Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets

Tooth loss, occluding pairs, and prosthetic status of Chinese adults

The objectives of this analysis were to describe the numbers of teeth lost and those indicated for extraction, dental prosthetic status, and occluding tooth pairs among adults in Southern China and to investigate factors affecting tooth mortality. A sample consisting of 1573 35- to 44-year-old and 1515 65- to 74-year-old urban and rural Chinese was examined clinically by calibrated examiners. Teeth not present for any reason were defined as missing (MT). The sum of MT and teeth indicated for extraction (IMT) was defined as adjusted missing teeth (AMT). Only 4.4% of the urban and 3.4% of the rural 65- to 74-year-olds were edentulous. MT were not significantly different between urban and rural residents, but more IMT were found in rural residents. Women, those who had a lower education level, and those who were less wealthy had more AMT in both age groups. Smoking was found to be associated with AMT in the 35- to 44-year-olds. Eighteen percent of the urban and 27% of the rural elderly had no occluding tooth pairs after IMT were accounted for, and only 38% and 30%, respectively, had 10 or more occluding pairs. Fifty-one percent of the urban and 43% of the rural elderly were found to have some form of dental prostheses in either jaw. A partial denture was more common in urban residents in both age groups.published_or_final_versio

Ozone production in four major cities of China: sensitivity to ozone precursors and heterogeneous processes

Abstract. Despite a large volume of research over a number of years, our understandings of the key precursors that control tropospheric ozone production and the impacts of heterogeneous processes remain incomplete. In this study, we analyze measurements of ozone and its precursors made at rural/suburban sites downwind of four large Chinese cities – Beijing, Shanghai, Guangzhou and Lanzhou. At each site the same measurement techniques were utilized and a photochemical box model based on the Master Chemical Mechanism (v3.2) was applied, to minimize uncertainties in comparison of the results due to differences in methodology. All four cities suffered from severe ozone pollution. At the rural site of Beijing, export of the well-processed urban plumes contributed to the extremely high ozone levels (up to an hourly value of 286 ppbv), while the pollution observed at the suburban sites of Shanghai, Guangzhou and Lanzhou was characterized by intense in-situ ozone production. The major anthropogenic hydrocarbons were alkenes and aromatics in Beijing and Shanghai, aromatics in Guangzhou, and alkenes in Lanzhou. The ozone production was found to be in a VOCs-limited regime in both Shanghai and Guangzhou, and a mixed regime in Lanzhou. In Shanghai, the ozone formation was most sensitive to aromatics and alkenes, while in Guangzhou aromatics were the predominant ozone precursors. In Lanzhou, either controlling NOx or reducing emissions of olefins from the petrochemical industry would mitigate the local ozone production. The potential impacts of several heterogeneous processes on the ozone formation were assessed. The hydrolysis of dinitrogen pentoxide (N2O5), uptake of the hydroperoxyl radical (HO2) on particles, and surface reactions of NO2 forming nitrous acid (HONO) present considerable sources of uncertainty in the current studies of ozone chemistry. Further efforts are urgently required to better understand these processes and refine atmospheric models

Coronal and root caries in Southern Chinese adults

Southern China is the most prosperous part of China, but information useful for oral care planning is very limited. A large-scale epidemiological survey was conducted in 1996-97. The objectives of this report were to describe the coronal and root caries of the adult Southern Chinese and to analyze the influence of selected demographic and socio-economic factors on the disease pattern. A total sample of 1573 35- to 44-year-olds and 1515 65- to 74-year-olds from 8 urban and 8 rural survey sites in Guangdong Province participated in an oral health interview and underwent clinical examination. World Health Organization examination procedures and diagnostic criteria were used. The weighted mean DMFT scores of the middle-aged and the elderly subjects were 4.8 and 16.1, respectively. People living in rural areas had a higher DMFT score than those living in urban areas (4.9 vs. 4.3 in the 35- to 44-year-olds and 16.5 vs. 14.7 in the 65- to 74-year-olds). In both age groups, MT was the major component of the DMFT score. Analysis of covariance showed that women and those who were economically less well off had higher DMFT scores in both age groups. The weighted prevalence rates of decayed/filled roots were 12% and 37%, with a mean of 0.2 and 0.7 teeth affected, in the middle-aged and the elderly, respectively. In conclusion, socio-economic factors had a considerable effect on the dental caries status of adults in Southern China.published_or_final_versio

The technology of large-scale pharmaceutical plasmid purification by cetyltrimethylammonium bromide and Tritonx-114

Many methods for plasmid purification have been developed, and the whole process must be designed to remove the host RNA, protein, genomic DNA and endotoxin. Currently, plasmid is mostly purified by time-consuming chromatographies. As an alternative, a new plasmid purification technology with cetyltrimethylammonium bromide (CTAB) is described. After lysis with alkali, the CTAB was directly titrated into the supernatant for plasmid precipitation, then the coprecipitated pellets were dealt with 3 M KAc and TritonX-114. Quality detection showed that the purified plasmids were free from the contamination of host RNA. In 1 mg purified plasmid, the bacterial genomic DNA, host endotoxin and protein were less than 10 g/ mg, 50 EU/ mg and 10 g/mg, respectively. The ratio of OD260/OD280 was between 1.75 - 1.85, more than 90% of the prepared plasmid presented in the supercoiled form. Further test demonstrated that the pcDNAlacZ purified with CTAB and authoritative endotoxin-free plasmid Kit had the similar transfection efficiency in vivo and in vitro. CTAB can be used for plasmid purification; the main advantages of the DNAs purified with CTAB include the avoidance of animal-derived enzymes, toxic substance like chloroform and phenol. More attractive is that the whole process has the predominance of low cost

A 60-year record of 129I in Taal Lake sediments (Philippines): Influenceof human nuclear activities at low latitude region

The influence of human nuclear activities on environmental radioactivity is not well known at low latitude regions that are distant from nuclear test sites and nuclear facilities. A sediment core collected from Taal Lake in the central Philippines was analyzed for 129I and 127I to investigate this influence in a low-latitude terrestrial system. A baseline of 129I/127I atomic ratios was established at (2.04e5.14) * 10-12&nbsp;in the pre-nuclear era in this region. Controlled by the northeasterly equatorial trade winds, increased 129I/127I ratios of (20.1e69.3) * 10-12 suggest that atmospheric nuclear weapons tests at the Pacific Proving Grounds in the central Pacific Ocean was the major source of 129I in the sediment during 1956-1962. The 129I/127I ratios, up to 157.5*10-12 after 1964, indicate a strong influence by European nuclear fuel reprocessing plants. The East Asian Winter Monsoon is found to be the dominant driving force in the atmospheric dispersion of radioactive iodine (129I) from the European nuclear fuel reprocessing plants to Southeast Asia, which is also important for dispersion of other airborne pollutants from the middle-high to low latitude regions. A significant 129I/127I peak at 42.8 cm in the Taal Lake core appears to be the signal of the Chernobyl accident in 1986. In addition, volcanic activities are reflected in the iodine isotope profiles in the sediment core, suggesting the potential of using iodine isotopes as an indicator of volcanic eruptions.<br style="line-height: normal; text-align: -webkit-auto; text-size-adjust: auto;" /

An oral health survey in Southern China, 1997: Background and methodology

Relatively limited information is available about the oral health in the Guangdong Province of Southern China, the closest neighbor to Hong Kong. The study intended to explore the oral health status, knowledge, attitudes, and dental care utilization in the Guangdong population as a basis for formulating strategies for oral health prevention and treatment. Through multi-stage stratified and quota-sampling, individuals from urban as well as rural communities were selected (5- to 6-; 12-; 35- to 44-; and 65- to 74-year-olds; total N = 6251). Structured interviews and clinical examinations were performed. Inter-examiner reliability was high (K = 0.60-0.96). Samples of community water were taken for fluoride assessment. Overall, the sample surveyed was acceptably representative of the population, with some under-representation of rural residents and agricultural workers. Re-weighting was performed in appropriate analyses. The data analysis model used in the Second International Collaborative Study was used as a guide for the present data analysis. This approach has not previously been used on a Mainland Chinese population.published_or_final_versio

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers