Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

Experimental study on molecular targeted diagnosis and treatment of pancreatic cancer with multifunctional nanodroplets as ultrasound contrast agents / 中华超声影像学杂志

Objective:To investigate the effect of self-made phase-change nanodroplets IR780/FA-Nds-DTX as molecular targeted ultrasound contrast agents for accurate diagnosis and combined targeted therapy of pancreatic cancer.Methods:Pancreatic cancer cell lines were cultured in vitro and 50 tumor bearing nude mouse models were established. The experimental group (IR780/ FA-NdS-DTX) and four control groups[ normal saline, Nds(FITC), FA-Nds (FITC) and IR-780] were divided to verify dual-mode targeted imaging. The imaging using the IVIS Imaging System verified the high-efficiency targeted detection ability and near-infrared fluorescence imaging of IR780/FA-Nds-DTX for tumors in vivo, phase transformation induced by low-intensity focused ultrasound and further contrast-enhanced ultrasound imaging verified the high-efficiency aggregation of IR780/FA-Nds-DTX in local tumors and accurate evaluation of tumor contour. The therapeutic effect was observed in the experimental group (IR780/FA-Nds-DTX) and four control groups (FA-Nds-IR780, FA-Nds-DTX, FA-Nds and normal saline). After low-intensity focused ultrasound irradiation for 30s induced microbubble blasting after phase transformation in each group, 808nm photothermal therapy apparatus was used to irradiate tumor area in each group. Two-dimensional ultrasound was used to monitor the changes in tumor volume in each group before and at 3 d, 9 d, 15 d after treatment, and the changes in tumor volume rate and inhibition in each group were statistically analyzed and compared.Results:The amount of IR780/ FA-Nds-DTX locally targeted aggregation was the largest, and the average fluorescence intensity of tumor in the experimental group was significantly higher than that of the control groups: IR780/ FA-Nds-DTX group compared with Nds(FITC) group[(5.12±0.69)×10 7 vs (1.06±0.23)×10 7, P<0.05], IR780/FA-Nds-DTX group compared with FA-Nds (FITC) group [(5.12±0.69)×10 7 vs (2.98±0.34)×10 7, P<0.05], IR780/FA-Nds-DTX group compared with IR-780 group [(5.12±0.69)×10 7 vs (1.54±0.42)×10 7, P<0.05], and there was no fluorescence in tumor area in saline group. Further contrast-enhanced ultrasound imaging after nanodroplet phase transformation could more accurately locate the tumor boundary. After 15 days of photothermal ablation combined with chemotherapy, the growth rate of tumor volume in the IR780/ FA-Nds-DTX treatment group was significantly lower than that in the control groups: IR780/FA-Nds-DTX group compared with FA-Nds-IR780 group[(0.105±0.075) vs (0.405±0.175), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds-DTX group [(0.105±0.075) vs (1.385±0.035), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds group [(0.105±0.075) vs (2.255±0.105), P<0.05], IR780/ FA-Nds-DTX group compared with normal saline group [(0.105±0.075) vs (2.185±0.155), P<0.05]. And the tumor inhibition rate increased significantly: IR780/ FA-Nds-DTX group compared with FA-Nds-IR780 group [(0.93±0.06) vs (0.48±0.17), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds-DTX group [(0.93±0.06) vs (-0.51±0.105), P<0.05], IR780/ FA-Nds-DTX group compared with FA-Nds group [(0.93±0.06) vs (-1.63±0.115), P<0.05], IR780/ FA-Nds-DTX group compared with normal saline[(0.93±0.06) vs (-1.35±0.245), P<0.05]. Conclusions:The self-made phase-change ultrasound contrast agents IR780/FA-Nds-DTX have good potential clinical value in targeted detection and combined therapy of pancreatic cancer with small lesions or even metastases.

Relation among personality, self-control and procrastination in young people / 中国心理卫生杂志

Objective:To explore the relationship between personality traits and procrastination in young people and the mediating role of self-control.Methods:A total of 344 college students (191 males and 153 females) were assessed with the Mini-IPIP Scale (Mini-IPIP), Dual-Mode of Self-Control Scale (DMSC-S, including control system and impulse system) and General Procrastination Scale (GPS).Results:The GPS scores were negatively correlated with scores of agreeableness subscale and conscientiousness subscale (r=-0.13, -0.53, Ps＜0.05), and positively correlated with scores of neuroticism subscales (r=0.27, P＜0.01).The structural equation modeling supported the impulse system fully mediated the relationship between neuroticism and procrastination (η2=0.15, 95％CI=0.02-0.25), and those two systems partly mediated the relationship between conscientiousness and procrastination (η2=0.20, 0.20;95％CI=-0.38——0.05, -0.70——0.24).Conclusion:The relationship between youth personality and procrastination may be mediated by a dual system of self-control.Additionally, the degree to how self-control affects the relationship between big five personality trait and procrastination is different under the different types of personality.

Contrast-enhanced dual mode imaging: photoacoustic imaging plus more

Conventional biomedical imaging modalities in wide clinical use, such as ultrasound imaging, X-ray computed tomography, magnetic resonance imaging, and positron emission tomography, can provide morphological, anatomical, and functional information about biological tissues. However, single mode imaging in conventional medicine provides only limited information for definitive diagnoses. Thus, combinational diagnosis using multiple imaging modalities has become increasingly important. Recently, photoacoustic imaging (PAI) has gained significant attention, and several PAI prototypes have been used in clinical trials. At the same time, PAI has been tested in combination with conventional imaging modalities. For all these imaging modalities, various contrast-enhancing agents have been developed for various purposes. In this review article, we will focus on recent progress in developing dual mode contrast agents for PAI in combination with other conventional imaging modalities.

Synchronous Detection of Rat Neural Spike Firing and Neurochemical Signals Based on Dual-mode Recording Instrument / 分析化学

A dual-mode recording system used for synchronous detection of neuroeletrical and neurochemical signals was developed, and a dual-mode synchronous detection experiment was carried out using the instrument. The device comprised 64-channel neuroelectricity recording module with voltage resolution of 0. 3 μV and 4-channel neurochemistry recording module with current resolution of 1 pA. The software had many basic features, including Spike separation and sort, chronoamperometry, cyclic voltammetry, etc. In particular, the software could observe and analyze the dual-mode neural signals synchronously. The performance of the system was demonstrated in the single mode detection experiments. In neuroeletrical experiments, 64-channel simulate neural signals were detected and the signal to noise ratio ( S/N) of Spike recorded from cortex of Sprague-Dawley ( SD ) rat was 6. In the K3 [ Fe ( CN )6 ] and ascorbic acid measurement experiments, the current response of K3 [ Fe ( CN)6 ] in the range of 0. 1-10 mmol/L was obtained by cyclic voltammetry, with a correlation coefficient of 0. 9889, and the current response of ascorbic acid ( concentration:10-800 μmol/L) by chronoamperometry increased linearly with a correlation coefficient of 0. 9841. Based on the rat model of global cerebral ischemia, a dual-mode detection experiment was carried out. In the experiment, the neuroelectrical and neurochemical signals were synchronously recorded in the SD rat primary visual cortex. According to the experimental results, we got the conclusion that the concentration of ascorbic acid negatively related to the Spike firing in the SD rat primary visual cortex.

A revisit of the mode of interaction of small transcription inhibitors with genomic DNA.

One class of small molecules with therapeutic potential for treatment of cancer functions as transcription inhibitors via interaction with double-stranded DNA. Majority of the studies of the interaction with DNA have so far been reported under conditions nonexistent in vivo. Inside the cell, DNA is present in the nucleus as a complex with proteins known as chromatin. For the last few years we have been studying the interaction of these DNA-binding small molecules at the chromatin level with emphasis on the drug-induced structural alterations in chromatin. Our studies have shown that at the chromatin level these molecules could be classified in two broad categories: single-binding and dual-binding molecules. Single-binding molecules access only DNA in the chromatin, while the dual-binding molecules could bind to both DNA and the associated histone(s). Structural effects of the DNA-binding molecules upon chromatin in light of the above broad categories and the associated biological implications of the two types of binding are discussed.