Silicon-based cross-coupling has been recognized as one of the most reliable alternatives for constructing carbon-carbon bonds. However, the employment of such reaction as an efficient ring expansion ...strategy for silacycle synthesis is comparatively little known. Herein, we develop the first intermolecular silacyclization strategy involving Pd-catalyzed silicon-based C(sp
2
)-C(sp
3
) cross-coupling. This method allows the modular assembly of a vast array of structurally novel and interesting sila-benzo
b
oxepines with good functional group tolerance. The key to success for this reaction is that silicon atoms have a stronger affinity for oxygen nucleophiles than carbon nucleophiles, and silacyclobutanes (SCBs) have inherent ring-strain-release Lewis acidity.
Herein, we develop the first silacyclization between 2-halophenols and SCBs, which allows the modular assembly of sila-benzo
b
oxepines with good functional group tolerance and can be applied for the late-stage modification of biologically active molecules.
Background
High incidence of asymptomatic venous thromboembolism (VTE) has been observed in severe COVID‐19 patients, but the characteristics of symptomatic VTE in general COVID‐19 patients have not ...been described.
Objectives
To comprehensively explore the prevalence and reliable risk prediction for VTE in COVID‐19 patients.
Methods/Results
This retrospective study enrolled all COVID‐19 patients with a subsequent VTE in 16 centers in China from January 1 to March 31, 2020. A total of 2779 patients were confirmed with COVID‐19. In comparison to 23,434 non‐COVID‐19 medical inpatients, the odds ratios (ORs) for developing symptomatic VTE in severe and non‐severe hospitalized COVID‐19 patients were 5.94 (95% confidence interval CI 3.91–10.09) and 2.79 (95% CI 1.43–5.60), respectively. When 104 VTE cases and 208 non‐VTE cases were compared, pulmonary embolism cases had a higher rate for in‐hospital death (OR 6.74, 95% CI 2.18–20.81). VTE developed at a median of 21 days (interquartile range 13.25–31) since onset. Independent factors for VTE were advancing age, cancer, longer interval from symptom onset to admission, lower fibrinogen and higher D‐dimer on admission, and D‐dimer increment (DI) ≥1.5‐fold; of these, DI ≥1.5‐fold had the most significant association (OR 14.18, 95% CI 6.25–32.18, p = 2.23 × 10−10). A novel model consisting of three simple coagulation variables (fibrinogen and D‐dimer levels on admission, and DI ≥1.5‐fold) showed good prediction for symptomatic VTE (area under the curve 0.865, 95% CI 0.822–0.907, sensitivity 0.930, specificity 0.710).
Conclusions
There is an excess risk of VTE in hospitalized COVID‐19 patients. This novel model can aid early identification of patients who are at high risk for VTE.
Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations have excellent response to EGFR tyrosine kinase inhibitors (TKIs), but T790M ...mutation accounts for most TKI drug resistance. This study used highly sensitive methods to detect T790M before and after TKI therapy and investigated the association of T790M and its mutation frequencies with clinical outcome.
Direct sequencing, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and next-generation sequencing (NGS) were used to assess T790M in the following two cohorts of patients with NSCLC: TKI-naive patients (n = 107) and TKI-treated patients (n = 85). Results were correlated with TKI treatment response and survival.
MALDI-TOF MS was highly sensitive in detecting and quantifying the frequency of EGFR-activating mutations and T790M (detection limits, 0.4% to 2.2%). MALDI-TOF MS identified more T790M than direct sequencing in TKI-naive patients with NSCLC (27 of 107 patients, 25.2% v three of 107 patients, 2.8%, respectively; P < .001) and in TKI-treated patients (before TKI: 23 of 73 patients, 31.5% v two of 73 patients, 2.7%, respectively; P < .001; and after TKI: 10 of 12 patients, 83.3% v four of 12 patients, 33.3%, respectively; P = .0143). The EGFR mutations and their frequencies were confirmed by NGS. T790M was an independent predictor of decreased progression-free survival (PFS) in patients with NSCLC who received TKI treatment (P < .05, multivariate Cox regression).
T790M may not be a rare event before or after TKI therapy in patients with NSCLC with EGFR-activating mutations. The pretreatment T790M mutation was associated with shorter PFS with EGFR TKI therapy in patients with NSCLC.
Dyslipidemia in pregnancy are associated with gestational diabetes mellitus (GDM), preeclampsia, preterm birth and other adverse outcomes, which has been extensively studied in western countries. ...However, similar studies have rarely been conducted in Asian countries. Our study was aimed at investigating the associations between maternal dyslipidemia and adverse pregnancy outcomes among Chinese population.
Data were derived from 934 pairs of non-diabetic mothers and neonates between 2010 and 2011. Serum blood samples were assayed for fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) concentrations during the first, second and third trimesters. The present study explored the associations between maternal lipid profile and pregnancy complications and perinatal outcomes. The pregnancy complications included GDM, preeclampsia and intrahepatic cholestasis of pregnancy (ICP); the perinatal outcomes included preterm birth, small/large for gestational age (SGA/LGA) infants and macrosomia. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated and adjusted via stepwise logistic regression analysis. Optimal cut-off points were determined by ROC curve analysis.
After adjustments for confounders, every unit elevation in third-trimester TG concentration was associated with increased risk for GDM (OR = 1.37, 95% CI: 1.18-1.58), preeclampsia (OR = 1.50, 95% CI: 1.16-1.93), ICP (OR = 1.28, 95% CI: 1.09-1.51), LGA (OR = 1.13, 95% CI: 1.02-1.26), macrosomia (OR = 1.19, 95% CI: 1.02-1.39) and decreased risk for SGA (OR = 0.63, 95% CI: 0.40-0.99); every unit increase in HDL-C concentration was associated with decreased risk for GDM and macrosomia, especially during the second trimester (GDM: OR = 0.10, 95% CI: 0.03-0.31; macrosomia: OR = 0.25, 95% CI: 0.09-0.73). The optimal cut-off points for third-trimester TG predicting GDM, preeclampsia, ICP, LGA and SGA were separately ≥ 3.871, 3.528, 3.177, 3.534 and ≤ 2.530 mmol/L. The optimal cut-off points for third-trimester HDL-C identifying GDM, macrosomia and SGA were respectively ≤ 1.712, 1.817 and ≥ 2.238 mmol/L.
Among Chinese population, maternal high TG in late pregnancy was independently associated with increased risk of GDM, preeclampsia, ICP, LGA, macrosomia and decreased risk of SGA. Relative low maternal HDL-C during pregnancy was significantly associated with increased risk of GDM and macrosomia; whereas relative high HDL-C was a protective factor for both of them.
Myelodysplastic syndrome (MDS) is clonal disease featured by ineffective haematopoiesis and potential progression into acute myeloid leukaemia (AML). At present, the risk stratification and prognosis ...of MDS need to be further optimized. A prognostic model was constructed by the least absolute shrinkage and selection operator (LASSO) regression analysis for MDS patients based on the identified metabolic gene panel in training cohort, followed by external validation in an independent cohort. The patients with lower risk had better prognosis than patients with higher risk. The constructed model was verified as an independent prognostic factor for MDS patients with hazard ratios of 3.721 (1.814‐7.630) and 2.047 (1.013‐4.138) in the training cohort and validation cohort, respectively. The AUC of 3‐year overall survival was 0.846 and 0.743 in the training cohort and validation cohort, respectively. The high‐risk score was significantly related to other clinical prognostic characteristics, including higher bone marrow blast cells and lower absolute neutrophil count. Moreover, gene set enrichment analyses (GSEA) showed several significantly enriched pathways, with potential indication of the pathogenesis. In this study, we identified a novel stable metabolic panel, which might not only reveal the dysregulated metabolic microenvironment, but can be used to predict the prognosis of MDS.
Background and Purpose
Disruption of intestinal barriers plays a vital role in the pathogenesis of colitis. The aryl hydrocarbon receptor (AhR) is a recognition sensor that mediates intestinal immune ...homeostasis and minimizes intestinal inflammation. Astragalus polysaccharide (APS) exerts pharmacological actions in colitis; however, the mechanism has not been elucidated. We investigated whether APS protects through AhR‐dependent autophagy.
Experimental Approach
The symptoms of dextran sulfate sodium (DSS)‐induced colitis in mice involving intestinal barrier function and inflammatory injury were evaluated after APS administration. Intestinal‐specific Becn1 conditional knockout (Becn1 cKO) mice were constructed and compared with wild‐type mice. Autophagy and the effects of APS were investigated after the deactivation of AhRs. The relationship between APS‐induced AhRs and autophagic Becn1 was investigated using a dual‐luciferase reporter system and chromatin immunoprecipitation (ChIP)‐quantitative polymerase chain reaction assay. Caco‐2 cells were used to investigate inflammatory responses and AhR‐dependent autophagy.
Key Results
APS improved intestinal barrier function in inflammatory injury in colitis mice. APS triggered autophagic flow; however, knockout of Becn1 in the gut increased susceptibility to colitis, leading to diminished epithelial barrier function and severe intestinal inflammation, impairing the protective effects of APS. Mechanistically, APS‐triggered autophagy depends on AhR expression. Activated AhR binds to the promoter Becn1 to operate transcription of genes involved in anti‐inflammation and intestinal barrier repair, while deactivation of AhR correlated with intestinal inflammation and the therapeutic function of APS.
Conclusions and Implications
APS protects colitis mice by targeting autophagy, especially as the AhR stimulates the repair of damaged intestinal barrier functions.
A novel nickel‐catalyzed practical and simple synthesis of thioesters from amides and disulfides has been developed. Diverse substituted aromatic amides are capable of coupling with diaryl or dialkyl ...disulfides via C−N/S−S bonds cleavage to produce the desirable thioesters in moderate to good yields. This procedure features cheap metals, novel and easily preparative substrates, providing a simple and practical access to a variety of thioesters without toxic thiols or CO gas.
A novel nickel‐catalyzed practical and simple synthesis of thioesters from amides and disulfides has been developed. Diverse substituted aromatic amides are capable of coupling with diaryl or dialkyl disulfides via C−N/S−S cleavage to produce the desirable thioesters in moderate to good yields. This procedure features cheap metals, novel and easily preparative substrates, providing a simple and practical access to a variety of thioesters without toxic thiols or CO gas.
A surface-emitting distributed feedback (DFB) laser with second-order gratings typically excites an antisymmetric mode that has low radiative efficiency and a double-lobed far-field beam. The ...radiative efficiency could be increased by using curved and chirped gratings for infrared diode lasers, plasmon-assisted mode selection for mid-infrared quantum cascade lasers (QCLs), and graded photonic structures for terahertz QCLs. Here, we demonstrate a new hybrid grating scheme that uses a superposition of second and fourth-order Bragg gratings that excite a symmetric mode with much greater radiative efficiency. The scheme is implemented for terahertz QCLs with metallic waveguides. Peak power output of 170 mW with a slope-efficiency of 993 mW A
is detected with robust single-mode single-lobed emission for a 3.4 THz QCL operating at 62 K. The hybrid grating scheme is arguably simpler to implement than aforementioned DFB schemes and could be used to increase power output for surface-emitting DFB lasers at any wavelength.
Accurate classification of different Burkholderia cepacia complex (BCC) species is essential for therapy, prognosis assessment and research. The taxonomic status of BCC remains problematic and an ...improved knowledge about the classification of BCC is in particular needed.
We compared phylogenetic trees of BCC based on 16S rRNA, recA, hisA and MLSA (multilocus sequence analysis). Using the available whole genome sequences of BCC, we inferred a species tree based on estimated single-copy orthologous genes and demarcated species of BCC using dDDH/ANI clustering.
We showed that 16S rRNA, recA, hisA and MLSA have limited resolutions in the taxonomic study of closely related bacteria such as BCC. Our estimated species tree and dDDH/ANI clustering clearly separated 116 BCC strains into 36 clusters. With the appropriate reclassification of misidentified strains, these clusters corresponded to 22 known species as well as 14 putative novel species.
This is the first large-scale and systematic study of the taxonomic status of the BCC and could contribute to further insights into BCC taxonomy. Our study suggested that conjunctive use of core phylogeny based on single-copy orthologous genes, as well as pangenome-based dDDH/ANI clustering would provide a preferable framework for demarcating closely related species.
This article was reviewed by Dr. Xianwen Ren.
A practical and efficient synthetic route to construct a variety of 3-amidated quinoxalin-2(1
H
)-ones was developed
via
transition-metal free direct oxidative amidation of quinoxalin-2(1
H
)-ones ...with amidates using Selectfluor reagent as a mild oxidant. This protocol features mild reaction conditions, operational simplicity, broad substrate scope, and good to excellent yields.
An efficient and convenient protocol for the synthesis of 3-amidated quinoxalin-2(1
H
)-ones was developed
via
transition-metal free direct oxidative amidation of quinoxalin-2(1
H
)-ones with amidates using Selectfluor reagent as a mild oxidant.
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