ShaShen-MaiDong decoction attenuates bleomycin-induced pulmonary fibrosis by inhibiting TGF-ß/smad3, AKT/MAPK, and YAP/TAZ pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulmonary fibrosis (PF) is progressive and terminal lung disease, which is also the most common sequelae of Corona Virus Disease (2019) (COVID-19) survivors. Unfortunately, there is currently no cure for PF. ShaShen-MaiDong decoction (SMT), a traditional Chinese medicine, has been employed in treating various lung diseases, which may offer potential therapeutic benefits for PF. AIM OF THE STUDY: To investigate the antifibrotic efficacy of SMT and its major active ingredients as well as the underlying mechanisms for treating PF. MATERIALS AND METHODS: Fist, we build the UPLC-MS based qualitative and quantitative profiling for the quality control of SMT. Then, the antifibrotic efficacy of SMT was investigated in bleomycin (BLM)-induced PF mice model. Network pharmacology was used to predict the mechanism and active components of SMT for the treatment of PF, which was further verified in vitro and in vivo. RESULTS: SMT improved the weight loss and attenuated hydroxyproline, inflammatory cytokines, and collagen deposition in BLM-induced PF mice model in a dose-dependent manner. Mechanistically, as predicted by network pharmacology analysis, SMT and its active compounds (kaempferol, quercetin, and isorhamnetin) regulated the mitogen-activated protein kinase (MAPK) signaling pathways, TGF-ß/Smad signaling pathway, and YAP/TAZ signaling pathway, which was further verified in the PF mice and TGF-ß-induced A549 cell model. Moreover, SMT balanced the proportions of increased CD4+ and decreased CD8+ T cells in the peripheral blood of PF mice model. CONCLUSIONS: Considering the high mortality and complex pathogenesis of fibrotic diseases, our results provide novel evidence that SMT would be beneficial for pulmonary fibrosis therapy by modulating MAPK, TGF-ß/Smad, and YAP/TAZ signaling pathways at same time.

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

[Clinical Features and Prognosis of Acute T-cell Lymphoblastic Leukemia in Children--Multi-Center Data Analysis in Fujian].

OBJECTIVE: To evaluate the efficacy of acute T-cell lymphoblastic leukemia (T-ALL) in children and explore the prognostic risk factors. METHODS: The clinical data of 127 newly diagnosed children with T-ALL admitted to five hospitals in Fujian province from April 2011 to December 2020 were retrospectively analyzed, and compared with children with newly diagnosed acute precursor B-cell lymphoblastic leukemia (B-ALL) in the same period. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and event-free survival (EFS), and COX proportional hazard regression model was used to evaluate the prognostic factors. Among 116 children with T-ALL who received standard treatment, 78 cases received the Chinese Childhood Leukemia Collaborative Group (CCLG)-ALL 2008 protocol (CCLG-ALL 2008 group), and 38 cases received the China Childhood Cancer Collaborative Group (CCCG)-ALL 2015 protocol (CCCG-ALL 2015 group). The efficacy and serious adverse event (SAE) incidence of the two groups were compared. RESULTS: Proportion of male, age≥10 years old, white blood cell count (WBC)≥50×109/L, central nervous system leukemia, minimal residual disease (MRD)≥1% during induction therapy, and MRD≥0.01% at the end of induction in T-ALL children were significantly higher than those in B-ALL children (P <0.05). The expected 10-year EFS and OS of T-ALL were 59.7% and 66.0%, respectively, which were significantly lower than those of B-ALL (P <0.001). COX analysis showed that WBC≥100×109/L at initial diagnosis and failure to achieve complete remission (CR) after induction were independent risk factors for poor prognosis. Compared with CCLG-ALL 2008 group, CCCG-ALL 2015 group had lower incidence of infection-related SAE (15.8% vs 34.6%, P =0.042), but higher EFS and OS (73.9% vs 57.2%, P EFS=0.090; 86.5% vs 62.3%, P OS=0.023). CONCLUSIONS: The prognosis of children with T-ALL is worse than children with B-ALL. WBC≥100×109 /L at initial diagnosis and non-CR after induction (especially mediastinal mass has not disappeared) are the risk factors for poor prognosis. CCCG-ALL 2015 regimen may reduce infection-related SAE and improve efficacy.

Novel Pyrazole Acyl(thio)urea Derivatives Containing a Biphenyl Scaffold as Potential Succinate Dehydrogenase Inhibitors: Design, Synthesis, Fungicidal Activity, and SAR.

As part of a program to discover novel succinate dehydrogenase inhibitor fungicides, a series of new pyrazole acyl(thio)urea compounds containing a diphenyl motif were designed and synthesized. Their structures were confirmed by 1H NMR, HRMS, and single X-ray crystal diffraction analysis. Most of these compounds possessed excellent activity against 10 fungal plant pathogens at 50 µg mL-1, especially against Rhizoctonia solani, Alternaria solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Cercospora arachidicola. Interestingly, compounds 3-(difluoromethyl)-1-methyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9b, EC50 = 0.97 ± 0.18 µg mL-1), 1,3-dimethyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9a, EC50 = 2.63 ± 0.41 µg mL-1), and N-((4'-chloro-[1,1'-biphenyl]-2-yl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4-carboxamide (9g, EC50 = 1.31 ± 0.15 µg mL-1) exhibited activities against S. sclerotiorum that were better than the commercial fungicide bixafen (EC50 = 9.15 ± 0.05 µg mL-1) and similar to the positive control fluxapyroxad (EC50 = 0.71 ± 0.11 µg mL-1). These compounds were not significantly phytotoxic to monocotyledonous and dicotyledonous plants. Structure-activity relationships (SAR) are discussed by substituent effects/molecular docking, and density functional theory analysis indicated that these compounds are succinate dehydrogenase inhibitors.

Epidemiological characteristics of hand-foot-mouth disease in Ganzhou city from 2017 to 2020 / 新乡医学院学报

Objective To analyze the epidemiological characteristics of hand-foot-mouth disease(HFMD)in Gan-zhou.Methods The epidemiological data of HFMD reported by the Infectious Disease Surveillance System,a sub-system of China Disease Prevention and Control Information System,from 2017 to 2020 were analyzed by descriptive methods.Enterovirus(EV)nucleic acid and typing detections via throat swabs,anal swabs or herpes fluid of patients was detected by real-time fluo-rescent polymerase chain reaction.The change in HFMD epidemic characteristics was compared between 2020 and 2017-2019.Results The incidence of HFMD in Ganzhou in 2020 was significantly lower than that from 2017 to 2019(x2=50.587,P＜0.05).In 2020,the incidence of HFMD in counties and districts of Ganzhou(except Huichang County)signifi-cantly decreased compared with that in 2017-2019(P＜0.05).From 2017 to 2019,the incidence of HFMD was obviously seasonal,with a high incidence in summer and autumn,and two significant incidence peaks were formed in June and September in 2017 and 2018,respectively.In 2019,there was a summer peak in June.The epidemic trend in 2020 was different,with a very low epidemic trend in summer and autumn,and a peak in winter.The incidence of HFMD in men,women and all ages in 2020 significantly decreased compared with that in 2017-2019(P＜0.05),and the age of onset was mainly distributed in 1-5 years,especially in children aged 1 to 3 years.There was a significant difference in the incidence of HFMD among different ages(P＜0.05).The positive rate of EV in Ganzhou in 2020 was lower than that from 2017 to 2019(x2=47.273,P＜0.05).The positive rate of EV in January,March to September in 2020 was significantly lower,and the positive rate of EV in November,December 2020 was significantly higher than that in the same period in 2017 to 2019(P＜0.05).Strain CA16 showed an increasing trend year by year from 2017 to 2019,and became the dominant strain in 2019.The proportion of patients infected with CA6 strain was on the fise from 2018 to 2020,and CA6 became the dominant strain in 2020.Conclusion The HFMD in Ganzhou has obvious population characteristics and seasonality,and the pathogen spectrum is constantly changing.

Effect of alisol A on cerebral ischemia reperfusion injury by protecting blood brain barrier and its mechanism / 中国药理学通报

Aim To investigate whether alisol A (AA) could improve the blood brain barrier (BBB) mediated cortex cerebral ischemia-repeifusion injury (CIRI) by inhibiting matrix metalloproteinase 9 (MMP-9). Methods The global cerebral ischemia- reperfusion (GCI/R) model in mice was established, and the AA was intragastric injected subsequently for seven days. The modified neurological severity scores (mNSS), open field test and Y-maze test were applied to detect neurological function. Magnetic resonance spectroscopy (MRS) was used to detect relevant neu- rosubstance metabolism in cortex of mice. Transmission electron microscope (TEM) was employed to observe the ultrastructure of BBB in cortex. Western blot and immunohistochemistry were used to detect the MMP-9 level in cortex. The binding possibility of A A and MMP-9 was determined by molecular docking. Results Compared with Sham group, mice in GCI/R group have an increased mNSS score but decreased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01). While mice in GCI/R + AA group have a decreased mNSS score but increased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test (P<0.01) compared with GCI/R group. MRS results found that in cortex of GCI/R group mice, the level of GABA and NAA significantly decreased while the Cho, mI and Tau level increased (P<0.01). Whereas in GCI/R + AA group mice, the GABA and NAA level increased and the Cho, ml and Tau decreased significantly (P<0.01). By TEM we observed that the basilemma of cerebral microvessels collapsed, the lumen narrowed, the endothelial cells were active and plasma membranes ruffled, gaps between cells were enlarged and tight junctions were damaged and the end feet of astrocytes were swollen in GCI/R group mice. While in GCI/R + AA group mice, the lumen was filled, plasma membranes of endothelial cells were smooth, tight junctions were complete and end feet of astrocytes were in normal condition. Western blot and immunohistochemistry both found that the MMP-9 level increased in GCI/R group mice (P < 0.01) and decreased in GCI/R + AA group mice (P < 0.05). Molecular docking proved the binding between aliso A and MMP9 through TYR-50 and ARG-106, and the binding energy was calculated as -6.24 kcal · mol

Discovery of Fungicidal Hydrazide Lead Compounds Derived from Sinapic Acid and Mycophenolic Acid.

Structure optimization based on natural products has become an effective way to develop new green fungicides. In this project, thirty-two novel NPs-derived hydrazide compounds were designed and synthesized by introducing the bioactive hydrazide substructure into sinapic acid and mycophenolic acid. The fungicidal bioassays indicated that the obtained hydrazide compounds showed excellent and selective fungicidal activity against specific pathogens, especially compounds C8, D7, and D8 with EC50 values of 0.63, 0.56, and 0.43 µg mL-1 against M. oryzae, respectively. SAR indicated that the introduction of 4-fluoro, 4-chloro, and 2,4-difluoro groups was conducive to improving the fungicidal activity, while the extension of the hydrazide bridge would affect the selectivity for inhibitory activity. Subsequently, the effects of hydrazide compounds on rice seedling and zebrafish growth were also investigated. The fungicidal mechanism implied that treatment with compound B4 would cause significant changes in metabolites of plasma membrane-related linolenic acid metabolism, arachidonic acid metabolism, and α-linolenic acid metabolism pathways, which further led to the wrinkled hyphae and the blurred plasma membrane and cytoplasm. Finally, the frontier molecular orbitals and charge distribution were calculated to analyze the differences in bioactivity from a structural perspective. These results provide important guidance for the development and practical application of novel fungicides.

Effect of early relapse on the therapeutic efficacy and survival for patients with multiple myeloma and analysis of risk factors of early relapse / 白血病·淋巴瘤

Objective:To investigate the therapeutic efficacy and prognosis of multiple myeloma (MM) patients with early relapse and the influencing factors of early relapse.Methods:The clinical data of 164 patients with newly diagnosed MM admitted to Affiliated Hospital of Hebei University from January 2018 to January 2021 were retrospectively analyzed, and 53 cases (32.3%) relapsed at the end of the follow-up. According to the recurrence within 12 months or not, the patients were divided into early relapse group and advanced relapse group; the clinical characteristics, overall response rate (ORR) and overall survival (OS) of both groups were compared. Logistic regression was used to analyze if the following indexes including age, gender, albumin, lactate dehydrogenase (LDH), β 2-microglobulin (β 2-MG), hemoglobin, creatinine, serum calcium, bone marrow plasma cell ratio, extramedullary disease, high-risk fluorescent in situ hybridization (FISH) were the influencing factors of the early relapse. Based on 7 published clinical trials, simplified early relapse MM (S-ERMM) scoring system was constructed to subgroup all relapsed patients. The difference in risk stratification between early relapsed patients and advanced relapsed patients was compared. Results:The median follow-up time of 164 newly diagnosed MM patients was 26 months (12-48 months). Among 53 relapsed MM patients, 24 cases had early relapse and 29 cases had advanced relapse. The ORR of patients with early relapse was decreased compared with that of those with advanced relapse [70.8% (17/24) vs. 89.7% (26/29), χ2 = 3.04, P = 0.001]. The median OS of the early relapse group was shorter than that of the advanced relapse group (24 months vs. not reached, P < 0.001). The OS of patient in the early relapse group with the best response ≥ complete remission (CR), ≥ very good partial remission (VGPR) and ≥ partial remission (PR) during initial induction therapy was worse than that of those in the advanced relapse group, and the differences were statistically significant ( P values were 0.008, 0.011, 0.012, respectively). Multivariate Logistic regression analysis showed low albumin (<35 g/L vs. ≥35 g/L: OR = 1.644, 95% CI 1.076-2.511, P = 0.022) and high LDH (< the upper limit of normal value vs. ≥ the upper limit of normal value: OR = 0.998, 95% CI 0.985-1.011, P = 0.030) were independent influencing factors of early relapse. Among 24 early relapse patients, there were 5 cases (20.8%), 13 cases (54.2%), 6 cases (25.0%), respectively in the S-ERMM scoring system low-risk, middle-risk, high-risk groups; among 29 advanced relapse patients, there were 18 cases (62.1%),9 cases (31.0%), 2 cases (6.9%), respectively in the S-ERMM scoring system low-risk, middle-risk, high-risk groups; the difference in risk stratification of the S-ERMM scoring system between the early relapse group and the advanced relapse group was statistically significant ( χ2 = 9.09, P = 0.003). Conclusions:MM patients with early relapse have poor therapeutic efficacy and prognosis. The prognosis is not affected by the depth of remission to first-line therapy. Low albumin and high LDH may be independent risk factors of MM patients with early relapse.

Venetoclax combined with azacitidine in the treatment of newly diagnosed chronic myelomonocytic leukemia-2: report of 4 cases and review of literature / 白血病·淋巴瘤

Objective:To explore the efficacy of venetoclax plus azacitidine (VA) in the treatment of patients with newly diagnosed chronic myelomonocytic leukemia (CMML).Methods:The clinical data of 4 newly diagnosed CMML-2 patients treated with VA regimen in the Affiliated Hospital of Hebei University from February 2022 to March 2023 were retrospectively analyzed, and the related literature was reviewed.Results:All 4 CMML-2 patients achieved the effect of ≥ partial bone marrow remission (PMR) after 1 course of treatment, and with the deepened extension of treatment course, the overall response rate and complete remission (CR) rate was 100% and 50%, respectively. In terms of dose adjustment, the dose and usage day of venetoclax were determined by using dynamic frailty assessment and adverse events. Among the 2 patients who achieved CR, 1 patient initially received venetoclax 200 mg for 14 days, and 1 patient received venetoclax 400 mg for 28 days and then the usage reduced to venetoclax 200 mg for 14 days due to hematological adverse events. All 4 patients maintained CR status. The most common grade 3 and 4 adverse events were neutropenia and thrombocytopenia.Conclusions:The first-line application of VA regimen in the treatment of newly diagnosed CMML-2 patients may achieve faster remission and better safety compared with traditional HMA monotherapy.

A multicenter study of R-ISS staging combined with frailty biomarkers to predict the prognosis and early death in newly diagnosed elderly multiple myeloma patients / 中华老年医学杂志

Objective:To improve the prognosis stratification, especially early mortality(EM), of elderly patients with newly diagnosed multiple myeloma(NDMM).Methods:In this retrospective study, univariate and multivariate Cox regression analysis were conducted to identify the independent prognostic factors associated with overall survival(OS)and the chi-square test and multivariate Logistic analysis were used to identify the prognostic factors associated with EM in 223 elderly patients(age≥65 years)with NDMM from three centers in the country.Results:Increased NT-pro-BNP(≥300 pg/ml), ECOG-PS≥2 and stage Ⅲ R-ISS were identified as three independent adverse prognostic factors of OS.The rates of EM3, EM6, EM12 and EM24 were 12.1%, 20.1%, 32.2% and 60%, respectively.The most common cause for EM6(particularly EM3)was disease-related complications resulting from ineligibility for treatment due to poor physical performance, severe organ dysfunction or treatment discontinuation due to treatment intolerance, while the most common cause for EM12(particularly EM24)was disease progression or relapse mainly as a result of inadequate treatment.R-ISS staging failed to predict EM, while decreased eGFR, ECOG-PS≥2, and increased NT-pro-BNP were able to estimate the risk of EM, with increased NT-pro-BNP as a common independent factor for EM12( P=0.03)and EM24( P=0.015). Conclusions:R-ISS staging, which primarily reflects MM biology, cannot predict EM.However, factors such as NT-pro-BNP, eGFR and ECOG-PS associated with frailty and impairment of organ functions can be used to estimate the risk of EM, among which NT-pro-BNP may be the most important independent factor for EM.Therefore, incorporation of these frailty-related biomarkers into R-ISS staging may be able to more precisely estimate the prognosis and particularly early death of elderly patients with NDMM.

Cognitive function of patients with comorbid borderline personality disorder and bipolar disorder / 四川精神卫生

BackgroundThe comorbidity rate of bipolar disorder and borderline personality disorder （BPD） is high， and the cognitive impairment of comorbidity patients is more serious. ObjectiveTo explore the difference of cognitive function between bipolar disorder patients with BPD or not， so as to provide references for clinical diagnosis and treatment. MethodsUsing simple random sampling， 60 patients with bipolar disorder comorbidity BPD treated in the First Hospital of Hebei Medical University from April 2021 to April 2022 were selected as the research group， including 33 patients with bipolar depression and 27 patients with bipolar mania. At the same time， 60 patients with bipolar disorder were randomly selected as the control group， including 35 patients with bipolar depression and 25 patients with bipolar mania. The cognitive function of patients was evaluated by the Chinese version of Repeatable Battery for the Assessment of Neuropsychological Status （RBANS） and the Stroop Color Word Test. ResultsThe immediate memory， visual span， speech function and total score of RBANS in the comorbid group were lower than those in the non-comorbid group， and the differences were statistically significant （t=-2.356， -2.138， -3.306， -2.729， P<0.05 or 0.01）. The single word time， single color time， double word time and double color time in Stroop Color Word Test in comorbid group were longer than those in non-comorbid group， and the differences were statistically significant （t=4.808， 3.341， 5.249， 5.167， P<0.01）. The immediate memory， visual span， speech function and total score in RBANS of bipolar depression patients with comorbid BPD were lower than those of bipolar depression patients without comorbid BPD （t=-2.446， -2.407， -2.231， -2.078， P<0.05）， and the time of single word， single color， double word and double color in Stroop Color Word Test were longer than those of non-comorbid BPD patients （t=-3.652， 3.035， 4.406， 5.016， P<0.01）. The speech function and total score of RBANS in bipolar manic patients in comorbid group were higher than those in non-comorbid group （t=-2.777， -2.347， P<0.05 or 0.01）， and the time of single word， single color， double word and double color in Stroop Color Word Test were longer than those in non-comorbid group （t=3.600， 2.658， 2.943， 4.337， P<0.05 or 0.01）. ConclusionThe cognitive impairment of bipolar disorder patients comorbid with BPD is more severe than that of patients without comorbid with BPD. ［Funded by Medical Science Research Project of Hebei Province in 2022 （number， 20221407）］

Synthesis, crystal structure, herbicidal activity and mode of action of new cyclopropane-1,1-dicarboxylic acid analogues.

A new series of cyclopropane-1,1-dicarboxylic (CPD) acid analogues were designed and synthesized. CPD is an inhibitor of ketol-acid reductoisomerase (KARI), an enzyme of the branched chain amino acid pathway in plants. The structures of CPD analogues were characterized by 1H NMR and HRMS. The structure of N,N'-bis(4-(tert-butyl)phenyl)cyclopropane-1,1-dicarboxamide was further elucidated by X-ray diffraction. The herbicidal activities of these compounds were tested against lettuce (Lactuca sativa) and bentgrass (Agrostis stolonifera). Most of these compounds exhibited low herbicidal activity against both plant species. Among them, N,N'-bis(2-ethylphenyl)cyclopropane-1,1-dicarboxamide displayed moderate activity against bentgrass. Inhibition of KARI activity by the CPD analogues was also assessed experimentally and by molecular docking simulation with results supporting inhibition of KARI as their mode of action. These results provide the basis for design of more effective KARI inhibitors.

Synthesis, herbicidal activity and soil degradation of novel 5-substituted sulfonylureas as AHAS inhibitors.

BACKGROUND: Chlorsulfuron, metsulfuron-methyl and ethametsulfuron can damage sensitive crops in rotation pattern as a result of their long persistence in soil. To explore novel sulfonylurea (SU) herbicides with favorable soil degradation rates, four series of SUs were synthesized through a structure-based drug design (SBDD) strategy. RESULTS: The target compounds, especially Ia, Id and Ie, exhibited prospective herbicidal activity against dicotyledon oil seed rape (Brassica campestris), amaranth (Amaranthus retroflexus), monocotyledon barnyard grass (Echinochloa crusgalli) and crab grass (Digitaria sanguinalis) at a concentration of 15 a.i. g ha-1 . Additionally, Ia, Id and Ig displayed excellent inhibitory effects against AtAHAS, with Kapp i values of 59.1, 34.5 and 71.8 µm, respectively, which were much lower than that of chlorsulfuron at 149.4 µm. The π-π stack and H-bonds between the Ia conformation and AtAHAS in the molecular docking results confirmed the series of compounds to be conventional AHAS inhibitors. In alkaline soil (pH = 8.46), compounds Ia-Ig revealed various degrees of acceleration in the degradation rate compared with chlorsulfuron. Besides, compound Ia showed considerable wheat and corn safety under postemergence at the concentration of 30, 60 and even 120 a.i. g ha-1 . CONCLUSION: Overall, based on the synthetic procedure, herbicidal activity, soil degradation and crop safety, the Ia sulfonylureas series were chosen to be investigated as prospective AHAS inhibitors. The 5-dimethylamino group on SUs accelerated the degradation rate at different levels in alkaline soils which seems to be controllable in conventional cropping systems in their further application. © 2022 Society of Chemical Industry.

A Chromosome Level Genome Assembly of a Winter Turnip Rape (Brassica rapa L.) to Explore the Genetic Basis of Cold Tolerance.

Winter rapeseed (Brassica rapa L.) is an important overwintering oilseed crop that is widely planted in northwest China and suffers chronic low temperatures in winter. So the cold stress becomes one of the major constraints that limit its production. The currently existing genomes limit the understanding of the cold-tolerant genetic basis of rapeseed. Here we assembled a high-quality long-read genome of B. rapa "Longyou-7" cultivar, which has a cold-tolerant phenotype, and constructed a graph-based pan-genome to detect the structural variations within homologs of currently reported cold-tolerant related genes in the "Longyou-7" genome, which provides an additional elucidation of the cold-tolerant genetic basis of "Longyou-7" cultivar and promotes the development of cold-tolerant breeding in B. rapa.

Preparation of pleated flower-like manganese-cobalt-silicate bimetallic electrode materials for supercapacitors.

Transition metal silicates (TMSS) have been studied as potential electrode materials for rechargeable batteries and supercapacitors (SCs), and delicate structural design can further enhance the capacity performance and cycling stability of TMSS electrode materials. Herein, a bimetallic doping modulation strategy was employed, and a novel metal-silicate structure was constructed to obtain SC anode materials with excellent electrochemical properties. Manganese cobalt silicate (AMMnCo) with a pleated flower-like structure was obtained by the reaction of Mn2+ and Co2+ with acid-etched montmorillonite (AM) substrates using a simple hydrothermal method. The benign, competitive bimetallic mechanism accelerates the growth of manganese silicate and cobalt silicate on treated montmorillonite (MMT), which results in more folded ion-transport channels on the lamellae and improves the electrochemical properties of the transition-metal silicates. AMMnCo exhibits a higher specific capacitance (979F·g-1/0.5 A·g-1) and better cycling performance (84 %/10,000 cycles) than its monometallic counterparts. Additionally, AMMnCo//AC (where AC is activated carbon), a hybrid supercapacitor (HSC) device, has a high mass specific capacitance and an energy density reaching 13.7 Wh·kg-1 at a power density of 246.9 W·kg-1. Therefore, AMMnCo is a prospective electrode material for high-performance SC applications.

[Comparison of the Early Efficacy and Serious Adverse Events between CCCG-ALL 2015 and CCLG-ALL 2008 in the Treatment of Pediatric Patients with Acute Lymphoblastic Leukemia].

OBJECTIVE: To evaluate the early efficacy and serious adverse events (SAE) related to chemotherapy of different protocols in the treatment of pediatric patients with acute lymphoblastic leukemia (ALL), so as to improve the overall survival rate. METHODS: A comparison of the early efficacy and SAE was performed between pediatric patients treated with Chinese Children Cancer Group-ALL 2015 (CCCG-ALL 2015) protocol from January 2019 to June 2020 and those treated with Chinese Children Leukemia Group-ALL 2008 (CCLG-ALL 2008) protocol from January 2017 to December 2018. RESULTS: The remission rate before consolidation chemotherapy between the two groups was not significantly different (P=0.198), but the negative conversion rate of minimal residual disease (MRD) in CCLG-ALL 2008 group was significantly higher than that in CCCG-ALL 2015 group (P=0.000). The incidence of SAE in CCCG-ALL 2015 group was significantly lower than that in CCLG-ALL 2008 group (P=0.021), and the incidence of infection-related SAE was significantly higher in the latter (P=0.001), while the difference of non-infection-related SAE was not statistically significant (P=0.623). In addition, the treatment-related mortality in CCCG-ALL 2015 group was significantly lower than that in CCLG-ALL 2008 group (P=0.003). CONCLUSION: CCCG-ALL 2015 regimen reduces the intensity of chemotherapy, which can significantly decrease the chemotherapy-related SAE (especially infection-related SAE), as well as treatment-related mortality. However, the MRD negative conversion rate is low before consolidation treatment, and the overall long-term efficacy remains to be further observed.

Photochromic and electrochromic properties of a viologen-based multifunctional Cd-MOF.

A pair of novel multifunctional MOF materials [Cd2(L)2(D/L-Lm)(H2O)2]·5H2O (denoted as D/L-Cd-MOF) has been synthesized by combining the viologen-functionalized ligand H2L+Cl- and chiral D/L-tartaric acid (H2Lm) with a simple solvothermal method. Due to the unique photoelectric response properties of the viologen units, reversible photochromic and electrochromic properties have been combined in D/L-Cd-MOF, which points to a new way of designing and constructing multifunctional photoelectric materials.

Alkaline Soil Degradation and Crop Safety of 5-Substituted Chlorsulfuron Derivatives.

Sulfonylurea herbicides can lead to serious weed resistance due to their long degradation times and large-scale applications. This is especially true for chlorsulfuron, a widely used acetolactate synthase inhibitor used around the world. Its persistence in soil often affects the growth of crop seedlings in the following crop rotation, and leads to serious environmental pollution all over the world. Our research goal is to obtain chlorsulfuron-derived herbicides with high herbicidal activities, fast degradation times, as well as good crop safety. On account of the slow natural degradation of chlorsulfuron in alkaline soil, based on the previously reported results in acidic soil, the degradation behaviours of 5-substituted chlorsulfuron analogues (L101-L107) were investigated in a soil with pH 8.39. The experimental data indicated that 5-substituted chlorsulfuron compounds could accelerate degradation rates in alkaline soil, and thus, highlighted the potential for rational controllable degradation in soil. The degradation rates of these chlorsulfuron derivatives were accelerated by 1.84-77.22-fold, compared to chlorsulfuron, and exhibited excellent crop safety in wheat and corn (through pre-emergence treatment). In combination with bioassay activities, acidic and alkaline soil degradation, and crop safety, it was concluded that compounds L104 and L107, with ethyl or methyl groups, are potential green sulfonylurea herbicides for pre-emergence treatment on wheat and corn. This paper provides a reference for the further design of new sulfonylurea herbicides with high herbicidal activity, fast, controllable degradation rates, and high crop safety.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial.

BACKGROUND: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer's disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss. OBJECTIVE: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton. METHODS: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement. RESULTS: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo). CONCLUSION: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects.

Rapid Screening of Lipase Inhibitors from Ophiopogonis Radix Using High-Performance Thin Layer Chromatography by Two Step Gradient Elution Combined with Bioautographic Method.

In this study, a high-performance thin layer chromatography (HPTLC) method by two step gradient elution with two mobile phases was developed for the simultaneous analysis of seven constituents in Ophiopogonis Radix. The chromatography was performed on silica gel 60 F254 plate with dichloromethane-methanol-ethyl acetate-water (70:25:12:3, v/v/v/v) and dichloromethane-methanol (300:1, v/v) as the mobile phase for two step gradient elution. Then, the HPTLC profiles were observed after derivatization with 10% sulfuric acid in ethanol solution. The obtained HPTLC images were further analyzed by chemometric approaches and the samples could be clustered based on regions and/or growth years, which were two important factors affecting the constituents in Ophiopogonis Radix. Furthermore, five compounds including ophiopogonin D, ophiopojaponin C, ophiopogonin D', ophiopogonin C' and methylophiopogonanone B were screened as potential lipase inhibitors from Ophiopogonis Radix by the HPTLC-bioautographic method. The binding modes and interactions between the five compounds and lipase were further explored by molecular docking analysis. The developed HPTLC method could be used for quality control of Ophiopogonis Radix and screening of the potential lipase inhibitors.