Pd(II)/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Synthesis of Cyclic Quaternary Centers and Mechanistic Investigations.

A Pd(II)/N,N'-disulfonyl bisimidazoline-catalyzed asymmetric 1,4-conjugate addition reaction of low-cost arylboronic acids with readily available ß-substituted cyclic enones is described, providing a straightforward way of constructing cyclic all-carbon quaternary stereocenters with high enantioselectivity, in which ≥96% ee was obtained in most cases. The reaction proceeded without the protection of inert gas, making the operation process simple. Theoretical calculations have been applied to understand the origins of enantioselectivity.

A pharmacodynamic simulation to evaluate tigecycline in treatment of nosocomial pneumonia caused by multidrug-resistant Acinetobacter baumannii.

The shortage of effective antibiotics against multidrug-resistant Acinetobacter baumannii (MDR-Ab) has posed great threat to the public health. But the advent of tigecycline gives us new hope. The goal of our research was to assess the clinical efficacy of tigecycline at different doses by using a pharmacokinetic/pharmacodynamic (PK/PD) model which can incorporate pharmacokinetic data of tigecycline from patients with pneumonia and MICs of MDR-Ab from a tertiary hospital. A 10000-patient Monte-Carlo Simulation based on the PK/PD model was conducted to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of tigecycline. 97% isolates displayed susceptibility and 3% were tigecycline-intermediate strains and the values of MIC ranged from 0.125 to 4 µ g/ml. A CFR of 61.62% was predicted for tigecycline at current dosage (50 mg q12h). When the dosage was increased, the predicted CFRs for 75 mg q12h, 100 mg q12h, 125 mg q12h, 150 mg q12h were 81.00%, 89.86%, and 94.57%, 96.77%, respectively. Despite presented higher susceptibility, the CFR obtained was not optimal at current dosage. A higher CFR indicating a better clinical efficacy can be gained by the increased dosage.

Olefin skeletal rearrangement enabling access to multiarylated N-sulfonyl amidines.

A base-promoted olefin skeletal rearrangement strategy from para-quinone methides (p-QMs) and N-fluoroarenesulfonamides is reported, enabling direct nitrogen insertion of olefins to produce a series of multiarylated (Z)-N-sulfonyl amidines with complete stereoselectivity and generally good yields. Using p-QMs without o-hydroxy substituents gave triarylated N-sulfonyl amidines, whereas tetraarylated N,N'-disulfonyl amidines were synthesized with the existence of o-hydroxy groups.

Construction of central and axial chirality via Pd(II)/Bim-catalyzed asymmetric dearomative Michael reaction of polycyclic tropones.

A highly enantioselective Pd/Bim-catalyzed dearomative Michael reaction applying polycyclic tropones as non-benzenoid aromatic Michael acceptors and arylboronic acids as aryl pronucleophiles has been developed. The bridged biaryls bearing central and axial chirality, including pentacyclic cyclohepta[b]indoles and 6,7-dihydrodibenzo[a,c][7]annulen-5-ones, are generally generated in good to high yields and excellent enantioselectivities and can be readily transformed into useful derivatives.

[The human body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls in residents' human breast milk from Beijing in 2007].

OBJECTIVE: To investigate contamination levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in human breast milk from Beijing residents, and evaluate the human body burden of PCDD/Fs and dl-PCBs of general population. METHODS: A total of 110 human milk samples were collected from 11 regions in Beijing in 2007. After 11 pooled samples were made, concentrations of PCDD/Fs and dl-PCBs in breast milk pooled samples were measured by a high resolution gas chromatography - high resolution mass spectrometry (HRCG-HRMS) with isotope dilution. RESULTS: For congeners of PCDD/Fs and dl-PCBs in human breast milk from Beijing, the highest content of congeners was octachlorodibenzo-p-dioxin (OCDD), polychlorinated biphenyl (PCB)-118, and PCB-105 with the median of 20.6 pg/g fat, 4.07 ng/g fat and 1.63 ng/g fat, respectively. The concentration median of total dioxins in 11 pooled human milk samples from Beijing was 7.4 pg TEQ/g fat. The highest was 13.5 pg TEQ/g fat from Tongzhou, and the lowest was 4.3 pg TEQ/g fat from Pinggu. CONCLUSION: The contamination level of PCDD/Fs and dl-PCBs in human milk from Beijing is relatively low. However, with the rapid industrialization in China, the human body burden of PCDD/Fs and dl-PCBs will be likely to rise. Thus, further studies should be conducted to continuously monitor the trend of contamination level.

Azofuran activation for annulative rearrangement enabled by gold(I)/Brønsted acid relay catalysis.

A novel gold(I)/Brønsted acid relay catalysis enabling azofuran activation to induce annulative rearrangement from 3-yne-1,2-diols and aryldiazonium tetrafluoroborates is reported, producing a series of furan-2-yl-substituted pyrrol-2-ones bearing a quaternary carbon center with good yields. Exchanging aryldiazonium tetrafluoroborate for azofuran led to skeletally identical but substituent-diverse furan-2-yl-containing pyrrol-2-ones with good yields, supporting the key azofuran activation and annulative rearrangement by gold/Brønsted acid relay catalysis.

Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. METHODS: Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis. RESULTS: Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs. CONCLUSION: CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders.

Prevalence, risk factors, and prediction of inappropriate use of non-vitamin K antagonist oral anticoagulants in elderly Chinese patients with atrial fibrillation: A study protocol.

Background: Atrial fibrillation (AF) is an arrhythmia that is prevalent globally, and its incidence grows exponentially with aging. Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed in recent years, and it challenges the supremacy of warfarin for thromboembolism prophylaxis in AF. Nevertheless, there are limited data specifically evaluating the real-life use of NOACs in elderly patients with AF in China. Methods: This is a national, multicenter, non-interventional, cross-sectional study that enrolls patients with AF aged 75 years and above from 31 institutions across China. Data were collected using the Hospital Information System. The primary outcomes include (1) profiles of NOAC use in the elderly; (2) frequency of inappropriate NOAC use based on guidelines and approved labeling recommendations; (3) exploring potential risk factors related to NOACs inappropriate use; and (4) creating a prediction tool for inappropriate NOACs use. Conclusion: The results of this study reveal the prevalence, risk factors, and corresponding prediction tool of inappropriate NOACs use in older patients with AF in China, as well as provide valuable insights into the clinical application of NOACs in high-risk populations in the real-world setting. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05361889.

The relationship between absolute counts of lymphocyte subsets and clinical features in patients with pulmonary tuberculosis.

BACKGROUND: The aim of the present study is to investigate the clinical value and characteristics of peripheral blood lymphocyte subsets in patients with pulmonary tuberculosis (PTB) using flow cytometry. METHODS: The absolute counts of T, CD4+ T, CD8+ T, natural killer (NK), NKT and B lymphocytes in 217 cases of PTB were detected, and the variations in lymphocyte subset counts between different ages and genders and between aetiological detection results and chest radiography results were analysed. RESULTS: In 75.3% of the patients with PTB, six subset counts were lower than the normal reference range, and 44% showed lower-than-normal CD4+ T lymphocyte levels. The counts of T, CD4+ T, CD8+ T and B lymphocytes were significantly lower in patients aged >60 years, and the NKT cell counts were significantly lower in female patients than in male patients. Among the patients with positive aetiological results, 40.8% had reduced CD8+ T counts; these were significantly lower than those in patients with negative aetiological results (P = 0.0295). The cell counts of T, CD4+ T, CD8+ T and B lymphocytes reduced as lesion lobe numbers increased. The counts of T, CD4+ T and CD8+ T lymphocytes were significantly higher in the group with lesions affecting one lobe than in the groups with two to three lobes or four to five lobes, and the counts of B lymphocytes were significantly higher in the group with one lobe and the group with two to three lobes than in the group with four to five lobes. The counts of CD4+ T and CD8+ T lymphocytes were highest in the no cavity group and showed a downward trend with the increase in cavities; the T lymphocyte count was significantly higher in the no cavity group than in the group with five or more cavities (P = 0.014), and the CD8+ T lymphocyte count was significantly higher in the no cavity group than in the group with one to two cavities and the group with five or more cavities (P = 0.001 and 0.01, respectively). CONCLUSIONS: In most patients with tuberculosis, immune function is impaired. The absolute counts of peripheral blood lymphocyte subsets are closely related to the aetiological results and lesion severity in patients with PTB; this could be used as evidence for immune intervention and monitoring curative effects.

Fast analysis of polybrominated diphenyl ethers in eggs using selective pressurized liquid extraction coupled with online GPC-GC/MS.

This article reports the applicability of online gel permeation chromatography (GPC)-GC/MS for the determination of seven predominant polybrominated diphenyl ethers (PBDEs) in eggs to effectively eliminate matrix interference. Selective pressurized liquid extraction using acidic alumina as a fat retainer was used for cleanup of the PBDEs in eggs. It was selected because of its advantages: simpler operation, minimum time spent on sample handing to get fat-free extracts, and low volume of solvent consumption. After concentration, the extract was directly injected for online GC/MS operated in the negative ion chemical ionization mode with a 15 m capillary column. Recoveries of spiked samples were between 75.1 and 102.0%, with RSDs (n=3) ranging from 3.69-11.47% when spiked at levels of 2 and 20 ng/g, dry mass. The LOD varied from 0.25-34 ng/g, dry mass. The proposed method was proven to be rapid, efficient, and reliable for the trace determination of PBDEs in eggs.