Intimate interplay of theory and experiments in model catalysis

We briefly summarize our joint effort to understand catalytic reactions on the model catalyst RuO₂(1 1 0) on the atomic scale, applying state-of-the-art density functional theory calculations and surface chemical characterizations in parallel. This intimate theory/experiment interplay allows us to gain new and deep insights into a catalytic system under investigation and to save recourses such as experimental and computing time as well as (wo)man power. Here we illustrate the utility of this intimate theory/experiment approach with a variety of recent examples related to the extraordinary activity of RuO₂. The identification of RuO₂(1 1 0) as the catalytically active state in the oxidation of CO on Ru(0 0 0 1) (Science 287 (2000) 1474) triggered a paradigm shift in model catalysis from the view of a rigid catalyst towards a structural and chemically flexible catalyst which adapts itself to the reaction conditions.     

Modeling polarization-dependent gain in fiber Raman amplifiers with randomly varying birefringence

We report a new stochastic model for studying the polarization-dependent gain in Raman fiber amplifiers with randomly varying birefringence as a function of the pump state of polarization and the polarization mode dispersion parameter. Our theoretical results agree with the previously obtained experimental data.     

Floating Electrode Dielectric Barrier Discharge Plasma in Air Promoting Apoptotic Behavior in Melanoma Skin Cancer Cell Lines

Initiation of apoptosis, or programmed cell death, is an important issue in cancer treatment as cancer cells frequently have acquired the ability to block apoptosis and thus are more resistant to chemotherapeutic drugs. Targeted and perhaps selective destruction of cancerous tissue is desirable for many reasons, ranging from the enhancement of or aid to current medical methods to problems currently lacking a solution, i.e., lung cancer. Demonstrated in this publication is the inactivation (killing) of human Melanoma skin cancer cell lines, in vitro, by Floating Electrode Dielectric Barrier Discharge (FE-DBD) plasma. Not only are these cells shown to be killed immediately by high doses of plasma treatment, but low doses are shown to promote apoptotic behavior as detected by TUNEL staining and subsequent flow cytometry. It is shown that plasma acts on the cells directly and not by “poisoning” the solution surrounding the cells, even through a layer of such solution. Potential mechanisms of interaction of plasma with cells are discussed and further steps are proposed to develop an understanding of such systems.     

Life and health insurance behaviour of individuals having undergone a predictive genetic testing programme for hereditary non-polyposis colorectal cancer

Objective and Methods: We describe the insurance behaviour of subjects (n=271) who had previously taken a predictive genetic test for hereditary non-polyposis colorectal cancer (HNPCC); 31% of them were mutation positive, indicating a high risk of cancer. One year after testing, subjects were sent a questionnaire including questions about their present life and health insurance before participation in the study, and their actual and planned purchase of the insurance policies during the testing programme which compromised a pre-test counseling session, a period for reflection, the testing, and a test disclosure session. Results: Thirty percent reported that they already had a life insurance and 14% a health insurance before participating in the study. The mutation-positive subjects possessed a health insurance significantly more often than the mutation-negative individuals (21 vs. 11%, p=0.02) and similar trend was observed for life insurance (36 vs. 28%, p=0.12). Life and health insurance policies purchased just before testing was reported by 3 and 2% of the subjects, respectively. Life and health insurance policies purchased after testing were reported by 3 and <1% respectively, and planned purchase by 3 and 2%, respectively. No statistically significant differences were found between the groups defined by mutation status in reports of life or health insurance behaviour during or after the programme. Conclusion: According to self-reported data, the mutation-positive subjects did not differ from the others in the purchase of life or health insurance policies. However, the mutation-positive individuals reported that they possessed health insurance policies before entering the study more often than their counterparts.     

Characterization of cyanide-trapped methylated metabonates formed during reactive drug metabolite screening in vitro

Reactive metabolites are estimated to be one of the main reasons behind unexpected drug-induced toxicity, by binding covalently to cell proteins or DNA. Due to their high reactivity and short lifespan, reactive metabolites are analyzed after chemical trapping with nucleophilic agents such as glutathione or cyanide. Recently, unexplained and uncharacterized methylated reaction products were reported in a human liver microsome based reactive metabolite trapping assay utilizing potassium cyanide as a trapping agent. Here, a similar assay was utilized to produce mono- or dimethylated and further cyanide-trapped reaction products from propranolol, amlodipine and ciprofloxacin, followed by ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC/TOF-MS) and ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) experiments for their more detailed structural elucidation. Formation of all observed cyanide-trapped products was clearly NADPH-dependent and thus metabolism-mediated. The suggested reaction pathways included N-methylation leading to iminium formation in primary and/or secondary amines preceded by cytochrome P450 (CYP)-mediated reactions. As the methylation reaction was suggested to be involved in formation of the actual reactive iminium ion, the observed cyanide-trapped products were experimental artifacts rather than trapped reactive metabolites. The results stress that to avoid overestimating the formation of reactive metabolites in vitro, this methylation phenomenon should be taken into account when interpreting the results of cyanide-utilizing reactive metabolite trapping assays. This in turn emphasizes the importance of identification of the observed cyano conjugates during such studies. Yet, metabolite identification has a high importance to avoid overestimation of in vitro metabolic clearance in the cases where this kind of metabonate formation has a high impact in the disappearance rate of the compound.     

Predicting binding energies of CDK6 inhibitors in the hit-to-lead process

The main challenge for the ??hit-to-lead?? stage in the drug discovery process relies on the accuracy of existing docking methods. In fact, accuracy of docking methods depends not only on the scoring function used to rank the poses but also on the ability of the docking method to reproduce the experimental binding mode. At this purpose, the performance of different approximations to properly dock and score compounds with known activity in a narrow range of IC₅₀ values was analyzed. A set of five ATP-competitive CDK6 inhibitors and three receptor conformations for CDK6 were considered for analysis, and three methodologies were used and analyzed in order to include different degrees of receptor flexibility. Thus, a completely rigid receptor is considered when using Glide, while the so-called Induced Fit Docking Protocol accounts for receptor sidechain rearrangements. Finally, force field calculations were also performed in order to consider a completely flexible receptor.     

Revealing indigenous Indonesian traditional medicine: anti-infective agents

Indonesia is rich in medicinal plants which the population has used traditionally from generation to generation for curing diseases. Our interest in the treatment of infectious diseases has lead to the investigation of traditional Indonesian treatments. In this review, we present a comprehensive review of ethnopharmacologically directed screening in Indonesian medicinal plants to search for new anti-viral, antimalarial, anti-bacterial and anti-fungal agents. Some potent drug leads have been isolated from Indonesian medicinal plants. Further research is still required for the lead development as well as the search for new bioactive compounds from the enormous medicinal plant resources.     

Coherence and anticoherence resonance in high-concentration erbium-doped fiber laser

We report an experimental study of low-frequency (~10 kHz) self-pulsing of the output intensity in a high-concentration erbium-doped fiber laser. We suggest that the fast intensity fluctuations caused by multimode and polarization instabilities play the role of an external noise source, leading to low-frequency auto-oscillations through a coherence resonance scenario.