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

Enhanced electrochemical reduction of hydrogen peroxide by Co3O4 nanowire electrode

Crystalline Co3O4 nanowire arrays with different morphologies grown on Ni foam were investigated by varying the reaction temperature, the concentration of precursors, and reaction time. The Co3O4 nanowires synthesized under typical reaction condition had a diameter range of approximately 500–900 nm with a length of 17 µm. Electrochemical reduction of hydrogen peroxide (H2O2) of the optimized Co3O4 nanowire electrode was studied by cyclic voltammetry. A high current density of 101.8 mA cm−2 was obtained at −0.4 V in a solution of 0.4 M H2O2 and 3.0 M NaOH at room temperature compared to 85.8 mA cm−2 at −0.35 V of the Co3O4 nanoparticle electrode. Results clearly indicated that the Ni foam supported Co3O4 nanowire electrode exhibited superior catalytic activity and mass transport kinetics for H2O2 electrochemical reduction

Tanshinone IIA Attenuates the Inflammatory Response and Apoptosis after Traumatic Injury of the Spinal Cord in Adult Rats

BACKGROUND: Spinal cord injury (SCI), including immediate mechanical injury and secondary injury, is associated with the inflammatory response, apoptosis and oxidative stress in response to traumatic injury. Tanshinone IIA (TIIA) is one of the major extracts obtained from Salvia miltiorrhiza BUNGE, which has anti-inflammatory and anti-apoptotic effects on many diseases. However, little is known about the effects of TIIA treatment on SCI. Therefore, the aim of the present study is to evaluate the pharmacological action of TIIA on secondary damage and the underlying mechanisms of experimental SCI in rats. METHODOLOGY/PRINCIPAL FINDINGS: SCI was generated using a weight drop device on the dorsal spinal cord via a two-level T9-T11 laminectomy. SCI in rats resulted in severe trauma, characterized by locomotor disturbance, edema, neutrophil infiltration, the production of astrocytes and inflammatory mediators, apoptosis and oxidative stress. TIIA treatment (20 mg/kg, i.p.) after SCI induced significant effects: (1) improved motor function (Basso, Beattie and Bresnahan scores), (2) reduced the degree of tissue injury (histological score), neutrophil infiltration (myeloperoxidase activity) and the expression of astrocytes, (3) inhibited the activation of SCI-related pathways, such as NF-κB and MAPK signaling pathways, (4) decreased the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and iNOS, (5) reduced apoptosis (TUNEL staining, and Bcl-2 and caspase-3 expression) and (6) reversed the redox state imbalance. CONCLUSIONS/SIGNIFICANCE: The results clearly show that TIIA has a prominent protective effect against SCI through inhibiting the inflammatory response and apoptosis in the spinal cord tissue after SCI

Long-term outcomes of early childhood science education: insight from a cross-national comparative case study on conceptual understanding of science

The purpose of this research was to explore the long term outcomes of either participating or not participating in early childhood science education on Grade 6 students’ conceptual understanding of science. The research is situated in a conceptual framework that evokes Piagetian developmental levels as both potential curriculum constraints and potential models of efficacy. The research design was a multiple case study of Grade 6 children from three schools in China (n=140) who started formal science education in the third grade, and Grade 6 children from three matched schools in Australia (n=105) who started learning science in kindergarten. The students’ understanding was assessed by a science quiz and in-depth interview. The data showed that participating children from the high socio-economic schools in China and Australia had similar understandings of science. Divergence between the medium and low socio-economic schools, however, indicated that the grounding in early childhood science education in Australia may have placed these children at an advantage. Alternative explanations for the divergence including the nature of classroom instruction in the two countries are discussed

Coherent methods in the X-ray sciences

X-ray sources are developing rapidly and their coherent output is growing extremely rapidly. The increased coherent flux from modern X-ray sources is being matched with an associated rapid development in experimental methods. This article reviews the literature describing the ideas that utilise the increased brilliance from modern X-ray sources. It explores how ideas in coherent X-ray science are leading to developments in other areas, and vice versa. The article describes measurements of coherence properties and uses this discussion as a base from which to describe partially-coherent diffraction and X-ray phase contrast imaging, with its applications in materials science, engineering and medicine. Coherent diffraction imaging methods are reviewed along with associated experiments in materials science. Proposals for experiments to be performed with the new X-ray free-electron-lasers are briefly discussed. The literature on X-ray photon correlation spectroscopy is described and the features it has in common with other coherent X-ray methods are identified. Many of the ideas used in the coherent X-ray literature have their origins in the optical and electron communities and these connections are explored. A review of the areas in which ideas from coherent X-ray methods are contributing to methods for the neutron, electron and optical communities is presented.Comment: A review articel accepted by Advances in Physics. 158 pages, 29 figures, 3 table

Guanosine reduces apoptosis and inflammation associated with restoration of function in rats with acute spinal cord injury

Spinal cord injury results in progressive waves of secondary injuries, cascades of noxious pathological mechanisms that substantially exacerbate the primary injury and the resultant permanent functional deficits. Secondary injuries are associated with inflammation, excessive cytokine release, and cell apoptosis. The purine nucleoside guanosine has significant trophic effects and is neuroprotective, antiapoptotic in vitro, and stimulates nerve regeneration. Therefore, we determined whether systemic administration of guanosine could protect rats from some of the secondary effects of spinal cord injury, thereby reducing neurological deficits. Systemic administration of guanosine (8 mg/kg per day, i.p.) for 14 consecutive days, starting 4 h after moderate spinal cord injury in rats, significantly improved not only motor and sensory functions, but also recovery of bladder function. These improvements were associated with reduction in the inflammatory response to injury, reduction of apoptotic cell death, increased sparing of axons, and preservation of myelin. Our data indicate that the therapeutic action of guanosine probably results from reducing inflammation resulting in the protection of axons, oligodendrocytes, and neurons and from inhibiting apoptotic cell death. These data raise the intriguing possibility that guanosine may also be able to reduce secondary pathological events and thus improve functional outcome after traumatic spinal cord injury in humans

Prevalence and trend of hepatitis C virus infection among blood donors in Chinese mainland: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Blood transfusion is one of the most common transmission pathways of hepatitis C virus (HCV). This paper aims to provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for HCV infection among blood donors in Chinese mainland, so as to help make prevention strategies and guide further research.</p> <p>Methods</p> <p>A systematic review was constructed based on the computerized literature database. Infection rates and 95% confidence intervals (95% CI) were calculated using the approximate normal distribution model. Odds ratios and 95% CI were calculated by fixed or random effects models. Data manipulation and statistical analyses were performed using STATA 10.0 and ArcGIS 9.3 was used for map construction.</p> <p>Results</p> <p>Two hundred and sixty-five studies met our inclusion criteria. The pooled prevalence of HCV infection among blood donors in Chinese mainland was 8.68% (95% CI: 8.01%-9.39%), and the epidemic was severer in North and Central China, especially in Henan and Hebei. While a significant lower rate was found in Yunnan. Notably, before 1998 the pooled prevalence of HCV infection was 12.87% (95%CI: 11.25%-14.56%) among blood donors, but decreased to 1.71% (95%CI: 1.43%-1.99%) after 1998. No significant difference was found in HCV infection rates between male and female blood donors, or among different blood type donors. The prevalence of HCV infection was found to increase with age. During 1994-1995, the prevalence rate reached the highest with a percentage of 15.78% (95%CI: 12.21%-19.75%), and showed a decreasing trend in the following years. A significant difference was found among groups with different blood donation types, Plasma donors had a relatively higher prevalence than whole blood donors of HCV infection (33.95% <it>vs </it>7.9%).</p> <p>Conclusions</p> <p>The prevalence of HCV infection has rapidly decreased since 1998 and kept a low level in recent years, but some provinces showed relatively higher prevalence than the general population. It is urgent to make efficient measures to prevent HCV secondary transmission and control chronic progress, and the key to reduce the HCV incidence among blood donors is to encourage true voluntary blood donors, strictly implement blood donation law, and avoid cross-infection.</p