Evaluating Antimycobacterial Screening Schemes Using Chemical Global Positioning System-Natural Product Analysis.

Most of the targeted discoveries in tuberculosis research have covered previously explored chemical structures but neglected physiochemical properties. Until now, no efficient prediction tools have been developed to discriminate the novelty of screened compounds at early stages. To overcome this deficit, a drastic novel approach must include physicochemical properties filters provided by Chemical Global Positioning System-Natural Product analysis (ChemGPS-NP). Three different screening schemes GSK, GVKBio, and NIAID provided 776, 2880, and 3779 compounds respectively and were evaluated based on their physicochemical properties and thereby proposed as deduction examples. Charting the physiochemical property spaces of these sets identified the merits and demerits of each screening scheme by simply observing the distribution over the chemical property space. We found that GSK screening set was confined to a certain space, losing potentially active compounds when compared with an in-house constructed 459 highly active compounds (active set), while the GVKBio and NIAID screening schemes were evenly distributed through space. The latter two sets had the advantage, as they have covered a larger space and presented compounds with additional variety of properties and activities. The in-house active set was cross-validated with MycPermCheck and SmartsFilter to be able to identify priority compounds. The model demonstrated undiscovered spaces when matched with Maybridge drug-like space, providing further potential targets. These undiscovered spaces should be considered in any future investigations. We have included the most active compounds along with permeability and toxicity filters as supplemented material.

Charting Angiosperm Chemistry: Evolutionary Perspective on Specialized Metabolites Reflected in Chemical Property Space.

Plants possess an outstanding chemical diversity of specialized metabolites developed to adapt to environmental niches and increase fitness. The observed diversity is hypothesized to result from various evolutionary mechanisms, such as the continuous branching off and extension of existing biosynthetic pathways or enhanced levels of catalytic promiscuity in certain enzymes. In this study, ChemGPS-NP has been employed to chart the distribution and diversity of physicochemical properties for selected types of specialized metabolites from the angiosperms. Utilizing these charts, it is analyzed how different properties of various types of specialized metabolites change in different plant groups, and the chemical diversity from the volume they occupy in chemical property space is evaluated. In this context, possible underlying evolutionary mechanisms are discussed, which could explain the observed distribution and behavior in chemical property space. Based on these studies, it is demonstrated that evolutionary processes in plant specialized metabolism and the resultant metabolic diversification are reflected in chemical property space.

Briaviolides K-N, New Briarane-Type Diterpenoids from Cultured Octocoral Briareum violaceum.

Four new briarane diterpenoids, briaviolides K-N (1-4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1-4 were identified. This study employed an in vitro model of lipopolysaccharide (LPS)-induced inflammation in the murine macrophage RAW 264.7 cell line, and found that among the four briaranes, briarane 2 possessed anti-inflammatory activity against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in cells. In addition, principal component analysis using the chemical global positioning system (ChemGPS) for natural products (ChemGPS-NP) was employed in order to analyze the structure-activity relationship (SAR), and the results indicated that the ring conformation of the compound has a leading role in suppressing the expressions of pro-inflammatory iNOS and COX-2 proteins in macrophages.

35 Years of Marine Natural Product Research in Sweden: Cool Molecules and Models from Cold Waters.

Currents efforts in marine biodiscovery have essentially focused on temperate to tropical shallow water organisms. With more than 6000 species of marine plants and animals, the Kosterfjord area has the richest marine biodiversity in Swedish waters, but it remains understudied. The overall objective of our marine pharmacognosy research is to explore and reveal the pharmacological potential of organisms from this poorly explored region. More generally, we wish to understand aspects of structure-activity relationships of chemical interactions in cold-water marine environment (shallow and deep). Our strategy is based on ecologically guided search for compounds through studies of physiology and organism interactions coupled to identification of bioactive molecules guided by especially in vivo assays. The research programme originated in the beginning of the 1980s with a broad screening of Swedish marine organisms using both in vitro and in vivo assays, resulting in isolation and identification of several different bioactive molecules. Two congenerous cyclopeptides, i.e. barettin and 8,9-dihydrobarettin, were isolated from the deep-sea sponge Geodia barretti, and structurally elucidated, guided by their antifouling activity and their affinity to a selection of human serotonin receptors. To optimize the activity a number of analogues of barettin were synthezised and tested for antifouling activity. Within the EU project BlueGenics, two larger homologous peptides, barrettides A and B, were isolated from G. baretti. Also, metabolic fingerprinting combined with sponge systematics was used to further study deep-sea natural product diversity in the genus Geodia. Finally, the chemical property space model 'ChemGPS-NP' has been developed and used in our research group, enabling a more efficient use of obtained compounds and exploration of possible biological activities and targets. Another approach is the broad application of phylogenetic frameworks, which can be used in prediction of where-in which organisms-to search for novel molecules or better sources of known molecules in marine organisms. In a further perspective, the deeper understanding of evolution and development of life on Earth can also provide answers to why marine organisms produce specific molecules.

Spasmolytic Mechanism of Aqueous Licorice Extract on Oxytocin-Induced Uterine Contraction through Inhibiting the Phosphorylation of Heat Shock Protein 27.

Licorice derived from the roots and rhizomes of Glycyrrhiza uralensis Fisch. (Fabaceae), is one of the most widely-used traditional herbal medicines in China. It has been reported to possess significant analgesic activity for treating spastic pain. The aim of this study is to investigate the spasmolytic molecular mechanism of licorice on oxytocin-induced uterine contractions and predict the relevant bioactive constituents in the aqueous extract. The aqueous extraction from licorice inhibited the amplitude and frequency of uterine contraction in a concentration-dependent manner. A morphological examination showed that myometrial smooth muscle cells of oxytocin-stimulated group were oval-shaped and arranged irregularly, while those with a single centrally located nucleus of control and licorice-treated groups were fusiform and arranged orderly. The percentage of phosphorylation of HSP27 at Ser-15 residue increased up to 50.33% at 60 min after oxytocin stimulation. Furthermore, this increase was significantly suppressed by licorice treatment at the concentration of 0.2 and 0.4 mg/mL. Colocalization between HSP27 and α-SMA was observed in the myometrial tissues, especially along the actin bundles in the oxytocin-stimulated group. On the contrary, the colocalization was no longer shown after treatment with licorice. Additionally, employing ChemGPS-NP provided support for a preliminary assignment of liquiritigenin and isoliquiritigenin as protein kinase C (PKC) inhibitors in addition to liquiritigenin, isoliquiritigenin, liquiritin and isoliquiritin as MAPK-activated protein kinase 2 (MK2) inhibitors. These assigned compounds were docked with corresponding crystal structures of respective proteins with negative and low binding energy, which indicated a high affinity and tight binding capacity for the active site of the kinases. These results suggest that licorice exerts its spasmolytic effect through inhibiting the phosphorylation of HSP27 to alter the interaction between HSP27 and actin. Furthermore, our results provide support for the prediction that potential bioactive constituents from aqueous licorice extract inhibit the relevant up-stream kinases that phosphorylate HSP27.

Cytotoxic Lanostanoids from Poria cocos.

Six new and 16 known lanostanoids were isolated from the sclerotia of Poria cocos. The structures of the new isolates were elucidated to be 16α-hydroxy-3-oxo-24-methyllanosta-5,7,9(11),24(31)-tetraen-21-oic acid (1), 3ß,16α,29-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (2), 3ß,16α,30-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (3), 3ß-acetoxy-16α,24ß-dihydroxylanosta-7,9(11),25-trien-21-oic acid (4), 3ß,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (5), and 3α,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (6), based on extensive spectroscopic analyses. The absolute configuration of 4 was determined using Mosher's method. The antiproliferative activity of the isolated compounds (except 3 and 4) was evaluated against four leukemic cell lines (Molt 4, CCRF-CEM, HL 60, and K562). Dehydropachymic acid (9), dehydroeburicoic acid (12), pachymic acid (14), and lanosta-7,9(11),24-trien-21-oic acid (20) exhibited an antiproliferative effect on the CCRF-CEM cancer cell line with IC50 values of 2.7, 6.3, 4.9, and 13.1 µM, respectively. Both dehydropachymic acid (9) and dehydroeburicoic acid (12) showed antiproliferative effects against Molt 4 (IC50 13.8 and 14.3 µM) and HL 60 (IC50 7.3 and 6.0 µM) leukemic cell lines. Primary computational analysis using a chemical global positioning system for natural products (ChemGPS-NP) on the active lanostanoids from P. cocos suggested that targets other than topoisomerases may be involved in the antiproliferative activity.

Anti-Dengue Virus Constituents from Formosan Zoanthid Palythoa mutuki.

A new marine ecdysteroid with an α-hydroxy group attaching at C-4 instead of attaching at C-2 and C-3, named palythone A (1), together with eight known compounds (2-9) were obtained from the ethanolic extract of the Formosan zoanthid Palythoa mutuki. The structures of those compounds were mainly determined by NMR spectroscopic data analyses. The absolute configuration of 1 was further confirmed by comparing experimental and calculated circular dichroism (CD) spectra. Anti-dengue virus 2 activity and cytotoxicity of five isolated compounds were evaluated using virus infectious system and [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays, respectively. As a result, peridinin (9) exhibited strong antiviral activity (IC50 = 4.50 ± 0.46 µg/mL), which is better than that of the positive control, 2'CMC. It is the first carotene-like substance possessing anti-dengue virus activity. In addition, the structural diversity and bioactivity of the isolates were compared by using a ChemGPS-NP computational analysis. The ChemGPS-NP data suggested natural products with anti-dengue virus activity locate closely in the chemical space.

Investigating Pharmacological Similarity by Charting Chemical Space.

In this study, biologically relevant areas of the chemical space were analyzed using ChemGPS-NP. This application enables comparing groups of ligands within a multidimensional space based on principle components derived from physicochemical descriptors. Also, 3D visualization of the ChemGPS-NP global map can be used to conveniently evaluate bioactive compound similarity and visually distinguish between different types or groups of compounds. To further establish ChemGPS-NP as a method to accurately represent the chemical space, a comparison with structure-based fingerprint has been performed. Interesting complementarities between the two descriptions of molecules were observed. It has been shown that the accuracy of describing molecules with physicochemical descriptors like in ChemGPS-NP is similar to the accuracy of structural fingerprints in retrieving bioactive molecules. Lastly, pharmacological similarity of structurally diverse compounds has been investigated in ChemGPS-NP space. These results further strengthen the case of using ChemGPS-NP as a tool to explore and visualize chemical space.

A recently transferred cluster of bacterial genes in Trichomonas vaginalis--lateral gene transfer and the fate of acquired genes.

BACKGROUND: Lateral Gene Transfer (LGT) has recently gained recognition as an important contributor to some eukaryote proteomes, but the mechanisms of acquisition and fixation in eukaryotic genomes are still uncertain. A previously defined norm for LGTs in microbial eukaryotes states that the majority are genes involved in metabolism, the LGTs are typically localized one by one, surrounded by vertically inherited genes on the chromosome, and phylogenetics shows that a broad collection of bacterial lineages have contributed to the transferome. RESULTS: A unique 34 kbp long fragment with 27 clustered genes (TvLF) of prokaryote origin was identified in the sequenced genome of the protozoan parasite Trichomonas vaginalis. Using a PCR based approach we confirmed the presence of the orthologous fragment in four additional T. vaginalis strains. Detailed sequence analyses unambiguously suggest that TvLF is the result of one single, recent LGT event. The proposed donor is a close relative to the firmicute bacterium Peptoniphilus harei. High nucleotide sequence similarity between T. vaginalis strains, as well as to P. harei, and the absence of homologs in other Trichomonas species, suggests that the transfer event took place after the radiation of the genus Trichomonas. Some genes have undergone pseudogenization and degradation, indicating that they may not be retained in the future. Functional annotations reveal that genes involved in informational processes are particularly prone to degradation. CONCLUSIONS: We conclude that, although the majority of eukaryote LGTs are single gene occurrences, they may be acquired in clusters of several genes that are subsequently cleansed of evolutionarily less advantageous genes.

Anti-inflammatory and Antiphytopathogenic Fungal Activity of 2,3-seco-Tirucallane Triterpenoids Meliadubins A and B from Melia dubia Cav. Barks with ChemGPS-NP and In Silico Prediction.

Two new rearranged 2,3-seco-tirucallane triterpenoids, meliadubins A (1) and B (2), along with four known compounds, 3-6, were isolated from the barks of Melia dubia Cav. Compound 2 exhibited a significant inflammatory inhibition effect toward superoxide anion generation in human neutrophils (EC50 at 5.54 ± 0.36 µM). It bound to active sites of a human inducible nitric oxide synthase (3E7G) through interactions with the residues of GLU377 and PRO350, which may benefit in reducing the neutrophilic inflammation effect. The ChemGPS-NP interpretation combined with bioactivity assay and in silico prediction results suggested 2 to be an agent for targeting iNOS with different mechanisms as compared to a selected set of current approved drugs. Moreover, compounds 1 and 2 showed remarkable inhibition against the rice pathogenic fungus Magnaporthe oryzae in a dose-dependent manner with IC50 values of 137.20 ± 9.55 and 182.50 ± 18.27 µM, respectively. Both 1 and 2 displayed interactions with the residue of TYR223, a key active site of trihydroxynaphthalene reductase (1YBV). The interpretation of 1 and 2 in the ChemGPS-NP physical-chemical property space indicated that both compounds are quite different compared to all members of a selected set of reference compounds. In light of demonstrated biological activity and in silico prediction experiments, both compounds possibly exhibited activity against phytopathogenic fungi via a novel mode of action.

In vitro and in silico evaluation of Ononis isoflavonoids as molecules targeting the central nervous system.

Isoflavonoids with various structural elements show a promising potential effect on central nervous system activities. Despite their favorable medicinal properties, the pharmacokinetic characteristics of this thoroughly investigated group of natural phenolics have only been described to a limited extent. Regarding the lack of information about the BBB permeability of isoflavones, isoflavanones, and pterocarpans found in Ononis species, the aim of our study was to investigate their physico-chemical properties influencing their absorption and distribution. Furthermore, we aimed to characterize the possible MAO-B inhibiting features of Ononis isoflavonoids in silico. Octanol-water partitioning and BBB-PAMPA permeability of formononetin, calycosin D, onogenin, sativanone, medicarpin and maackiain were assessed for the first time in our study. The log P values ranged from 2.21 to 3.03 and log D7.4 values from 2.48 to 3.03, respectively, indicating optimal polarity for BBB permeation. The results of PAMPA-BBB expressed as log Pe values fell between -5.60 and -4.45, predicting their good permeation capability as well. The effective permeability values showed structure-dependent differences, indicating that the pterocarpan type skeleton was the most preferred type, followed by isoflavanones, then isoflavones. The methoxy or methylenedioxy substitution of the same skeleton did not influence the permeability significantly, contrary to an additional hydroxyl group. Membrane retention showed a similar structure dependent pattern to that of effective permeability, ranging from 16% to 70%. For the identification of volumes of chemical space related to particular biological activities the ChemGPS-NP framework was used. The MAO-B inhibitory potency and selectivity were also predicted and validated. Based on our results, MAO-B inhibitory potency could be predicted with good precision, but in the case of selectivity, only the direction could be concluded (favors MAO-B or MAO-A), not the magnitude. Our finding reflects that Ononis isoflavonoid aglycones show an excellent fit with the suggested parameters for BBB permeability and this is the first study to confirm the highly favorable position of these natural products for MAO-B inhibition.

Stability Study of Alpinia galanga Constituents and Investigation of Their Membrane Permeability by ChemGPS-NP and the Parallel Artificial Membrane Permeability Assay.

Alpinia galanga Willd., greater galangal, has been used for thousands of years as a spice as well as in traditional medicine. Its central nervous system (CNS) stimulant activity and neuroprotective effects have been proved both in animal models and human trials. However, the compounds responsible for these effects have not been identified yet. Therefore, the main constituents (p-OH-benzaldehyde (1), trans-p-coumaryl-alcohol (2), p-coumaryl-aldehyde (4), galanganol A (5), galanganol B (6), trans-p-acetoxycinnamyl alcohol (7), 1'S-1'-acetoxychavicol acetate (ACA, 9), and 1'S-1'-acetoxyeugenol acetate (AEA, 10)) were isolated to investigate their aqueous stability and passive diffusion across the gastro-intestinal tract (GIT) membrane and the blood-brain barrier (BBB) by the parallel artificial membrane permeability assay (PAMPA). Our positive results for compounds 1, 2, 4, 7, 9, and 10 suggest good permeability, thus potential contribution to the effects of greater galangal in the CNS. The results of the PAMPA-BBB were corroborated by in silico chemography-based ChemGPS-NP framework experiments. In addition, examination of the chemical space position of galangal compounds in relation to known psychostimulants revealed that all the molecules in proximity are NET/SERT inhibitors. As ACA and AEA did not show much proximity to either compound, the importance of further investigation of their degradation products becomes more pronounced.

Survival and growth of saprotrophic and mycorrhizal fungi in recalcitrant amine, amide and ammonium containing media.

The elimination of hazardous compounds in chemical wastes can be a complex and technically demanding task. In the search for environmental-friendly technologies, fungal mediated remediation and removal procedures are of concern. In this study, we investigated whether there are fungal species that can survive and grow on solely amine-containing compounds. One compound containing a primary amine group; 2-diethylaminoethanol, one compound with a primary amide group; 2,6-dichlorobenzamide (BAM), and a third compound containing a quaternary ammonium group; N3-trimethyl(2-oxiranyl)methanaminium chloride, were selected. The choice of these compounds was motivated by their excessive use in large scale manufacturing of protein separation media (2-diethylaminoethanol and the quaternary amine). 2,6-dichlorobenzamide, the degradation product of the herbicide 2,6-dichlorobenzonitrile (dichlobenil), was chosen since it is an extremely recalcitrant compound. Utilising part of the large fungal diversity in Northern European forests, a screening study using 48 fungal isolates from 42 fungal species, including saprotrophic and mycorrhizal fungi, was performed to test for growth responses to the chosen compounds. The ericoid (ERM) mycorrhizal fungus Rhizoscyphus ericae showed the best overall growth on 2-diethylaminoethanol and BAM in the 1-20 g L-1 concentration range, with a 35-fold and 4.5-fold increase in biomass, respectively. For N3-trimethyl(2-oxiranyl)methanaminium chloride, the peak growth occurred at 1 g L-1. In a second experiment, including three of the most promising fungi (Laccaria laccata, Hygrophorus camarophyllus and Rhizoscyphus ericae) from the screening experiment, a simulated process water containing 1.9% (w/v) 2-diethylaminoethanol and 0.8% (w/v) N3-trimethyl(2-oxiranyl)methanaminium chloride was used. Laccaria laccata showed the best biomass increase (380%) relative to a control, while the accumulation for Rhizoscyphus ericae and Hygrophorus camarophyllus were 292% and 136% respectively, indicating that mycorrhizal fungi can use amine- and amide-containing substrates as nutrients. These results show the potential of certain fungal species to be used in alternative green wastewater treatment procedures.

Decoding Multiple Biofunctions of Maca on Its Anti-allergic, Anti-inflammatory, Anti-thrombotic, and Pro-angiogenic Activities.

Four active partition layers and ten isolates, including (5R)- and (5S)-macapyrrolidone A (1a, 1b), and four new alkaloids, (5R)- and (5S)-macapyrrolidone B (2a, 2b) and macapyrrolins D, E (3, 4), were isolated from maca (Lepidium meyenii Walp.), an indigenous food plant from Peru. Derived from the n-hexane layer, the macamide-rich fraction exhibited pro-angiogenic activity on EPC and HUVEC cells. Anti-thrombotic activity was displayed by the polar part of maca extracts (n-butanol and water layers). Both 75% methanol aq. (midlower polar part) and n-hexane (low polar part) layers, which showed signs of fatty acid content, markedly inhibited superoxide and elastase release in an anti-inflammatory assay. The 75% methanol aq. layer showed strong anti-allergic activity, and macapyrrolin A (5) was found active based on ß-hexosaminidase release inhibition assays and a ChemGPS-NP experiment. These valuable bioactivity results suggest that maca is a food plant with good benefits for human health.

Natural products in modern life science.

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure-activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science.

Allergic disease and risk of stress in pregnant women: a PreventADALL study.

BACKGROUND: Maternal stress during pregnancy may negatively affect the health of mother and child. We therefore aimed to identify the proportion of women reporting high maternal stress in mid and late pregnancy and explore whether symptoms of maternal allergic disease are associated with perceived maternal stress in late pregnancy. METHOD: The population-based Preventing Atopic Dermatitis and Allergy in Children (PreventADALL) study enrolled 2697 pregnant women at their 18-week routine ultrasound examination in Norway and Sweden. Information about sociodemographic factors, symptoms and doctor-diagnosed asthma, allergic rhinitis, atopic dermatitis, food allergy, and anaphylaxis and stress using the 14-item perceived stress scale (PSS) was collected at 18 weeks (mid) and 34 weeks (late) pregnancy. High stress was defined as a PSS score ≥29. Scores were analysed using multivariate logistic and linear regression. RESULTS: Among the 2164 women with complete PSS data, 17% reported asthma, 20% atopic dermatitis, 23% allergic rhinitis, 12% food allergy and 2% anaphylaxis. The proportion of women reporting high stress decreased from 15% at mid to 13% at late pregnancy (p<0.01). The adjusted odds ratio for high stress in late pregnancy was 2.25 (95% CI 1.41-3.58) for self-reported symptoms of asthma, 1.46 (95% CI 1.02-2.10) for allergic rhinitis and 2.25 (95% CI 1.32-3.82) for food allergy. A multivariate linear regression model confirmed that symptoms of asthma (ß coefficient 2.11; 0.71-3.51), atopic dermatitis (ß coefficient 1.76; 0.62-2.89) and food allergy (ß coefficient 2.24; 0.63-3.84) were independently associated with increased PSS score. CONCLUSION: Allergic disease symptoms in pregnancy were associated with increased stress, highlighting the importance of optimal disease control in pregnancy.

Secondary chemistry and ribosomal DNA data congruencies in Arnica (Asteraceae).

To investigate possible congruencies between DNA sequence data and secondary chemistry, we compared nuclear ribosomal DNA (nrDNA) sequence data, sesquiterpene lactone (STL) contents, and cytometric data from 35 accessions of 16 Arnica (Asteraceae) species and two outgroup taxa (Layia hieracioides and Madia sativa), using phylogenetic inference and principal component analysis (PCA). Several groups supporting multiple accessions of the same species (of A. montana, A. longifolia, A. gracilis, and A. chamissonis) are congruent between the phylogenetic trees based on nrDNA and STL data. Sesquiterpene lactone profiles were found to be highly consistent within multiple samples of A. montana and A. longifolia respectively. Moreover, sesquiterpene lactone data support subspecies classifications of A. chamissonis and A. parryi, with additional support from DNA sequence data and cytometric data. Morphology, STL data (PCA), cytometric data and DNA sequence data suggest a hybrid origin of one accession (A. gracilis × longifolia). In A. gracilis, A. latifolia, and Layia hieracioides, previously not investigated for STLs, we found large amounts of xanthalongin derivatives. This is the first time STLs have been reported from subtribe Madiinae. © The Willi Hennig Society 2009.

ChemGPS-NP(Web): chemical space navigation online.

Internet has become a central source for information, tools, and services facilitating the work for medicinal chemists and drug discoverers worldwide. In this paper we introduce a web-based public tool, ChemGPS-NP(Web) (http://chemgps.bmc.uu.se), for comprehensive chemical space navigation and exploration in terms of global mapping onto a consistent, eight dimensional map over structure derived physico-chemical characteristics. ChemGPS-NP(Web) can assist in compound selection and prioritization; property description and interpretation; cluster analysis and neighbourhood mapping; as well as comparison and characterization of large compound datasets. By using ChemGPS-NP(Web), researchers can analyze and compare chemical libraries in a consistent manner. In this study it is demonstrated how ChemGPS-NP(Web) can assist in interpreting results from two large datasets tested for activity in biological assays for pyruvate kinase and Bcl-2 family related protein interactions, respectively. Furthermore, a more than 30-year-old suggestion of "chemical similarity" between the natural pigments betalains and muscaflavins is tested.

Structure and function of Rubisco.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is the major enzyme assimilating CO(2) into the biosphere. At the same time Rubisco is an extremely inefficient catalyst and its carboxylase activity is compromised by an opposing oxygenase activity involving atmospheric O(2). The shortcomings of Rubisco have implications for crop yield, nitrogen and water usage, and for the global carbon cycle. Numerous high-resolution crystal structures of different forms of Rubisco are now available, including structures of mutant enzymes. This review uses the information provided in these structures in a structure-based sequence alignment and discusses Rubisco function in the context of structural variations at all levels--amino acid sequence, fold, tertiary and quaternary structure--with an evolutionary perspective and an emphasis on the structural features of the enzyme that may determine its function as a carboxylase.

Factors related to tobacco use among teenagers.

AIM: To examine tobacco use among teenagers, identify factors related to tobacco use, as well as evaluate the outcome of a smoking prevention program. METHODS: From age 7/8 to 14/15, annual questionnaires about asthma and allergy have been completed in the OLIN paediatric study in Northern Sweden. From 12/13 years, questions about tobacco use, i.e. smoking and snuff, were added. A smoking prevention program was performed during 2 years. RESULTS: Any tobacco use increased from 5.0% at age 12/13 years, to 14.4% at age 14/15. At age 14/15 years, the prevalence of tobacco use was significantly higher among boys than girls (16.7 and 12.0%, respectively). More girls than boys smoked (8.9 and 2.8%, respectively), while use of snuff was more common among the boys (15.6 and 4.2%, respectively). Significant risk factors for smoking were any of the family members currently smoking, OR 6.1 (95% CI 4.0-9.3) and a physician-diagnosed asthma at the age of 14/15 years, OR 1.9 (95% CI 1.2-3.0). A protective factor against tobacco use was participation in sports, OR 0.3 (95% CI 0.2-0.4). The prevention program did not result in less tobacco use, although it may have delayed smoking initiation. CONCLUSION: The patterns of tobacco use differed significantly between boys and girls. Though any tobacco use was more common among boys, girls were more likely to smoke, and boys were more likely to use snuff. Having asthma did not prevent the teenagers from smoking. Since having a smoking family member was the major risk factor for tobacco use, prevention programs should be directed at smoking families in addition to the individuals.