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

Unveiling the critical role of TiO2-supported atomically dispersed Cu species for enhanced photofixation of N2 to nitrate

Nitrate products are widely used in manufacturing as crucial raw materials and fertilizers. The traditional nitrate synthesis process involves high energy consumption and emission, thereby opposing the goals of zero-carbon emission and green chemistry. Thus, a sustainable roadmap for nitrate synthesis that uses green energy input, clean N sources, and direct catalytic processes is urgently required (e.g., developing a novel photosynthesis system). Here, we synthesized TiO2-supported atomically dispersed Cu species for N2 photofixation to nitrate in a flow reactor. The optimized photocatalyst yielded a high nitrate photosynthesis rate of 0.93 μmol h−1 and selectivity of ∼90%, which is superior to most of the values reported thus far. Further, experimental results and in-situ investigations revealed that the atomically dispersed Cu sites in the as-designed sample significantly enhanced the separation and transfer efficiency of photogenerated carriers, adsorption and activation of reactants, and the formation of chemisorbed NOx intermediates, thereby realizing the excellent photofixation of N2 to nitrate

The interplay of dental pulp stem cells and endothelial cells in an injectable peptide hydrogel on angiogenesis and pulp regeneration in vivo

Securing an adequate blood supply for the survival of cell transplants is critical for a successful outcome in tissue engineering. Interactions between endothelial and progenitor/stem cells are important for vascularization of regenerating tissue. Recently, self-assembling peptide nanofibers were described as a promising environment for pulp regeneration due to their synthetic nature and controlled physicochemical properties. In this study, the peptide hydrogel PuraMatrix™ was used as a scaffold system to investigate the role of dental pulp stem cells (DPSCs) in triggering angiogenesis and the potential for regenerating vascularized pulp in vivo. Human umbilical vein endothelial cells (HUVECs), DPSCs, or cocultures of both cell types were encapsulated in three-dimensional PuraMatrix. The peptide nanofiber microenvironment supported cell survival, cell migration, and capillary network formation in the absence of exogenous growth factors. DPSCs increased early vascular network formation by facilitating the migration of HUVECs and by increasing vascular endothelial growth factor (VEGF) expression. Both the DPSC-monoculture and coculture groups exhibited vascularized pulp-like tissue with patches of osteodentin after transplantation in mice. The cocultured groups exhibited more extracellular matrix, vascularization, and mineralization than the DPSC-monocultures in vivo. The DPSCs play a critical role in initial angiogenesis, whereas coordinated efforts by the HUVECs and DPSCs are required to achieve a balance between extracellular matrix deposition and mineralization. The findings of this study also highlighted the importance of a microenvironment that supports cell-cell interactions and cell migration, which contribute to successful dental pulp regeneration.published_or_final_versio

Induction of resistance in cucumber against seedling damping-off by plant growth-promoting rhizobacteria (PGPR) Bacillus megaterium strain L8

Bacillus megaterium L8, a plant growth-promoting rhizobacterium (PGPR), was isolated and evaluated for its ability to induce resistance in cucumber against seedling damping-off caused by Pythium aphanidermatum. Root-splitting challenge experiments showed that L8 treatment of cucumber roots more effectively suppressed seedling damping-off than did the control as judged by seedling survival rate (83.45 versus 31.68% at 28 days), indicating that strain L8 is capable of inducing systemic disease resistance in cucumber. To explore the potential mechanism underlying the induced systemic resistance (ISR) mediated by L8, the expression profile of several plant defense-related enzymes: superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), polyphenol oxidase (PPO) and phenylalanine ammonia-lyase (PAL) were monitored in the roots treated with L8 or P. aphanidermatum and untreated leaves in a time course of 13 days. Levels of SOD, POD, CAT, PPO and PAL activities in the treated roots and untreated leaves of cucumber seedlings were all significantly higher as compared with the control and respectively peaked in the roots at 3, 3, 5, 5 and 5 days and correspondingly in the leaves at 5, 3, 5, 5 and 5 days post-inoculation. The enhanced expression patterns of the above enzymes following L8 or P. aphanidermatum treatment suggested that systemic induction of plant defense enzymes by L8 might account for its ability to provide effective protection for cucumber from seedling damping-off caused by the soil-borne fungal pathogen P. aphanidermatum.Key words: Plant growth-promoting rhizobacteria (PGPR), defense enzymes, damping-off of cucumber seedlings, induced resistance

Isolation and characterization of Rhodococcus ruber CGMCC3090 that hydrolyzes aliphatic, aromatic and heterocyclic nitriles

A bacterial strain was isolated from soil samples that had been polluted by nitrile compounds. This strain converts acrylonitrile to acrylamide with high activity. The nitrile hydrolysis activity was tested using eight substrates, including aliphatic, aromatic and heterocyclic (di)nitriles. All of the nitrilecompounds were hydrolyzed by the resting cells. The main (cyano-)amide products demonstrated that nitrile hydratase was abundantly produced in this strain and that it mediated monohydrolysis. The specific conversion rate decreased in the following order: acrylonitrile > 3-cyanopyridine > valeronitrile> adiponitrile > 2,3,4,5,6-pentafluorobenzonitrile >  -hydroxyphenylacetonitrile > 3-indoleaceto-nitrile > phthalonitrile, suggesting a higher conversion capability towards aliphatic nitriles. The strain that hadbroad substrate spectra was identified and named Rhodococcus ruber CGMCC3090 based on the 16S rDNA sequence

Surface runoff and phosphorus (P) loss from bamboo (Phyllostachys pubescens) forest ecosystem in southeast China

The effect of different fertilization treatments on runoff and nutrient losses under field conditions was investigated through setting runoff plots in bamboo (Phyllostachys pubescens) forests in a catchment of Taihu Lake. The results showed that, the runoff loss reached 356, 361 and 342 m3/hm2, while the soil particle loss reached 393, 392 and 442 kg/hm2, respectively, in the period from June 2009 to May 2010, under the treatments of control (CK), site-specific nutrient management (SSNM) and farmers’ fertilizer practice (FFP). The runoff and soil particle losses were highly correlated with the precipitation during the period. The largest phosphorus losses happened in August, when it had the largest rainfall of that year. The total phosphorus (TP) concentration of the 95% of the observed runoff samples exceeded 0.10 mg/l. The average bioavailable phosphorus (BAP) concentration of the runoff was 0.23 mg/l and the various phosphorus forms lost was strongly inter-correlated. Compared with FFP, the SSNM treatment reduced total P (TP) by 5%, total dissolved phosphorus (DP) loss by 15% and total bioavailable phosphorus (BAP) loss by 8%.Key words: Phyllostachys pubescens, ecosystem, surface runoff, phosphorus (P) loss

State observation problem for a class of semi-linear hyperbolic systems

2004-2005 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Active MR k-space Sampling with Reinforcement Learning

Deep learning approaches have recently shown great promise in accelerating magnetic resonance image (MRI) acquisition. The majority of existing work have focused on designing better reconstruction models given a pre-determined acquisition trajectory, ignoring the question of trajectory optimization. In this paper, we focus on learning acquisition trajectories given a fixed image reconstruction model. We formulate the problem as a sequential decision process and propose the use of reinforcement learning to solve it. Experiments on a large scale public MRI dataset of knees show that our proposed models significantly outperform the state-of-the-art in active MRI acquisition, over a large range of acceleration factors.Comment: Presented at the 23rd International Conference on Medical Image Computing and Computer Assisted Intervention, MICCAI 202