at P<0.05). There were significant differences in total corneal HOA and spherical aberration at different postoperative time points between the two groups (total HOA: Fgroup=8.093, P=0.008; Ftime=125.019, P<0.01.spherical aberration: Fgroup=4.771, P=0.037; Ftime=34.033, P<0.01). Compared with SMILE group, the total corneal HOA and spherical aberration were significantly increased in FS-LASIK group at different postoperative time points (all at P<0.05). Compared with before surgery, postoperative total HOA of the anterior corneal surface and spherical aberration at different postoperative time points were significantly increased in both groups (all at P<0.05). In both groups, the 12-month postoperative corneal spherical aberration was significantly reduced in comparison with the 1- and 3-month postoperative ones (all at P<0.05). There was a significant difference in coma between before and after surgery ( Ftime=30.829, P<0.01). Compared with before surgery, the postoperative coma was significantly increased at different time points in both groups (all at P<0.05). Conclusions:Both FS-LASIK and SMILE increase the HOA of the anterior corneal surface and the whole cornea.Compared with FS-LASIK, SMILE introduces less HOA of the anterior corneal surface and the whole cornea as well as spherical aberrations.

Non-Contrast Cine Cardiac Magnetic Resonance Derived-Radiomics for the Prediction of Left Ventricular Adverse Remodeling in Patients With ST-Segment Elevation Myocardial Infarction

Objective@#To investigate the predictive value of radiomics features based on cardiac magnetic resonance (CMR) cine images for left ventricular adverse remodeling (LVAR) after acute ST-segment elevation myocardial infarction (STEMI). @*Materials and Methods@#We conducted a retrospective, single-center, cohort study involving 244 patients (random-split into 170 and 74 for training and testing, respectively) having an acute STEMI (88.5% males, 57.0 ± 10.3 years of age) who underwent CMR examination at one week and six months after percutaneous coronary intervention. LVAR was defined as a 20% increase in left ventricular end-diastolic volume 6 months after acute STEMI. Radiomics features were extracted from the oneweek CMR cine images using the least absolute shrinkage and selection operator regression (LASSO) analysis. The predictive performance of the selected features was evaluated using receiver operating characteristic curve analysis and the area under the curve (AUC). @*Results@#Nine radiomics features with non-zero coefficients were included in the LASSO regression of the radiomics score (RAD score). Infarct size (odds ratio [OR]: 1.04 (1.00–1.07); P = 0.031) and RAD score (OR: 3.43 (2.34–5.28); P < 0.001) were independent predictors of LVAR. The RAD score predicted LVAR, with an AUC (95% confidence interval [CI]) of 0.82 (0.75–0.89) in the training set and 0.75 (0.62–0.89) in the testing set. Combining the RAD score with infarct size yielded favorable performance in predicting LVAR, with an AUC of 0.84 (0.72–0.95). Moreover, the addition of the RAD score to the left ventricular ejection fraction (LVEF) significantly increased the AUC from 0.68 (0.52–0.84) to 0.82 (0.70–0.93) (P = 0.018), which was also comparable to the prediction provided by the combined microvascular obstruction, infarct size, and LVEF with an AUC of 0.79 (0.65–0.94) (P = 0.727). @*Conclusion@#Radiomics analysis using non-contrast cine CMR can predict LVAR after STEMI independently and incrementally to LVEF and may provide an alternative to traditional CMR parameters.

Research advances on dihydrofolate reductase inhibitors in the treatment of tumors and bacterial infections / 药学学报

Dihydrofolate reductase (DHFR) is a well-known key target in the treatment of tumors, bacterial infections, and parasitic infections; and it plays a critical role in the biosynthesis of cellular DNA. DHFR inhibitors interfere with one-carbon metabolism by inhibiting substrate binding to DHFR, thereby inhibiting cell proliferation. Research on DHFR inhibitors has continued since the 1940s. To date, a variety of DHFR inhibitors have come into the market, primarily used for anti-tumor, antibacterial, antiparasitic, and anti-inflammatory therapy. This review summarizes the research progress of DHFR inhibitors with antitumor or antibacterial effects in recent years based on the classification of single-target and dual-target and looks forward to the opportunities and challenges faced by the work in this field.

Functional characterization of CYP81C16 involved in the tanshinone biosynthetic pathway in Salvia miltiorrhiza / 中国天然药物

Danshen, the dried roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza), is widely used in the treatment of cardiovascular and cerebrovascular diseases. Tanshinones, the bioactive compounds from Danshen, exhibit a wide spectrum of pharmacological properties, suggesting their potential for future therapeutic applications. Tanshinone biosynthesis is a complex process involving at least six P450 enzymes that have been identified and characterized, most of which belong to the CYP76 and CYP71 families. In this study, CYP81C16, a member of the CYP71 clan, was identified in S. miltiorrhiza. An in vitro assay revealed that it could catalyze the hydroxylation of four para-quinone-type tanshinones, namely neocryptotanshinone, deoxyneocryptotanshinone, and danshenxinkuns A and B. SmCYP81C16 emerged as a potential broad-spectrum oxidase targeting the C-18 position of para-quinone-type tanshinones with an impressive relative conversion rate exceeding 90%. Kinetic evaluations andin vivo assays underscored its highest affinity towards neocryptotanshinone among the tested substrates. The overexpression of SmCYP81C16 promoted the accumulation of (iso)tanshinone in hairy root lines. The characterization of SmCYP81C16 in this study accentuates its potential as a pivotal tool in the biotechnological production of tanshinones, either through microbial or plant metabolic engineering.

The best practice for microbiome analysis using R

With the gradual maturity of sequencing technology, many microbiome studies have published, driving the emergence and advance of related analysis tools. R language is the widely used platform for microbiome data analysis for powerful functions. However, tens of thousands of R packages and numerous similar analysis tools have brought major challenges for many researchers to explore microbiome data. How to choose suitable, efficient, convenient, and easy-to-learn tools from the numerous R packages has become a problem for many microbiome researchers. We have organized 324 common R packages for microbiome analysis and classified them according to application categories (diversity, difference, biomarker, correlation and network, functional prediction, and others), which could help researchers quickly find relevant R packages for microbiome analysis. Furthermore, we systematically sorted the integrated R packages (phyloseq, microbiome, MicrobiomeAnalystR, Animalcules, microeco, and amplicon) for microbiome analysis, and summarized the advantages and limitations, which will help researchers choose the appropriate tools. Finally, we thoroughly reviewed the R packages for microbiome analysis, summarized most of the common analysis content in the microbiome, and formed the most suitable pipeline for microbiome analysis. This paper is accompanied by hundreds of examples with 10,000 lines codes in GitHub, which can help beginners to learn, also help analysts compare and test different tools. This paper systematically sorts the application of R in microbiome, providing an important theoretical basis and practical reference for the development of better microbiome tools in the future. All the code is available at GitHub github.com/taowenmicro/EasyMicrobiomeR.

Development of the Scientific, Transparent and Applicable Rankings (STAR) tool for clinical practice guidelines / 中华医学杂志(英文版)

BACKGROUND@#This study aimed to develop a comprehensive instrument for evaluating and ranking clinical practice guidelines, named Scientific, Transparent and Applicable Rankings tool (STAR), and test its reliability, validity, and usability.@*METHODS@#This study set up a multidisciplinary working group including guideline methodologists, statisticians, journal editors, clinicians, and other experts. Scoping review, Delphi methods, and hierarchical analysis were used to develop the STAR tool. We evaluated the instrument's intrinsic and interrater reliability, content and criterion validity, and usability.@*RESULTS@#STAR contained 39 items grouped into 11 domains. The mean intrinsic reliability of the domains, indicated by Cronbach's α coefficient, was 0.588 (95% confidence interval [CI]: 0.414, 0.762). Interrater reliability as assessed with Cohen's kappa coefficient was 0.774 (95% CI: 0.740, 0.807) for methodological evaluators and 0.618 (95% CI: 0.587, 0.648) for clinical evaluators. The overall content validity index was 0.905. Pearson's r correlation for criterion validity was 0.885 (95% CI: 0.804, 0.932). The mean usability score of the items was 4.6 and the median time spent to evaluate each guideline was 20 min.@*CONCLUSION@#The instrument performed well in terms of reliability, validity, and efficiency, and can be used for comprehensively evaluating and ranking guidelines.

High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

ETCM v2.0: An update with comprehensive resource and rich annotations for traditional Chinese medicine

Existing traditional Chinese medicine (TCM)-related databases are still insufficient in data standardization, integrity and precision, and need to be updated urgently. Herein, an Encyclopedia of Traditional Chinese Medicine version 2.0 (ETCM v2.0, http://www.tcmip.cn/ETCM2/front/#/) was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books, 9872 Chinese patent drugs, 2079 Chinese medicinal materials and 38,298 ingredients. To facilitate the mechanistic research and new drug discovery, we improved the target identification method based on a two-dimensional ligand similarity search module, which provides the confirmed and/or potential targets of each ingredient, as well as their binding activities. Importantly, five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0, which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy, to summarize the rules of prescription use, and to find alternative drugs for endangered Chinese medicinal materials. Moreover, ETCM v2.0 provides an enhanced JavaScript-based network visualization tool for creating, modifying and exploring multi-scale biological networks. ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs, the TCM-derived drug discovery and repurposing, and the pharmacological mechanism investigation of TCMs against various human diseases.

Study of the B-Dot Sensor for Aircraft Surface Current Measurement.

The B-dot sensor is a type of Rogowski coil widely used in the measurement of current. However, the accuracy of the B-dot for measuring aircraft high-frequency lightning current is greatly affected by factors such as numerical integration drift, high-frequency oscillation, and calibration. In this study, a new design and optimization for improving the B-dot measuring accuracy was carried out. To correct the drift of the numerical integral of the measurement signal in differential mode, the measuring current was reconstructed based on the nonlinear least squares method. The sensor was then optimized by isolating the sampling resistance and matching the impedance with a voltage follower. A low-cost coaxial loop calibration system was also designed to calibrate the high frequency and strong magnetic fields more accurately. Finally, the optimized B-dot sensor accuracy was greatly improved with a measuring range of 30 kA/m, an error of 3.1%, and a high-frequency response of 50 MHz. Our study greatly increases the accuracy of measuring aircraft high-frequency lightning current.