Comparison of quantitative NMR and IRMS for the authentication of 'Polish Vodka'.

BACKGROUND: The production of 'Polish Vodka' is restricted by law to the ethyl alcohol of agricultural origins obtained from rye, wheat, barley, oat, triticale and potatoes grown on the territory of the Republic of Poland. The current labeling system should guarantee that the spirit is authentic and of good quality but not all producers are honest. Unfortunately, authentic 'Polish Vodka' is the most often counterfeited by the addition of cheaper and more accessible maize spirits. These illegal practices significantly reduce costs of the spirit production. Therefore, determination of the botanical origin of alcohol in Poland is highly relevant. RESULTS: Quantitative 2 H nuclear magnetic resonance and isotope ratio mass spectrometry were used to investigate the authenticity of 30 samples of Polish spirits. Several isotopic parameters were used to determine the botanical origin of 10 unknown samples. Both approaches led to the same conclusions regarding the percentage of maize-derived ethanol addition. CONCLUSIONS: Applied techniques are a valuable tool in the fight against counterfeiting of products. © 2018 Society of Chemical Industry.

Diaryl ethers with carboxymethoxyphenacyl motif as potent HIV-1 reverse transcriptase inhibitors with improved solubility.

In search of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved solubility, two series of novel diaryl ethers with phenacyl moiety were designed and evaluated for their HIV-1 reverse transcriptase inhibition potentials. All compounds exhibited good to excellent results with IC50 at low micromolar to submicromolar concentrations. Two most active compounds (7e and 7 g) exhibit inhibitory potency comparable or even better than that of nevirapine and rilpivirine. Furthermore, SupT1 and CD4+ cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity.

Oxygen binding isotope effects of triazole-based HIV-1 reverse transcriptase inhibitors indicate the actual binding site.

Binding isotope effects (BIEs) associated with binding of four triazole-based ligands to HIV-1 reverse transcriptase have been calculated at the QM/MM MD level of theory. Two main binding sites: allosteric cavity and RNase H active site, as well as three other sites reported in the literature (the Knuckles, the NNRTI Adjacent, and Incoming Nucleotide Binding) have been considered. The interactions between inhibitors and these protein sites have been quantified by binding free energies obtained from free energy perturbation (FEP) calculations, supported by interaction energy analysis. It has been shown that binding in the allosteric cavity can be distinguished from binding to other sites based on BIEs as it is associated with normal 18O-BIEs of the carbonyl oxygen atom while binding to RNase H active site is characterized by inverse binding isotope effect (18O-BIE < 1). For other sites 18O-BIEs close to unity are predicted. This information points to oxygen binding isotope effects of carbonyl group as indicative of the actual binding site of studied inhibitors.

Evaluation of biological properties of 3,3',4,4'-benzophenonetetracarboxylic dianhydride derivatives and their ability to inhibit hexokinase activity.

This investigation has explored the properties of 3,3',4,4'-benzophenonetetracarboxylic dianhydride (BDTA) derivatives with regard to their being prospective inhibitors of hexokinase II (HKII). A pluripotent embryonic carcinoma cell line P19 (ECC), was used as the biological target for newly generated potential inhibitors of HKII. The results obtained from Virtual High-Throughput Screening (VHTS), molecular modeling and biological activity studies showed BDTA to be a promising leading structure with a good binding score and simplest functionalization. The inhibitory effect was measured after 72h incubation. Of selected BDTA derivatives, the most active was compound 3b, containing 3-hydroxyphenyl moiety in the para position, being able at 100µM to decrease the mass of differentiated P19dCs cells by 30%, changing both the mitochondrial transmembrane potential and reactive oxygen species level. Under these conditions, only compound 3b had the ability to decrease hexokinase activity in a dose-dependent manner.

A Search for Dual Action HIV-1 Reverse Transcriptase, Bacterial RNA Polymerase Inhibitors.

Using molecular modeling approach, potential antibacterial agents with triazole core were proposed. A moderate to weak level of antibacterial activity in most of the compounds have been observed, with best minimal inhibitory concentration (MIC) value of 0.003 mg/mL, as shown by the 15 against S. epidermidis. Studied compounds were also submitted to the antifungal assay. The best antifungal activity was detected for 16 with MIC at 0.125 and 0.25 mg/mL against C. albicans and C. parapsilosis, respectively.

Simulation-Based Algorithm for Two-Dimensional Chemical Structure Diagram Generation of Complex Molecules and Ligand-Protein Interactions.

Computer programs for structure diagram generation (SDG) are indispensable cheminformatic tools that translate one- or three-dimensional (1D or 3D) chemical structure data stored in electronic formats to human-readable 2D depictions. Although many such programs are known, only a moderate part of chemical space can be handled by existing algorithms. For many classes of natural and synthetic compounds the results obtained with current SDG methods are illegible. A new algorithm based solely on a physical simulation of a molecule has been developed. The method allows for a general and global approach to avoid overlapping atoms and substituents. While the algorithm shows no advantage for trivial molecules, it shows superior performance over existing methods in depicting the most challenging compounds. The algorithm can generate chemically correct and legible 2D structure diagrams of many classes of natural and synthetic compounds that are intractable with existing SDG algorithms. The use of the method for generating schematic ligand-receptor interaction diagrams is also discussed.

Searching for novel scaffold of triazole non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Azoles are a promising class of the new generation of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). From thousands of reported compounds, many possess the same basic structure of an aryl substituted azole ring linked by a thioglycolamide chain with another aromatic ring. In order to find novel extensions for this basic scaffold, we explored the 5-position substitution pattern of triazole NNRTIs using molecular docking followed by the synthesis of selected compounds. We found that heterocyclic substituents in the 5-position of the triazole ring are detrimental to the inhibitory activity of compounds with four-membered thioglycolamide linker and this substitution seems to be viable only for compounds with shorter two-membered linker. Promising compound, N-(4-carboxy-2-chlorophenyl)-2-((4-benzyl-5-methyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetamide, with potent inhibitory activity and acceptable aqueous solubility has been identified in this study that could serve as lead scaffold for the development of novel water-soluble salts of triazole NNRTIs.

Hepatoblastoma Biology Using Isotope Ratio Mass Spectrometry: Utility of a Unique Technique for the Analysis of Oncological Specimens.

INTRODUCTION: Hepatoblastoma is the most common primary liver tumor in children. However, it occurs rarely, with an incidence of 0.5-1.5 cases per million children. There is no clear explanation of the relationship between clinicopathologic features, therapy, and outcome in hepatoblastoma cases, so far. One of the most widely accepted prognostic factors in hepatoblastoma is histology of the tumor. The aim of the study was to determine the potential differences in biology of hepatoblastoma histological subtypes at the atomic level using the unique method of isotope ratio mass spectrometry, which is especially valuable in examination of small groups of biological samples. MATERIAL/METHODS: Twenty-four measurements of nitrogen stable isotope ratio, carbon stable isotope ratio and total carbon to nitrogen mass ratio in fetal and embryonal hepatoblastoma tissue were performed using a Sercon 20-22 Continuous Flow Isotope Ratio Mass Spectrometer (CF-IRMS) coupled with a Sercon SL elemental analyzer for simultaneous carbon-nitrogen-sulfur (NCS) analysis. RESULTS: A difference of about 1.781‰ in stable nitrogen isotope 15N/14N ratio was found between examined hepatoblastoma histological subtypes. CONCLUSIONS: The prognosis in liver tumors cases in children may be challenging particularly because of the lack of versatile methods of its evaluation. Isotope ratio mass spectrometry allows one to determine the difference between hepatoblastoma histological subtypes and clearly indicates the cases with the best outcome.

Rhabdomyosarcoma in children in the light of isotope ratio mass spectrometry.

Rhabdomyosarcoma is the third most common solid tumor in children and the most common soft tissue sarcoma in this age group. However, 5-year survival is only observed in approximately 70% of cases, and the prognosis for patients with progressive disease is still poor. The authors hypothesize that the still unidentified differences in embryonal and alveolar tumor biology reflect the complex chemical reactions occurring during cell growth and metabolism and may be pursued in isotopic fractionation processes. Presented herein is the first evaluation of the nitrogen and carbon isotope ratio using isotope ratio mass spectrometry in the two major rhabdomyosarcoma histologic types. 15N enrichment was found in tumor tissues of embryonal histological type. The obtained result may indicate that individual patient considerations such as isotope ratio, in addition to widely accepted prognostic factors, may facilitate patient classification in terms of risk groups.

Assessing molecular docking tools for relative biological activity prediction: a case study of triazole HIV-1 NNRTIs.

Molecular docking is a technique widely used in drug design. Many studies exist regarding the general accuracy of various docking programs, but case studies for a given group of related compounds are rare. In order to facilitate identification of novel triazole HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), several docking and scoring programs were evaluated for their ability to predict relative biological activity of 111 known 1,2,4-triazole and 76 other azole type NNRTIs. Glide, FlexX, Molegro Virtual Docker, AutoDock Vina, and Hyde were used. Different protocols, settings, scoring functions, and interaction terms were analyzed. We have found that the programs performance was dependent on the data set, indicating the importance of choosing good quality target data for any comparative study. The results suggest that after optimization and proper validation, some of the molecular docking programs can help in predicting relative biological activity of azole NNRTIs.

Bringing the Clinic Home: An At-Home Multi-Modal Data Collection Ecosystem to Support Adaptive Deep Brain Stimulation.

Adaptive deep brain stimulation (aDBS) shows promise for improving treatment for neurological disorders such as Parkinson's disease (PD). aDBS uses symptom-related biomarkers to adjust stimulation parameters in real-time to target symptoms more precisely. To enable these dynamic adjustments, parameters for an aDBS algorithm must be determined for each individual patient. This requires time-consuming manual tuning by clinical researchers, making it difficult to find an optimal configuration for a single patient or to scale to many patients. Furthermore, the long-term effectiveness of aDBS algorithms configured in-clinic while the patient is at home remains an open question. To implement this therapy at large scale, a methodology to automatically configure aDBS algorithm parameters while remotely monitoring therapy outcomes is needed. In this paper, we share a design for an at-home data collection platform to help the field address both issues. The platform is composed of an integrated hardware and software ecosystem that is open-source and allows for at-home collection of neural, inertial, and multi-camera video data. To ensure privacy for patient-identifiable data, the platform encrypts and transfers data through a virtual private network. The methods include time-aligning data streams and extracting pose estimates from video recordings. To demonstrate the use of this system, we deployed this platform to the home of an individual with PD and collected data during self-guided clinical tasks and periods of free behavior over the course of 1.5 years. Data were recorded at sub-therapeutic, therapeutic, and supra-therapeutic stimulation amplitudes to evaluate motor symptom severity under different therapeutic conditions. These time-aligned data show the platform is capable of synchronized at-home multi-modal data collection for therapeutic evaluation. This system architecture may be used to support automated aDBS research, to collect new datasets and to study the long-term effects of DBS therapy outside the clinic for those suffering from neurological disorders.

Development of copper based drugs, radiopharmaceuticals and medical materials.

Copper is one of the most interesting elements for various biomedical applications. Copper compounds show vast array of biological actions, including anti-inflammatory, anti-proliferative, biocidal and other. It also offers a selection of radioisotopes, suitable for nuclear imaging and radiotherapy. Quick progress in nanotechnology opened new possibilities for design of copper based drugs and medical materials. To date, copper has not found many uses in medicine, but number of ongoing research, as well as preclinical and clinical studies, will most likely lead to many novel applications of copper in the near future.

Robustness of Beta Desynchronization from Chronically Implanted Cortical Electrodes on Multiple Time Scales.

Adaptive deep brain stimulation (aDBS) promises a significant improvement in patient outcomes, compared to existing deep brain stimulation devices. Fully implanted systems represent the next step to the clinical adoption of aDBS. We take advantage of a unique longitudinal data set formed as part of an effort to investigate aDBS for essential tremor to verify the long term reliability of electrocorticography strips over the motor cortex as a source of bio-markers for control of adaptive stimulation. We show that beta band event related de-synchronization, a promising bio-marker for movement, is robust even when used to trigger aDBS. Over the course of several months we show a minor increase in beta band event related de-synchronization in patients with active deep brain stimulation confirming that it could be used in chronically implanted systems.Clinical relevance - We show the promise and practicality of cortical electrocorticography strips for use in fully implanted, clinically translatable, aDBS systems.

The first investigation of Wilms' tumour atomic structure-nitrogen and carbon isotopic composition as a novel biomarker for the most individual approach in cancer disease.

The paper describes a novel approach to investigating Wilms' tumour (nephroblastoma) biology at the atomic level. Isotope Ratio Mass Spectrometry (IRMS) was used to directly assess the isotope ratios of nitrogen and carbon in 84 Wilms' tumour tissue samples from 28 cases representing the histological spectrum of nephroblastoma. Marked differences in nitrogen and carbon isotope ratios were found between nephroblastoma histological types and along the course of cancer disease, with a breakout in isotope ratio of the examined elements in tumour tissue found between stages 2 and 3. Different isotopic compositions with regard to nitrogen and carbon content were observed in blastemal Wilms' tumour, with and without focal anaplasia, and in poorly- and well-differentiated epithelial nephroblastoma. This first assessment of nitrogen and carbon isotope ratio reveals the previously unknown part of Wilms' tumour biology and represents a potential novel biomarker, allowing for a highly individual approach to treating cancer. Furthermore, this method of estimating isotopic composition appears to be the most sensitive tool yet for cancer tissue evaluation, and a valuable complement to established cancer study methods with prospective clinical impact.

Species differences in total mercury concentration in gulls from the Gulf of Gdansk (Southern Baltic).

Aquatic birds occupy a high position in the trophic pyramid of the Baltic Sea. This means that they accumulate the greatest amount of harmful substances, including mercury, in their bodies. This element penetrates into their systems mainly via the alimentary canal. The amount of mercury absorbed from food depends on how badly the environment is polluted with this metal. The aim of this study was to discover the concentrations of total mercury (HgT) in the contour feathers, muscles, brain, lungs, liver, kidneys, heart and blood of four gull species Herring Gull (Larus argentatus), Common Gull (Larus canus), Black-headed Gull (Larus ridibundus) and Great Black-backed Gull (Larus marinus) and organic mercury (Hgorg) in the liver and brain of Herring Gull. The most important characteristic of the results obtained for the studied gulls was the statistically significant differences between the four species, probably resulting from their different diets-confirmed by stable-isotopes analysis (δ(15)N and δ(13)C). A logarithmic dependence was found between HgT in the blood and HgT in the brain of the Herring Gull. The authors suggest that among gulls burdened with the greatest mercury load, it is possible that the brain is protected by higher Hg accumulation in the muscles. The percentage share of Hgorg in the brain and liver of the Herring Gull depended on the concentration of HgT in these tissues and was always higher in the brain. In none of the cases, did the mercury levels assayed in the internal gulls' tissues exceed values associated with adverse health effects.

Mercury in the eggs of aquatic birds from the Gulf of Gdansk and Wloclawek Dam (Poland).

The aim of this paper was to assess the influence of diet on the concentrations of total mercury (HgTOT) in the eggs of aquatic birds. Trophic level was determined using stable isotopes (δ(15)N, δ(13)C). Analysis was carried out on eggs (laid in 2010-2012) belonging to two species of terns nesting at the River Vistula outlet on the Gulf of Gdansk and on herring gulls nesting both in Gdynia harbour and on the Vistula dam in Wloclawek. The results show that seafood diet causes the highest load of mercury, that which is transferred into terns eggs. The amounts of accumulated mercury obtained were found to be different in the particular egg components with Hgalbumen > Hgyolk > Hgmembrane > Hgshell. In the herring gull eggs, three stages of embryo development with varying levels of mercury were determined. It was observed that mercury received from the albumen and yolk was most effectively removed when developing embryo into down.