Design, synthesis and evaluation of pyrrolo[2,1-c][1,4]benzodiazepines containing endo/exo unsaturation.

The work presented in this thesis focused on developing new approaches to the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). These compounds are generating interest because of their potential use as anti-tumour or disease-related gene targeting agents. According to SAR studies, PBDs containing endolexo unsaturation in the pyrrolo C-ring are required for maximum biological potency, and thus PBDs of such type have been selected as target molecules. Three novel PBD monomers (ZC-14, ZC-96 and ZC-99), four novel PBD dimers (ZC-204, ZC-207, ZC-209 and ZC-211) and one natural product (porothramycin B) have been successfully synthesized. The synthetic approach involves application of palladium mediated coupling reactions, including Heck, Suzuki and Stille reactions, to introduce various side chains at the C2-position of the PBD C-ring. Use of such versatile coupling reactions at a late stage in the synthesis has the potential to provide access to a wide range of analogues in the future. Extensive method development work has been carried out during the research programme and the yields of several initially low-yielding reactions have been significantly improved. The work includes protection of reactive sites in key intermediates and an investigation of an alternative N 10-amino protecting group. All novel PBDs displayed potent activity in initial in vitro cytotoxicity assays performed by the NCI. Both PBD monomers and dimers exhibited GI50 values of less than 10 nM in the majority of cell lines. The cytotoxicity of these molecules was also evaluated in the K562 cell line at UCL. Dimers generally showed enhanced activity compared with their corresponding monomers in this test. In the DNA cross-linking efficiency assay for novel PBD dimers, ZC-204 gave extremely low XL50 values, ZC-207 and ZC-211 also exhibited significant activity, however, ZC- 209 showed only moderate cross-linking efficiency

The Call of Modernity: Chinese School Songs in the Early Twentieth Century

This thesis studies the Chinese school songs (xuetangyuege 学堂乐歌) of the early twentieth century, a genre at the origins of Chinese musical modernity. I propose that it is necessary to study this subject through a political lens, particularly one that focuses on the questions of modernization and that is framed by the overall context of semicolonialism. I argue that school songs constituted the major musical activity of early Chinese modernity, manifesting a cultural imaginary of modern Chinese civilization marked by the building of a coherent nation. Chapter 1 analyzes the use of national landscape in school songs as a rhetorical strategy that aimed at the political goal of nation-building. Chapter 2 examines the discourse about women’s healthiness, femininity, and nationalist militarism in school songs.Master of Art

Clinical Distribution and Drug Resistance of 224 Strains of Pseudomonas Aeruginosa

Objective: To provide evidence for a rational and effective prevention and treatment of Pseudomonas aeruginosa, the clinical characteristics and the resistance to various antibiotics of were investigated.Methods：A retrospective analysis of 224 strains of Pseudomonas aeruginosa isolated from various specimens from various clinical departments of our hospital (April 1, 2018 to June 31, 2019) were conducted. Identification and drug susceptibility test of isolated strains was performed using a fully automatic bacterial identification analyzer (MicroScan WalkAway-96 plus), and data analysis was performed using WH0NET5.6 software. Result：Among all the bacteria isolated in our hospital during the above period, Pseudomonas aeruginosa accounted for 10.09% of them all and 12.57% of Gram-negative bacilli, respectively. These isolates were mainly derived from sputum specimens (68.75%), mainly from male patients (70.54%), and mostly 61-70 (27.23%) or 51-60 (22.77%) years old. Pseudomonas aeruginosa isolates are mainly from Rehabilitation Ward, ICU, and Liver Transplantation Unit, accounted for 29.91%, 12.95% and 10.27% of all isolates, respectively. The sensitivity of Pseudomonas aeruginosa to various antibacterial drugs, in the order of high to low were carbapenems, aztreonam, quinolones, cephalosporins, piperacillin/ tazobactam, aminoglycoside, with a lowest resistance rate (2.4%) to amikacin and a highest resistance rate to imipenem (33.0%). Conclusion：The isolation rate of Pseudomonas aeruginosa was relatively stable during the study period, and among all the P. aeruginosa detected, most of them were from the respiratory secretions of elderly male patients. The resistance rate of Pseudomonas aeruginosa isolates to various antibiotics is mainly within 30%. Clinical units such as Rehabilitation Ward, ICU, and Liver Transplantation Unit have a high detection rate, therefore, these departments should be monitored in a focused manner. Our research provide a scientific basis for the rational use of antibiotics and a better control of Pseudomonas aeruginosa infection

Combined Detection of Mean Platelet Volume and Immunoglobins as a Strategy for the Diagnosis of Systemic Lupus Erythematosus

Objective:To explore the possibility of diagnosing and monitoring patients with systemic lupus erythematosus (SLE) using the combination of mean platelet volume (MPV) and routine immunoglobulin test. Method:116 patients with SLE were divided into 3 groups according to their clinical characteristics, including 29 patients with renal impairment, 44 cases of active stage and 43 cases of inactive patients. 40 healthy subjects were randomly selected as controls. Subjects were tested for routine blood test and plasma Immunoglobins, such as IgG, IgA, IgM, C3, C4, CH50, CRP. The results were analyzed and the characteristics of each group of subjects were determined, the correlation between test results and diagnosis were studied. Result: In comparison to the control group, the serum level of MPV, C3 and C4 were decreased (P<0.05), and C reactive protein level was elevated (P<0.001) in the three groups of SLE patients. The IgG level in active and inactive SLE patients was increased (P<0.0001), CH50 level was decreased in patients with inactive SLE (P<0.05), IgA level of active SLE subjects was found to be elevated (P<0.05), IgM in patients with renal impairment was decreased (P<0.05). Other than that, no other significant characteristic were found. Conclusion: The pathogenesis of SLE is a complex process involving multiple factors. The changes of MPV, IgG, IgA, IgM, C3, C4, CH50 and CRP in SLE patients are characteristic parameters. The combination of the above indicators can help to determine the diagnosis and staging of SLE. The timely diagnosis and treatment of SLE patients has important clinical significance in protecting the organ function of SLE patients and improving the prognosis

In Vitro Antibacterial Activity of Galla Chinensis Combined with Different Antibacterial Drugs against Carbapenem-Resistant E.Coli

Objective: To evaluate the antibacterial effects of meropenem and levofloxacin respectively combined with Galla chinensis on carbapenem-resistant Escherichia coli in vitro. Methods： The protocol was designed with checkerboard method and the carbapenem-resistant E.coli was isolated in our hospital. The minimum inhibitory concentrations(MICs) of G. chinensis alone and combined with 2 antimicrobial agents against carbapenem-resistant E.coli were determined by broth dilution method and the fractional inhibitory concentration index (FICI) was calculated according to MICs results. Result： the combined use of G. chinensis and meropenem (or levofloxacin) significantly decreased both MIC50 and MIC90; After the combination of G. chinensis and meropenem, the synergistic effect was 86.7%, and the additive effect was 13.3%, no irrelevant and antagonistic effects. After combined use of G. chinensis and levofloxacin, the synergistic effect was 66.7%, and the additive effect was 33.3%. No irrelevant and antagonistic effects. Conclusion： Galla chinensis combined with meropenem or levofloxacin has synergistic and additive antibacterial effect, with certain combined antibacterial activity