Fine‐Tuning Covalent Inhibition of Bacterial Quorum Sensing

Emerging antibiotic resistance among human pathogens has galvanized efforts to find alternative routes to combat bacterial virulence. One new approach entails interfering with the ability of bacteria to coordinate population‐wide gene expression, or quorum sensing (QS), thus inhibiting the production of virulence factors and biofilm formation. We have recently developed such a strategy by targeting LasR, the master regulator of QS in the opportunistic human pathogen Pseudomonas aeruginosa, through the rational design of covalent inhibitors closely based on the core structure of the native ligand. We now report several groups of new inhibitors, one of which, fluoro‐substituted ITC‐12, displayed complete covalent modification of LasR, as well as effective QS inhibition in vitro and promising in vivo results. In addition to their potential clinical relevance, this series of synthetic QS modulators can be used as a tool to further unravel the complicated QS regulation in P. aeruginosa.     

Inhibitory Effects of Semiochemicals on the Attraction of an Ambrosia Beetle <Emphasis Type="Italic">Euwallacea</Emphasis> nr. <Emphasis Type="Italic">fornicatus</Emphasis> to Quercivorol

The Euwallacea fornicatus (Eichhoff) species complex includes the polyphagous shot hole borer (PSHB), an ambrosia beetle infesting avocado limbs, Persea americana Mill. Synthetic quercivorol, a monoterpene alcohol, is known to attract females (males are flightless) over a range of release rates spanning three orders of magnitude. The upper release dose was extended 10-fold using sticky traps baited with quercivorol released at 1× (0.126 mg/day), 10×, and 108× relative rates to obtain a dose?response curve fitting a kinetic formation function. Naturally infested limbs of living avocado trees were wrapped with netting to exclude the possibility of catching emerging beetles on the encircling sticky traps. The results indicate PSHB are significantly attracted to infested limbs. Ethanol released over a 64-fold range (lowest rate of 7.5 mg/day) was moderately inhibitory of PSHB attraction to 1× quercivorol. β-caryophyllene and eucalyptol did not appear to affect attraction at the rates tested. A field test of potential inhibitors of 1× quercivorol was done using ~1 mg/day releases of monoterpene ketones: (?)-(S)-verbenone, (+)-(R)-verbenone, 3-methyl-2-cyclo-hexen-1-one (MCH or seudenone), piperitone, (+)-(S)-carvone, and racemic cryptone. Only piperitone and the two enantiomers of verbenone were strongly inhibitory. A blend of piperitone and verbenone tested together at different distances (0, 0.5, 1, 2, and 4 m) from a 1× quercivorol baited sticky trap became increasingly ineffective in inhibiting the attractant as separation distance increased. Due to the relatively short-range repellency (<1 m), the inhibitors would need to be released from several places on each tree to effectively repel PSHB from avocado trees. Effective attraction radii, EAR, and circular EARc are estimated for the quercivorol baits released at 1×, 10× and 108× rates. Push-pull simulations of moving beetles were performed in 1 ha plots with 2, 4, or 16 traps of 10× EARc and 400 trees (0, 1, or 3 inhibitors per tree) of which ten had an infested limb (EARc?=?0.5 m). The simulations indicate that push-pull methods would be more effective in reducing PSHB mating than simply using mass-trapping alone.     

The morphogenesis of motor rituals in rats treated chronically with the dopamine agonist quinpirole.

Rats injected repeatedly with the dopamine agonist quinpirole develop motor rituals that evolve through a cascade of 4 behavioral processes. The 1st involves increased activity. The 2nd involves increased path stereotypy, reflected in traveling repeatedly along the same few paths. The 3rd is an increase in the frequency of stopping in a few places, along with a decrease in stopping in other places. The 4th is a decrease in the repetition of movements performed in the specific stopping places. Altogether, these processes culminate in stereotypy, a typical short set of movements composed of a single performance of each movement type. Thus, stereotypy arises from changes in the temporal and spatial organization, but not the content, of behavioral patterns. These results provide a model for the development of motor rituals and their linkage to normal behavior and to the physical properties of the environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anti-proliferative activities,phytochemical levels and fruit quality of pepper (Capsicum spp.) following prolonged storage

Peppers are rich in health-promoting phytochemicals, which are involved in the defence mechanisms against cancer. To select a lead variety of pepper with anti-proliferative activity against colon cancer cells and liver cancer cells, high antioxidant activity, and high concentrations of capsaicin, flavonoids and phenolics, we compared these attributes in nine different pepper accessions belonging to Capsicum annuum and C. chinense. Quality parameters such as weight loss and total soluble solids content were tested as well. The different parameters were determined immediately after harvest and after prolonged storage and marketing simulation. A significant variation of these traits was detected among the accessions. C. chinense line 1745 had the highest antioxidant activity, the highest levels of capsaicin and flavonoids, a high and specific anti-cancer activity, and the lowest weight loss level during postharvest storage. It is proposed that line 1745 has potential for use as a source for health-promoting traits and should be further evaluated for use as a nutraceutical for the prevention and treatment of colon and liver cancers.     

Understanding the Antibacterial Mechanism of CuO Nanoparticles: Revealing the Route of Induced Oxidative Stress

To date, there is still a lack of definite knowledge regarding the interaction of CuO nanoparticles with bacteria and the possible permeation of the nanoparticles into bacterial cells. This study was aimed at shedding light on the size‐dependent (from the microscale down to the small nanoscale) antibacterial activity of CuO. The potent antibacterial activity of CuO nanoparticles was found to be due to ROS‐generation by the nanoparticles attached to the bacterial cells, which in turn provoked an enhancement of the intracellular oxidative stress. This paradigm was confirmed by several assays such as lipid peroxidation and reporter strains of oxidative stress. Furthermore, electron microscopy indicated that the small nanoparticles of CuO penetrated the cells. Collectively, the results reported herein may reconcile conflicting concepts in the literature concerning the antibacterial mechanism of CuO nanoparticles, as well as highlight the potential for developing sustainable CuO nanoparticles‐based devices for inhibiting bacterial infections.     

Rational Design of Multifunctional Polymer Therapeutics for Cancer Theranostics

Although anti-angiogenic agents offer great therapeutic potential, preclinical and clinical studies suggest that these agents, used as monotherapies, have a delayed onset of activity and may have only limited effects on advanced malignancies. Multimodality targeted polymer therapeutics that include anti-angiogenic agents and chemotherapeutics offer the potential for improved efficacy and diminished toxicity in the treatment of cancer and other angiogenesis-dependent diseases. We have recently designed and characterized novel combined anti-angiogenic and antitumor polymer–drug conjugates that target both the tumor and its microenvironment. These conjugates include combined anti-angiogenic and chemotherapeutic drugs, such as TNP-470 and paclitaxel, respectively. Several conjugates also incorporate bisphosphonates as targeting moieties for bone metastases and osteosarcomas or RGD peptidomimetics that target integrins overexpressed on tumor endothelial cells and several tumor cells. Using molecular imaging techniques, we have successfully established dormant and fast-growing tumor mouse models to intravitally non-invasively follow-up tumor progression and response to novel polymer therapeutics. Our results point at our polymer therapeutics as novel bi-specific conjugates targeting both the tumor epithelial and endothelial compartments, warranting their use on a wide spectrum of primary as well as metastatic tumors. The use of these novel architectures will potentially shed light on the molecular mechanisms underlying tumor dormancy and hopefully transform cancer into a chronically-manageable disease.     

The Art of Organic Synthesis in the Age of Automation

Recent progress in the automation of chemical synthesis is part of a broad ongoing trend that is based on incorporating machine learning algorithms to improve automated performance in different tasks. However, what are the implications on the art of organic synthesis? Will robotic chemists replace us in the next 50–100 years? Will they be able to outperform a master organic chemist in the study of mechanisms, the development of new reactions, the optimization of reaction conditions, catalysts, or synthetic routes? What would be our role as human chemists in this automation revolution? In this essay, these questions will be reflected upon through the progress in the synthesis of strychnine since 1954.     

Competencies for managing change

Organisational changes are recognised as a specific project type that can benefit from the application of project management skills, tools and techniques. Associated with this trend is evidence of rivalry in the marketplace between Project Managers and Change Managers concerning who should be managing business change. And these are not the only contenders. Corporate executives and senior managers, although they may engage the assistance of both Project Managers and Change Managers, generally see themselves as taking the leading roles in managing major organisational changes and transformations. As such endeavours are most likely to take the form of programs, comprising multiple projects across the organization, Program Managers are seen by some as being most likely to be responsible for managing organisational change initiatives. This paper reports on research undertaken to explore the differences in approach and practice of Project, Program and Change Managers as a basis for determining the competencies required to effectively manage change initiatives.     

On the exploitation of CDF based wireless scheduling

Channel-aware scheduling strategies – such as the CDF scheduler (CS) algorithm – provide an effective mechanism for utilizing the channel data rate for improving throughput performance in wireless data networks by exploiting channel fluctuations. A highly desired property of such a scheduling strategy is that its algorithm is stable, in the sense that no user has incentive “cheating” the algorithm in order to increase his/hers channel share (on the account of others). Considering a single user we show that no such user can increase his/hers channel share by misreporting the channel capacity. In contrast, considering a group of users, we present a scheme by which coordination allows them to gain permanent increase in both their time slots share and in their throughput at the expense of others, by misreporting their rates. We show that for large populations consisting of regular and coordinated users in equal numbers, the ratio of allocated time slots between a coordinated and a regular user converges to e − 1 ≈ 1.7. Our scheme targets the very fundamental principle of CS (as opposed to just attacking implementation aspects), which bases its scheduling decisions on the Cumulative Distribution Function (CDF) of the channel rates reported by users. Our scheme works both for the continuous channel spectrum and the discrete channel spectrum versions of the problem. Finally, we outline a modified CDF scheduler immune to such attacks.